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International Journal of Clinical and Experimental Neurology
ISSN (Print): 2379-7789 ISSN (Online): 2379-7797 Website: https://www.sciepub.com/journal/ijcen Editor-in-chief: Zhiyou Cai, MD
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International Journal of Clinical and Experimental Neurology. 2016, 4(1), 9-18
DOI: 10.12691/ijcen-4-1-2
Open AccessReview Article

Neurological Complications in Sickle Cell Disease

Hassan A. Al-Jafar1, , Raed Alroughani2, Thamer A.Abdullah3 and Fatma Al-Qallaf4

1Consultant Hematologist, Kuwait, Amiri hospital

2Consultant Neurologist & Director of Multiple Sclerosis clinic at Alamiri Hospital, Kuwait

3Senior specialist in Radiologist, Amiri Hospital

4Consultant Neurologist, Kuwait, Mubark Al-Kabeer Hospital

Pub. Date: August 12, 2016
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Cite this paper:
Hassan A. Al-Jafar, Raed Alroughani, Thamer A.Abdullah and Fatma Al-Qallaf. Neurological Complications in Sickle Cell Disease. International Journal of Clinical and Experimental Neurology. 2016; 4(1):9-18. doi: 10.12691/ijcen-4-1-2

Abstract

Sickle cell disease is a common inherited blood disorder that affects red blood cells. It is a hemoglobinopathy characterized by hemoglobin polymerization, erythrocyte stiffening, and subsequent vaso-occlusions. These changes can lead to microcirculation obstructions, tissue ischemia, infarction and acute stroke. In addition, chronic cerebral ischemia and cerebral vascular anomalies are considered among the most disabling problems in sickle cell disease. Neurological complications of sickle cell disease include, Ischaemic Stroke, hemorrhagic stroke, transient ischemic attack, silent cerebral infarction, headache, Moyamoya disease, neuropathic pain, and neurocognitive impairment. Early diagnosis and proper management of sickle cell disease neurological complications require specialised hematological and neurological experties. The newly used medications under ongoing research foster the hope to overcome this devastating disease and its complications.

Keywords:
sickle cell anemia cerebral vascular accident infarction hemorrhage

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]  Karin P. Patoka, Mark T. Gladwin. Vasculopathy and pulmonary hypertension in sickle cell disease. American Journal of Physiology - Lung Cellular and Molecular Physiology (2015), L314-L324.
 
[2]  Diallo D, Tchernia G: Sickle Cell Disease in Africa. Curre Opin Hematol 2002, 9(2):111-116.
 
[3]  Tanya G, Chen, Robert P. Lathrop, Sergey S. Shevkoplyas.The Case for Rapid Diagnosis of Sickle Cell Disease:A Literature Review. Journal of Global Health Perspective. (2012 Aug 1.).
 
[4]  Hillery CA, Panepinto JA. Pathophysiology of stroke in sickle cell disease. Microcirculation 2004; 11: 195-208.
 
[5]  Kirk GR, Haynes MR, Palais S, Brown C, Burns TG, McCormick M, et al. Regionally specific cortical thinning in children with sickle cell disease. Cereb Cortex 2009; 19: 1549-1556.
 
[6]  Hebbel RP, Mohandas N. Sickle cell adherence. In Embury SH, Hebbel RP, Mohandas N, Steinburg MH, eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York: Raven Press; 1994.
 
[7]  Paula S. Walmet, James R. Eckman and Timothy M. Wick. Inflammatory Mediators Promote Strong Sickle Cell Adherence to Endothelium Under Venular Flow Conditions. American Journal of Hematology (2003) 73:215-224.
 
[8]  Morey A. Blinder1 and Sarah Russel. Exertional sickling: questions and controversy. Hematol Rep. 2014 Nov 19; 6(4): 5502.
 
[9]  Verduzco LA, Nathan DG. Sickle cell disease, and stroke. Blood 2009; 114: 5117-5125.
 
[10]  Becker M, Axelrod DJ, Oyesanmi O, Markov DD, Kunkel EJ. Hematologic problems in psychosomatic medicine. Psychiatr Clin North Am 2007; 30:739-759.
 
[11]  Alison E. Niebanck, Avrum N. Pollock, Kim Smith-Whitley, Leslie J. Raffini, Robert A. Zimmerman, Kwaku Ohene-Frempong, and Janet L. Kwiatkowski. Headache in Children with Sickle Cell Disease.-Prevalence and Associated Factors. J Pediatr. 2007:1(1): 67-72.e1.
 
[12]  Michael Henry, M. Catherine Driscoll, Marijean Miller; Taeun Chang, and Caterina P. Minniti. Pseudo tumor Cerebri in Children with Sickle Cell Disease: A Case Series.PEDIATRICS Vol. 113 No. 3 March 2004.
 
[13]  Nath KA, Shah V, Haggard JJ, et al. Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease. Am J Physiol Regul Integr Comp Physiol.2000;279 :R1949-R1955
 
[14]  Kirkham FJ, Calamante F, Bynevelt M, et al. Perfusion magnetic resonance abnormalities in patients with sickle cell disease. Ann Neurol.2001;49 :477-485.
 
[15]  Michael M Dowling, Michael J Noetzel, Mark J Rodeghier, PhD, Charles T Quinn, Deborah G Hirtz, Rebecca N Ichord, Janet L Kwiatkowski, E Steven Roach, Fenella J Kirkham, James F Casella, and Michael R DeBaun, M.D. Headache and Migraine in Children with Sickle Cell Disease are Associated with Lower Hemoglobin and Higher Pain Event Rates but not Silent Cerebral Infarction. J Pediatr. 2014 May; 164(5): 1175-1180.e1.
 
[16]  Zaijie J. Wang, Diana J. Wilkie, RN, FAAN, and Robert Molokie. Neurobiological Mechanisms of Pain in Sickle Cell Disease. Hematology Am SocHematolEduc Program. 2010; 2010: 403-408.
 
[17]  MesslingerK. What is a nociceptor?[Article in German] Anaesthesist. 1997 Feb; 46(2): 142-53.
 
[18]  Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch. Neurol. 2003; 60: 1524-34.
 
[19]  Steinberg MH, Forget BG, Higgs DR, et al. Ballas SK, Eckman JR. Biology of pain and treatment of the sickle cell pain. In: Steinberg MH, Forget BG, Higgs DR, et al., editors. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. 2nd Ed. Cambridge, MA: Cambridge University Press; 2009. p. 497-524.
 
[20]  Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood 2012; 120: 3647-3656.
 
[21]  David J. Mayer, Jianren Mao, Jason Holts, and Donald D. Price. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions.
 
[22]  Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009; 139: 267-284.
 
[23]  Romain-Daniel Gosselin,Marc R. Suter,Ru-Rong JL, Isabelle Decosterd. Glial Cells and Chronic Pain. Neuroscientist. 2010 Oct; 16(5): 519-531.
 
[24]  Chu K., Chandran P., Joshi S.K., Jarvis P.R., McGaraughty S. TRPV1-related modulation of spinal neuronal activity and behavior in a rat model of osteoarthritic pain.(2011). Brain Res. 1369:158-166.
 
[25]  Hillery CA, Kerstein PC, Vilceanu D, Barabas ME, Retherford D, Brandow AM, et al. Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease. Blood 2011; 118: 3376-3383.
 
[26]  Atlas of Stroke Mortality. Racial and ethnic disparities in stroke. Centers for Disease Control and Prevention. http://www.cdc.gov/dhdsp/atlas/stroke_mortality_atlas/docs/Section_one.pdf.
 
[27]  Philip B. Gorelick, Steven M. Weisman. Risk of Hemorrhagic Stroke With Aspirin Use An Update. Stroke 2005; 36: 1801-1807.
 
[28]  Sasikhan Geibprasert, SirintaraPongpech, PakornJiarakongmun, Manohar M. Shroff, Derek C. Armstrong, and TimoKrings. Radiologic Assessment of Brain Arteriovenous Malformations: What Clinicians Need to Know. RadioGraphics 2010; 30:483-501.
 
[29]  Khurshid I1, Anderson L, Downie GH, Pape GS. Sickle cell disease, extreme hyperbilirubinemia, and pericardial tamponade: case report and review of the literature. Crit Care Med. 2002 Oct;30(10):2363-7.
 
[30]  Steen RG, Emudianughe T, Hankins GM, Wynn LW, Wang WC, Xiong X, et al. Brain imaging findings in pediatric patients with sickle cell disease. Radiology. 2003;228:216-25.
 
[31]  J. Stephen Huff, MD. Stroke Differential Diagnosis - Mimics and Chameleons. Foundation for Education and Research in Neurological Emergencies. https://www.uic.edu/com/ferne/pdf2.
 
[32]  Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 1998; 50: 1746-9.
 
[33]  Oluwatoyin Olatundun Ilesanmi. Pathological basis of symptoms and crises in sickle cell disorder: implications for counseling and psychotherapyHematol Rep. 2010 Jan 26; 2(1): e2. Published online 2010 Apr 13.
 
[34]  Adams RJ. Big strokes in small persons. Arch Neurol 2007; 64: 1567-74.
 
[35]  Hassan A, Markus HS. Genetics and ischaemic stroke. Brain 2000; 123 (Pt. 9):1784-1812.
 
[36]  36. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11.
 
[37]  Special report from the National Institute of Neurological Disorders and Stroke (1990) Classification of cerebrovascular diseases III. Stroke 21(4):637-676.
 
[38]  Ay H, Oliveira-Filho J, Buonanno FS, et al. (2002) ‘Footprints’ of transient ischemic attacks: a diffusion-weighted MRI study. Cerebrovasc Dis 14(3-4):177-186.
 
[39]  DeBaun MR. Secondary prevention of overt strokes in sickle cell disease: therapeutic strategies and efficacy. Hematology Am SocHematolEduc Program 2011;2011:427-433.
 
[40]  Robert D. Brown, Jr, George W. Petty, W. Michael O’Fallon, David O. Wiebers, Jack P. Whisnant. Incidence of Transient Ischemic Attack in Rochester, Minnesota, 1985–1989. © 1998 American Heart Association, Inc. Online ISSN: 1524-4628.
 
[41]  Transient Ischemic Attack (TIA)-Mayo Clinic (1998-2015) Mayo Foundation for Medical Education and Research. http://www.lb7.uscourts.gov/documents/2-14-CV-246.pdf.
 
[42]  Awad I, Spetzler RF, Hodak JA, Awad CA, Carey R. Incidental subcortical lesions identified on magnetic resonance imaging in the elderly, I: correlation with age and cerebrovascular risk factors. Stroke. 1986;17: 1084-1089.
 
[43]  Shinkawa A, Ueda K, Kiyohara Y, Kato I, Sueishi K, Tsuneyoshi M, Fujishima M. Silent cerebral infarction in a community-based autopsy series in Japan: the Hisayama Study. Stroke. 1995;26: 380-385.
 
[44]  Weisberg LA, Stazio A. Neurologically asymptomatic patients with a single cerebral lacuna. South Med J. 1989;82:981-984.
 
[45]  Sang-Chol Lee, Sang-Joon Park, Hyun-Kyun Ki, Hyeon-CheolGwon, Chin-Sang Chung, Hong SikByun, Kyung-Ja Shin, Myung-Hee Shin, Won Ro Lee. Prevalence and Risk Factors of Silent Cerebral Infarction in Apparently Normal Adults. Hypertension. 2000 Jul; 36(1):73-7.
 
[46]  Schmidt, WP; Roesler, A; Kretzschmar, K; Ladwig, KH; Junker, R; Berger, K (2004). "Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population". Journal of the American Geriatrics Society 52 (7): 1045-50.
 
[47]  Miwa, K; Hoshi, T; Hougaku, H; Tanaka, Makiko; Furukado, Shigetaka; Abe, Yuko; Okazaki, Shuhei; Sakaguchi, Manabu; et al. (2010). "Silent cerebral infarction is associated with incident stroke and TIA independent of carotid intima-media thickness". Internal medicine (Tokyo, Japan) 49 (9): 817-22.
 
[48]  Herderscheê, D; Hijdra, A; Algra, A; Koudstaal, PJ; Kappelle, LJ; Van Gijn, J (1992). "Silent stroke in patients with transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group". Stroke; a journal of cerebral circulation 23 (9): 1220-4.
 
[49]  Vermeer, SE; Koudstaal, PJ; Oudkerk, M; Hofman, A; Breteler, MM (2002). "Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study". Stroke; a journal of cerebral circulation 33 (1): 21-5.
 
[50]  Price, TR; Manolio, TA; Kronmal, RA; Kittner, SJ; Yue, NC; Robbins, J; Anton-Culver, H; O'Leary, DH (1997). "Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group". Stroke; a journal of cerebral circulation 28 (6): 1158-64.
 
[51]  Corea, F; Tambasco, N; Luccioli, R; Ciorba, E; Parnetti, L; Gallai, V (2002). "Brain CT-scan in acute stroke patients: Silent infarcts and relation to outcome". Clinical and experimental hypertension (New York, N.Y.: 1993) 24 (7-8): 669-76.
 
[52]  Adams, R; McKie, V; Nichols, F; Carl, E; Zhang, DL; McKie, K; Figueroa, R; Litaker, M; et al. (1992). "The use of transcranial ultrasonography to predict stroke in sickle cell disease". The New England Journal of Medicine 326 (9): 605-10.
 
[53]  Franklin G. Moser, Scott T. Miller, Jacqueline A. Bello, Charles H. Pegelow, Robert A.Zimmerman, Winfred C. Wang, KwakuOhene-Frempong, Alan Schwartz, Elliott P. Vichinsky, Dianne Gallagher, and Thomas R. Kinney. The Spectrum of Brain MR Abnormalities in Sickle-Cell Disease: A Report from the Cooperative Study of Sickle Cell Disease. American Society of Neuroradiology. AJNR 17:965-972.
 
[54]  Robert J. Adams, MS.Sickle Cell and the Brain.ASH Education Book January 1, 2001 vol. 2001 no. 1 31-46.
 
[55]  Dobson SR, Holden KR, Nietert PJ, Cure JK, Laver JH, Disco D, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood 2002;99:3144-3150.
 
[56]  Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med 2009;360:1226-1237.
 
[57]  Gorrotxategi P, Reguilon MJ, Gaztanaga R, Hernandez Abenza J, Albisu Y. [Moya-moya disease in a child with multiple malformations]. Rev Neurol 1995;23:403-405.
 
[58]  Yamashita M, Tanaka K, Matsuo T, 36. Yokoyama K, Fujii T, Sakamoto H. Cerebral dissecting aneurysms in patients with moyamoya disease: report of two cases. J Neurosurg 1983;58: 120-5.
 
[59]  Oka K, Yamashita M, Sadoshima S, 37. Tanaka K. Cerebral haemorrhage in Moyamoya disease at autopsy. Virchows Arch A PatholAnatHistol 1981;392:247-61.
 
[60]  Nahavandi M, Tavakkoli F, Wyche MQ, Trouth AJ, Tavakoli N, Perlin E. Effect of transfusion on cerebral oxygenation, flow velocity in a patient with sickle cell anemia and Moyamoya disease: a case report. Hematology 2006; 11:381-383.
 
[61]  Al-Jafar H, Hashem K, Alhasan AA, Lamdhade S, AlDallal S, et al. Moyamoya Disease: A Rare Sickle Cell Trait Neurological Complication. J Neurol Psychol. 2016; 4 (1): 1-3.
 
[62]  Smith ER, Scott RM. Progression of disease in unilateral moyamoya syndrome. Neurosurg Focus 2008;24:E17.
 
[63]  Chiu D, Shedden P, Bratina P, Grotta JC. Clinical features of moyamoya disease in the United States. Stroke 1998;29: 1347-1351.
 
[64]  Edward R. Smith. Moyamoya Biomarkers. J Korean Neurosurg Soc. 2015 Jun; 57(6): 415-421.
 
[65]  Smith ER, McClain CD, Heeney M, Scott RM. Pialsynangiosis in patients with moyamoya syndrome and sickle cell anemia: perioperative management and surgical outcome. Neurosurg Focus 2009;26:E10.
 
[66]  Cerebral Atrophy Information Page: National Institute of Neurological Disorders and Stroke (NINDS).
 
[67]  R Peters. Ageing and the brain. Postgrad Med J. 2006 Feb; 82(964): 84-88.
 
[68]  Castillo V1, Bogousslavsky J, Ghika-Schmid F. [Etiology and mechanism in cerebral infarction]. Schweiz Med Wochenschr. 1996 Mar 23;126(12):489-92.
 
[69]  Ekaterini Solomou, Pantelis Kraniotis, Alexandra Kourakli, and Theodore Petsas. Extent of Silent Cerebral Infarcts in Adult Sickle-Cell Disease Patients on Magnetic Resonance Imaging: Is There a Correlation with the Clinical Severity of Disease? Hematol Rep. 2013 Jan 25; 5(1): 8-12.
 
[70]  Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998; 91:288-94.
 
[71]  Seibert JJ, Glasier CM, Kirby RS, et al. Transcranial doppler, MRA, and MRI as a screening examination for cerebrovascular disease in patients with sickle cell anemia: an 8-year study. Pediatr Radiol. 1998; 28:138-42.
 
[72]  (AFTD). 2007-2016. The Association for Frontotemporal Degeneration. Evaluation & Diagnosis. http://www.theaftd.org/understandingftd/diagnosis.
 
[73]  (NINDS) cerebral atrophy information page. National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/cerebral_atrophy/cerebral_atrophy.htm.
 
[74]  Catherine Bootha, Baba Inusab and Stephen K. Obaro. Infection in sickle cell disease: A review.International Journal of Infectious Disease (2010) 14, e2-e12.
 
[75]  Michael J. Burns. Chapter 183: The Immunocompromised Patient. Slremeducation.org (2015)
 
[76]  James K. Onwubalili. Sickle cell disease and infection. Journal of Infection. Volume 7, Issue 1, July 1983.
 
[77]  Babamahmoodi F. Davoudi A, Babamahmoodi A and Sepehremanesh M; Epidemiologic characteristics of patient treated in a referral center with the diagnosis of central nervous infection in North of Iran, from March 2008 to March 2012: A retrospective observational registry sudy. Archives of Neuroscience 2014;1(2): 82-87.
 
[78]  S. Kuruvatha, S. Basua, J.P. Elwitigalab, A. Yanezab, S.S. Namnyakb, A.R. Aspoas. Salmonella enteritidis brain abscess in a sickle cell disease patient: case report and review of the literature. International Journal of Infectious Disease (2008) 12, 298-302.
 
[79]  Dee, R. R., and B. Lorber. 1986. Brain abscess due to Listeria monocytogenes: case report and literature review. Rev. Infect. Dis. 8:968-977.
 
[80]  Eckburg, P. B., J. G. Montoya, and K. L. Vosti. 2001. Brain abscess due to Listeria monocytogenes: five cases and a review of the literature. Medicine (Baltimore) 80:223-35.
 
[81]  Armstrong, R. W., and P. C. Fung. 1993. Brainstem encephalitis (rhombencephalitis) due to Listeria monocytogenes: case report and review. Clin. Infect. Dis. 16:689-702.
 
[82]  Uldry, P. A., T. Kuntzer, J. Bogousslavsky, F. Regli, J. Miklossy, J. Bille, P. Francioli, and R. Janzer. 1993. Early symptoms and outcome of Listeria monocytogenes rhombencephalitis: 14 adult cases. J. Neurol. 240:235-242.
 
[83]  Brouwer, MC; Coutinho, JM; van de Beek, D (Mar 4, 2014). "Clinical characteristics and outcome of brain abscess: systematic review and meta-analysis". Neurology. 82 (9): 806-13.
 
[84]  A.B. Haimes, R.D. Zimmerman, S. Morgello, K. Weingarten, R.D. Becker, R. Jennis, et al. MR imaging of brain abscesses. Am J Roentgenol, 152 (1989), pp. 1073-1085.
 
[85]  K.N. Fountas, E.Z. Kapsalaki, S.D. Gotsis, J.Z. Kapsalakis, H.F. Smisson III, K.W. Johnston, et al.In vivo proton magnetic resonance spectroscopy of brain tumors.Stereotact Funct Neurosurg, 74 (2000), pp. 83-94.
 
[86]  Salzman C, Tuazon CU. Value of the ring-enhancing sign in differentiating intracerebral hematomas and brain abscesses. Arch Intern Med 1987;147:951e2.
 
[87]  Hernando Alvis Miranda, Sandra Milena Castellar-Leones, Mohammed Awad Elzain and Luis Rafael Moscote-Salazar. Brain abscess: Current management. J Neurosci Rural Pract. 2013 Aug; 4(Suppl 1): S67-S81.
 
[88]  Dattatraya Muzumdar, Sukhdeep Jhawar, A. Goel. Brain abscess: An overview. International Journal of Surgery 9 (2011) 136e144.
 
[89]  Steen RG, Miles MA, Helton KJ, Strawn S, Wang W, Xiong X, et al. Cognitive impairment in children with hemoglobin SS sickle cell disease: relationship to MR imaging findings and hematocrit. AJNR Am J Neuroradiol 2003; 24:382-389.
 
[90]  Berkelhammer LD, Williamson AL, Sanford SD, Dirksen CL, Sharp WG, Margulies AS, et al. Neurocognitive sequelae of pediatric sickle cell disease: a review of the literature. Child Neuropsychol 2007; 13:120-131.
 
[91]  Brandling-Bennett EM, White DA, Armstrong MM, Christ SE, DeBaun M. Patterns of verbal long-term and working memory performance reveal deficits in strategic processing in children with frontal infarcts related to sickle cell disease. DevNeuropsychol 2003; 24:423-434.
 
[92]  White DA, Salorio CF, Schatz J, DeBaun M. Preliminary study of working memory in children with stroke related to sickle cell disease. J ClinExpNeuropsychol 2000; 22:257-264.
 
[93]  Nabors NA, Freymuth AK. Attention deficits in children with sickle cell disease. Percept Mot Skills 2002; 95:57-67.
 
[94]  Hijmans CT, Grootenhuis MA, Oosterlaan J, Last BF, Heijboer H, Peters M, et al. Behavioral and emotional problems in children with sickle cell disease and healthy siblings: Multiple informants, multiple measures. Pediatr Blood Cancer 2009;53:1277-1283.
 
[95]  Schatz J, Roberts CW. Short-term memory in children with sickle cell disease: executive versus modality-specific processing deficits. Arch ClinNeuropsychol 2005;20:1073-1085.
 
[96]  Angelo Onofria, Maria Montanarob, PatriziaRampazzoa, RaffaellaColombattib, Filippo Maria Farinaa, Renzo Manarac, Laura Sainatib, Mario Ermania, Claudio Baracchinia, Giorgio Meneghettia Intellectual impairment and TCD evaluation in children with sickle cell disease and silent stroke.New Trends in Neurosonology and Cerebral Hemodynamics – an Update.Volume 1, Issues 1-12, September 2012, Pages 272-274.
 
[97]  Steen RG, Xiong X, Mulhern RK, Langston JW, Wang WC. Subtle brain abnormalities in children with sickle cell disease: relationship to blood hematocrit. Ann Neurol 1999;45:279-286
 
[98]  Fowler MG, Whitt JK, Lallinger RR, Nash KB, Atkinson SS, Wells RJ, et al. Neuropsychologic and academic functioning of children with sickle cell anemia. J DevBehavPediatr 1988;9: 213-220.
 
[99]  Brown, R. T, Buchanan, I., Doepke, K., Eckman, J. R., Baldwin, K., Goonan, B., &Schoenherr, S. (1993). Cognitive and academic functioning in children with sickle-cell disease. Journal of Clinical Child Psychology, 22, 207 -218.
 
[100]  Gualandro SF, Fonseca GH, Gualandro DM. Cardiopulmonary complications of sickle cell disease [Article in Portuguese]. Rev Bras HematolHemoter. 2007;(29)3:291-8.
 
[101]  Angulo IL. Stroke and other vascular complications of the central nervous system in sickle cell disease [Article in Portuguese]. Rev Bras HematolHemoter. 2007;29(3):262-67.
 
[102]  Ausavarungnirun P, Sabio H, Kim J, Tegeler CH. Dynamic vascular analysis shows a hyperemic flow pattern in sickle cell disease. J Neuro-imaging. 2006;16:311-317.
 
[103]  Kofi A Anie. Psychological complications in sickle cell disease.British Journal of Haematology, 129, 723-729.
 
[104]  Armstrong, F.D., Thompson, R.J., Wang, W., Zimmerman, R., Pegelow, C.H., Miller, S., Moser, F., Bello, J., Hurtig, A. & Vass, K.(1996). Cognitive functioning and brain magnetic resonance imaging in children with sickle cell disease. Pediatrics, 97, 864-870.
 
[105]  Schatz, J., Finke, R.L., Kellett, J.M. & Kramer, J.H. (2002a) Cognitive functioning in children with sickle cell disease: a meta-analysis.Journal of Pediatric Psychology, 27, 739-748.
 
[106]  Manfre, L., Giarratano, E., Maggio, A., Banco, A., Vaccaro, G. &Lagalla R. (1999). MR imaging of the brain: findings in asymptomatic patients with thalassemia intermedia and sickle cell-thalassemia disease. American Journal of Roentgenology, 173, 1477-1480.
 
[107]  Wang, W., Enos, L., Gallagher, D., Thompson, R., Guarini, L.,Vichinsky, E., Wright, E., Zimmerman, R. & Armstrong, F.D.(2001). Neuropsychologic performance in school-aged children with sickle cell disease: a report from the Cooperative Study of Sickle Cell Disease. Journal of Pediatrics, 139, 391-397.
 
[108]  Prohovnik, I., Sano, M., DeVivo, D., Hurlet, A., Keilp, J. &Piomelli, S.(1995). Frontal lobe dysfunction in sickle-cell anemia. Journal of Cerebral Blood Flow and Metabolism, 15, S800.
 
[109]  Stefan Lorenzl, Ingo Füsgen, SoheylNoachtar.Acute Confusional States in the Elderly—Diagnosis and Treatment.DtschArztebl Int. 2012 May; 109(21): 391-400.
 
[110]  Madeleine Purchas.Guidelines for the Diagnosis and Management of Acute Confusion (delirium) in the Elderly. Royal Cornwall Hospital (NHS).16th Dec 2005.
 
[111]  Saxena S., Lawley D. (2009). Delirium in the elderly: a clinical review. Postgrad. Med. J. 85, 405-41310.
 
[112]  William T. Zempsky. Evaluation and Treatment of Sickle Cell Pain in the Emergency Department: Paths to a Better Future. ClinPediatrEmerg Med. 2010 Dec 1; 11(4): 265-273.
 
[113]  Richard N. Jones, Tamara G. Fong, Eran Metzger, Samir Tulebaev, Frances M. Yang, David C. Alsop, Edward R. Marcantonio, L. Adrienne Cupples, Gary Gottlieb, and Sharon K. Inouye. Aging, Brain Disease, and Reserve: Implications for Delirium.Am J Geriatr Psychiatry. 2010 Feb; 18(2): 117-127.
 
[114]  Koho Miyoshi and Yasushi Morimura. Clinical Manifestations of Neuropsychiatric Disorders Springer 2010.
 
[115]  MedlinePlus. Psychosis. Bethesda, MA, US: National Library of Medicine, National Institutes of Health, Department of Health and Human Services. Information published online, accessed November 21st, 2013.
 
[116]  Freudenreich O, Weiss AP, Goff DC. Psychosis and schizophrenia. In: Stern TA, Rosenbaum JF, Fava M, Biederman J, Rauch SL, editors. Massachusetts General Hospital Comprehensive
 
[117]  Muideen OwolabiBakare. Case Report: Psychosis in an adolescent with sickle cell disease. Child Adolesc Psychiatry Ment Health. 2007; 1: 6.
 
[118]  GP Guidance: Emerging Psychosis & Young People - What You Need to Know; Forum for Mental Health in Primary Care
 
[119]  Psychosis and schizophrenia in adults: treatment and management; NICE Clinical Guideline (Feb 2014)
 
[120]  Montserrat Sanmarti, Laura Ibáñez, Sonia Huertas, DolorsBadenes, David Dalmau, Mark Slevin, Jerzy Krupinski, AurelPopa-Wagner and Angeles Jaen. HIV-associated neurocognitive disorders. Journal of Molecular Psychiatry2014. 2:2.
 
[121]  Ruoxian Deng, Wei Xiong, and XiaofengJia.Electrophysiological Monitoring of Brain Injury and Recovery after Cardiac Arrest. Int J Mol Sci. 2015 Nov; 16(11): 25999-26018.
 
[122]  Edward C. Jauch, Jeffrey L. Saver. Guidelines for the Early Management of Patients With Acute Ischemic Stroke. AHA/ASA Guideline. (2013); 44: 870-947.
 
[123]  Tan IL, McArthur JC; HIV -Associated Neurological Disorders: A Guide to Pharmacotherapy. CNS Drugs. 2011 Dec 23.
 
[124]  Lara MilevojKopcinovic and JelenaCulej. Pleural, peritoneal and pericardial effusions – a biochemical approach.Biochem Med (Zagreb). 2014 Feb; 24(1): 123-137.
 
[125]  Samir K. Ballas, Muge R. Kesen, Morton F. Goldberg. Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management. Scientific World Journal. 2012; 2012: 949535.
 
[126]  Killian A Welch. Neurological Complications of Alcohol and Misuse of Drugs. Practical Neurology. Pract Neurol. 2011; 11(4): 206-219.
 
[127]  Kathleen Ryan, AnjuChawla, Sharon Space, and Matthew Heeney, MD. Prevention and Treatment of Stroke for Pediatric Patients with Sickle Cell Disease.@ New England Pediatric Sickle Cell Consortium. Finalized December 2003.
 
[128]  Galimi R. Nonconvulsive status epilepticus in pediatric populations: diagnosis and management. Minerva Pediatr 2012; 64: 347-355.
 
[129]  Mader EC, Jr., Villemarette-Pittman NR, Kashirny SV, Santana-Gould L, Olejniczak PW. Typical Spike-and-Wave Activity in Hypoxic-Ischemic Brain Injury and its Implications for Classifying Nonconvulsive Status Epilepticus. Clin Med Insights Case Rep 2012;5:99-106.
 
[130]  Kennel C, Michas-Martin A, Berman BD, Poisson S. Nonconvulsive status epilepticus masquerading as stroke. Am J Emerg Med 2014.
 
[131]  Pegelow CH, Macklin EA, Moser FG, Wang WC, Bello JA, Miller ST, et al. Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease. Blood 2002;99:3014-3018.
 
[132]  Silva GS, Vicari P, Figueiredo MS, Junior HC, Idagawa MH, Massaro AR. Migraine-mimicking headache and sickle cell disease: a transcranial Doppler study. Cephalalgia 2006;26: 678-683.
 
[133]  Trisha E. Wong, Amanda M. Brandow, Wendy Lim, Richard Lottenberg. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 2014 124:3850-3857.
 
[134]  European Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use. 2008. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006488.pdf.
 
[135]  Chou ST. Transfusion therapy for sickle cell disease: a balancing act. Hematology Am SocHematolEduc Program 2013;2013:439-446.
 
[136]  Lasalle-Williams M, Nuss R, Le T, Cole L, Hassell K, Murphy JR, et al. Extended red blood cell antigen matching for transfusions in sickle cell disease: a review of a 14-year experience from a single center (CME). Transfusion 2011;51:1732-1739.
 
[137]  Giancarlo Liumbruno, Francesco Bennardello, Angela Lattanzio, PierluigiPiccoli and Gina Rossetti. Recommendations for the transfusion of red blood cells. Blood Transfus. 2009 Jan; 7(1): 49-64.
 
[138]  Fenella J Kirkham. Insight: stroke risk and its management in patients with sickle cell disease. Nature Clinical Practice Neurology (2007)3,264-278.
 
[139]  Chimowitz MI, Furlan AJ, Nayak S, Sila CA. Mechanism of stroke in patients taking aspirin. Neurology 1990;40:1682-1685.
 
[140]  Toth L, Muszbek L, Komaromi I. Mechanism of the irreversible inhibition of human cyclooxygenase-1 by aspirin as predicted by QM/MM calculations. J Mol Graph Model 2013;40:99-109.
 
[141]  Sandercock PA, Counsell C, Tseng MC, Cecconi E. Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2014;3:CD000029.
 
[142]  The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997;349:1569-1581.
 
[143]  Stead LG. Evidence-based emergency medicine/systematic review abstract. Antiplatelet agents for acute ischemic stroke. Ann Emerg Med 2003;42:423-425.
 
[144]  Simmons BB, Yeo A, Fung K, American Heart A, American Stroke A. Current guidelines on antiplatelet agents for secondary prevention of noncardiogenic stroke: an evidence-based review. Postgrad Med 2010;122:49-53.
 
[145]  Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B. Risk-benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic stroke: a systematic review and meta-analysis. Ann Intern Med 2013;159:463-470.
 
[146]  Roach ES. Stroke in Children. Curr Treat Options Neurol 2000;2:295-304.
 
[147]  Hassana Fathallah and George F. Atweh. Induction of FetalHemoglobin in the Treatment of Sickle Cell Disease. ASH Education Book vol. 2006 no. 1 58-62.
 
[148]  E. Du, Laurel Mendelsohn, James S. Nichols, Ming Dao and Gregory J. Kato. Quantification of Anti-Sickling Effect of Aes-103 in Sickle Cell Disease Using an in Vitro Microfluidic Assay. Volume: 124 Issue: 21 Pages: 2699-2699.
 
[149]  Global Blood Therapeutics’ (GBT440) Demonstrates Ability to Positively Impact Fundamental Sickle Cell Disease (SCD) Processes in Studies Presented at 2014 American Society of Hematology (ASH) Conferenc
 
[150]  Ferrone, F. A. (2016), GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol.
 
[151]  Marilyn J. Telen, Ted Wun, Timothy L. McCavit, Laura M. De Castro, LakshmananKrishnamurti, Sophie Lanzkron, Lewis L. Hsu, Wally R. Smith, Seungshin Rhee, John L. Magnani10, and Helen Thackray. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Volume: 125. Issue: 17 Pages: 2656-2664.
 
[152]  Abdullah Kutlar, Kenneth I. Ataga, Lillian McMahon. A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease. American Journal of Hematology. Volume 87, Issue 5, pages 536-539, May 2012.
 
[153]  Qari MH1, Aljaouni SK, Alardawi MS, Fatani H, Alsayes FM, Zografos P, Alsaigh M, Alalfi A, Alamin M, Gadi A, Mousa SA. Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. ThrombHaemost. 2007 Aug;98(2):392-6.
 
[154]  Shaker A. Mousa. Method and composition of glycosaminoglycans in sickle cell and vascular disorders. (2015) US20150150818 A1.
 
[155]  Ekre, Hans-peter, Leitgeb, Ann, Wahlgren, Mats, Pikas, Dagmar. Use of Chemically Modefied Heparin Derivatives in Sickle Cell Disease. (Dec 11-2014) USPatent Application 20140364369.
 
[156]  Jakubowski JA, Zhou C, Small DS, Winters KJ, Lachno DR, Frelinger AL 3rd, Howard J, Mant TG, Jurcevic S, Payne CD. A phase 1 study of prasugrel in patients with sickle cell disease: pharmacokinetics and effects on ex vivo platelet reactivity. Br J ClinPharmacol. 2013 Jun;75(6):1433-44.
 
[157]  Geoffrey Burnstock and Michael Williams.P2 Purinergic Receptors: Modulation of Cell Function and Therapeutic Potential. JPET December 1, 2000 vol. 295 no. 3 862-869
 
[158]  DeepaManwani and Paul S. Frenette. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013 Dec 5; 122(24): 3892-3898.
 
[159]  Joshua J Field and David G Nathan.Advances in Sickle Cell Therapies in the Hydroxyurea Era.Mol Med. 2014; 20(Suppl 1): S37-S42.
 
[160]  Megan D. Hoban, Stuart H. Orkin and Daniel E. Bauer. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease Volume: 127 Issue: 7 Pages: 839-848.
 
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