Thalassemia Sickle Cell Disease

1. NEUROLOGICAL MANIFESTATIONS OF
HEMOGLOBINOPATHIES
Ade Wijaya, MD – January
2019

2. INTRODUCTION
Hemoglobinopathies are inherited single gene disorders that in most
cases are autosomal co-dominant traits.
(a) Thalassemia syndromes
- Hb synthesis disorders
(b) Structural hemoglobin variants (abnormal hemoglobins)
- Changes in Hb structure
(c) Mixed forms that combine features of both groups, e.g. β0/β+-
thalassemias, HbSC disease and HbE α-thalassemias
Weatherall DJ, Clegg JB. The thalassaemia syndromes. 4th edn. Oxford: Blackwell Science Ltd. 2001.

3. THALASSEMIA
Mettananda S, Gibbons RJ, Higgs DR. α-Globin as a molecular target in the treatment of β-thalassemia. Blood. 2015 Jun 11;125(24):3694-701.

4. SICKLE CELL DISEASE
Steinberg MH. Sickle cell anemia, the first molecular disease: overview of molecular etiology, pathophysiology, and therapeutic approaches. The Scientific World Journal. 2008;8:1295-324.

5. NEUROLOGICAL MANIFESTATIONS IN
THALASSEMIA
• Extramedullary haematopoiesis
• Stroke
• Chelation neurotoxicity
• Neurocognitive dysfunction
• CNS Infections
Delicou S. Neurological Manifestations of Hemoglobinopathies

6. EXTRAMEDULLARY
HAEMATOPOIESIS
• Is a non-neoplastic proliferation of hematopoietic tissue outside the
bone marrow and peripheral blood that is typically a reaction to
various hematologic disorders that result in abnormal bone marrow
production or function
• Clinical presentations including: back pain, parasthesia, paraparesis,
paraplegia, ankle clonus, spasic gait, exaggerated or brisk tendon
reflexes, Babinski response, or urgency of urination and bowel
incontinence
• Diagnosis: MRI
• Treatment: Hyper transfusion therapy, Hydroxyl-urea, Radiation
Delicou S. Neurological Manifestations of Hemoglobinopathies

7. STROKE
Hypercoagulable state:
• Procoagulant activity of damaged circulating red blood cells (RBCs)
• Co-inheritance of coagulation defects
• Depletion of antithrombotic factors
• Endothelial inflammation and conditions that increase thrombotic
burden which results in thromboembolic events involving major
organs including the brain
Iron deposition
.Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood. 2002; 99: 36-43.

8. CHELATION NEUROTOXICITY
• There are three major iron chelators used in thalassemia namely
Desferrioxamine, Deferiprone and Deferasirox
• Auditory and ocular neurotoxicity
Porter JB, Jaswon MS, Huehns ER, East CA, Hazell JW. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol.
1989; 73: 403-409.

9. NEUROCOGNITIVE DYSFUNCTION
Anemia, which leads to hypoxia and iron deposition, leads to brain
damage in the long term
Iron deposition
 implicit and explicit memory
Monastero R, Monastero G, Ciaccio C, Padovani A, Camarda R. Cognitive deficits in beta-thalassemia major. Acta Neurol Scand.

10. CNS INFECTIONS
• Splenic function is lost when the spleen has been surgically removed,
is congenitally absent, has atrophied following repeated infarction
(eg, sickle cell disease), or following splenic artery thrombosis
 CNS infections
Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011; 378: 86-97.
Overturf GD, Powars D, Baraff LJ. Bacterial meningitis and septicemia in sickle cell disease. Am J Dis Child. 1977; 131: 784-787.
Yanni E, Grosse SD, Yang Q, Olney RS. Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002. J Pediatr. 2009; 154: 541-545.
Hamideh D, Alvarez O. Sickle cell disease related mortality in the United States (1999-2009). Pediatr Blood Cancer. 2013; 60: 1482- 1486

11. NEUROLOGICAL
MANIFESTATIONS IN
SICKLE CELL DISEASE
• Headache
• Stroke
• Neurocognitive dysfunction
• Mental disorders
• CNS infections
Delicou S. Neurological Manifestations of Hemoglobinopathies

12. HEADACHE
• Children and adolescents with sickle cell disease (SCD) have a high
prevalence of recurrent headaches (24.0–43.9 %)
• Etiology: vascular diseases (stroke, hemorrhage, venous sinus
thrombosis, moyamoya, posterior reversible encephalopathy
syndrome), facial and orbital bone infarcts, dental pain, and
osteomyelitis.
Millichap J. Headache in Sickle Cell Disease. Pediatr Neurol Briefs. 2007; 21.
Niebanck AE, Pollock AN, Smith-Whitley K, Raffini LJ, Zimmerman RA, Ohene-Frempong K, et al. Headache in children with sickle cell disease: prevalence and associated factors. J Pediatr. 2007; 151: 6

13. STROKE
• Stroke (or cerebrovascular accident) is one of the common
complications of severe sickle cell disease (SCD).
• Red cell transfusion to lessen the anaemia, reduce tissue hypoxia
and reduce the percentage of HbS is the mainstay of treatment
• Chronic transfusion therapy is the most effective known method to
reduce recurrences of stroke.
• Hydroxyurea
Bennett JS. Vasoocclusion in sickle cell anemia: are platelets really involved? Arterioscler Thromb Vasc Biol. 2006; 26: 1415-1416
Switzer JA, Hess DC, Nichols FT, Adams RJ. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006; 5: 501-512.
Gulbis B, Haberman D, Dufour D, Christophe C, Vermylen C, Kagambega F, et al. Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience. Bl
2005; 105: 2685-2690.
Scothorn DJ, Price C, Schwartz D, Terrill C, Buchanan GR, Shurney W, et al. Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years after init

14. NEUROCOGNITIVE DYSFUNCTION
• Declining IQ scores, learning difficulties, and impairment of
executive function
• Silent infarcts frequently involve frontal lobe lesions, resulting in
deficits in attention and executive skills
• The majority of adult patients with SCA found to have lower
neurocognitive performance associated with hemoglobin level, age,
and education
• Impact on quality of life, employment, and personal relationships
Delicou S. Neurological Manifestations of Hemoglobinopathies

15. MENTAL DISORDERS
• SCD pain can be as intense as post-operative pain  drug
dependent
• Delirium and confusional
• Depression and other psychiatric disorders
Solomon LR. Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void. Blood. 2008; 111: 997-1003.
Thompson RJ Jr, Gil KM, Burbach DJ, Keith BR, Kinney TR. Role of child and maternal processes in the psychological adjustment of children with sickle cell disease. J Consult Clin Psychol.
1993; 61: 468-474.
Cameron DJ, Thomas RI, Mulvihill M, Bronheim H. Delirium: a test of the Diagnostic and Statistical Manual III criteria on medical inpatients. J Am Geriatr Soc. 1987; 35: 1007-1010.

16. CNS INFECTIONS
• Splenic function is lost when the spleen has been surgically removed,
is congenitally absent, has atrophied following repeated infarction
(eg, sickle cell disease), or following splenic artery thrombosis
 CNS infections
Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011; 378: 86-97.
Overturf GD, Powars D, Baraff LJ. Bacterial meningitis and septicemia in sickle cell disease. Am J Dis Child. 1977; 131: 784-787.
Yanni E, Grosse SD, Yang Q, Olney RS. Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002. J Pediatr. 2009; 154: 541-545.
Hamideh D, Alvarez O. Sickle cell disease related mortality in the United States (1999-2009). Pediatr Blood Cancer. 2013; 60: 1482- 1486

17. SUMMARY
1. Hemoglobinopathies ( thalassemia and SCD )  causing
neurological complications
2. Need to be detected and treated (impact QOL)
3. Thalassemia: EMH, stroke, chelation neurotoxicity, neurocognitive
dysfunctions, CNS infections
4. SCD: headache, stroke, neurocognitive, mental disorders, CNS
infections

18. THANK YOU