The epidemiology of stroke in sickle cell patients in Yaounde, Cameroon

Journal of the Neurological Sciences 250 (2006) 79 – 84 www.elsevier.com/locate/jns

The epidemiology of stroke in sickle cell patients in Yaounde, Cameroon A.K. Njamnshi a,b,⁎, E.N. Mbong a , A. Wonkam c , P. Ongolo-Zogo a , V.-de-P. Djientcheu a , F.L. Sunjoh a , C.S. Wiysonge d , R. Sztajzel b , D. Mbanya a , K. Ngu Blackett a , L. Dongmo a , W.F.T. Muna a a

c

Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Cameroon b Department of Neurology, University Hospitals of Geneva, Switzerland Department of Genetic Medicine and Development, University Hospitals of Geneva, Switzerland d Cardiac Clinic, Department of Medicine, University of Cape Town, South Africa Received 20 February 2006; received in revised form 14 June 2006; accepted 10 July 2006 Available online 14 August 2006

Abstract Background and purpose: Stroke, a severe and recurrent but preventable complication of sickle cell disease (SCD), has not been well studied in Cameroon. To obtain baseline data towards the development of a national stroke prevention programme in SCD, we studied a sample of sickle cell patients with the aim of determining stroke prevalence, clinical presentation and management practices. Patients and methods: Homozygous sickle cell patients in two centres in Yaounde were screened for stroke, in a cross-sectional study. Stroke was diagnosed clinically and confirmed where possible with brain computerized tomography. The National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS) were used to assess stroke severity. Management practices were noted from patient charts. Results: One hundred and twenty patients aged 7 months to 35 years (mean age 13.49 ± 8.79 years) were included. Eight cases of stroke (mean age 16.6 ± 11.2 years) were identified, giving a stroke prevalence of 6.67%. Cerebral infarction was thrice as common as cerebral hemorrhage and clinical presentation was classical. Cerebral infarction was more frequent in patients aged below 20 years and hemorrhage in those above 20 (p = 0.11). The annual recurrence rate was 25%. Missed diagnosis rate by attending physician was 25%. The NIHSS and mRS showed high stroke severity. Stroke management practices were insufficient and no patient received any form of stroke prophylaxis. Conclusion: Stroke prevalence and presentation in sickle cell patients in Yaounde is similar to that observed in developed countries, but the wide management gap calls for rapid action. Our situation is ideal for the study of the natural history of stroke in sickle cell disease. © 2006 Elsevier B.V. All rights reserved. Keywords: Sickle cell disease; Stroke; Epidemiology; Cameroon; Sub-Saharan Africa

1. Introduction Cerebrovascular disease, a major cause of morbidity and mortality in patients with sickle cell disease (SCD) [1], may present as cerebral infarction or cerebral haemorrhage [2]. Recent studies show that 11% of sickle cell patients before the age of 20 suffer from an overt stroke [3,4,15], two-thirds of whom will recur if prophylactic treatment is not instituted ⁎ Corresponding author. Head-Neurology Service, Central Hospital Yaounde, BP 25625, Yaounde, Cameroon. Tel.: +237 761 99 64; fax: +237 223 45 79. E-mail address: [email protected] (A.K. Njamnshi). 0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.07.003

[2]. Moreover, patients without an overt stroke often present with asymptomatic focal brain infarcts, the so-called ‘silent’ infarcts, on cerebral imaging [5]. Silent infarcts are responsible for cognitive and behavioural changes in some patients and represent a risk factor for overt stroke [2]. Stroke is now known to be a preventable complication of SCD especially if at-risk children are detected early using transcranial Doppler (TCD) ultrasonography and put on chronic transfusion therapy (CTT) [6] or Hydroxyurea (HU) [7] or given bone marrow transplant (BMT) [8]. SCD is estimated to affect about 2–3% of Cameroon's 16 million inhabitants [9]. Obama et al. [10], found sickle cell disease to be the most common cause of stroke in

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children, accounting for almost a third of the reported stroke cases in Yaounde. However, only a few case reports have been published in Cameroon since then [11,12]. In an effort to obtain some baseline epidemiologic data towards the development of a stroke prevention programme in sickle cell disease in Cameroon, we set out to determine the prevalence, clinical manifestations and contemporary management of stroke in sickle cell patients in Cameroon. 2. Subjects and methods This was a descriptive cross-sectional study carried out from October to December 2003 in two sickle cell centres in Yaounde: Central Hospital and Mvolye Catholic Centre. The study was approved by the Ethics Committee of the Faculty of Medicine and Biomedical Sciences Yaounde and the respective committees of both sickle cell centres. Informed consent for participation into the study was obtained from patients, parents or guardians. All patients with sickle cell disease (confirmed by haemoglobin electrophoresis) who visited either centre during the study period and gave verbal informed consent were included. For under-aged children, consent was obtained from parents. Cases of stroke were patients presenting with an acute stroke or a past history of stroke confirmed by a physical examination and (when possible) a cerebral computerised tomographic (CT) scan, done at least 5 days after the initial stroke symptoms. 2.1. Definition of clinical events

in the cases at the Medical Imaging Service of Central Hospital Yaounde and reviewed by an independent neuroradiologist. 2.3. Statistical analysis Statistical analysis was performed using the Epi Info version 2000 software package. Crude and age-specific prevalence rates were calculated as the number of patients with a stroke divided by the total number of patients in the relevant subgroup. Descriptive statistics are presented as percentages and means ± 1 standard deviation (S.D.). All P values are two sided and a P value of <0.05 is considered significant. 3. Results 3.1. The general characteristics of the patients studied One hundred and twenty sickle cell patients (Haemoglobin SS) were screened, 80% of whom were 20 years or younger as shown in Table 1. The youngest patient seen was 7 months old and the oldest 35 years. The mean age was 13.49 ± 8.79 years. Foetal haemoglobin (Hgb F) was present in 26 patients (21.67%). More than half of study subjects with Hgb F were aged 5 years and below and 80% less than 10 years of age. Hgb F was less than 20% of total haemoglobin in half of the patients and less than 30% in 83.33% of the patients.

We defined a cerebrovascular event as a stroke or a transient ischaemic attack (TIA). Stroke was defined according to the recommended WHO standard, as a focal (or at times global) neurological impairment of sudden onset, and lasting more than 24 h or leading to death and of presumed vascular origin [13]. Infarction or haemorrhage were further distinguished where possible by brain CTs. For practical purposes, TIA was defined as focal neurological symptoms of duration shorter than 24 h and without any scannographic changes.

3.2. Stroke prevalence

2.2. Data collection

3.3. The clinical presentation of stroke

Patients were recruited consecutively and after obtaining a confirmation of the diagnosis of sickle cell disease by haemoglobin electrophoresis result showing haemoglobin SS, a complete history was taken and a physical examination done. This included a thorough neurological evaluation by one and the same consultant neurologist. Chart review was done to confirm case histories and some clinical findings and to obtain laboratory data and management practices. All collected data were entered into a pre-prepared worksheet. The severity of stroke in the cases was assessed using the National Institutes of Health Stroke score (NIHSS) and the modified Rankin scale (mRS). Cerebral CT scans were done

A sudden focal motor deficit was the most common presenting complaint, present in 3 of the 8 cases of stroke

We found a stroke prevalence of 6.67% (8 of 120 patients). One of the cases was an acute initial stroke and two (25% of stroke cases) were recurrences: 1 ischaemic stroke 12 months after the first and the other an ischaemic stroke 9 months after a TIA. The other five cases were initial stroke cases. The sex ratio of the stroke patients was 1:1. Only 1 stroke patient still had haemoglobin F. The mean age of stroke patients was 16.6 ± 11.2 years (range: 4–33 years).

Table 1 General characteristics of the study sample of SCD patients (n = 120) Age group

Male

Female

Total

%

0–5 >5–10 >10–15 >15–20 >20 Total %

16 12 12 15 10 65 54.17

10 12 12 7 14 55 45.83

26 24 24 22 24 120 100.0

21.67 20.00 20.00 18.33 20.00 100.00

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Table 3 The NIHSS and mRS of the stroke patients (n = 8)

(37.5%). An altered level of consciousness (and later coma), motor aphasia with nausea (1 case) and a sudden severe headache (1 case), were the next most common presenting symptoms. In two stroke patients (25%), the diagnosis of stroke was missed by the attending physician who was not part of the study team. In three (37.5%) patients, stroke occurred during a painful crisis. Some patients had more than one presenting complaint. The findings of the neurological examination are summarized in Table 2.

NIHS scores N (%) mRS scores N (%)

1–5 1 (12.5) 1–2 0 (0.0)

6–10 1 (12.5) 3–4 5 (62.5)

11–13 1 (12.5) 5 3 (37.5)

>13 5 (62.5)

3.5. Cerebral CT scan findings Five stroke patients (62.50%) could afford a Cerebral CT scan (Table 2), all of which were pathologic. Three scans were consistent with clinical findings and two showed diffuse cortical atrophy in patients with focal signs and symptoms suggestive of a middle cerebral artery lesion.

3.4. Stroke subtype Six of the eight cases (75%) of stroke presented with signs and symptoms of an ischaemic stroke while two (25%) others presented with signs and symptoms suggestive of haemorrhagic stroke (Table 2). One of the two cases of haemorrhagic stroke was intraparenchymal (confirmed by CT scanning to be a rupture of the left posterior cerebral artery) and the other a sub-arachnoid haemorrhage. All cases of ischaemic stroke occurred in the vascular territory of the middle cerebral artery.

3.6. Stroke severity assessment The stroke severity assessment is shown in Table 3, using the National Institutes of Health Stroke Score (NIHSS) and the modified Rankin Scale (mRS): Five of the eight stroke patients were younger than 20 years, but there was no difference in the mean NIHSS and

Table 2 Summary of clinical, laboratory and brain CT findings in the stroke patients Case Sex Age: Hgb First/second PMH Clinical syndrome number (years) electrophoresis stroke ACS TCD TIA 1

M

4

SS

First

No

ND

No

2

M

8

SS F: 9 %

First

No

ND

No

3

F

9

SS

Second

No

ND

Yes

4

F

13

SS

Second

No

ND

No

5

F

15

SS

First

No

ND

No

6

M

25

SS

First

No

ND

No

7

F

28

SS

First

No

ND

No

8

M

33

SS

First

Yes

ND

No

WBC count and Hgb level

Right-sided pyramidal syndrome NA with right upper motor neuron (UMN) facial palsy. Right-sided pyramidal syndrome NA with urinary incontinence and no cranial nerve involvement. Left-sided pyramidal syndrome NA with right UMN facial palsy. Left pyramidal syndrome and sensory deficit; left UMN facial palsy, dysarthria, apraxia, paraphasia and urinary incontinence. Right pyramidal syndrome predominant in upper limb with left UMN facial palsy. Right pyramidal syndrome predominant in the lower limb with expressive aphasia, left UMN facial palsy, right lateral homonymous hemianopsia; later coma. Acute severe headache with signs of meningeal irritation and later left-sided sensory-motor signs. Left pyramidal syndrome predominant in the upper limb, bilateral Babinski sign; no cranial nerve involvement.

Brain CT scan results

ND

ND

Hypodense lesion: left internal capsule with oedema. WBC: Hypodense lesion: right 12,000/mm3: parietal region with normal differential sequellae of a left count. Hgb: 6.5 g/dl internal capsule ischaemia. NA Diffuse cortical atrophy with no signs of ischemia WBC: Intraparenchymal left 21,000/ mm3 with parieto-occipital normal differential haematoma with a mass count, Hgb 8.5 g/dl effect on the posterior limb of the left ventricle NA

ND

WBC: Diffuse cortical atrophy 19,000/mm3; normal differential count, Hgb 8.0 g/dl

ACS: acute chest syndrome; Hgb: haemoglobin; ND: not done; WBC: white blood cells; UMN: upper motor neuron; PMH: past medical history NA: not available.

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mRS scores of patients younger than 20 compared to those older than 20 (ANOVA t-statistic p = 0.19). 3.7. Management and stroke prophylaxis The general management by the attending physician during the stroke phase consisted of hyperhydration of the patients, administration of a nonsteroidal anti-inflammatory drug (Aspirin), and cerebral ‘oxygenators’: Almitrine bis mesilate sulfonate (DUXIL®) and dihydroergokryptine mesylate (VASOBRAL®). None of the patients received any exchange blood transfusions. Both patients with CVD recurrences were put on salicylic acid 100 mg p.o. daily, by attending physician and neither was on CTT nor hydroxyurea for secondary stroke prophylaxis. 4. Discussion This preliminary work, conducted for the first time in a context where patients have never received any form of prophylactic stroke treatment, provides an ideal opportunity for the study of the natural history of stroke in sickle cell disease. We found the prevalence of stroke in sickle cell patients to be 6.67%. This prevalence rate is similar to that obtained in France (6.70%) in sickle cell patients (Hgb SS) who were mostly of African descent [14]. It is slightly greater than the rate in a Jamaican cohort of sickle cell SS patients (5.5%) and greater than 3.75% obtained by OheneFrempong et al. [15], in the stroke in sickle cell study of the American Cooperative Study of Sickle Cell Disease Study (CSSCD) Group. The presence of double heterozygous and mixed forms of SCD in the CSSCD study (in which the prevalence of stroke is reported to be lower) as well as the large sample size (4082 patients) may explain the low crude prevalence of stroke. These forms of the disease are more common in North American Blacks than in the Central African region where our study was carried out [16,17]. Furthermore, in the CSSCD, the age-adjusted stroke prevalence of 4.96% in SS patients was several times higher than that in patients with heterozygous forms of the disease (SC-0.80; Sβ+ − 1.48 and Sβ0 − 1.58). However, we still think that the prevalence rate in the present study is an underestimation, given that we could not do more sensitive procedures like magnetic resonance imaging or standardised neuropsychological testing [2,5] on our subjects. Indeed, based on data from genetic studies [18,19,20] and the results of the current study, we have presented the argument that sickle cell disease patients in Cameroon may be at higher risk of stroke than those of other countries [21]. More studies are needed to further elucidate how genetic predisposition to higher stroke risk in Cameroonian sickle cell patients, may interplay with known or unknown environmental risk factors. In our study as well as in the CSSCD stroke study [15], sex was not found to be a predisposing factor for stroke in SCD. However, Sarnaik and Ballas [19] found stroke to be

more prevalent in female sickle cell patients. In the present study, the stroke prevalence doubled from the 0–5 to >5–10 age group (3.84–8.33%), remained stable in the 10–15 years age group and dropped to zero in the 15–20 years age group. This was so despite the fact that most of the patients in this study (83.33%) who still had haemoglobin F (which has been shown to protect against the occurrence of stroke in sicklers [22]) were younger than 10 years and just 11.11% in the 15–20 years age group. This increase in the prevalence of stroke in patients less than 10 years of age compared to those between the ages of 10 and 20 was also observed by OheneFrempong et al. [15], who proposed that a subset of patients may have additional risk factors for early stroke. This observation is further demonstrated by the prevalence of stroke in patients in our study less than 10 years of age which was greater than that in patients in the 10–20 years age group (6.00% as against 4.30%). Though this prevalence in patients older than 20 years was twice that in patients less than 20 years of age (12.50% as against 5.21%), this difference was not significant (OR = 0.28; p = 0.11) probably because of the small numbers. All the cases of stroke in the patients aged below 20 years were infarctions. In the group aged more than 20 years, infarction was thrice as common as haemorrhagic stroke (75.00% as against 25%). These results are consistent with literature and similar to that obtained in the CSSCD stroke study in which the prevalence of cerebral haemorrhagic stroke was twice that for cerebral infarction. We found cerebral haemorrhage only in patients older than 20 years. This is also consistent with medical literature and with the CSSCD stroke study in which the incidence of infarctive stroke was highest in SS patients younger than 20 years of age and that of haemorrhagic stroke highest in patients between the ages of 20 and 29 years and low in children less than 20. The higher prevalence and incidence of haemorrhagic stroke compared to infarctive stroke in older patients may be to the fact that haemorrhage is most often due to the rupture of aneurysms (resulting from the chronic vasculopathy brought about by the action of sickle-red cells on the vessel wall), which take more time to develop [2]. Cerebrovascular disease responsible for infarctive stroke may progress and lead to a hemorrhagic stroke at a later age [2]. The clinical presentation of infarctive stroke and hemorrhagic stroke in the present study was classical. Cerebral infarction presented with more of focal neurological deficits with little or no alteration of the level of consciousness, while cases cerebral haemorrhage presented as alterations in the level of consciousness, signs of intracranial hypertension, mass effect on adjacent structures and meningeal irritation in the case of sub-arachnoid haemorrhage. While overt stroke in SCD patients may be dramatic enough to be a presenting complaint at a consultation and as such be diagnosed easily, subtle motor changes and transient episodes of weakness or numbness may be missed especially in young children [2,4]. In 25% of our stroke cases, the diagnosis was not suspected by the attending physician, who

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was generally the primary care physician. This may suggest a low level of awareness of the neurological complications of SCD, on the part of the primary care physicians in our context. A paretic, limping young child may be misdiagnosed as having a sign of a painful episode. It has been observed that stroke is often missed for other more common diagnosis [2,6] by attending physicians as well as the patients themselves and their caretakers [2,4]. Stroke recurrence rates as high as 67% per year, after the first stroke, have been reported [2]. We observed a 25% annual recurrence in this study. Both patients with recurrent CVA in this study were on antiplatelet aggregation drug (acetyl salicylic acid). This drug is effective in preventing recurrence of stroke or a first stroke after a TIA in stroke of atherosclerotic origin, but there is yet no evidence of its efficacy for secondary prophylaxis of stroke in sickle cell disease [2]. None of these patients was on chronic transfusion therapy (CTT) which has been shown to substantially reduce this risk of stroke recurrence to 10% per year in children with sickle cell disease [2,6]. No patient was on alternative prophylaxis such as hydroxyurea whose effectiveness has been demonstrated as an alternative to CTT [2,7]. This may be due either to lack of knowledge or the relatively high cost of hydroxyurea, and the very limited health insurance schemes available. HLA-matched bone marrow transplant (BMT) which has been shown to prevent stroke recurrence after a first stroke, [2,8] is not yet practiced in Cameroon. Most of the patients (7 out of the 8 cases) with stroke had an NIHSS score >5 which generally would warrant some form of rehabilitation depending on the spheres of deficits. Out of this number, 5 (71.42%) had a score higher than 13 which is considered by some authors to be an indication for admission in a nursing home facility [23]. Similarly, just one patient had an MRS score <3. However, rehabilitation and nursing home facilities are nonexistent in Cameroon. Besides, the introduction of these facilities will have to take into account the challenges of our socio-cultural context. Imaging techniques in patients with a clinical diagnosis of stroke in Cameroon are limited to a cerebral Computer Tomography (CT) scan. CT is relatively cheaper than MRI (not yet available in Cameroon) and sensitive enough to rule out intraparenchymal haemorrhage [2]. CTs nevertheless are less sensitive than MRI for cerebral infarction [2]. None of the patients who had haemorrhagic stroke (both the case with intraparenchymal haemorrhage and that with subarachnoid haemorrhage) could afford to do cerebral angiography (available but financially inaccessible to most patients) to rule out aneurysms and other malformations such as a moyamoya malformations which are associated with a high risk for recurrence of stroke in sickle cell disease [24]. None of the patients studied had ever undergone a transcranial Doppler (TCD) screening, which has been proven to identify patients at high risk of a primary stroke

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who can benefit substantially from primary stroke prevention by the use of a chronic transfusion regimen [25]. There is a need to make this non-invasive technology both available and accessible to the developing and sub-Saharan African nations with a high sickle cell disease burden [26]. 5. Conclusion Stroke prevalence in sickle cell children in Yaounde, Cameroon, is 6.67% (possibly an underestimation). This prevalence rate and the clinical presentation are similar to observations in developed countries. However, there is still a wide management gap between the developed countries and Cameroon, for stroke in sickle cell disease. There is a real and urgent need to develop a national comprehensive programme on stroke prevention in sickle cell disease in Cameroon, including transcranial Doppler ultrasonography screening and prophylactic management of at-risk patients. Nevertheless, the current situation of stroke in sickle cell disease in Cameroon provides an ideal opportunity for the study of the natural history of this condition. Acknowledgements The authors thank Dr T. Ntandzi, Dr T. Nfor for assistance with the work and Pr T. Munsat for suggestions on the manuscript. The staff of the following institutions who assisted in this study are hereby acknowledged: Sickle Cell Centre, Neurology and Physical Medicine Service of the Yaoundé Central Hospital, Mvolye Catholic Dispensary, Yaoundé University Hospital Centre and the Essos Hospital Centre. References [1] Platt OS, Brambilla JD, Rosse FW, et al. Mortality in sickle cell disease: life expectancy and risk for early death. N Engl J Med 1994;330(23):1639–44. [2] Adams RJ, Ohene-Frempong K, Wang W. Sickle cell and the brain. Am J Hematol 2001;(1):31–46. [3] Driscoll MC, Hurlet A, Styles L, Mckie V, Files B, Olivieri N, et al. Stroke risk in sibling with sickle cell anaemia. Blood 2003;101 (6):2401–4. [4] Wethers DL. Sickle cell disease in childhood: part II. Diagnosis and treatment of major complications and recent advances in treatment. Am Fam J 2000 (Sept 15);62(6):1309–14. [5] Pegelow CH. Stroke in children with sickle cell anaemia: aetiology and treatment. Pediatria 2001;3(6):421–32. [6] 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 anaemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339(1):5–11. [7] Sumoza A, de Bisotti R, Sumoza D, Fairbanks V. Hydroxyurea (HU) for the prevention of reccurent stroke in sickle cell anaemia (SCA). Am J Hematol 2002;71(3):161. [8] Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symtomatic sickle cell disease: an interim report. Blood 2000;95:1918–24. [9] Ministry of Public Health, Department of Disease Control, SubDepartment of Non Endemic Diseases, Yaounde–Cameroon. Plan

84

[10] [11]

[12]

[13] [14]

[15]

[16]

[17]

[18]

A.K. Njamnshi et al. / Journal of the Neurological Sciences 250 (2006) 79–84 Stratégique National de Lutte contre la Drépanocytose au Cameroun; 2005. Obama MT, Dongmo L, Nkemayim C, Mbede J, Hagbe P. Stroke in children in Yaounde, Cameroon. Indian Pediatr 1994;31(7):791–5. Mbonda E, Thuret I, Pinsard N. Ischemic cerebrovascular accidents in homozygous sickle cell anemia: two case reports. Ann Pediatr 1993;40 (1):23–7. Njamnshi AK, Chetcha B, Ngang P, Djientcheu VdP, Ongolo-Zogo P, Dongmo L, et al. Stroke in sickle cell children: the need for more studies. Cameroon J Med 2003;1(1):32. WHO:http://www.who.int/ncd_surveillance/steps/stroke/en/steps_ stroke_manual (v1.4).pdf p11. Neonato MG, Guilloud-Bataille M, Beauvais P, et al. Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur J Haematol 2000;65:155–64. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Moohr J, Wethers D, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91(1):288–94. Zamedjo E. Etude du polymorphisme des hémoglobines humaines à Yaoundé par la méthode d'isoélectrofocalisation. Thèse de Doctorat en Médecine. CUSS, Université de Yaoundé I; 1983. Benz EJ. Hemoglobinopathies. In: Fauci Kasper Huaser, et al, editor. Harrisson's Principle and Practice of Internal Medicine, vol. 15. USA: McGraw Hill Inc.; 2000. p. 666–73. Lapoumeroulie C, Dunda O, Ducrocq R, Trabuchet G, Mony-Lobe M, Bodo JM, et al. A novel sickle cell mutation of yet another origin in Africa: the Cameroon type. Hum Genet 1992 (May);89(3):333–7.

[19] Sarnaik SA, Ballas SK. Molecular characteristics of paediatric patients with sickle cell anaemia and stroke. Am J Hematol 2001;67 (3):179–82. [20] Lyra IM, Goncalves MS, Braga JA, Gesteira Mde F, Carvalho MH, Saad ST, et al. Clinical, hematological, and molecular characterization of sickle cell anemia pediatric patients from two different cities in Brazil. Cad Saude Publica 2005 (Jul–Aug);21(4):1287–90. [21] Njamnshi AK, Wonkam A, Djientcheu VdeP, Ongolo-Zogo P, Obama MT, Muna WFT, et al. Stroke may appear to be rare in Saudi-Arabian and Nigerian children with sickle cell disease but not in Cameroonian sickle cell patients. Br J Haematol 2006 (Apr);133(2):210. [22] Balkaran B, Char G, Morrris JS, et al. stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr 1992;120:360–6. [23] Schlegel D, Kolb SJ, Luciano JM, Tovar JM, et al. Utility of the NIH stroke scale as a predictor of hospital disposition. Stroke 2003;34:134–7. [24] Dobson SR, Holde KR, Nietert PJ, Laver JH, Disco D, Abboud MR. Moyamoya Syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood 2002;99 (9):3144–50. [25] Adams R, Mckie V, Nicholas F, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med 1992;326:605–10. [26] Njamnshi AK, Mbong EN, Ongolo-Zogo P, Djientcheu V, Dongmo L, Mbanya D, et al. Stroke in sickle cell patients in Yaounde. J Neurol Sci 2005;238(1):S424 Abstracts of the VIII World Congress of Neurology (Nov 5–11, 2005), Sydney–Australia.