ArticlesNocturnal hypoxaemia and central-nervous-system events in sickle-cell disease
Introduction
Sickle-cell disease is a group of inherited haemoglobin disorders, including sickle-cell anaemia (homozygous SS), SC disease, and Sβ-thalassaemia. Sickle-cell disease is the most common cause of childhood stroke, with an incidence of 0·28–0·61%, similar to normal elderly adults;1, 2, 3 25% and 10% of patients with SS and SC, respectively, have had a stroke by age 45 years.2 Stenosis or occlusion of the basal cerebral vessels, especially distal-internal-carotid or proximal-middle-cerebral arteries, is characteristic.4 Cerebrovascular disease is seen in young children5 with ischaemic stroke, and cerebral haemorrhage arises mainly in adults. Seizures are more common in patients with sickle-cell disease than in the rest of the population,6 can be difficult to distinguish from transient ischaemic attacks, and are associated with imaging abnormalities.7 Cerebral infarction (overt and covert) is associated with cognitive difficulties.8
Risk factors for ischaemic stroke include low fetal haemoglobin,9 recent chest crisis,3 and hypertension.3 Infants with dactylitis, haemoglobin values less than 7 g/dL, or leucocytosis are at risk of adverse outcomes, including stroke,2, 10 and might be candidates for prophylactic therapy—for example, hydroxyurea to increase fetal haemoglobin concentrations. Transcranial doppler sonography predicts stroke risks of 40%, 7%, and 2% over the following 40 months in patients with velocities of more than 200 or more than 170, or less than 170 cm/s, respectively, in the internal-carotid or middle-cerebral arteries.11 Primary stroke prevention with long-term blood transfusion is possible in children with velocities greater than 200 cm/s.12 The risks of infection, alloimmunisation, and iron overload, needing parenteral chelating agents, make this approach punishing and potentially life threatening, however, which justifies the investigation of alternative preventative strategies.
Snoring is a risk factor for stroke in adults.13 Both episodic and continuous nocturnal hypoxaemia are common in sickle-cell disease,14 possibly because of upper-airway obstruction secondary to adenotonsillar hypertrophy. The reported association between obstructive sleep apnoea and central-nervous-system (CNS) events in sickle-cell disease15, 16 has not been studied prospectively. We tested the hypothesis that nocturnal hypoxaemia, documented by overnight pulse oximetry, offers better prediction of CNS events than clinical, haematological, or transcranial doppler sonography variables.
Section snippets
Patients
Permission for the study was granted by the Great Ormond Street Hospital Local Research Ethics committee, and written informed consent was received from all patients. From Jan 1, 1991, we invited all patients who had not had a stroke and were regularly attending the haemoglobinopathy clinic of Queen Elizabeth Hospital, London, UK, to participate. Follow-up was discontinued on April 30, 2000.
Study protocol
We used a TC-64B (Eden Medical Electronics, Uberlingen, Germany) or a Companion (Nicolet, Warwick, UK)
Results
We enrolled 147 patients. Overnight pulse oximetry was done in 65% of these (table 1) at a median time of 218 days after recruitment. Before 1994, most had overnight pulse oximetry at home; thereafter patients were offered hospital sleep studies but often found it difficult to attend.
19 patients (17 with sickle-cell anaemia) had CNS events during follow-up (six ischaemic and one haemorrhagic stroke, eight transient ischaemic events, and four seizures). One patient with Sβ-fhalassaemia had a
Discussion
Our data suggest that nocturnal hypoxaemia predicts CNS events in patients with sickle-cell disease. The association between sleep-disordered breathing and stroke or transient ischaemic attack could involve either the generation of cerebrovascular disease or reduction of the threshold for infarction in the at-risk territory of a stenosed or occluded artery, or both. Hypoxia promotes polymerisation of sickle haemoglobin and the adhesion of red cells to endothelium via binding molecules such as
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Sickle cell disease
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