Clinical features are represented by pale grey boxes while white boxes/black arrows refer to mechanisms likely to lead to pathology (red for those for which there is evidence in sickle cell disease, SCD) and dark grey boxes/pale blue arrows refer to potentially protective mechanisms. Red boxes denote mechanisms involving the red cell postulated to be involved in vasodilatation in response to local hypoxia. In chronic sustained hypoxia, hypoxia-inducible factor stabilization leads to upregulation of erythropoietin and growth factors. In addition, there is increased nitric oxide synthesis, although in SCD free haemoglobin secondary to chronic haemolysis and the superoxide generated by increased xanthine oxidase activity may reduce bioavailability and tip the delicate balance between vasodilatation and vasoconstriction in favour of the latter. Vasconstriction is also favoured by the release of endothelin in response to hypoxia. Increased 2,3 dihydophosphoglycerate (2,3 DPG) further increases P₅₀ and decreases Haemoglobin S solubility. Adhesion molecules, such as VCAM-1, are upregulated and favour monocyte adhesion to the endothelium. Upregulation of haem-oxygenase-1 (HO-1) may have protective effects, including vasodilatation and reduction of P₅₀ secondary to the generation of carboxyhaemoglobin, and the antioxidant effects of bilirubin reductase, but also further upregulates vascular endothelial growth factor and may increase carbon monoxide levels locally. The ventilatory response may be increased, probably facilitated by repetitive intermittent hypoxia. Cerebral infarction, atrophy and cognitive problems may be related to a number of mechanisms related to chronic sustained and intermittent hypoxia, including perhaps demyelination secondary to chronically high carbon monoxide levels, the adverse effects of reactive oxygen species generated by repetitive intermittent hypoxia on proteins, nucleic acids and lipids, downregulation of the mitochondrial respiratory chain enzymes and upregulation of amyloid β peptide, as well as the effect of sleep disruption. Chronically hypoxic patients with SCD may be preconditioned and therefore relatively protected from the effects of acute hypoxia, e.g. vasogenic oedema secondary to increased vascular endothelial growth factor, opening of ion channels and venous thrombosis. However, the very rapid polymerization of HbS may cause such severe hypoxia that immediately available compensatory mechanisms, such as increased glycolysis, relative hypertension secondary to catecholamine release, and vasodilatation secondary to release of nitric oxide by S-nitrosylated haemoglobin (SNO-Hb), are overwhelmed and acute neurological complications, such as headache, seizures, cerebral oedema, as well as stroke, are inevitable.

This 8-year-old boy (Patient 1, Tables 2 and 3), one of twins, had uncomplicated sickle cell disease (SCD) but at the age of 6 years, had overnight pulse oximetry classified prospectively as normal (Kirkham et al., 2001) although the mean was less than the 5th percentile for age (Urschitz et al., 2003). His twin developed conditionally high internal carotid/middle cerebral artery velocities on transcranial Doppler (TCD) (maximum 192 cm/sec at the age of 8) but has not had a neurological event over follow-up of 13 years. This patient’s TCD remained normal (maximum 144 cm/sec at the age of 8) but 2 months after this recording, he developed seizures and coma after surgery to drain a painful swelling of his left cheek, associated with fever, after a fall. Preoperative preparation had included hydration and blood transfusion to achieve a haemoglobin of 11.9 g/dl and haemoglobin S of 36% and blood pressure was above 110/50 mmHg (mean arterial blood pressure, MAP 70 mmHg) pre- and post-operatively even after the onset of coma. Intracranial pressure (ICP) was not measured. Initial T2-weighted MRI showed acute infarction with increased signal and swelling in both anterior arterial borderzones and the right posterior arterial borderzone, with mature infarction at follow-up as shown in the figure. TCD, Magnetic Resonance, including arteriography and venography, and four vessel cerebral angiography were normal. Motor function recovered completely. Psychometry showed significant cognitive impairment; compared to premorbid testing full scale IQ was reduced by 30 and performance IQ by 50 points (WISCIII). Covert infarction in the borderzones between the anterior and middle and posterior and middle cerebral arteries are common in SCD, probably because these areas are vulnerable to acute reductions in cerebral blood flow secondary to reduced cerebral perfusion pressure (CPP = MAP − ICP); this patient appears to have had an acute reduction in CPP despite maintenance of blood pressure, perhaps in relation to the cerebral oedema and undiagnosed raised ICP in a child with inadequate preconditioning for the insult experienced and normal cerebral vessels.

This young woman with haemoglobin SS was born in Africa and immigrated to the United Kingdom aged 13 yrs where she remained well, with no painful or chest crises, until age 18 when she presented acutely with pain and dyspnoea. Blood pressure was 120/70 mmHg and oxyhaemoglobin saturation was 81% on admission. Haemoglobin was 3.8 with a white cell count of 66. Chest X-ray showed bilateral pulmonary infiltrates, reported as compatible with pulmonary oedema. Echocardiography showed moderate left atrial enlargement with left ventricular size at upper limit of normal; systolic function was good and tricuspid regurgitation trivial. She was confused with a Glasgow coma score (GCS) of 13/15 and appeared to have seizures with lip smacking and repetitive jerking of the right leg. When she regained full consciousness (GCS 15/15), she had a right hemianopia. Tone and power were normal in all limbs but reflexes were absent. TCD and MRA were normal. Axial T2 weighted MRI in the acute phase showed high signal changes in the left posterior occipital and bilateral high parietal regions (A, B, C) with hippocampal involvement (A). Repeat MRI 4 weeks later (D, E) showed resolution of all changes but the patient continued to have seizures with visual aura, staring, twitching of right hand, a sharp sensation on the right, hallucinations and memory loss. This is an example of reversible posterior leukencephalopathy (a poor term as there is obviously grey matter involvement and other regions are often affected) secondary to very acute and severe hypoxia in a patient with inadequate preconditioning and normal cerebral vessels. The involvement of the hippocampus in the acute process links this hypoxic insult to the subsequent intractable epilepsy.

This patient was born with a left capillary haemangioma in the V1–2 distribution and demonstration of a pial angioma confirmed the diagnosis of Sturge-Weber syndrome. She presented at age 4 months with 6 days of frequent treatment-resistant seizures lasting up to 2 hours. T2-weighted imaging (B) and diffusion imaging (C) were performed 6, 12 and 25 days after initial presentation. The apparent diffusion coefficient (ADC) maps obtained at 6 days after initial onset of the seizures showed evidence of ongoing restricted diffusion throughout a substantial part of the abnormal left hemisphere (C). Representative regions showed an ipsi/contralateral ADC ratio of 0.79 (shown graphically in G, compared with values of the order of 0.5 in the first 48 hours in a child with a stroke and 1.0 in controls, shown graphically in F). The ADC remained low in the affected areas at 12 and 25 days after presentation (shown graphically in G, ipsi/contralateral ADC ratio 0.81 and 0.84 respectively). Throughout this period, the T2-weighted images showed hypointensity in corresponding regions. The patient developed a right hemiparesis and chronic epilepsy. A sleep study showed mean and minimum oxyhaemoglobin saturation (SpO₂) of 95.8% and 91% respectively (97% is the 5th percentile in normal children; Urschitz et al., 2003). A follow-up scan was performed at the age of 14 months (D, E); the ADC remained low with an ipsi/contralateral ADC ratio of 0.79 (shown graphically in G). At the age of 15 months, her development was delayed to the 10-month level. Persistently low ADC, suggesting ongoing ischaemia, was again demonstrated on MR scans at 16 (G) and 30 months. The patient underwent a hemispherectomy for intractable epilepsy at the age of 33 months and has remained seizure-free post-operatively. It is possible that chronic exposure to mild overnight hypoxaemia had a deleterious effect on brain tissue compromised by chronic venous hypertension and ischaemia.

Magnetic resonance angiogram (MRA) and imaging (MRI) from a girl (Patient 10, Tables 2 and 3) with sickle cell anaemia who had a sleep study showing dips and high transcranial velocities (up to 267 cm/second) for 8 years without symptoms but presented with a hemiparesis in the context of acute aplastic anaemia secondary to Parvovirus. Although the MRA shows severe turbulence with some ‘moyamoya’ collaterals (arrow), the MRI shows only a small infarct (arrow) and the patient made a complete recovery. This might be an example of the preconditioning effect of prior exposure to hypoxia in limiting the extent of tissue injury at the time of acute stroke but at the cost of irreversible vascular change.