A number of quite easily diagnosed haematological disorders, many of which are common, may very occasionally cause ischaemic stroke and TIA (Hart and Kanter 1990; Markus and Hambley 1998).
Polycythaemia is usually defined as a haematocrit above 0.50 in males and 0.47 in females, provided the patient is rested and normally hydrated, and blood is taken without venous occlusion. Polycythaemia rubra vera (primary polycythaemia) may be complicated by TIAs, ischaemic stroke, or intracranial venous thrombosis (Silverstein et al. 1962; Pearson and Wetherley-Mein 1978). This is both because the platelet count is raised and platelet activity possibly enhanced, and because of increased whole-blood viscosity. Paradoxically there may also be a haemostatic defect as a result of defective platelet function, so causing intracranial haemorrhage. Relative polycythaemia is due to reduced plasma volume (as a result of diuretics, hypertension, alcohol, dehydration, obesity, etc.) and secondary polycythaemia is due to a raised red cell mass (as a result of chronic hypoxia, smoking, congenital cyanotic heart disease, renal tumour, cerebellar haemangioblastoma, etc.); in both, the raised haematocrit may be a weak risk factor for stroke (Section 27.2.7).
Essential thrombocythaemia (idiopathic primary thrombocytosis) is another myeloproliferative disorder. The platelet count is raised (usually over 1000 × 109/l, but it may be as low as 500) with circulating erythroid and/or megakaryocyte progenitors. Other causes for thrombocytosis include malignancy, splenectomy, hyposplenism, surgery, trauma, haemorrhage, iron deficiency, infections, polycythaemia rubra vera, myelofibrosis, and the leukaemias. There is a tendency for arterial and venous thrombosis and, paradoxically, intracranial haemorrhage because the platelets are haemostatically defective (Preston et al. 1979; Murphy et al. 1983; Michiels et al. 1993; Arboix et al. 1995; Harrison et al. 1998).
Leukaemia is more commonly a cause of intracranial haemorrhage (because of the haemostatic defect or CNS leukaemic infiltration) than cerebral venous or arterial occlusion due to the increased whole-blood viscosity (Davies-Jones 1995). Intravascular lymphoma is a very rare cause of stroke-like episodes fading into a progressive global encephalopathy (Lennox et al. 1989). Asparaginase treatment is another possible cause of ischaemic or haemorrhagic stroke (Feinberg and Swenson 1988).
Sickle-cell disease (and rarely other haemoglobinopathies) may be complicated by ischaemic stroke or, sometimes, intracranial haemorrhage (Adams et al. 1988; Pavlakis et al. 1988). The patients are usually homozygote children, although sometimes a sickle-cell crisis, provoked in an adult heterozygote by hypoxia, can be responsible (Greenberg and Massey 1985; Feldenzer et al. 1987). Small and large arteries, as well as veins, develop a fibrous vasculopathy and are occluded by thrombi as a result of the abnormally rigid red blood cells and raised whole blood viscosity, thrombocytosis and impaired fibrinolytic activity (Adams et al. 1997; Steen et al. 1998). Stroke may also complicate haemoglobin SC disease (Fabian and Peters 1984) and maybe thalassaemia (Aessopos et al. 1997).
Iron deficiency anaemia
Iron deficiency anaemia, if severe, causes non-specific neurological symptoms (presumably hypoxic in origin) such as faintness, poor concentration, giddiness, tiredness, and general weakness. Just occasionally, TIAs and even ischaemic stroke seem to be provoked by profound anaemia, but usually in association with severe extracranial occlusive arterial disease, or thrombocytosis (Siekert et al. 1960; Akins et al. 1996).
The paraproteinaemias, multiple myeloma and macroglobulinaemia, are associated with anaemia because of defective erythropoesis, and this causes non-specific neurological symptoms (see above). A haemostatic defect due to reduced platelet number, and perhaps reactivity as a result of complicating uraemia, may cause intracranial haemorrhage. However, most of the ‘cerebral’ features of these patients can be explained by the ‘hyperviscosity syndrome’ which is characterized by headache, ataxia, diplopia, dysarthria, lethargy, drowsiness, poor concentration, visual blurring, and deafness (the same syndrome can be seen in primary polycythaemia, leukaemia, etc.). Similar symptoms may also be due to complicating hypercalcaemia, uraemia, and lymphoma. The retina shows characteristic changes with dilatation and tortuosity of the veins, venous occlusions, papilloedema, and haemorrhages. The abnormal circulating proteins and tendency to red cell aggregation are responsible for the raised whole-blood viscosity, although to some extent the effects are ameliorated by the low haematocrit. Cerebral infarction may occur (arterial or venous) and at post-mortem the microcirculation is occluded with acidophilic material thought to be precipitates of the abnormal proteins. It is exceptional for patients with neurological involvement not to have a raised ESR, which gives the clue to performing protein electrophoresis, so confirming the diagnosis (Preston et al. 1978; Scheithauer et al. 1984; Davies-Jones 1995).
Paroxysmal nocturnal haemoglobinuria
Paroxysmal nocturnal haemoglobinuria is a very rare acquired disorder in which haemopoetic stem cells become peculiarly sensitive to complement-mediated lysis. Venous, and perhaps arterial, thrombosis occurs in the brain and elsewhere. Almost always patients are anaemic at neurological presentation and there may be a history of dark urine, evidence of haemolysis, and a low platelet and granulocyte count (Al-Hakim et al. 1993; Socie et al. 1996).
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is a rare acute or subacute disease in adults, rather similar to the haemolytic-uraemic syndrome in children. Haemorrhagic infarcts due to platelet microthrombi occur in many organs, and in the brain they may cause stroke-like episodes. More commonly, the presentation is with a global encephalopathy on the background of systemic malaise, fever, skin purpura, renal failure, haematuria, and proteinuria. The blood film shows thrombocytopenia, haemolytic anaemia, and fragmented red cells (Ridolfi and Bell 1981; Sheth et al. 1986; Kay et al. 1991; Oberlander et al. 1995; Garrett el al 1996). The differential diagnosis includes systemic lupus erythematosus, infective endocarditis, idiopathic thrombocytopenia, heparin-induced throbocytopenia with thrombosis, non-bacterial thrombotic endocarditis, and disseminated intravascular coagulation.
Disseminated intravascular coagulation
Disseminated intravascular coagulation: the neurological complications are usually submerged in the features of the underlying serious illness. Widespread haemorrhagic brain infarcts and intracranial haemorrhages tend to cause an acute or subacute global encephalopathy rather than stroke-like episodes. The diagnosis is confirmed by a low platelet count, low plasma fibrinogen, and raised fibrin degradation products and D-dimer (Schwartzman and Hill 1982; Baglin 1996). The differential diagnosis includes non-bacterial thrombotic endocarditis, cerebral hypoxia, hepatic failure, and uraemia.
The thrombophilias and other causes of ‘hypercoagulability’ are very rare causes of any sort of ‘stroke’ (Greaves 1993; Schafer 1994). Antithrombin III deficiency (Arima et al. 1992), protein S deficiency (Koelman et al. 1992; Rich et al. 1993; Nighoghossian et al. 1994), protein C deficiency (Vieregge et al. 1989; Kazui et al. 1993; Confavreux et al. 1994; van Kuijck et al. 1994; Blecic et al. 1996), activated protein C resistance due to factor V Leiden mutation (Hourihane et al. 1997) and plasminogen abnormality or deficiency (Schutta et al. 1991; Nagayama et al. 1993) can all cause peripheral and intracranial venous thrombosis (usually recurrent and often with a family history). However, they have seldom been convincingly reported to cause arterial thrombosis (but paradoxical embolism must always be considered as an explanation of arterial occlusion). To complicate matters, there are many asymptomatic patients with these deficiencies and to make any causal link it is important to exclude other causes of stroke, for the deficiency to be demonstrated more than once and some months after the stroke to avoid any acute effects of the stroke itself, and preferably in family members as well (Forsyth and Dolan 1995; Munts et al. 1998).
The nephrotic syndrome, certain snake bites, the antiphospholipid antibody syndrome, widespread cancer, antifibrinolytic drugs, intravenous immunoglobulin and desmopressin are other occasional causes of ‘hypercoagulability’ and ischaemic stroke. The role of coagulation proteins as vascular risk factors has already been discussed (Section 27.2.7).