Handbook of Practical Medicine Stroke

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 364 364 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack The antiphospholipid syndrome cannot be diagnosed on the basis of a single raised titre of antibody in the serum. The titre must be substantially raised on several occasions and associated not only with cerebral ischaemia but also with some combination of deep venous thrombosis, recurrent miscarriage, livedo reticularis, cardiac valvular vegetations, thrombocytopenia and migraine. Because thrombosis appears to be more of an issue in the APS than in SLE, long-term warfarin has become the most commonly used treatment, with a target INR of about 3.0 (notwithstanding the serious lack of random- ized trials of any size in patients with arterial rather than venous thrombosis where the evidence is better). Presumably aspirin would provide some protection in those unable or unwilling to take warfarin for the rest of their lives, or if prescribed by physicians who are unconvinced by the weak evidence supporting warfarin. 108,109 It is unclear whether ischaemic stroke patients with the antiphospholipid syndrome gain more protection from recurrent ischaemic events when given long- term warfarin rather than aspirin, and whether the risks of haemorrhage are less than any benefits. 7.3.5 Sneddon syndrome Sneddon syndrome – most commonly seen in young women – is the rare combination of widespread and prominent livedo reticularis (Fig. 7.9) which is a rather non-specific skin appearance 110 (Table 7.2), ischaemic stroke/transient ischaemic attacks but rarely intra- cerebral haemorrhage, and sometimes autoantibodies associated with SLE (particularly antiphospholipid anti- bodies and the lupus anticoagulant), if not the full- blown syndrome (sections 7.3.3 and 7.3.4). 111–113 It might be one variety of the antiphospholipid syndrome, itself part of the spectrum of SLE. 114,115 It is unclear Fig. 7.9 The typical appearance of livedo reticularis affecting whether it should be treated more like SLE with the legs. Also reproduced in colour in the plate section. immunosuppression, or the antiphospholipid syndrome with an antithrombotic drug, or with both. are rare. But ischaemia and haemorrhage can affect the 7.3.6 Primary systemic vasculitis 118–123 brain and eye, with clinical features rather like SLE. This is a group of related multisystem disorders which However, in contrast to SLE, the vascular lesion is are defined rather variably: classic polyarteritis nodosa, generally but not always a vasculitis affecting small and Wegener’s granulomatosis, the Churg–Strauss syndrome medium-sized arteries, arterioles, venules and capillaries. and microscopic polyangiitis. 116,117 While involvement The serum antibodies characteristic of SLE are seldom of the kidneys, lungs, peripheral and cranial nerves, and present while eosinophilia, raised serum ANCA and skin is quite common, cerebrovascular complications haematuria are all more likely. .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 365 7.3 Inflammatory vasculopathies and connective tissue diseases 365 Table 7.2 The causes of livedo reticularis. most common serious complication, occasionally there are neurological features: aseptic meningitis, facial palsy, Vessel wall disease epileptic seizures and encephalopathy. 69 Vasculitis (section 7.3) Atherosclerosis Intravascular obstruction 7.3.8 Henoch–Schönlein purpura Hypercoagulability (section 7.9.11) This small-vessel vasculitis, mainly occurring in children, Paraproteinaemia (section 7.9.10) typically involves the skin, gut and kidneys and is asso- Mixed essential cryoglobulinaemia (section 7.3.14) Cholesterol embolization syndrome (section 7.7) ciated with arthritis. Subacute encephalopathy, perhaps Disseminated intravascular coagulation (section 7.9.12) with focal features, and peripheral nerve involvement Decompression sickness are both rare. 125,126 Meningoccocal meningitis is an Infections important differential diagnosis. Tuberculosis Meningococcal septicaemia Endocarditis 7.3.9 Rheumatoid disease Syphilis Rheumatoid disease is very rarely complicated by cere- Typhus fever 127–129 bral vasculitis. Atlanto-occipital dislocation can Drugs cause symptomatic vertebral artery compression with Amantadine posterior circulation ischaemia. 130 Quinine Catecholamines Metabolic/endocrine 7.3.10 Sjögren syndrome Cushing’s disease Hypothyroidism Dry eyes and dry mouth as a result of inflammation and Pellagra destruction of the lacrimal and salivary glands are the Miscellaneous defining features of Sjögren syndrome – a systemic Cardiac failure 131 autoimmune disorder. Characteristically, antinuclear Lymphoma and antibodies to SS-A/Ro or SS-B/La, as well sometimes Oxalosis as rheumatoid factor, are present. Peripheral neuropathy Acute pancreatitis is the most frequent neurological complication. Rarely, there is a systemic and cerebral vasculitis, the latter caus- ing transient or permanent focal neurological deficits, aseptic meningitis and global encephalopathy. 132–136 Depending on the clinical severity, treatment is generally with a combination of prednisolone (60 mg 7.3.11 Behçet’s disease per day, oral) perhaps preceded by high-dose iv methyl- prednisolone (1 g daily for 3 days), and cysclo- This is an inflammatory relapsing and remitting syn- phophamide (2–3 mg per kg per day, oral) and then, drome of orogenital ulceration and uveitis, often along once the disease is under control, tapering prednisolone with skin, joint and gut involvement and recurrent over several months and substituting the rather safer venous thrombosis. Both a large- and small-vessel vas- azathioprine (2 mg/kg/day, oral) for the cyclopho- culitis is well described, but florid necrotizing vasculitis sphamide. Normally rheumatologists rather than appears to be distinctly unusual. neurologists take the lead in treatment because they Behçet’s disease can be complicated by chronic aseptic are more familiar with these disorders and the use of meningitis which affects cerebral arteries, perhaps more cyclophosphamide. commonly those supplying the brainstem, to cause ischaemic stroke/transient ischaemic attack and intra- cerebral and sometimes subarachnoid haemorrhage. 137–140 7.3.7 Kawasaki disease A more global subacute and relapsing encephalopathy is This is another systemic vasculitis, but more or less well recognized, as often with low-grade inflammation confined to infants and children. 124 The illness is self- within the brain as in the vessels, while intracranial limiting and acute, with fever, conjunctival injection, venous thrombosis (section 7.21) is probably the most fissuring of the lips, cervical lymphadenopathy, rash and commonly encountered neurological complication of reddening of the palms of the hands and soles of the feet. the disease – presenting with intracranial hypertension While coronary arteritis with aneurysm formation is the without other neurological features, as well as with .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 366 366 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack intracerebral haemorrhagic infarction. The neurological 7.3.15 Malignant atrophic papulosis symptoms tend to start a few years after the onset of the (Kohlmeier–Degos disease) disease and coincide with flare-ups of the mucocutaneo- ocular symptoms, but can antedate them. Malignant atrophic papulosis is another very rare vascu- There are no specific circulating autoantibodies and lopathy. Crops of painless but occasionally itchy, umbil- the diagnosis is usually made by the clinical manifesta- icated, pinkish papules appear mainly on the trunk, tions and sometimes a positive pathergy test (cutaneous which heal to form distinctive, circular, porcelain-white needle prick causes an erythematous nodule 48 h later). scars. Intimal endothelial proliferation and thrombosis Thalidomide, colchicine, corticosteroids, azathioprine in small arteries can cause ischaemia and haemorrhage and ciclosporin are all recommended as treatments but, in the brain, spinal cord, gut and other organs. 152,153 although there are randomized trials, none have been in Muscle and nerve are sometimes affected. patients with neuro-Behçet’s disease. 139 7.3.16 Sarcoid vasculitis 7.3.12 Relapsing polychondritis Sarcoidosis is a systemic, multiorgan, non-caseating, Relapsing polychondritis is a very rare condition charac- granulomatous disorder which mostly affects the lungs, terized by febrile episodes of inflammation affecting the lymph nodes, eyes and skin. 154–156 The illness tends to be cartilage of the ears, nose, larynx, trachea and ribs. It subacute and self-limiting, but it may recur, and it is affects men and women in middle age. There is often an occasionally chronic. arthropathy, inflammation in the eyes and optic nerve, As well as intracerebral granulomatous mass lesions, deafness and vertigo, anaemia and a high ESR. 141 It is aseptic meningitis and cranial nerve palsies, typically sometimes complicated by a systemic and cerebral vas- with marked CT or MR contrast enhancement of the culitis with subacute aseptic meningitis, cranial nerve leptomeninges, sarcoid can cause a vasculitis of the small palsies, global encephalopathy, epileptic seizures, stroke/ arteries and veins of the meninges and brain. This may transient ischaemic attack, aortic arch syndromes and lead to a subacute global encephalopathy. Focal cerebral peripheral neuropathy. 142–145 There are no specific dia- ischaemia and haemorrhage causing stroke is much gnostic tests. rarer. Because involvement of the nervous system without any systemic features at all is so unusual, the diagnosis should be reasonably obvious from the almost 7.3.13 Progressive systemic sclerosis invariable non-neurological features, such as hilar Progressive systemic sclerosis is characterized by wide- lymphadenopathy, uveitis, etc. A raised serum (or CSF) spread and slowly progressive fibrous sclerosis affecting angiotensin-converting enzyme level is neither sensitive the skin, lungs, kidneys, gut and heart. It is hardly ever nor specific so, as usual with suspected vasculitis, a tissue complicated by stroke, but a carotid and cerebral arteritis biopsy may be necessary for diagnosis, either of a lymph has been described as well as nondescript intracerebral node or very occasionally of brain and meninges. 157–159 small-vessel disease. 146,147 Linear scleroderma has also There are no randomized trials specifically in neuro- been associated with an inflammatory vascular disorder sarcoidosis and so the usual treatment for pulmonary of the brain. 148 sarcoidosis is generally used; corticosteroids are the first choice and, if necessary for steroid sparing, antimalarials or cytotoxics. 155,156 Recently some success has been re- 7.3.14 Mixed essential cryglobulinaemia 160 ported with infliximab, a TNF alpha inhibitor. Peripheral neuropathy is the most common neurological complication of this chronic disease manifested by 7.3.17 Primary angiitis of the central nervous purpura, Raynaud’s phenomenon, arthralgia, hepatic system dysfunction and progressive renal failure. Plasma cryo- globulins are present without any evidence of other Primary – or isolated – angiitis of the central nervous causes of cryoglobulinaemia such as malignancy, infec- system is a rare disorder affecting mainly young adults tions or circulating monoclonal and/or polyclonal and the middle-aged (about 1–2 cases per million per immunoglobulins. 149,150 There can be a widespread sys- year). Occasionally a similar vasculitis is associated with temic vasculitis and there have been occasional reports herpes zoster infection, lymphoma and cerebral amyloid of cerebral vasculitis, although in some cases the vessel angiopathy. 161–163 wall itself was histologically normal while the lumen A focal and segmental vasculitis affects the small lepto- was plugged with immunoglobulin-rich deposits. 151 meningeal, cortical and spinal cord blood vessels to .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 367 7.3 Inflammatory vasculopathies and connective tissue diseases 367 cause a subacute global encephalopathy with headache 7.3.19 Buerger’s disease (thromboangiitis and seizures, with or without stroke-like episodes caused obliterans) by ischaemia or occasionally haemorrhage, and some- times a myelopathy or even radiculopathy. 164,165 Systemic Buerger’s disease is a rare, but seemingly distinct, inflam- symptoms are uncommon, but sometimes there is fever, matory disorder of mainly distal small and medium raised ESR and a raised CSF protein with lymphocytosis. arteries and veins, in the lower and upper limbs of young A definite diagnosis can only be made from meningeal/ adults, causing digital gangrene. It is much more com- cortical biopsy of non-dominant frontal lobe, or an mon in men than women, and almost all are smokers. 171 affected area shown on brain imaging. Although biopsy It is often associated with superficial thrombophlebitis is somewhat risky, a positive result is helpful so that and Raynaud’s phenomenon but not with the systemic treatment can be confidently given, and sometimes a or laboratory disturbances so often seen in other forms completely unexpected and yet treatable disorder is of vasculitis. Cerebrovascular complications have very discovered (e.g. encephalitis, lymphoma, sarcoidosis, occasionally been described, but without a stand- TB). 166,167 ardized definition of the vasculopathy it is difficult to So-called benign cases have been described (section know if the cases reported have all been of the same 7.3.18). However, unless there is confirmatory histo- condition. 172–175 pathology, any diagnosis of vasculitis is speculative, even if based on cerebral angiography because it is so 7.3.20 Paraneoplastic vasculitis non-specific 168 (Table 7.1). Although there are no randomized trials, high-dose Cutaneous and systemic vasculitis of various types, corticosteroids have become the standard treatment sometimes affecting the brain, is recognized as being and usually some improvement can be expected. It is very rarely associated with some malignant tumours, however extremely difficult to monitor the dose, and particularly lymphoproliferative disorders. 176,177 to know when to withdraw treatment, because there are no markers for disease activity (e.g. ESR). Some add 7.3.21 Therapeutic drugs cyclophosphamide, either from the start or only if the patient does not improve with steroids. Despite this, Various therapeutic drugs have been implicated, with many patients deteriorate and die. varying levels of evidence, in hypersensitivity reactions which may include cerebral vasculitis, e.g. allopurinol and deoxycoformycin. 178 Non-therapeutic drugs of 7.3.18 Idiopathic reversible cerebral abuse are discussed in section 7.15.1. ‘vasoconstriction’ This is a curious and rather poorly characterized syn- 7.3.22 Acute posterior multifocal placoid pigment drome in which apparently healthy adolescents or epitheliopathy young adults suffer severe headaches which may start suddenly, nausea and vomiting, fluctuating and This is a well-defined but rare sporadic chorioretinal sometimes bilateral focal neurological deficits and disorder with bilateral, rapidly deteriorating, central seizures. 169,170 On cerebral angiography there is seg- vision which usually recovers spontaneously in mental narrowing and dilatation of cerebral arteries weeks or months. It is occasionally complicated by a which is assumed to be caused by vasoconstriction, systemic, including cerebral, vasculitis with stroke/ notwithstanding the numerous other causes of this transient ischaemic attack, aseptic meningitis and global appearance (Table 7.1). This syndrome may be a rela- encephalopathy. 179 tively benign form of primary angiitis of the central nervous system (section 7.3.17), but without any histo- 7.3.23 Susac syndrome logy to demonstrate the vascular pathology one cannot be sure – in fact, in a few biopsied cases there has been The combination of a microangiopathy of the brain and no evidence of vasculitis. retina, with bilateral sensorineural hearing loss, is The arterial changes, if not the neurological impair- known as Susac syndrome. Microinfarcts in the brain ments, seem to resolve, usually completely, over a matter lead to personality change, subacute encephalopathy of weeks, and it is unclear if corticosteroids affect the and stroke/transient ischaemic attack-like episodes natural history. A similar syndrome has been described which tend to relapse and remit and then become self- with the use of triptans and in the puerperium (section limiting. It is much more common in young women 7.14), and in some drug users (section 7.15.1). than men. 180,181 .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 368 368 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack 7.3.24 Eales disease This rare sporadic disorder predominantly affects young men who develop retinal ‘perivasculitis’ causing recur- rent, bilateral, retinal and vitreous haemorrhage. Stroke and transient ischaemic attack have been described as the result of cerebral and leptomeningeal vasculitis, but myelopathy is more common. 182,183 7.3.25 Cogan syndrome This is another rare, sporadic, subacute syndrome seen in children and adults. 184 It is characterized by non- syphilitic interstitial keratitis together with vertigo, tinnitus and deafness mimicking Meniere syndrome. There are systemic symptoms along with a vasculitis which can affect the aorta, medium and small vessels, sometimes involving the brain. 185,186 (a) 7.4 Congenital arterial anomalies There are several rather unusual arterial abnormalities which are probably congenital, and which may be an occasional cause of cerebral and ocular ischaemia. 7.4.1 Fibromuscular dysplasia Fibromuscular dysplasia (FMD) is an uncommon, sometimes familial, segmental disorder of medium- sized arteries presenting at any age, more commonly in females than males, and usually affecting more than one artery in an individual. 187–189 The renal arteries are the most commonly involved, causing renovascular hyper- tension. In the neck, the mid to high cervical portion of the internal carotid artery (ICA) and the vertebral artery at the level of the first two cervical vertebrae are (b) the most common sites, i.e. well away from the usual sites of atheroma. Fig. 7.10 Selective catheter angiogram showing fibromuscular dysplasia of the internal carotid artery. Note the irregular The pathology is neither atheromatous nor inflamma- ‘beaded’ appearance of (a) the right and (b) the left carotid tory: the arterial wall is fibrosed and thickened in one or arteries. more segments, so the typical angiographic appearance is of a ‘string of beads’, or tubular segmental or longer areas of stenosis (Fig. 7.10). Sometimes there is enlarge- uncomplicated FMD causes thrombosis and embolism. ment, and a fibrous ‘web’ obstructing the proximal Therefore, when FMD is found on an angiogram (much ICA, which looks more smooth and regular than typical less often with duplex ultrasound), it is not necessarily atherothrombotic stenosis. 190 FMD is occasionally asso- relevant to any neurological symptoms. ciated with intracranial aneurysms and vascular mal- It is uncertain whether either antithrombotic drugs formations, and can itself be complicated by aneurysm or angioplasty/stenting are sensible treatments, particu- formation and dissection. It is unknown how often larly as the natural history is not really known. The .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 369 7.5 Moyamoya syndrome 369 blood pressure should be carefully monitored for life, with a low threshold for investigation for renal artery stenosis. 7.4.2 Hypoplastic carotid and vertebral arteries Hypoplastic, or even absent, carotid arteries have been described. 191 Presumably the brain is then more likely to become ischaemic, especially when atheroma develops in the other extracranial arteries, and intracranial hae- morrhage from fine collaterals can occur. This anomaly is usually an incidental finding when angiography is performed for some unrelated reason, or absent carotid canals are noticed on CT of the skull base. 192 A hypo- plastic, or absent, vertebral artery is much more com- mon, and usually the other vertebral artery is enlarged to compensate; there is some recent evidence that vertebral artery hypoplasia makes a posterior circulation stroke more likely, but it is unclear whether the associated strokes are more severe. 193 It is important not to confuse these anomalies with the appearances of dissection on Fig. 7.11 Lateral view of a selective carotid catheter angiogram imaging. from a patient with moyamoya syndrome. The internal carotid artery ends in numerous small dilated lenticulostriate arteries (thin arrows) and meningeal and ophthalmic artery collaterals 7.4.3 Internal carotid artery loops (fat arrow and open arrow, respectively). Courtesy of Professor Internal carotid artery loops are probably congenital and Takenori Yamaguchi, National Cardiovascular Centre, Osaka, of no consequence unless complicated by aneurysmal Japan. swelling (section 7.6), hypoglossal nerve palsy or, pos- sibly, pulsatile tinnitus. 194,195 Focal ischaemia on head movement must be extraordinarily rare. An association thalamoperforating and pial arteries at the base of the with carotid dissection has been suggested. 196 Some brain; orbital and ethmoidal branches of the external degree of kinking, buckling and tortuosity of the carotid carotid artery (ECA); leptomeningeal collaterals from the artery is quite common, becomes more common with posterior cerebral artery; and transdural vessels from increasing age, and is likely to be caused by atheroma branches of the ECA. This pattern of collaterals looks or fibromuscular dysplasia, but it can be congenital. 197 like a puff of smoke (moyamoya in Japanese) in the basal Although various surgical procedures to ‘normalize’ the ganglia region on the cerebral angiogram (Fig. 7.11). anatomy have been described, there is no good evidence There can be associated intracranial aneurysms. 201 they reduce the risk of stroke. The moyamoya syndrome is a radiologically defined pattern of arterial occlusion at the base of the brain displayed by cerebral angiography. There are several causes but often there is no explanation. 7.5 Moyamoya syndrome This pattern of arterial obstruction is found mostly, but not entirely, in Japanese and other East Asians. It Moyamoya is as rare as the name is memorable. It is not a can be familial 202,203 or congenital, and various acquired specific vascular pathology, but a radiologically defined disorders can cause arterial occlusion including basal pattern of severe stenosis or occlusion of one, or more meningeal or nasopharyngeal infection; vasculitis (sec- often both, distal internal carotid arteries (ICA), fre- tion 7.3); irradiation (section 7.12); trauma; fibrom- quently with additional involvement of parts of the cir- uscular dysplasia (section 7.4.1); a generalized fibrous cle of Willis and sometimes of the proximal cerebral and disorder of arteries; 204,205 sickle cell disease (section basilar arteries. 198,199 It may progress after diagnosis. 200 7.9.8); Down syndrome; 206 neurofibromatosis (section Numerous tiny collaterals develop from the lenticulostriate, 7.20.5); and primary oxalosis (section 7.20.6). Atheroma .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 370 370 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack more likely cause, and no possibility of vasospasm complicating rupture of an intracranial aneurysm. This course of events has occasionally been described with intracranial saccular and fusiform aneurysms. 210,211 It also occurs with extracranial carotid or vertebral aneurysms caused by blunt or penetrating trauma, infec- tion, carotid surgery, irradiation, atheroma, fibromus- cular dysplasia or inherited disorders of connective tissue such as Marfan syndrome and Ehlers–Danlos syndrome type IV. 212–215 The diagnosis of the aneurysm, and demonstration of any contained thrombus, is made by catheter, CT or magnetic resonance angiography (Fig. 7.12). Extracranial aneurysms should be suspected if there is a pulsatile swelling in the neck or pharynx, dysphagia, a Horner syndrome or compression of the lower cranial nerves at the base of skull; compression of the spinal cord and roots is exceptional. 216 Fig. 7.12 Selective carotid catheter angiogram showing a traumatic extracranial aneurysm of the internal carotid 7.7 The cholesterol embolization syndrome artery (arrow). Courtesy of Dr Evelyn Teasdale, Institute of Neurological Sciences, Glasgow, UK. This is a rarely recognized clinical syndrome in patients with widespread atheroma, although it may be much is very rarely responsible, perhaps because it is not more common than is currently diagnosed. 217–219 It can usually distributed so distally in the ICA. In most cases, be spontaneous, but is more often a complication of however, no cause is found. instrumentation or surgical repair of large atheromatous Children with the syndrome present with recurrent arteries, such as the aorta, and possibly of anticoagulants focal cerebral ischaemia and infarction, cognitive impair- or thrombolytic therapy, all of which can release athero- ment, headache, seizures and, occasionally, involuntary matous debris and cholesterol crystals into the circula- movements, all presumably the consequences of low tion. 220 Cholesterol emboli are found occluding the cerebral blood flow. Adults can present in the same microcirculation throughout the body, including the way, but also with subarachnoid, intracerebral or intra- brain and spinal cord. ventricular haemorrhage caused by rupture of the Hours or days after instrumentation or surgery, a sub- collaterals, or of any associated aneurysms 207,208 (section acute syndrome develops with rather similar features 8.2.12). to systemic vasculitis or infective endocarditis. There is Not surprisingly, surgical revascularization of brain malaise, fever, proteinuria, haematuria, renal failure, distal to occluded arteries has been attempted, and suc- abdominal pain, gastrointestinal bleeding, drowsiness cess claimed, but it is impossible to know whether the and confusion, skin petechiae, splinter haemorrhages, natural history is changed for the better. 209 livedo reticularis, cyanosis of fingers and toes, peripheral gangrene, raised erythrocyte sedimentation rate, anaemia, thrombocytopenia, neutrophil leucocytosis, eosino- philia and hypocomplementaemia. 221–224 The diagnosis is made by demonstrating cholesterol 7.6 Embolism from arterial aneurysms debris in the microcirculation of biopsy material from kidney, skin or muscle. However, the specificity of this finding is uncertain because similar debris can be found Aneurysms may contain thrombus which can embolize in people without the syndrome, albeit rarely. distally, although it is difficult to be certain if this is Iloprost, a prostacyclin analogue, may be an effective the cause of cerebral ischaemia unless there is no other treatment. 225 .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 371 7.8 Migraine 371 Recurrent spontaneous extracranial internal carotid 7.8 Migraine artery (ICA) ‘vasospasm’ has been described, but not in a migraneur or with clearly the phenotype of migrainous stroke 230 and also in the extracranial ICA. 231 Migraine A ‘normal’ stroke (caused, say, by embolism from severe has very rarely been blamed for intracerebral haemor- carotid stenosis) can start during the course of a typical rhage (section 8.3.2). migrainous episode for that particular individual and Migrainous auras lasting the usual 20–30 min can be so appear to have been provoked by the migraine – confused with transient ischaemic attacks, a problem but both conditions are common and may coincide which has been discussed earlier (section 3.4.1). by chance. Sometimes a ‘normal’ stroke, or just asym- ptomatic low cerebral blood flow, can provoke migrain- A migrainous stroke is a well-defined clinical ous episodes with an aura previously experienced by that syndrome. It is not a diagnosis of exclusion or particular patient. And sometimes a ‘normal’ stroke can desperation. be followed by typical migraine with aura which has never been previously experienced. In practice, it is not 7.8.2 Migraine as a risk factor for stroke always easy to sort out the exact chronological, let alone the exact aetiological, relationship between migraine Migraine with, and possibly even without, aura may and stroke in a particular case. 226 However, strokes in be associated with about a doubling of the risk of migraineurs should be investigated in the same way as ischaemic stroke, possibly more in women on oral con- in non-migraineurs bearing in mind that, with a careful traceptives (section 7.13.1), although this estimate is history, it may be possible to recognize ‘migrainous’ based mainly on case–control rather than more reliable strokes (section 7.8.1). cohort studies where the association is less obvi- ous. 232–234 Any relationship with myocardial infarction is less certain, but recently has become rather more com- 7.8.1 Migrainous stroke 234,235 pelling. If the association with stroke is causal, A migrainous stroke should never be a diagnosis of de- the explanation cannot be ‘migrainous stroke’ because speration when no other cause for ischaemic stroke can this is too rare, and in any event this would not explain be found, but a positive statement to describe a charac- the association with myocardial infarction. Possibilities teristic clinical syndrome in the absence of no more include: likely cause of stroke (section 3.4.1). The occasional • some factor associated with migraine also causing stroke patient, from thousands, who has previously had and other vascular disorders, perhaps vasospasm, migrainous auras (with or without headache), may one platelet hyperaggregability, patent foramen ovale, 236 day, for no known reason, experience their typical or treatments for migraine such as ergotamine, trip- aura, which then persists as a focal neurological deficit. tans etc.; Brain imaging may or may not show a relevant lesion, • both migraine and stroke sharing some causal factor – presumed infarction. To make the diagnosis, there must possibly genetic; not be any reason to suspect that the stroke was caused • or that migraineurs simply have a worse vascular by anything else after full investigation, particularly risk profile and that observational epidemiological anything which can be associated or confused with studies have not been able to fully adjust for this as a migraine, such as arterial dissection (section 7.2), the confounder. 237 antiphospholipid syndrome (section 7.3.4), CADASIL (section 7.20.1), mitochondrial cytopathy (section 7.19) or even an arteriovenous malformation (section 8.2.4). 227,228 A migrainous stroke most often results in a homo- 7.9 Haematological disorders nymous hemianopia (reflecting the common visual dis- turbance in migrainous auras), seldom seems to cause persisting and severe disability, and perhaps does not Occasionally, ischaemic strokes, intracranial venous recur very often, although data are sparse. Arterial occlu- thrombosis and transient ischaemic attacks complicate sion has very rarely been demonstrated and it is not clear an underlying haematological disorder, which itself why it occurs. ‘Vasospasm’ is often postulated and is may be quite common (such as sickle cell disease in said to have been observed in the retinal circulation dur- Afro-Caribbeans) or extremely rare (such as protein S ing transient monocular blindness in a few patients. 229 deficiency) 238,239 (Table 7.3). The diagnosis is not usually .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 372 372 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack Table 7.3 Haematological disorders that Quantitative abnormalities of formed blood elements may cause or predispose to cerebral and Polycythaemia rubra vera (section 7.9.1) ocular ischaemia. Relative polycythaemia (section 7.9.1) Secondary polycythaemia (section 7.9.1) Essential thrombocythaemia (section 7.9.2) Thrombotic thrombocytopenic purpura and haemolytic–uraemic syndrome (section 7.9.3) Iron-deficiency anaemia (section 7.9.7) Qualitative abnormalities of formed blood elements Haemoglobinopathies (e.g. sickle cell disease, thalassaemia) (section 7.9.8) Paroxysmal nocturnal haemoglobinuria (section 7.9.9) Leukaemia (section 7.9.4) Intravascular lymphoma (section 7.9.5) Abnormalities of platelet secretion, adhesion, aggregation? (section 7.9.11) Hyperviscosity Polycythaemia (section 7.9.1) Waldenström’s macroglobulinaemia (section 7.9.10) Multiple myeloma (section 7.9.10) Coagulation disorders (thrombophilias) (section 7.9.11) Antithrombin III deficiency Protein S deficiency Protein C deficiency Activated protein C resistance most commonly caused by a mutation of factor V protein (factor V Leiden) Prothrombin (factor II) mutation Factor VII deficiency Elevated factor VIII Plasminogen abnormality or deficiency Elevated concentrations of factors II, VII, VIII Antifibrinolytic drugs Activated factor VIIa Prothrombotic states of uncertain cause Cancer (section 7.12) Disseminated intravascular coagulation (section 7.9.12) Pregnancy and the puerperium (section 7.14) Oral contraceptives (section 7.13.1) Heparin-associated thrombocytopenia with thrombosis (section 7.9.11) Antiphospholipid syndrome (section 7.3.4) l-asparaginase (section 7.12) Nephrotic syndrome (section 7.9.11) Desmopressin (section 7.9.11) Intravenous immunoglobulin (section 7.9.11) Androgens (section 7.9.11) Hypereosinophilic syndrome (section 7.9.11) Snake bite/scorpion bite/wasp sting (section 7.9.11) difficult because the routine first-line investigations will by – for example – coexistent atherothromboembolism. pick up most of the disorders (full blood count, platelet Exactly what the risk of vascular events is, including count and ESR) and, if there is no obvious other cause, stroke, in these conditions has not been at all well stud- fairly standard haematological tests will pick up the rest ied but presumably it is higher in those who have already (Table 6.14). But, as with cardiac embolism, it can be had an event than in those who are still event-free. difficult to know if a diagnosed haematological disorder However, because the haematological disorder often is the cause of an ischaemic stroke when there is also a needs treating in its own right (of course in collaboration competing cause, or whether a haematological disorder with haematologists), management decisions are usually has merely increased the risk or severity of stroke caused fairly straightforward. .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 373 7.9 Haematological disorders 373 7.9.1 Polycythaemia 7.9.3 Thrombotic thrombocytopenic purpura Polycythaemia is conventionally defined as a haemato- Although rare, thrombotic thrombocytopenic purpura crit above 0.50 in males and 0.47 in females, provided (TTP) is a treatable acute or subacute disease, rather similar the patient is rested and normally hydrated and the to and overlapping with the haemolytic–uraemic syndrome blood taken without venous occlusion. Above this level, in children. 249–252 Platelet microthrombi cause infarcts the exact diagnosis should be refined by measuring the in many organs, including the brain, leading to a fluct- red cell mass. uating encephalopathic illness, with confusion and Polycythaemia rubra vera (primary proliferative poly- epileptic seizures, with or without focal features, rather cythaemia) may be complicated by transient ischaemic than a simple stroke syndrome. 253–256 Brain CT and MRI attacks, ischaemic stroke or intracranial venous throm- may be normal or show infarcts and posterior cerebral bosis. The exact risk is unknown because the disease oedema; occasionally intracerebral haemorrhage occurs, is rare, and no reliable prospective studies are avail- possibly caused or exacerbated by therapeutic heparin- able. 240,241 In patients selected for a trial, the risk of ization or acute hypertension rather than the TTP stroke, myocardial infarction or vascular death was itself. 257 The patient is ill, with malaise, fever, skin pur- about 5% in the placebo group and 2% in the aspirin pura, renal failure, proteinuria and haematuria. The group over about 3 years, but this estimate must be blood film shows thrombocytopenia, microangiopathic imprecise being based on only 18 events. 242 The pre- haemolytic anaemia and fragmented red cells, and the sumed thrombotic tendency is not just a result of the plasma lactate dehydrogenase levels are very high. increased whole-blood viscosity; the platelet count is often raised, and platelet activity and endothelial 7.9.4 Leukaemia cell function may be altered as well. Curiously, there can also be a haemostatic defect which is the result of Leukaemia more often causes intracranial haemorrhage defective platelet function, so causing intracranial hae- (section 8.4.5) or the ‘hyperviscosity syndrome’ (sec- morrhage. The ‘hyperviscosity syndrome’ is another tion 7.9.10) than cerebral arterial or venous occlusion. complication (section 7.9.10). Vascular occlusion when it does occur may be the result Relative polycythaemia is caused by reduced plasma of increased whole-blood viscosity, opportunistic infec- volume (diuretics, alcohol, dehydration, hypertension, tions, or non-bacterial thrombotic endocarditis. 258 obesity) and secondary polycythaemia to a raised red cell mass (chronic hypoxia, smoking, cerebellar haeman- 7.9.5 Intravascular lymphoma (intravascular gioblastoma, renal tumour). Whether the raised haemato- lymphomatosis) crit of relative and secondary polycythaemia is a risk factor for stroke is unclear; a direct causal relationship Patients with this rare form of B-cell lymphoma, in which is rather unlikely (section 6.6.7). It is conceivable that neoplastic lymphocytes proliferate within the lumen of increased whole-blood viscosity might have a particu- small vessels in almost every organ, can present with larly adverse effect in the microcirculation of a cerebral multifocal stroke and transient ischaemic attack-like infarct caused by something else, e.g. embolism from the episodes, typically in late middle age. 259–262 But, more heart, so affecting recovery. often, the cerebral features are diffuse with subacute pro- gressive global dementia. Spinal cord, roots and peri- pheral nerves can also be involved. Characteristically, there 7.9.2 Essential thrombocythaemia are skin nodules and plaques, malaise and a raised plasma Essential thrombocythaemia (idiopathic primary thrombo- lactate dehydrogenase. Brain imaging is non-specific cytosis) defined by a sustained platelet count > 600 × with infarct-like and mass lesions, and sometimes men- 9 10 /L can be associated with both arterial and venous ingeal enhancement (Fig. 7.13). The diagnosis can only thrombosis. 243,244 Occasionally, paradoxically, there is a be made by biopsy, typically of skin or brain. The course bleeding tendency because platelet function is defective. is relentlessly progressive to death within a few months. Headache, transient focal and non-focal disturbances are the most common neurological symptoms. 245–248 Before 7.9.6 Lymphomatoid granulomatosis making the diagnosis, other causes of thrombocytosis should be excluded: malignancy, splenectomy or hypo- Lymphomatoid granulomatosis is a rare disorder, pos- splenism, surgery and other trauma, haemorrhage, sibly lymphomatous. It affects mostly the lungs with iron deficiency, infection, polycythaemia rubra vera, diffuse infiltration and nodules, but also the skin and the myelofibrosis and leukaemia. central and peripheral nervous systems with vascular .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 374 374 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack Fig. 7.13 Fluid-attenuated inversion recovery (FLAIR) MRI lymphoma. Areas of infarction are seen in grey (curved arrow) axial views in a patient with histologically proven intravascular and white matter (straight arrows). infiltration by abnormal lymphocytes and plasmacytoid the overall stroke risk is about 1% per annum – and also cells, and a necrotizing vasculitis. The neurological ‘silent’ cerebral infarction and cognitive decline. 271–275 syndrome is of a subacute encephalopathy, cranial Stroke is very much rarer in heterozygotes except perhaps neuropathies, seizures and stroke. 263–265 in the context of a hypoxia-provoked sickle cell crisis. 276,277 Small and large arteries and veins are occluded by thrombi not just as a result of the rigid red blood cells 7.9.7 Anaemia but also by their complex interactions with the endo- Iron-deficiency anaemia (and presumably other types of thelium, platelets, the coagulation system and leuco- anaemia as well), if severe, may it seems provoke tran- cytes. 278 There is also fibrous proliferation of the intima sient ischaemic attacks, particularly if there is already which causes arterial stenosis and ectasia of the main severe cerebral arterial disease. 266,267 Anaemia has also cerebral arteries which can be seen on catheter and MR been associated with intracranial venous thrombosis 268 angiography, and inferred from transcranial Doppler of and with ischaemic arterial stroke, perhaps because of the middle cerebral artery. 279,280 the associated thrombocythaemia. 269,270 In practice, Stroke prevention at present depends on prophylactic anaemia is much more likely to cause non-specific red cell transfusion in children at high risk, but there is a neurological symptoms such as generalized weakness, serious problem of iron overload. 281 fatigue, poor concentration and faintness. Of course, the Stroke may complicate haemoglobin SC disease 282 anaemia may be symptomatic of some other cause of and has also been associated with thalassaemia, perhaps stroke, such as non-bacterial thrombotic endocarditis in as a result of the associated thrombocythaemia, atrial a patient with cancer. fibrillation, cardiomyopathy, cardiac failure or pseudo- xanthoma elasticum. 283 7.9.8 Sickle cell disease 7.9.9 Paroxysmal nocturnal haemoglobinuria Homozygous children, and less often adults, very often develop ischaemic stroke and, sometimes, intracranial Paroxysmal nocturnal haemoglobinuria is a very rare haemorrhage due to fragile collaterals and aneurysms – acquired disorder in which haemopoietic stem cells .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 375 7.9 Haematological disorders 375 become peculiarly sensitive to complement-mediated investigated and not just assumed to have a thrombo- lysis. Venous, and exceptionally arterial, thrombosis philic stroke. Paradoxical embolism from the venous occurs in the brain and elsewhere. The patients are system is another possible cause, or even that a venous almost always anaemic at neurological presentation cerebral infarct has been misdiagnosed as an arterial and there may be a history of abdominal pain, recurrent stroke (Table 5.4). Another problem is that acute stroke deep venous thrombosis, dark urine, haemolysis and a (and pregnancy) may reduce the level of some of these low platelet and granulocyte count. 284,285 coagulation factors, so the tests must be repeated on several later occasions (with due allowance if the patient is anticoagulated). To make the diagnosis of familial 7.9.10 The paraproteinaemias deficiency, the family members must be tested too. The Waldenström’s macroglobulinaemia, multiple myeloma risks of recurrence and what if any treatment should be and the POEMS syndrome can all sometimes be com- are quite unknown, although many haematologists plicated by arterial or venous cerebral infarction as a favour lifelong anticoagulation, at least for venous if result of occlusion of vessels with acidophilic material, not arterial thrombosis. thought to be a precipitant of the abnormal plasma Therefore, it is very uncertain how relevant these proteins. 238,286–289 Intracranial haemorrhage also occurs coagulation abnormalities really are in ‘stroke’ patients, because of the reduced number and impaired reactivity and whether they should be looked for at all, but there of platelets, perhaps as a result of uraemia. However, is more of an argument in favour for venous compared patients seldom present with strokes or transient with arterial stroke. 295 ischaemic attacks but more often have the ‘hyperviscosity syndrome’ of rather uncertain pathology and varying If a coagulation abnormality (thrombophilia) is found severity: headache, ataxia, diplopia, dysarthria, lethargy, in a patient with an arterial or venous stroke, then the poor concentration, confusion, drowsiness, coma, visual abnormality must be confirmed weeks or months after blurring and deafness; the retina shows dilatation and the acute event before any persisting and definite tortuosity of the veins, venous occlusions, papilloedema ‘thrombophilia’ can be reliably diagnosed. Even then, and haemorrhages. 290 Similar symptoms may also be the cause of the stroke might be something else and caused by uraemia, hypercalcaemia or lymphoma com- the thrombophilia is either an additional cause, or plicating the paraproteinaemia. totally unrelated. Despite many attempts to relate quantitative abnorm- 7.9.11 Thrombophilias and other causes of alities of platelet behaviour, impaired fibrinolysis and an ‘hypercoagulability’ increase in coagulation factors to ischaemic stroke and The thrombophilias are a number of rare, usually fam- transient ischaemic attack in general, no definite cause- ilial, conditions in which spontaneous and recurrent and-effect relationship has been demonstrated (section venous thrombosis occurs (usually in the legs but some- 6.6.7). In most cases, any changes in these haemato- times in the head). Arterial thrombosis is very seldom logical variables are a consequence rather than the cause a presenting or complicating feature. 291–293 There may of the cerebral ischaemic event. be additional causes, or at least precipitants, of stroke A hypercoagulable state may occur with the following in the very small number of cases with thrombophilia conditions, but whether the arterial and venous strokes described (such as oral contraceptives, pregnancy, reported are due to this or something else, or are merely etc.). Furthermore, although familial deficiencies of coincidental, is often difficult to say: antithrombin III, protein C and protein S can un- • nephrotic syndrome can be complicated by ischaemic doubtedly cause venous thrombosis, as can activated arterial stroke and intracranial venous thrombosis, protein C resistance with factor V Leiden mutation perhaps as a result of ‘hypercoagulability’; 296,297 and the prothrombin G20210A mutation, the patients • antiphospholipid syndrome (section 7.3.4); are asymptomatic for most of their lives; these ab- • widespread malignancy (section 7.12); normalities may, therefore, be better regarded as risk • immune-mediated heparin-induced thrombocyto- factors rather than causes of thrombotic events, includ- penia is associated with an increased risk of thrombosis ing possibly stroke. The role of protein Z is very in cerebral arteries and veins; 298–300 uncertain. 294 • desmopressin; 301 In patients discovered to have these coagulation • intravenous immunoglobulin carries a small risk of abnormalities, it is very possible that the cause of any stroke and probably should be avoided in patients arterial ischaemic stroke is something quite different with known vascular disease or multiple vascular risk (e.g. arterial dissection), so they must be thoroughly factors; 302–304 .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 376 376 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack • androgens; 305 Table 7.4 Causes of stroke and transient ischaemic attacks • hypereosinophilic syndrome; 306,307 within hours or days of acute myocardial infarction. • antifibrinolytic drugs have been reported to cause both cerebral venous and arterial thrombosis; 308 Ischaemic stroke/transient ischaemic attack Embolism from left-ventricular mural thrombus • recombinant human erythropoietin (epoetin) by increas- (section 7.10) ing the haematocrit may induce a hypercoagulable Instrumentation of the aorta/coronary arteries state and so perhaps venous if not arterial ischaemic (section 7.18.1) stroke in dialysis patients and sportsmen; 309,310 Low-flow infarcts caused by hypotension/cardiac arrest • snake or scorpion bite are more likely to cause defibrin- (section 6.7.5) ation, acute hypertension and bleeding than ischaemic Atrial fibrillation and embolism from the left atrium stroke although this has been described, 311–314 as it has (section 6.5.1) after wasp stings. 315 Paradoxical embolism (section 6.5.12) Intracerebral haemorrhage Anticoagulants (section 8.4.1) 7.9.12 Disseminated intravascular coagulation Antiplatelet drugs (section 8.4.2) Thrombolytic drugs (section 8.4.3) Here there are widespread haemorrhagic cerebral infarcts Both myocardial infarction and ischaemic stroke caused by the and intracranial haemorrhages which cause an acute or same disorder subacute global encephalopathy rather than stroke-like Giant cell arteritis (section 7.3.1) episodes. 316–318 Because patients are so often critically ill Infective endocarditis (section 6.5.9) as a result of their primary disease – obstetric disasters, Aortic arch dissection (section 7.2.3) septicaemia, trauma, etc. – it can be very difficult to dis- Embolism from the heart to both cerebral and entangle any added effect of disseminated intravascular coronary arteries (e.g. from atrial myxoma, valvular coagulation (DIC) on the brain. The diagnosis is sup- vegetations) ported by a low platelet count, prolonged prothrombin and activated partial thromboplastin times, low plasma fibrinogen, raised fibrin degradation products in plasma, and raised d-dimers. embolism to the brain and elsewhere complicates less than 5% of all acute myocardial infarctions. 320–322 Furthermore, most patients with emboli detected with transcranial Doppler do not have a stroke. 323 Of course, 7.10 Stroke in association with acute ischaemic stroke after an acute myocardial infarction myocardial infarction can have other causes: emboli as a result of cardiac catheterization, 324 angioplasty or surgery (section 7.18.1), or atrial fibrillation (section 6.5.1); low-flow infarction Cerebral and coronary arterial atheroma are so often pre- caused by systemic hypotension or cardiac arrest (section sent in the same patient that it is hardly surprising that 6.7.5); or paradoxical embolism caused by deep venous there is a past history of myocardial infarction or current thrombosis and a patent foramen ovale (section 6.5.12). angina in about one-third of ischaemic stroke and TIA Rarely, some non-atheromatous pathological mech- patients (Table 6.3), and that myocardial infarction anism may cause more or less simultaneous brain and occurs not infrequently during their long-term follow- heart ischaemia (Table 7.4). Naturally it must never up (section 16.2.3). However, if a stroke (or transient be assumed that any stroke is ischaemic unless brain ischaemic attack) occurs within hours or days of an acute imaging has excluded intracerebral haemorrhage, which myocardial infarction, it is tempting, and often correct, is more likely in the present age of thrombolytic treat- to suspect a cause-and-effect relationship rather than a ment than it was as a consequence of anticoagulants coincidence (Table 7.4). or aspirin. Left ventricular mural thrombus, diagnosed by echo- The overall low stroke risk after acute myocardial cardiography, occurs within days of an acute myocardial infarction still seems much the same as ever it was before infarction in about 20% of patients, mostly in those with the thrombolytic era although if it does occur the case large anterior infarcts, although this frequency is prob- fatality is unsurprisingly high. 325–327 The risk of stroke is ably declining with more frequent use of antithrombotic even lower in patients with acute coronary syndromes drugs. 319 Such thrombi may embolize, but most seem without ST-segment elevation on the electrocardiogram to do little harm because clinically evident systemic (ECG). 328 .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 377 7.11 Infections 377 Table 7.5 Infections causing ischaemic stroke and transient Stroke complicating acute myocardial infarction is ischaemic attacks. not necessarily caused by embolism from the heart, or hypotension. It may be caused by intracerebral Chronic meningitis haemorrhage, often secondary to thrombolytic Tuberculosis treatment. Brain imaging is always required, as in Fungal (cryptococcus, candida, aspergillus, mucormycosis) other stroke patients. Syphilis Acute bacterial meningitis Occasionally, acute myocardial infarction can be Meningococcal clinically ‘silent’. The diagnostic clues are raised cardiac Pneumococcal enzymes if measured in an ischaemic stroke patient (but Haemophilus these may be unreliable because an increase can occur Borrelia solely as a result of the stroke) and, more tellingly, an Leptospirosis Viral ECG showing recent ischaemic changes, such as ST Herpes zoster elevation, particularly if the changes evolve typically Human immunodeficiency virus (HIV) (Table 7.6) over time. 329,330 Cytomegalovirus After the acute period, the risk of stroke is much lower, Hepatitis C about 8% within 5 years, but still higher than the back- Mycoplasma ground stroke risk in the population. 322,331–333 Not all Worms these strokes are caused by embolism from the heart. Neurotrichinosis Many of the patients have atherothrombosis of their Cysticercosis extra- and intracranial arteries as well as other non- Hydatid disease cardiac causes of stroke. 334 Whether a left ventricular Cat-scratch disease Carotid inflammation aneurysm adds to the risk of embolic stroke is unclear. Pharyngitis Tonsillitis Lymphadenitis Infective endocarditis (section 6.5.9) 7.11 Infections Table 7.6 Potential causes of stroke in HIV/AIDS. Intracranial haemorrhage Ischaemic stroke has long been known to complicate Disseminated intravascular coagulation (section 7.9.12) chronic meningeal infections which cause inflammation Thrombocytopenia (section 8.4.5) and so secondary thrombosis – and rarely rupture – of Ischaemic stroke/TIA arteries and veins on the surface of the brain. 335 There- Chronic tuberculous, syphilitic and fungal meningitis (section 7.11) fore, focal or multifocal ischaemic events in patients Herpes zoster vasculopathy (section 7.11) with tuberculous, 336 fungal, or syphilitic meningitis 337–339 Cytomegalovirus vasculopathy (section 7.11) are not unexpected (Table 7.5). Occasionally, acute bac- Infective endocarditis (section 6.5.9) terial meningitis can be similarly complicated by cerebral Non-bacterial thrombotic (marantic) endocarditis infarction. 340–342 (section 6.5.10) Herpes zoster can cause intracranial periarterial Irradiation (section 7.12) inflammation and thrombosis. As a result, stenosis and Aneurysms/ectasia occlusion of arteries at the base of the brain and of the main cerebral arteries – and very rarely, intracerebral meningitis, thrombocytopenia and drug use 349–352 haemorrhage – can occur a few weeks after ophthalmic (Table 7.6). The HIV-associated small vessel vasculopthy zoster and occasionally in other areas of the skin, 66,343–346 with hyaline change is probably not a direct cause of and sometimes after chickenpox. 347 A more widespread stroke 353 and stroke patients who are HIV positive are encephalopathy caused by varicella zoster results from very similar to those who are HIV negative. 354 At present, multiple infarcts and haemorrhages secondary to a small therefore, it does not seem that HIV is a direct cause of artery vasculopathy. 348 stroke – a positive HIV blood test is clearly not a reason to HIV infection can be complicated by ischaemic or stop looking for the cause of a stroke, either an indirect haemorrhagic stroke in a variety of indirect ways such cause as above or some other cause unrelated to HIV. as infectious or non-infectious endocarditis, non-HIV Various other infections have occasionally been implic- viral vasculitis, meningovascular syphilis, TB and fungal ated with ischaemic or haemorrhagic stroke, or both .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 378 378 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack – with varying proposed mechanisms (vasculitis, endo- carditis, hypercoagulability, etc.) and degrees of evidence: 7.12 Cancer and its treatment • borrelia; 355–358 • leptospirosis; 359 • chlamydia; 360 Stroke and cancer are both so common that their associ- • mycoplasma; 361,362 ation in an individual may be no more than coincidence, • hepatitis C virus related to essential cryoglobulin- rather than cause and effect. Any difficulty in sorting out aemia; 363,364 causal relationship is compounded by the fact that stroke • cytomegalovirus; 365 in cancer patients may not be fully investigated because • neurotrichinosis; 366 of their poor prognosis, and so the exact cause of any stroke • cysticercosis; 367–371 may be unclear, and because neurological problems can • cat-scratch disease; 372 also be caused by radiotherapy or chemotherapy. 377 In • hydatid cysts. 373–375 fact, there seem to be several ways that cancer patients Inflammation of the carotid artery in the neck, with may develop a stroke (Table 7.7) but knowing the exact secondary thrombosis, can very occasionally complicate cause in an individual makes little if any difference to the pharyngitis, tonsillitis and lymphadenitis, particularly stroke outcome, the risk of recurrence, or the overall in children. 376 prognosis – at least in most cases. 258,378–380 Table 7.7 Possible causes of stroke in Non-bacterial thrombotic (marantic) endocarditis with embolism to the brain patients with cancer. (section 6.5.10) Tumour embolism, sometimes with intracranial aneurysm formation and rupture to cause intracranial haemorrhage Opportunistic meningeal infections (herpes zoster, fungi) (section 7.11) Haemorrhage into primary tumours (section 8.5.1) malignant astrocytoma oligodendroglioma medulloblastoma haemangioblastoma Haemorrhage into metastases (section 8.5.1) melanoma bronchus germ cell tumours hypernephroma choriocarcinoma Subdural/extradural haemorrhage due to tumour invasion of dura/skull Carotid artery rupture complicating surgery or radiotherapy for neck cancer (section 7.12) Coagulopathy/thrombocytopenia and intracranial haemorrhage Thrombocythaemia (section 7.9.2) Hyperviscosity syndrome (section 7.9.10) ‘Hypercoagulability’ (section 7.9.11) Disseminated intravascular coagulation (section 7.9.12) Paraneoplastic vasculitis (section 7.3.20) Neoplastic compression/invasion of extra- or intracranial vessels Irradiation damage to extra- or intracranial arteries (section 7.12) Intracranial venous thrombosis caused by tumour infiltration or compression, hypercoagulability, etc. (section 7.21) Drugs (section 7.12) ciclosporin carboplatin l-asparaginase methotrexate + any causing haemostatic defect .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 379 7.13 Exogenous female sex hormones 379 syndrome may start suddenly enough to be mistaken for a posterior circulation stroke 387–389 (section 3.4.5). • Cisplatin and carboplatin cause similar problems 390 while cisplatin, mostly in association with other anti- cancer drugs, has been implicated in ischaemic stroke. 391 • L-asparaginase treatment for leukaemia can cause both cerebral ischaemia and haemorrhage. 392 • High doses of systemic methotrexate can be followed a few days later by various transient focal neurological symptoms, rather like a stroke, and merging into a more global encephalopathy with behavioural abnorm- alities and seizures. 393 • Tamoxifen approximately doubles the risk of ischaemic stroke. 394 Finally, a cerebral vasculitis has been reported after bone marrow transplantation for leukaemia. 395 7.13 Exogenous female sex hormones High-dose exogenous oestrogen given to men increases their risk of vascular death, and presumably also of stroke and other non-fatal vascular events. 396–398 Also ovarian induction therapy for in vitro fertilization has been Fig. 7.14 Arch aortogram showing narrowing (arrows) of the reported to cause both arterial and venous ischaemic large arteries in the neck 20 years after irradiation of cervical strokes in the midst of the ovarian hyperstimulation lymph nodes affected by Hodgkin’s disease. 399 syndrome. Irradiation of the head or neck can cause damage not 7.13.1 Oral contraceptives only to the microvasculature but also to intra- and extra- cranial large and medium-sized arteries (Fig. 7.14). 377,381–384 Women on oral contraceptives have about triple the Months or more often years after irradiation, a localized, risk of ischaemic stroke, but a smaller or perhaps no stenotic and accelerated atheromatous lesion in the radi- increased risk of haemorrhagic stroke; this excess risk ation field may become symptomatic, to cause ischaemic declines rapidly on stopping oral contraceptives. 400–404 stroke or transient ischaemic attack. Fibrosis of the However, these excess risks are only derived from observ- arterial wall and aneurysm formation with rupture have ational studies since no randomized trials have ever been also been described, as well as the moyamoya syndrome done, and the exact mechanisms to explain any associa- (section 7.5). 385,386 Ascribing any stroke to irradiation in tion are unknown (does the pill cause a specific coagu- an individual can be difficult unless: lopathy or vasculopathy, or does is it merely facilitate • the vascular lesion is in an unusual place for atheroma some other cause of stroke?). Modern oral contraceptives (e.g. terminal carotid artery) or for an aneurysm (e.g. with a low oestrogen content may have much the same well away from the circle of Willis); or a negligible risk compared with earlier preparations, • the lesion is directly within the radiation field; but this is difficult to quantify, in part perhaps because • and there is no other more likely cause. women perceived as being at higher risk of stroke may be Chemotherapy has been associated with stroke: preferentially prescribed the lowest dose pills. 405 The role • Ciclosporin, usually in transplant recipients, can cause of any progestogen component is also difficult to assess, headache, nausea, vomiting, cortical blindness, seizures, mainly because of small sample sizes in the studies. 406 confusion and coma as the result of a subacute and On the whole, probably the lower the oestrogen dose the reversible posterior leucoencephalopathy, perhaps in better, while it is not clear whether progestogen-only part because of a vasculopathy and hypertension. This pills are safer. .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 380 380 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack Increasing the very low risk of stroke in young women prescribe. In the last edition we pointed out that this by prescribing the pill by even three times makes little argument would never be properly resolved until appro- difference unless their background risk is raised as a priate randomized trials had been carried out. They now result of smoking, hypertension, by being over the age have been and despite the fact that oestrogen replace- of about 35 years, and perhaps by having migraine, ment, with or without progestogen: although it is very unclear whether this applies only to • is associated with a favourable lipid profile; 412–414 migraine with aura or to any migraine (section 7.8.2). • has a better haemostatic profile; 412,415 The blanket recommendation that young women with • and in observational studies there did not appear to be migraine with aura should avoid oestrogen-containing any increased risk of stroke; 416,417 and perhaps even a oral contraceptives seems over-cautious 407 and still reduced risk of myocardial infarction, 418 lingers in the British National Formulary. However, it is the randomized trials have shown, not a protective commonsense to stop oral contraception if a woman’s effect for vascular disease, but about a one-third increase migraines – with or without aura – become more frequent in the risk of ischaemic stroke, probably without any excess or severe while on the pill, or perhaps if she develops risk of haemorrhagic stroke. 419 Quite what the mech- migraine with aura for the first time. 408 Fortunately, anism is to explain this excess risk is unclear. Clearly where any stroke risk is deemed unacceptable, there the observational studies were biased, particularly by are several alternative contraceptive strategies. Clearly, hormone replacement therapy (HRT) being more likely when giving advice to women on contraception, any to be given to women without vascular risk factors, and small excess risk of stroke and other vascular disorders requested by women more likely to look after their must be set in the context of the risks of pregnancy, both health. 420 Of course the excess stroke risk has to be set unplanned and planned, and the reduced risk of ovarian against the advantages of HRT (less post-menopausal cancer. 409,410 In fact, oral contraceptives only account symptoms, less osteoporosis, possibly less colon cancer) for 2–8 strokes per 100 000 women years. and other disadvantages (more breast cancer, coronary In an individual case, whether the pill is the cause of a events and venous thromboemolism). 421 It would surely stroke, a contributory cause in the presence of some be unwise for a woman to take HRT if she is at high risk of other cause such as a patent foramen ovale perhaps, or stroke, or already has had an ischaemic stroke or transi- an innocent bystander is difficult if not impossible to ent ischaemic attack. say. Nonetheless, if a woman has a stroke, either arterial or venous, while on the pill, it seems very reasonable to If a woman on hormone replacement therapy has a stop oral contraceptives indefinitely, even if a plausible stroke, this is a very good reason to stop it. alternative cause of stroke emerges. If, despite thorough investigation, no cause is found then it is often assumed – without much proof – that the oral contraceptive was responsible for the stroke although, even in non-pill- 7.14 Pregnancy and the puerperium takers, strokes of unknown cause quite frequently occur. If a woman on any type of oral contraceptive Stroke complicating pregnancy and the puerperium is so has a stroke, do not jump to cause-and-effect rare – about 1 per 10 000 deliveries in developed coun- conclusions too easily. It is important to investigate tries – that it is impossible to estimate the exact risk, and for all potential causes of stroke in young women. even the size of any excess risk over and above what is Whether or not a cause is found, it is wise for expected in non-pregnant females of childbearing age. the woman to avoid oral contraception thereafter. It tends to occur more in the third trimester and puer- perium. 422–425 Among the usual causes of strokes in There seems to be an especially high risk of intra- non-pregnant young women, there are some which may cranial venous thrombosis in women who are both taking be particularly associated with pregnancy: oral contraceptives and carrying mutations for factor V • intracranial venous thrombosis is probably more likely Leiden and prothrombin 20210A. 411 in women with thrombophilia, much more often in the puerperium than during pregnancy, but with a low risk of recurrence in later pregnancies, it seems; 426 7.13.2 Hormone replacement therapy • acute middle cerebral or other large artery occlusion, There have been endless arguments about the balance of perhaps caused by paradoxical embolism from the legs risks and benefits of postmenopausal oestrogen replace- or pelvic veins; ment, along with considerable commercial pressure to • cervical arterial dissection during labour; 427 .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 381 7.15 Drugs, including drugs of misuse 381 • low-flow infarction or disseminated intravascular coagulation complicating obstetric disasters; 7.15 Drugs, including drugs of misuse • ergot-type, bromocriptine and other vasoconstricting drugs have been associated with so-called postpartum cerebral segmental vasoconstriction or puerperal 7.15.1 Drugs of misuse cerebral angiopathy 428,429 although this also occurs without any drug exposure and may be due to vas- Cocaine – snorted, smoked or injected – is the most com- culitis rather than ‘vasospasm’. 430–432 This subacute monly implicated drug of misuse causing stroke 440,441 syndrome of headache, seizures, focal infarcts and (sections 8.5.4 and 9.1.4). Within hours of administra- even intracranial haemorrhage may be related to or is tion, it can cause ischaemic stroke, transient ischaemic the same as idiopathic reversible cerebral ‘vasocon- attack, intracerebral, intraventricular and subarachnoid striction’ (section 7.3.18). Exactly how this syndrome haemorrhage, or paraplegia. 442–445 A vasculitis has been differs from postpartum eclampsia seems rather rarely described on brain biopsy but inferred much uncertain; 433,434 more commonly – probably wrongly – by non-specific • infective endocarditis (section 6.5.9); beading on cerebral angiography. 446,447 More likely • peripartum dilating cardiomyopathy and embolism; 435 explanations for stroke are an acute rise of systemic • sickle cell crisis (section 7.9.8); blood pressure causing rupture of an unsuspected arteri- • intracranial haemorrhage caused by anticoagulants, ovenous malformation or aneurysm; cerebral vasocon- disseminated intravascular coagulation, or rupture of striction with complicating thrombosis and ischaemia; an aneurysm or vascular malformation. and possibly cardiac dysrhythmias, myocardial infarc- Eclampsia causes a global encephalopathic syndrome tion or cardiomyopathy and so cerebral embolism. 448–453 with seizures, headache, cortical blindness and impaired Moyamoya has also been described. 454 consciousness. It is due to increasing blood pressure, Amphetamines seem occasionally to cause a small- cerebral oedema, and sometimes vasospasm and hae- vessel vasculopathy (in at least one case due to vasculitis) morrhage, complicated by disseminated intravascular leading to intracranial haemorrhage, but acute hyper- coagulation. 436–438 Typically, there are bilateral hypo- tension is another possible factor; ischaemic stroke is densities on CT and increased signal on T2-weighted much less common 455–458 (section 8.5.3). MRI, particularly in the occipital and parietal lobes. Other sympathomimetic drugs (often found in nasal It should be distinguished from focal cerebral infarc- decongestants and appetite suppressants) may cause tion or haemorrhage due to other causes, intracranial stroke in similar ways to amphetamines: venous thrombosis and postpartum cerebral segmental • ephedrine and pseudoephedrine; 459 vasoconstriction (if indeed it is a different entity to • ephedra alkaloids (ma huang); 460 the last). • phenylpropanolamine; 461–463 Haemorrhagic choriocarcinoma metastases can look • oxymetazoline; very like multiple intracerebral haemorrhages on CT, • diethylproprion; the diagnostic test being a raised serum human cho- • phentermine; rionic gonadotrophin level (sections 3.4.4 and 8.5.1). • fenfluramine; There is a curious tendency for migraine auras without • methylene dioxymethylamphetamine (‘ecstasy’). 464–466 headache to occur in pregnancy, and these should be Cannabis has been associated with ischaemic stroke differentiated from transient ischaemic attacks (sec- in a handful of case reports but whether this is a causal tion 3.4.1). relationship, and if so what the mechanism is, is In general therefore, stroke in pregnancy or the puer- unknown. 467 perium should be investigated in the same way as Additional causes of stroke, or stroke-like syndromes, any other stroke in a young, otherwise healthy female, likely in drug-users, should not be forgotten: bearing in mind fetal exposure to any diagnostic • infective endocarditis (section 6.5.9); irradiation – MR appears to be safe (section 5.5). The risk • head or neck trauma (section 7.1); of arterial stroke recurrence in any future pregnancy • embolization of intravenously injected particulate is surprisingly low, suggesting that most pregnancy- foreign matter; associated strokes must be due to ‘one off’ events • alcohol abuse (sections 6.6.13 and 8.5.2); rather than any persisting abnormality such as throm- • complications of human immunodeficiency virus bophilia; 439 the risk of future oral contraception is also infection (section 7.11); unknown, but this is perhaps best avoided as there are • syphilis (section 7.11); several alternatives. • hepatitis C (section 7.11). .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 382 382 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack 7.15.2 Anti-inflammatory drugs 7.16 Hypoglycaemia and other metabolic Rofecoxib (Vioxx), a selective cyclo-oxygenase (COX)-2 causes of stroke-like syndromes inhibitor non-steroidal anti-inflammatory drug which has now been withdrawn, is associated with a small increased risk of myocardial infarction and possibly Hypoglycaemia, almost always caused by hypogly- (although the numbers are small) of stroke too, a caemic drugs rather than an insulinoma, is the most problem which has become enveloped in political, common ‘metabolic’ cause of focal cerebral episodes. 478 scientific and corporate recriminations – plus a lot of Curiously, consciousness is usually normal and there confusion. 468,469 Similar concerns have been expressed are seldom any of the usual systemic manifestations over related drugs – valdecoxib, celecoxib, etoricoxib and of hypoglycaemia, such as sweating and tachycardia. lumiracoxib – presumably reflecting a class effect, most The episodes tend to occur soon after waking or after likely by inhibition of the production of prostacyclin in exercise. By the time the patient is seen, the blood the vascular endothelium. 470–472 It is, therefore, prudent glucose may well have returned to normal. 479–485 for ischaemic stroke survivors to avoid a COX-2 inhibitor The episodes may last hours or sometimes a day or so if possible, and if anti-inflammatory analgesia is really – focal changes on MR DWI have been reported 486 necessary they should probably use a traditional non- (section 3.4.5). steroidal anti-inflammatory (more COX-1 and less Hypo- and hypercalcaemia, 487–489 non-ketotic hyper- COX-2 inhibition) about which there is somewhat glycaemia 478,490–492 and hyponatraemia 478,493,494 have all less concern, at least in moderate dosage – naproxen occasionally been reported to cause transient ischaemic or ibuprofen perhaps being the safest. 471,473 And if they attack and stroke-like episodes, but some may some develop indigestion then adding a proton pump may actually have been partial epileptic seizures (sec- inhibitor may be preferable to switching to a COX-2 tion 3.4.5). inhibitor. 7.15.3 Atypical antipsychotic drugs In elderly patients with dementia, there have been 7.17 Gastrointestinal disorders concerns that both risperidone and olanzapine are associated with a modest increased risk of stroke, the mechanism for any causal association being unknown. There are a number of case reports of ischaemic stroke, This association is however rather uncertain at pre- transient ischaemic attack and intracranial venous sent. 474 And now concerns are emerging about conven- thrombosis complicating ulcerative and Crohn’s coli- tional antipsychotics. 475 tis. 495–500 The bowel disease is not necessarily active at the time and may even present after the stroke. Causal possibilities include thrombocytosis, hypercoagulab- 7.15.4 Sildenafil ility, immobility and paradoxical embolism from the Although one might expect sildenafil (Viagra) to cause legs, vasculitis and dehydration. Curiously, these colitic ischaemic stroke by acutely lowering the blood pres- patients, even without neurological symptoms, are sure, there are remarkably few case reports of this apparently more likely than controls to have what may complication. 476 be ‘vasculitic’ lesions on brain MRI. 501 Cerebral vasculitis has been described with coeliac disease but coeliac patients present neurologically more 7.15.5 Tibolone often with an encephalopathy than with a focal stroke- There is as yet incompletely published evidence that like syndrome. 502 tibolone – a drug to reduce osteoporosis – is associated Food embolism to the brain through an oesophageal– with an increased risk of stroke. 477 atrial fistula as a complication of oesophageal cancer is a curiosity. 503 .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 383 7.18 Perioperative stroke 383 Table 7.8 Possible causes of stroke and cognitive decline 7.18 Perioperative stroke complicating cardiac surgery. Embolization to the brain during surgery of: platelet aggregates 7.18.1 Cardiac surgery fibrin calcific valvular debris During surgery, or within the next few days, about 3% intracardiac thrombus of coronary artery bypass procedures are complicated atheromatous debris from the aorta by stroke, somewhat more often with valve surgery, and fat, air and silicone or particulate matter from the even more often after cardiac transplantation. 504–506 pump–oxygenator system Much more common are what seem to be clinically vegetations complicating infective endocarditis silent brain lesions on imaging 507 and, perhaps of Embolism after surgery from: more consequence, a diffuse neurological syndrome thrombus on suture lines or on prosthetic material with postoperative confusion, soft neurological signs, left ventricular thrombus complicating myocardial poor memory and other neuropsychological impair- infarction ments. 508–510 This syndrome, which must be distin- atrial fibrillation infective endocarditis guished from depression, mostly resolves in days or Global hypoperfusion and ischaemia resulting from weeks, perhaps coinciding with the resolution of the perioperative hypotension (section 6.7.5) brain swelling which has been demonstrated immedi- Haemodilution during surgery ately postoperatively. 511 Progressive long-term cognitive Simultaneous carotid endarterectomy under the same decline has been reported in some patients, perhaps due anaesthetic (section 16.14) to comorbid cerebrovascular disease rather than the Cholesterol embolization syndrome (section 7.7) surgery itself. 509 Thrombosis associated with heparin-induced There are many possible explanations for these com- thrombocytopenia (section 7.9.11) plications, the most common probably being embolism The systemic inflammatory response from the heart or aortic arch (Table 7.8). They are more Non-specific effect of general anaesthesia Intracranial haemorrhage caused by: likely with increasing age, previous stroke, other vascular thrombocytopenia disorders and risk factors, intraoperative hypotension, disseminated intravascular coagulation the use of aprotinin to reduce intraoperative bleeding, uncontrolled hypertension severe aortic arch atheroma and lengthy extracorporeal antithrombotic drugs circulation. 508,512–514 A risk index has been suggested Paradoxical embolism from postoperative deep venous but not yet externally validated. 510 It is now becoming thrombosis (section 6.5.12) increasingly clear from several randomized trials that off-pump beating heart surgery is associated with fewer strokes and perhaps less clinically relevant cognitive With recently symptomatic carotid stenosis the stroke decline than conventional coronary surgery under risk may be higher. 518 Pending a large, prospective and cardiopulmonary bypass. 515–517 methodologically sound study to clarify this issue, a Whether asymptomatic carotid stenosis or occlusion systematic review of all the available studies is much is causally associated with perioperative stroke is much needed. discussed. Certainly the extent of any association is Instrumentation of the coronary arteries and aorta may uncertain because: dislodge valvular, intracardiac or atheromatous aortic • the number of strokes in any one study is far too small and other large-artery thrombus and debris to cause cere- for precise estimates of relative risk even though the bral ischaemia. Although under 1% of procedures are absolute risk can appear quite high; complicated by stroke of any consequence, minor events • often patients who might have had a stroke have been including subtle neurocognitive abnormalities may well excluded from a series by having an elective carotid have passed unnoticed or been under-reported, while endarterectomy before cardiac surgery; apparently asymptomatic changes on MR DWI are fairly • the proportion of all operative strokes caused by severe common. 324,507,519,520 Thrombus may also form on the carotid disease, presumably in association with a fall in intra-arterial catheter tip, a fragment of catheter may systemic blood pressure, is probably rather small; break off and embolize, there may be systemic hypo- • most studies have been retrospective; tension, cerebral air embolism is a possibility, and the • and by no means all patients in the studies have had cholesterol embolization syndrome is a rare complica- imaging to assess the severity of any carotid stenosis. tion (section 7.7). Large doses of intravenous contrast .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 384 384 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack Table 7.9 Possible causes of stroke during or soon after general together with biochemical defects in the respiratory surgery. chain. 526–530 Many are now known to be caused by vari- ous deletions and point mutations in mitochondrial Intra- or postoperative hypotension causing low-flow DNA, where inheritance of point mutations is usually infarction, particularly if there are stenotic or occluded through the maternal line, and also sometimes by arteries supplying the brain (section 6.7.5) 529,531 defects in nuclear DNA. There are a number of Haemostatic defect resulting from antithrombotic drugs, or rather characteristic, but often overlapping, clinical disseminated intravascular coagulation, causing phenotypes, one of which can present as ‘stroke’: mito- intracranial haemorrhage Occlusion or dissection of neck arteries caused by faulty chondrial encephalopathy, lactic acidosis and stroke-like handling and positioning during general anaesthesia episodes (MELAS). (section 7.2.1) MELAS usually presents in children, adolescents Paradoxical embolism from postoperative deep venous or middle-aged adults with recurrent focal cerebral thrombosis (section 6.5.12) episodes, usually first affecting the occipital lobes, and Withdrawal of long-term warfarin therapy for stroke caused by lesions which were originally regarded as prevention infarcts but not corresponding with the territories of the Penetrating trauma of a neck artery during attempted 532,533 main cerebral arteries. These episodes tend to be venous catheterization or neck surgery (section 7.1.1) complicated in the acute stage, or later, by partial and Perioperative myocardial infarction or atrial fibrillation secondary generalized epileptic seizures. Eventually the Infective endocarditis (section 6.5.9) patient becomes demented and usually cortically blind. Fat embolism after long bone surgery (section 7.1.8) Air embolism (section 7.1.7) The cause of the brain lesions is uncertain; perhaps a The rather nebulous concept of postoperative defect in brain oxidative metabolism, or the structural ‘hypercoagulability’ changes that can be seen in small cerebral blood vessels rather than overt vessel occlusion, 534,535 the former pos- sibility being supported by MR DWI studies. 536 MELAS may cause temporary cortical blindness, and even patients are often rather short, with sensorineural deaf- normal doses can cause migrainous aura. 521,522 ness, migraine, episodic vomiting, diabetes mellitus and some learning disability. There may be additional features more characteristic of other mitochondrial 7.18.2 General surgery syndromes, such as proximal muscle weakness, myo- General surgery is less frequently complicated by stroke clonus, ataxia, exercise intolerance, cardiomyopathy, than cardiac surgery – less than 1% of operations depend- progressive external ophthalmoplegia, pigmentary ing on age – most often in patients with a past history retinopathy and ovarian and testicular failure. of stroke, widespread vascular disease or chronic The diagnosis of MELAS should be suspected in any obstructive airways disease. 523,524 As after cardiac surgery, young patient with an ischaemic stroke, particularly there is some evidence of early and perhaps longer- if it is in the occipital lobe and complicated by epilepsy, term postoperative cognitive decline, but the studies are and if there is no other fairly obvious cause. 537 CT fre- bedevilled with methodological problems. 525 There are quently shows basal ganglia calcification and also areas many possible causes of perioperative stroke but so often of low density in the grey and white matter of the cere- the stroke is not recognized very quickly in sick post- bral hemispheres, and these may show mass effect and operative patients, and investigation is generally less enhancement in the acute stage, and then disappear, than optimal in surgical wards (Table 7.9). Sometimes eventually to be followed by atrophy, more obvious on the stroke is coincidental, particularly in elderly people MRI 538 (Fig. 7.15). with multiple vascular risk factors who increasingly are The fasting plasma and, particularly, cerebrospinal having surgery as anaesthesia becomes safer. fluid (CSF) lactate is raised, usually at rest. However, CSF lactate may also be raised for some days after epileptic seizures, subarachnoid haemorrhage, meningitis and stroke and is anyway not diagnostically helpful because either an abnormal or normal test result must be fol- 7.19 Mitochondrial diseases lowed up if there is diagnostic suspicion in the first place – biochemical or molecular confirmation is ultimately always required. 539 In many but not all patients, muscle This large group of rare multisystem disorders is asso- biopsy shows ragged red fibres on Gomori’s trichrome ciated with structural abnormalities of mitochondria, staining and, with electron microscopy, large numbers .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 385 7.20 Single gene disorders 385 Fig. 7.15 Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): T2-weighted MR scan. The first scan (left-hand panel) shows an infarct-like hyperintensity in the parieto-occipital cortex (white arrow). The second scan (right-hand panel) was obtained 2 weeks later and shows a new lesion in the left parieto-occipital cortex (open white arrow); the earlier lesion has vanished. of abnormal mitochondria. The point mutation in mito- their 60s; early on, depressive symptoms and other chondrial DNA (usually at base pair 3243 but occasion- mood disorders are common. 547–550 However, affected ally at one of several other sites) can be demonstrated individuals vary in the frequency and severity of the in white blood cells, but sometimes only in muscle. various manifestations and age of onset, sometimes However, not all MELAS patients have known muta- within the same family, the phenotype is constantly tions, and sometimes the known mutations can be being expanded, and cognitive decline may even be found in other mitochondrial clinical syndromes, in present very early on. 551 relatives of MELAS patients who may or may not be On CT, and more obviously on MRI, there are very symptomatic, and in some normal people. 540–542 At pre- characteristic focal, diffuse and confluent lesions in the sent, there is no specific treatment. periventricular and subcortical cerebral white matter, Children with autosomal recessive cytochrome oxi- also sometimes in the brainstem, looking very similar to dase deficiency and lactic acidosis have been reported to ischaemic leukoaraiosis and even multiple sclerosis, but have stroke-like episodes. 543 typically there are also changes in the temporal poles which is not the case with either of these differential diagnoses; the MR changes very often start before the patients are symptomatic, and progress with time 187,552,553 (Fig. 7.16). Multifocal microhaemorrhages on gradient 7.20 Single gene disorders echo MRI – and at autopsy – are another common fea- ture, perhaps in part a consequence of antiplatelet drug treatment, hypertension or diabetes, although clinically apparent haemorrhagic stroke is unusual. 554–556 Catheter 7.20.1 Cerebral autosomal dominant arteriopathy angiography should be avoided because of the apparent with subcortical infarcts and leucoencephalopathy 557 excess risk of neurological complications. The CSF Cerebral autosomal dominant arteriopathy with sub- may show a mildly raised protein level, and very occa- cortical infarcts and leucoencephalopathy (CADASIL) is sionally unmatched oligoclonal bands. an increasingly recognized but rare autosomal dominant The changes in the vessel wall are distinctive with – and occasionally sporadic – disorder of small blood deposits of eosinophilic periodic-acid-Schiff positive vessels caused by various mutations of the Notch 3 gene material within the leptomeningeal and perforating on chromosome 19. 544–546 arteries of the brain. 558 The basal lamina of the affected Migraine with aura (which can be prolonged, compli- vessels is thickened by granular osmiophilic material cated and easily confused with strokes and transient which is dense under electron microscopy. Despite the ischaemic attacks) tends to develop in patients in their lack of any obvious clinical consequences, similar changes 20s, recurrent – mainly lacunar ischaemic – strokes and can be found in the small vessels of skin, muscle, nerve transient ischaemic attacks in their 40s, progressive sub- and other viscera which occasionally allows histological, cortical dementia in their 50s, and the patients die in and particularly electron microscopy, confirmation of .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 386 386 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack Fig. 7.16 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): FLAIR MR brain scan showing (a) numerous abnormal high signal areas in the cerebral white matter bilaterally and, typically, (b) in the anterior temporal lobes (arrows) which would be most (a) (b) unusual in multiple sclerosis, for example. the diagnosis from skin or muscle biopsy, although this 7.20.2 Homocystinuria may not always be reliable; 559–561 the utility can however be improved with immunostaining with a Notch 3 This rare autosomal recessive inborn error of metabolism, monoclonal antibody. 562 Genetic testing will generally usually caused by cystathione synthase deficiency, is detect known mutations but these vary in different complicated by cerebral arterial and intracranial venous populations, it is therefore time-consuming because thrombosis, usually in children and young adults, for there are so many mutations, and it may be negative. 563 reasons that are unclear. 565 The underlying vascular It is clear therefore that the diagnosis of CADASIL is pathology has rarely been studied but seems to be not as straightforward as it once seemed. The clinical atheromatous-like in some cases but not others. 566–569 phenotype varies and obviously overlaps with migraine, The diagnosis should be suspected if there are epileptic stroke and dementia – particularly in the early stages seizures, learning disability, marfanoid habitus, osteo- when only one manifestation may be present, such as porosis, high myopia and dislocated lenses but these are migraine; the MR scan is almost always abnormal but not invariably very obvious or even present. 568,570–572 shares many features with multiple sclerosis in young Hyperhomocysteinaemia, insufficiently severe to cause adults and ischaemic leukoaraiosis in older people; there the clinical syndrome of homocystinuria, may be a risk is not always a family history; the skin biopsy is not factor for degenerative vascular disease (section 6.6.8). always positive; and Notch 3 mutations are not always found, perhaps because not enough have been tested 7.20.3 Fabry’s disease for in an individual patient or there are more to be discovered. This rare, X-linked, recessive lysosomal storage disorder Other than paying attention to any vascular risk fac- in which there is a deficiency of alpha-galactosidase A tors in the normal way (Chapter 16), and perhaps adding results in the accumulation of glycolipids in vascular aspirin as an antithrombotic drug, there is no specific endothelial and other cells. 573,574 treatment. Genetic counselling is of course important, The patients are young males (and increasingly with all the problems inherent in a long-term but ulti- recognized heterozygous females) who are affected by mately fatal condition which can be predicted from a skin angiokeratomas in the bathing-trunks area, hypo- blood test, and which so often becomes manifest after hidrosis, and burning pain and paraesthesia in the hands those affected have themselves had children. and feet (but seldom any signs) caused by a small fibre Other even rarer familial small-vessel disorders have neuropathy. Additional complications include corneal also been described including cerebral autosomal reces- dystrophy, cataract, renal failure and secondary hyperten- sive arteriopathy with subcortical infarcts and leucoen- sion, cardiomyopathy, myocardial ischaemia and conduc- cephalopathy (CARASIL), hereditary endotheliopathy tion abnormalities. Death generally occurs in middle age. with retinopathy, nephropathy and stroke syndrome Clinically evident as well as ‘silent’ strokes, both cort- (HERNS), cerebroretinal vasculopathy, familial amyloid ical and subcortical, are caused by: occlusion of small angiopathy, and others as yet unnamed. 564 blood vessels; larger vessel ectasia; embolism from the .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 387 7.21 Intracranial venous thrombosis 387 heart; and rarely intracranial haemorrhage. 575 Fabry’s considered the diagnosis in patients with otherwise disease is worth looking for in young stroke patients with unexplained headache, focal deficits, seizures, impaired no obvious cause, particularly males, occurring in maybe consciousness, or combinations of these features; all too 1% or so. 576 often the diagnosis was made at postmortem – as it was in the first recorded case by Thomas Willis. 591 Not sur- prisingly it used to be regarded as a rare disease that was 7.20.4 Tuberous sclerosis commonly fatal, whereas now it is seen as a relatively This multisystem, autosomal dominant disorder may common disease which is rarely fatal. be complicated by cerebral emboli from a cardiac rhabdomyosarcoma. 577 It has also been uncertainly asso- 7.21.1 Predisposing factors ciated with intracranial aneurysms and the moyamoya syndrome (section 7.5). Unlike arterial thrombosis, damage to the vessel wall – due to infection, infiltration, or trauma to cortical veins or dural sinuses – is a causal factor in only about 10% of 7.20.5 Neurofibromatosis 592 patients with ICVT. More important are disorders of This is another multisystem, autosomal dominant dis- coagulation 592 (Table 7.10). The most common inherited order. It may be complicated by: distal carotid stenosis coagulation defect is factor V Leiden mutation, which is or occlusion, sometimes but not always the result of found in some 20% of patients without other obvious irradiation for optic nerve glioma, and this in turn may predisposing causes. 593–595 The third component of cause the moyamoya syndrome (section 7.5); ectasia Virchow’s triad of causes of thrombosis – stagnant flow – and occlusion of cerebral arteries; intracranial and extra- contributes no more than a few per cent (associated with cranial aneurysms perhaps; and tumour compression of dehydration or with dural puncture, sometimes in com- intracranial arteries. 578–580 bination with hyperosmolar contrast agents). 596 In about 20% of patients no contributing factors can be identified and the cause remains shrouded in mystery. Perhaps as 7.20.6 Primary oxalosis yet undiscovered prothrombotic mutations are respons- This rare autosomal recessive disorder is complicated by ible to some extent. renal stones and failure. It may rarely be complicated by Often there is no single cause but a combination of ischaemic stroke due to embolism from the heart, or the contributing factors, for example the postpartum period moyamoya syndrome. 581 and protein S deficiency, 597 pregnancy and Behçet’s dis- ease, 598 oral contraceptives and the factor V Leiden mutation, 599,600 or the same combinations with dural 7.20.7 Inherited disorders of connective and 601 puncture as a third factor. elastic tissue In neonates, ICVT is usually associated with acute Ehlers–Danlos syndrome type IV (section 9.1.1), pseudox- systemic problems such as perinatal complications or anthoma elasticum, Marfan’s syndrome and osteogenesis dehydration; in older children the most frequent under- imperfecta are all rare disorders which can affect arteries lying conditions are local infection (the leading cause and so occasionally be complicated by, or present with, until the antibiotic era), coagulopathy 602,603 and – more arterial dissection, local aneurysm formation or even in Mediterranean countries – Behçet’s disease. 604 rupture, intracranial aneurysm formation, caroticocav- ernous fistula and embolism from cardiac lesions. 582–587 7.21.2 Clinical features Unlike arterial ischaemic stroke, ICVT relatively more commonly affects neonates, infants, children and young adults than older people, but no age is exempt. The 7.21 Intracranial venous thrombosis clinical features consist essentially of headache, focal neurological deficits, epileptic seizures and impairment of consciousness, in different combinations and degrees The advent of non-invasive brain imaging in the 1980s of severity. The symptoms and signs depend to some resulted in greatly increased recognition of intracranial extent on which vein or venous sinus is affected, and to venous thrombosis (ICVT), although it is still far less an important extent on whether the thrombotic process frequent than arterial ischaemic stroke. 588–590 Before is limited to the dural sinuses or extends to the cortical then, only physicians with a high index of suspicion veins. 592 .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 388 388 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack Table 7.10 Predisposing factors for Prothrombotic states intracranial venous thrombosis. Pregnancy and puerperium, particularly in developing countries (section 7.14) Ovarian hyperstimulation syndrome (section 7.13) Hereditary coagulopathies Protein C or S deficiency (section 7.9.11) Antithrombin III deficiency (section 7.9.11) Factor II (prothrombin) gene mutations (section 7.9.11) Factor V Leiden mutations (section 7.9.11) von Willebrand’s disease 5,10 methylene tetrahydrofolate reductase mutation Homocystinuria (section 7.20.2) and hyperhomocysteinaemia Coagulopathies secondary to blood diseases Thrombocythaemia (section 7.9.2) Primary polycythaemia (section 7.9.1) Leukaemia (section 7.9.4) Paroxysmal nocturnal haemoglobinuria (section 7.9.9) Iron deficiency anaemia (section 7.9.7) Sickle cell disease (section 7.9.8) Disseminated intravascular coagulation (section 7.9.12) After bone marrow transplantation Secondary to systemic disease Behçet’s disease (section 7.3.11) Systemic lupus erythematosus/antiphospholipid syndrome (sections 7.3.3 and 7.3.4) Systemic vasculitis (section 7.3.6) Carcinoma (breast, prostate, etc.) (section 7.12) Lymphoma Hyperviscosity syndromes (section 7.9.10) Nephrotic syndrome (section 7.9.11) Ulcerative colitis or Crohn’s disease (section 7.17) Dehydration Sarcoidosis (section 7.3.16) Systemic infectious disease (bacterial, fungal) Drugs Oral contraceptives (section 7.13.1) Corticosteroids Dihydroergotamine Asparaginase (section 7.12) Androgens Ecstasy (section 7.15.1) Recombinant human erythropoietin Antifibrinolytic drugs Thalidomide? Local infection or infiltration Otitis, mastoiditis, sinusitis Dental abscess Tonsillitis Meningitis (acute or chronic, bacterial, fungal) Subdural empyema Obstruction of dural sinus by tumour Malignant meningitis Thrombosis of vein draining venous malformation Dural puncture Epidural anaesthesia Metrizamide myelography Diagnostic tap Trauma Head injury, open or closed, with or without fracture Jugular vein, including catheterization Neurosurgical procedures .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 389 7.21 Intracranial venous thrombosis 389 Dural sinus thrombosis causes raised intracranial pres- Involvement of the cortical veins, without sinus sure with headache and papilloedema (without hydro- thrombosis and its associated signs of increased CSF cephalus). In the past, patients with so-called ‘benign pressure, is rare but can present as ‘stroke’ and so may intracranial hypertension’ may well have had unrecog- be under-recognized, particularly when the clinical nized sinus thrombosis; although they are more often features are rather mild and there is no haemorrhagic non-obese males, they can be clinically indistinguish- transformation of any infarct, or any infarct at all, on able from patients with what should now be called imaging. 609,610,613 One wonders if ICVT is responsible for idiopathic intracranial hypertension. 605 Papilloedema many transient ischaemic attacks; presumably it must can cause transient visual obscurations and sometimes be, but is unrecognized. irreversible constriction of the visual fields, beginning Thrombosis of the deep venous system, including the in the inferonasal quadrants. 606 The increased pressure great vein of Galen, may lead to bilateral haemorrhagic of the cerebrospinal fluid may give rise to sixth nerve infarction of the corpus striatum, thalamus, hypo- palsies, and sometimes to other cranial nerve deficits. thalamus, the ventral corpus callosum, the medial The onset of the headache is usually gradual over occipital lobes and the upper part of the cerebellum. 614 some days, but in up to 15% of patients it is sudden, The clinical picture is dominated by coma, disordered which may initially suggest the diagnosis of a ruptured eye movements and pupillary reflexes, with a high case aneurysm intracranial. 607 Very few patients seem to go fatality. However, there are partial syndromes which on to develop problems with cortical venous infarction, can be survived, sometimes with surprisingly few although a few do. sequelae. 610,615,616 Involvement of cortical veins causes one or more Thrombosis of cerebellar veins leads to clinical features areas of venous infarction, which are usually highly resembling those of arterial territory infarcts in the cere- oedematous, with or without haemorrhagic trans- bellum (dominated by headache, vertigo, vomiting and formation. If the affected veins drain into the sagittal ataxia, sometimes followed by impaired consciousness), sinus, the venous infarcts are typically located near the but with a more gradual onset. 606,617,618 midline in the parasagittal and parieto-occipital regions, often on both sides. In the case of the lateral sinus, 7.21.3 Diagnosis and investigations the venous infarct is usually located in the posterior temporal area. If the thrombotic process extends to The main trick is to think of the diagnosis in a patient the petrosal sinus, the fifth or sixth cranial nerves may who appears to have idiopathic intracranial hyperten- be affected, and with jugular vein thrombosis the ninth sion, an encephalopathy with multiple cerebral ‘haemor- to eleventh cranial nerves; 592 sometimes the lower rhages’, sudden headache not due to subarachnoid cranial nerve palsies are isolated with no other clinical haemorrhage, or a ‘stroke’ (either ischaemic or haemor- signs. 608 rhagic) with epileptic seizures and headache in a young Clinically, the infarcts present typically with headache patient – particularly if the patient is or has recently been and focal epileptic seizures with or without secondary pregnant, has a past history of venous thrombosis else- generalization, and with focal deficits such as hemipare- where, or systemic risk factors for venous thrombosis. sis or aphasia (transient or more permanent). If unilat- However, these days the first suggestion often comes eral weakness develops (with thrombosis originating in from CT or MR imaging (section 5.8). Once the radio- the superior sagittal sinus), it tends to predominate in logical diagnosis is made, then clearly the cause has to the leg, in keeping with the parasagittal location of most be searched for along the lines outlined in Table 7.10. venous infarcts. Obstruction of cortical veins draining But even if one ‘cause’ is found, others must also be con- into the posterior part of the superior sagittal sinus, or sidered because so often one or more act synergistically into the lateral sinus, will relatively often lead to hemi- to cause ICVT, perhaps in half the cases. However, in anopia, aphasia or a confusional state. A generalized about 20% of cases no cause is found. D-dimer assay is encephalopathy with impairment of consciousness may neither specific nor sensitive enough to be useful. 590 result from multiple infarcts in the cerebral hemispheres, or from transtentorial herniation and compression of 7.21.4 Prognosis and treatment the brainstem. Either epilepsy or a focal deficit is a pre- senting feature in 10–15% of patients; 609 during the Dural sinus thrombosis alone generally has a very good course of the illness seizures occur in 10–60%, and focal prognosis without any treatment, and even patients deficits in 30–80%. 609–612 Occasionally the presentation with widespread haemorrhagic venous infarcts have can be with headache alone, mimicking subarachnoiod made surprising recoveries – venous infarcts are clearly haemorrhage. different from arterial infarcts in this respect. However, .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 390 390 Chapter 7 Unusual causes of ischaemic stroke and transient ischaemic attack ICVT can still be a very serious disorder and a few antiplatelet drug would have some useful antithrom- patients die, usually of transtentorial herniation. 619 In botic effect. Endovascular thrombolysis, with or without the acute phase of an encephalopathy, raised intra- mechanical clot disruption, has been attempted but cranial pressure may have to be treated with mannitol, there is no good evidence that it is effective; it should be large haemorrhagic infarcts removed surgically, and even reserved for randomized trials or patients who are doing decompressive hemicraniectomy may be required for badly even with anticoagulation. Naturally any underly- major cerebral swelling (despite the lack of formal evid- ing cause should be treated (infections, vasculitis, etc.) ence of benefit). It is uncertain whether corticosteroids and, if this is successful, anticoagulation can be with- are helpful. drawn in a matter of months. More difficult is whether The treatment of patients with just raised intracranial anticoagulation should be continued indefinitely in pressure should probably be along the same lines as patients with an inherited or aquired coagulopathy, or for idiopathic intracranial hypertension (acetazolamide, indeed in patients with no obvious ‘cause’; maybe it repeat lumbar punctures, CSF diversion), notwithstand- should be, particularly if recurrent venous thromboses ing the very poor evidence on which this is based. 620 have occurred, although the risk of recurrence of ICVT Some patients are left with residual neurological dis- appears to be very small, even in any subsequent ability, epilepsy and – exceptionally – a dural or pial pregnancy. 426 arteriovenous fistula. 621,622 Pulmonary embolism may be more frequent than For years the logical treatment for thrombosis within one might anticipate for the severity of any leg par- veins – anticoagulation – was avoided because of the alysis or length of bed rest, perhaps it is due to pro- fear of causing haemorrhagic transformation of venous pagation of thrombus from the intracranial sinuses to infarcts. However, as people became aware that this was the pulmonary veins, or because of an underlying seldom a problem, and that even if haemorrhagic trans- thrombophilia. 624 formation was actually present patients still seemed to do well on anticoagulants, three randomized trials were organized; in aggregate they showed a non-significant trend in favour of treatment: 54% relative reduction in death and disability (95% confidence interval 84– 7.22 The ischaemic stroke or transient 31% increase) 589,623 (Fig. 7.17). Under the circumstances, ischaemic attack case with no cause – most physicians are now prepared to heparinize pat- what to do? ients, even in the presence of haemorrhagic infarcts, and then to switch after a few days to warfarin with a target INR of 2–3. Presumably, if there is a definite Even over 50–60 years of age, ischaemic strokes should contraindication to anticoagulation, aspirin or another not carelessly be put down to ‘degenerative arterial Study Treatment Cotrol Relative Risk (Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI 1991 Enhaupl 0/10 3/10 36.5 0.14 [0.01, 2.45] 1999 CVST Group 4/30 6/29 63.5 0.64 [0.20, 2.05] Total (95% CI) 40 39 100.0 0.46 [0.16, 1.31] Total events: 4 (Treatment), 9 (Control) 2 Test for heterogeneity chi-square = 0.97 df = 1 P = 0.32 F = 0.0% Test for overall effect z = 1.45 P = 0.1 0.001 0.01 0.1 1 10 100 1000 Favours treatment Favours control Fig. 7.17 The Cochrane Review of anticoagulation treatment the horizontal line representing the 95% confidence interval for intracranial venous thrombosis. 623 The outcome is death (fixed effects method). The diamond represents the overall and dependency. Each of the two trials is represented by a box reduction in risk with its 95% confidence interval (copyright describing the relative reduction in risk of a poor outcome with Cochrane Collaboration, reproduced with permission). .. ..

9781405127660_4_007.qxd 10/13/07 11:00 AM Page 391 References 391 disease’ unless there are clear-cut risk factors (hyperten- If there is no obvious cause for a stroke or transient sion, smoking, etc.) and/or clear-cut evidence of arterial ischaemic attack, it is important to retake the history, disease elsewhere (bruits, claudication, angina) and no re-examine the patient and check not only that all the more obvious cause, such as giant-cell arteritis. Nor relevant investigations have been carried out but that should ischaemic strokes be ascribed to embolism from the results have been seen and discussed by the the heart unless there is a major and threatening cardiac medical team. If there is still no cause, then follow-up, source (e.g. atrial fibrillation, prosthetic heart valve, or a recurrence, may provide the crucial clue. etc.). Of course, there are many other, admittedly rare, possibilities to be considered from Fabry’s disease to If the ischaemic stroke or transient ischaemic attack CADASIL. But, after taking an exhaustive history, ex- diagnosis is secure, all the relevant investigations are amining the patient obsessionally and undertaking negative, the heart is normal, and there are no vascular appropriate investigations, there are still some patients risk factors or evidence of vascular disease outside the where no reasonable explanation for their stroke can be head, then there is little to be done except recommend found or in whom any putative cause is marginal (e.g. aspirin as an antithrombotic drug along perhaps with a uncomplicated mitral leaflet prolapse, patent foramen statin (at least for a while), await events and hope that ovale, oral contraceptives with no prothrombotic or any recurrence does not bring to light a diagnosis which other abnormality, an uncertain diagnosis of migrain- should have led to an effective treatment at the time of ous stroke); the stroke is then deemed ‘cryptogenic’. the first stroke. In general, the problem is seldom the lack Naturally, the intensity of the search for a cause must of a key investigation but more often the lack of a good depend on the previous level of dependency and the clinical history. Therefore, other than checking out all age of the patient, the severity of the stroke (aggressive the possible investigations in Tables 6.13 and 6.14, it is investigation is reasonable in milder strokes where there best to retake the history, re-examine the patient and is more to lose from a disabling recurrence), and the con- follow up the patient carefully, at least for a while. sequences of missing the diagnosis. For example, at any Fortunately, as far as one call tell, strokes with truly no age, it is vital to diagnose infective endocarditis as with- discernable cause seldom seem to recur. out treatment it can be fatal, whereas traumatic arterial dissection with no medicolegal consequences is perhaps less important because – as yet – there is no generally accepted treatment, and recurrence is unlikely. None- theless, the diagnosis of dissection or a migrainous stroke would at least stop the patient having to take the References full range of vascular risk-reducing drugs (Chapter 16) for the rest of their lives, and also improve their chances of getting life insurance. 1 Davis JM, Zimmerman RA. Injury of the carotid and In a puzzling case, it is important to go over the his- vertebral arteries. Neuroradiology 1983;25(2):55–69. 2 Inamasu J, Guiot BH. Iatrogenic vertebral artery injury. tory and examination again, re-read all the medical Acta Neurol Scand 2005; 112(6):349–57. records and to check not only that the appropriate invest- 3 Auer RN, Krcek J, Butt JC. Delayed symptoms and death igations have been carried out but also that the results after minor head trauma with occult vertebral artery have been discussed by the medical team and are avail- injury. J Neurol Neurosurg Psychiatry 1994; 57(4):500–2. able in the medical records. It may turn out that the 4 Viktrup L, Knudsen GM, Hansen SH. Delayed onset of fatal diagnosis of stroke or transient ischaemic attack has to basilar thrombotic embolus after whiplash injury. Stroke be revised, particularly if a ‘stroke’ patient deteriorates 1995; 26(11):2194–6. or fails to improve in a typical way after the acute stage, 5 Martin PJ, Humphrey PR. Disabling stroke arising five taking one back to the ‘stroke’ vs ‘not-stroke’ issues dis- months after internal carotid artery dissection. J Neurol cussed in Chapter 3. It is surprising how often, in young Neurosurg Psychiatry 1998; 65(1):136–7. people, multiple sclerosis can be confused with stroke, in 6 Nazir FS, Muir KW. Prolonged interval between vertebral artery dissection and ischemic stroke. Neurology 2004; elderly patients how the pseudobulbar palsy of motor 62(9):1646–7. neurone disease can be called a stroke, and at any age 7 Hughes JT, Brownell B. Traumatic thrombosis of the how migraine aura without headache can be confused internal carotid artery in the neck. J Neurol Neurosurg with transient ischaemic attacks. A ‘psychogenic’ dis- Psychiatry 1968; 31(4):307–14. order is also easily confused with stroke. So ‘no cause for 8 Hilton-Jones D, Warlow CP. Non-penetrating arterial a stroke’ may simply mean that the patient has not had trauma and cerebral infarction in the young. Lancet 1985; a stroke in the first place – double check. 1(8443):1435–8. .. ..