Extensive haemorrhagic transformation of infarct: might it be an ...

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Age and Ageing 2002; 31: 429–433

2002, British Geriatrics Society

REVIEW

Extensive haemorrhagic transformation of infarct: might it be an important cause of primary intracerebral haemorrhage? G ILLIAN E. M EAD, J OANNA M. W ARDLAW , M ARTIN S. D ENNIS , S TEPHANIE C. L EWIS Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK Address correspondence to: G. E. Mead, Department of Clinical and Surgical Sciences (Geriatric Medicine), 21 Chalmers Street, Edinburgh EH3 9EW, UK. Fax: (q44) 131 536 4536. Email: [email protected]

Abstract Data from prior studies using serial imaging and post mortem data support the possibility that at least some cases of apparent primary intracerebral haemorrhage are due to early haemorrhagic transformation of infarct. If some primary intracerabral haemorrhage is actually early haemorrhagic transformation of infarct, then secondary stroke prevention for ischaemic stroke might be appropriate and so future studies should obtain data to determine the frequency of early major haemorrhagic transformation of infarct. Keywords: stroke, cerebral infarct, cerebral haemorrhage, haemorrhagic transformation of infarct

Introduction It is traditional to regard primary intracerebral haemorrhage (PICH) as due either to ‘hypertensive’ intracranial vascular disease caused by degenerative changes in small perforating vessels, or ‘amyloid angiopathy’ (patchy deposits of amyloid in the muscle layer of small and medium sized arteries) [1]. On the other hand, most cerebral infarction is thought to be due to atherothromboembolism, intracranial small vessel disease or embolism from the heart [2]. Cerebral infarction can sometimes be complicated by bleeding into the infarct i.e. haemorrhagic transformation of infarct (HTI) [3]. Although cerebral infarction (with or without HTI) and PICH are usually considered to be distinct pathological entities, they share many of the same risk factors (e.g. hypertension), and on brain imaging, there are sometimes similarities between the appearances of HTI and PICH: for example, there is often a variable amount of low attenuation around PICH on computed tomography, which is thought to be due to secondary oedema and ischaemic necrosis. However, these observations would be consistent with the hypothesis that at least some PICH is due to extensive HTI.

If PICH is sometimes due to early HTI, this may have important implications. Firstly, the incidence of PICH in epidemiological studies may have been overestimated. Secondly, the same strategies for secondary stroke prevention may be appropriate for some PICH and ischaemic stroke. Thirdly, patients with extensive HTI (classified as PICH on brain imaging) may still have ischaemic neurones within the haemorrhagic area, which means that acute treatments for cerebral ischaemia e.g. neuroprotection may still be beneficial, particularly if administered early. In this review, we will discuss the evidence that some apparent PICH may actually be extensive HTI and will consider how future studies could be designed so that the proportion of apparent PICH, which are actually due to HTI, could be determined.

The evidence that PICH may sometimes be due to extensive HTI We have looked after a patient who suggests that ‘apparent’ PICH can sometimes be due to HTI. There is also a case series [4] and some unpublished post mortem

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Figure 2. Angiogram showing occluded middle cerebral artery with markedly dilated lenticulostriate arteries. Figure 1. CT scan showing an intracerebral haematoma. The underlying aetiology was thought to be a ruptured aneurysm, so the patient underwent angiography.

data (see below) from our hospital. In our own hospital, a 26-year-old woman was admitted with an acute stroke in 1995. A CT brain scan performed 2 hours after stroke showed intracerebral haematoma in the left anterior temporal lobe (Figure 1). Immediate angiography (on the assumption that the patient had an aneurysm or arteriovenous malformation), showed an occluded middle cerebral artery on the side of the haematoma with markedly dilated lenticulostriate arteries (Figure 2). The most likely explanation for these findings is that the initial lesion was acute cerebral infarction, followed by early extensive HTI which mimicked PICH. Bogossouslavsky et al. reported 15 patients with acute stroke who had a brain CT within 6 hours of stroke onset, which showed no evidence of bleeding [4]. A second CT performed within 18 hours showed ganglionic or lobar haemorrhage. Ten of these patients underwent the second scan because of neurological deterioration, and five were rescanned because the initial CT was not available. Had these patients not undergone the first scan, it would have been assumed that the initial pathology was PICH rather than early extensive HTI. How often does extensive HTI mimicking PICH occur after cerebral infarction? One of us, JMW (in collaboration with Dr R. Lindley), did a systematic review of studies performed prior to the widespread use of aspirin in acute ischaemic stroke. A total of 15 studies were identified where patients with ischaemic stroke (none of whom received antithrombotic treatment, anticoagulants or thrombolysis) underwent a second

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brain CT, and where data were available on the frequency of major HTI or haematoma [5–20]. Of the 1,183 patients recruited to the studies, 18 (1.5%) developed clinically symptomatic haematoma or major HTI within the first 2–3 weeks after the stroke. Unfortunately none of the patients in these studies were scanned rapidly enough after the initial stroke to determine what proportion of ischaemic strokes undergo very early major HTI, and therefore how many with what appeared to be PICH were actually major HTI.

What proportion of PICH are due to HTI? Although the imaging-based studies above suggest that only a small proportion of patients with ischaemic stroke develop major HTI, they do not provide any information about the proportion of apparent PICH which is actually due to extensive HTI. Extrapolating from the number known to have major HTI (1.5% of ;80/100 ischaemic strokes, or 1/100 strokes) would suggest that of the 15/100 considered to be due to PICH, 1/15 or 7% of PICH might actually be early major HTI. In our own hospital, all autopsy cases of ‘PICH’ (n=30) between October 1994 and November 1999 were examined by a consultant neuropathologist (G.A. Lammie). Twelve (40%) were due to hypertensive-type PICH, 8 (27%) due to amyloid angiopathy and 3 (10%) due to HTI (unpublished data, courtesy of Dr G. A. Lammie, Dept of Pathology, University of Wales, Cardiff, UK). Of HTI cases, two of the three patients had been taking warfarin. The remaining seven cases were due to miscellaneous other causes.

Extensive haemorrhagic transformation of infarct Several other post-mortem series have reported the causes of spontaneous cerebral haemorrhage, although all were published more than two decades ago (we were unable to find any more recently published post mortem series) [21–23]. In a review of 9 series recruiting 2,476 cases (published between 1949 and 1973) [21], 56% of cases were due to ‘hypertension’, 19% due to aneurysms, and the remainder were due to miscellaneous other causes, including 12 (0.5%) cases which were due to ‘infarcts’. We also identified two further post-mortem studies: in one study of 44 cases of ‘intracerebral haemorrhage’, almost all had hypertension, leading the authors to conclude that ‘primary intracerebral haemorrhage should not be diagnosed in the absence of hypertension [22], and the other study deliberately described only the pathological characteristics of ‘arterial intracerebral haematomas from hypertension’, and made this diagnosis on the basis of past clinical history and or ‘characteristic necropsy findings’ e.g. left ventricular hypertrophy [23]. The apparent low prevalence of HTI in these old series compared with a prevalence of 10% in our recent series (G.A. Lammie unpublished data) may simply be because our recent series was small, but could also be due to the possibility that HTI had not been considered in the early series (although we are aware that HTI was considered as a possible cause of PICH in the 1930s), or that the ‘cause’ of PICH has changed over the years. For example, hypertension was more prevalent in the past, treatments less available and blood pressure not so aggressively controlled as today. Hence, ‘hypertensive’ intracerebral haemorrhage may be less common now than it was in the past, and other causes may now be proportionally more common. Furthermore, CT had not been invented when the earlier studies were performed, and the diagnosis of ‘PICH’ in life used to be based on clinical signs (which are now known to be unreliable) and lumbar puncture. One more recent study reported the pathology underlying 31 intracranial haematomas which were removed surgically, where the cause of haemorrhage could not be determined prior to surgery [24]. In about half of the surgical specimens, the histological examination provided additional information about underlying aetiology (amyloid angiopathy, tumour or arteriovenous malformation), whilst only haematoma was identified in the remaining specimens. There was no indication of ischaemic neurones. The results of this study are difficult to interpret because the majority of patients with PICH do not undergo surgical evacuation of haematoma, and these are likely to have been highly selected cases. Other histopathological studies have selected subsets of patients where a specific aetiology is assumed (e.g. hypertensive cerebral haemorrhage) [25] rather than looking at intracranial haemorrhage generally, and are therefore unhelpful in trying to answer our specific question. How else might the proportion of PICH due to HTI be investigated? We reasoned that if most (as opposed to

just some) PICH is due to HTI, then the pattern of vascular risk factors in PICH should be similar to HTI. We therefore investigated the prevalence of vascular risk factors prospectively in 2,202 patients with stroke who presented to our hospital as either inpatients or outpatients over a 10-year period and entered into our stroke registry. On brain imaging, there were 197 (9%) PICH, 82 (4%) HTI (with or without haematoma) and 1,923 ischaemic strokes with no HTI. There was no difference in the proportion of men, the age of patients, the prevalence of hypertension or the proportion of current smokers in the HTI group compared with the PICH group. However, diabetes mellitus (OR 0.2, 95% CI 0.1– 0.5), prior atrial fibrillation (OR 0.3, 95% CI 0.1–0.5), ischaemic heart disease (OR 0.3, 95% CI 0.2–0.6) and peripheral vascular disease (OR 0.3, 95% CI 0.1–0.6) were significantly less common in PICH than HTI. The presence of significant differences in the pattern of risk factors between PICH and HTI does not support the hypothesis that most PICH is due to HTI, but the data are consistent with the hypothesis that some PICH is due to HTI. However, in this series there may have been some bias, as the mean time to imaging was 3 days for PICH, 13 days for ischaemic stroke and 12 days for HTI. (P-0.05 comparing HTI with PICH, but not with ischaemic stroke, t-test). Furthermore the use of risk factor profiles to determine whether two diseases might share a cause must be interpreted with caution. For example one could not assume that myocardial infarction and lung cancer were the same just because these share smoking as a risk factor, or that diabetes and major joint arthritis were the same because these share obesity as a risk factor. Examining the pattern of multiple risk factors (as we did) would be required to avoid this obvious problem — the more risk factors shared by two diseases, the greater the likelihood of their sharing an underlying cause.

Future studies How might the proportion of PICH due to HTI be determined more precisely? Post-mortem studies, where unselected patients who die from haemorrhagic stroke are included, and where the investigator does not have pre-conceived hypotheses about the aetiology of PICH, may provide useful information about the presence of ischaemic brain and/or recent ante-mortem clot within the intracranial arteries in patients with PICH and HTI. However, post-mortem studies, by definition, will be biased towards the more severe strokes, and this will limit their generalizability. Furthermore, in the UK and elsewhere, post-mortem examinations are becoming increasingly difficult to do. Increased awareness of the possibility that PICH could be early HTI might help clinicians and radiologists to consider this as a possibility. However so far there do not appear to be any truly reliable ways of distinguishing PICH from major HTI on parenchymal

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G. E. Mead et al. brain imaging (any imaging) once the HTI has occurred. A scan obtained in between the stroke and the later scan showing the haemorrhage is the only reliable way. Demonstration of an occluded artery supplying the territory in which the haematoma lies should strongly suggest HTI (though apparent occlusion can accompany space occupying haematoma causing arterial compression). Exclusion of major cerebral vein or venous sinus thrombosis as a cause of haemorrhagic stroke would be important. Other pointers to HTI rather than PICH might include a rather ‘patchy’ appearance to the haematoma (i.e. not a solid, uniform whiteness), or a greater proportion of hypodense (on CT) or hyperintense (on T2 MR) tissue around the haematoma early on (usually this develops after a day or so), but these characteristics are rather subjective and not well tested. Judicious use of advanced brain imaging e.g. magnetic resonance imaging might enable the underlying aetiology of PICH to be determined more accurately. For example, occluded intracranial vessels and small areas of hypoperfused or ischaemic brain may be visualized. It would be important to include as many patients as possible with apparent PICH in such studies so that the results are as generalizable as possible. Blood sensitive sequences (Gradient echo or T2) might provide evidence of micro or asymptomatic minor haemorrhages elsewhere in the brain as evidence of a general propensity to undergo haemorrhagic change in the brain. Hyperacute imaging with routine follow-up imaging (regardless of the presence or absence of clinical deterioration) of a large enough sample size might identify infarcts that undergo HTI to mimic PICH at 3–6 hours, but it will be almost impossible to ‘catch’ in this way people who undergo PICH mimicking HTI within 3 hours. A comparison of clotting factors, platelet function and other haematological parameters in PICH, HTI and cerebral infarction may allow similarities to be detected, particularly amongst subtypes of stroke, e.g. there may be much more overlap in risk factors between lacunar syndromes due to haemorrhage or infarct than major cortical events.

Conclusion In conclusion, there is reasonable evidence to suggest that at least some, but probably not most apparent ‘PICH’ is actually due to HTI. However, the precise proportion of ‘PICH’ which is due to HTI is difficult to determine from previous studies. If a substantial proportion of ‘PICH’ is actually due to HTI, this may have implications for the management of patients, e.g. acute stroke treatment and secondary prevention. Therefore, further studies are required to address this question.

Key points . Early HTI of cerebral infarction may be the cause of

some cases of apparent PICH. . Data obtained by extrapolation from prior studies

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using serial imaging and post mortem data would support the possibility that some cases at least of PICH are early major HTI. . There is also some evidence to support this from analysis of risk factors in patients with PICH, HTI and ischaemic stroke uncomplicated by haemorrhage in a stroke registry. . There are no reliable features for differentiating PICH from early major HTI. . If some PICH is actually early HTI, then secondary prevention measures for ischaemic stroke might be appropriate and so future studies should obtain data to determine the frequency of early major HTI and to distinguish PICH that is early major HTI from PICH due to other causes.

Acknowledgements We are very grateful to Dr G. A. Lammie for providing unpublished data from his post-mortem series. We are also grateful to Dr Richard Lindley for providing information on studies which investigated the frequency of HTI after ischaemic stroke.

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Received 17 December 2001; accepted in revised form 10 June 2002

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