473
STROKE OCTET Investigation of patients with stroke and transient ischaemic attacks GEOFFREY A. DONNAN
Investigation of patients who present with stroke has undergone a striking change over the past fifteen years, mainly because of new techniques of imaging the brain and cardiovascular system. Until the 1970s "brain imaging" in patients with cerebrovascular disease meant cerebral angiography, structural change in brain tissue being inferred from blood vessel displacement or occlusion. Development of computed tomography (CT) in 1973 enabled direct imaging of brain structure for the first time, and since then there have been numerous technical developments in the areas of ultrasound, magnetic resonance imaging (MRI), and non-invasive studies of cerebral perfusion and metabolism. In this article I will discuss the application of established techniques in the investigation of patients with transient ischaemic attacks (TIAs) and stroke and place recent advances in perspective.
Investigating what? The
term stroke encompasses a heterogeneous of disorders with various pathophysiological mechanisms. Investigations may assist clinicians to subcategorise patients at three specific levels: (a) to separate strokes from non-strokes such as cerebral tumours and subdural haematoma; (b) to distinguish haemorrhage from infarction; and (c) to identify specific pathophysiological subtypes of cerebral infarction, which is especially important since designation of subtype influences decisions concerning therapy and helps to determine prognosis. The ideal investigative technique should be inexpensive, accessible, non-invasive, accurate, and informative. The usefulness of investigative techniques is best appreciated according to the temporal sequence of acute stroke management.
group
generic
What
investigations to
use
and when
Efficient stroke management in the early stages is ultimately cost-effective because it allows more selective application of subsequent investigations (see table). Since most strokes and TIAs are acute events and the greatest risk of recurrence is within the ensuing few hours or days, investigations need to be done promptly so that appropriate therapy can be initiated. Cerebral imaging will provide the maximum information in the shortest time. CT and MRI are used most commonly. CT remains the workhorse of acute stroke management and is available in most centres whereas access to MRI is limited in many countries.
Brain
imaging
Computed tomography All patients who present with the acute onset of a focal neurological deficit should have a CT scan.1 CT scans are simple and quick to do, largely non-invasive, and extremely accurate in distinguishing haemorrhage from infarction even moments after the event. CT is cheaper than MRI. There are two major disadvantages of CT in the assessment of ischaemic stroke. First, CT cannot define the full extent of infarcted tissue for several days after the event: subtle changes may be seen within 4 hours2 but are difficult to interpret; final topographic distribution is best seen at day 7-10. A second plain CT scan is therefore recommended at this time to help determine infarct mechanism and prognosis. Some infarcts pass through a period of isodensity Department of Neurology, Austin Heidelberg 3084, Australia (Dr G. A. Donnan, FRACP).
ADDRESS
INVESTIGATION OF TIA AND STROKE
’Standard investigations may also be arranged at this time (see text) tSometlmes if patient under 55 years or repeated events definition may vary from centre to centre, but usually 50% stenosis and/or evidence of ulceration
Hospital,
474
,w
z
y
cm
..
Ya ii,
C,
.‘y,
.
z ..
.
z
.
ca z
.
,
, x We.... ..F
Fig 1-CT and MRI of 25-year-old CT (unenhanced) m the left panel shows indistinct changes haematoma (day 16).
in
woman
with sudden onset of
nausea.
left cerebellum (day 7). MR I in the right panel clearly shows
around day 3, which can hinder CT detection. Although intravenous contrast agents may help to overcome this difficulty, use of contrast media increases the complexity and risk of the procedure. The systemic reactions encountered with some agents are less common with non-ionic contrast media. The second disadvantage of CT is that brainstem structures are poorly displayed because of bony artifacts; accurate localisation of the site of infarction in the brainstem is unusual, with the possible exception of the cerebellum. Because CT defines the presence of haemorrhage so clearly as an area of hyperdensity, areas of haemorrhagic infarction are also identified (the sensitivity is less than that of necropsy). Distinction between confluent haemorrhagic infarction and primary intracerebral haemorrhage is sometimes difficult.3 CT may help to identify arterial abnormalities such as ectatic or occluded vessels and aneurysms. Saggital sinus thrombosis may be detected if the empty delta sign (a triangular hypodensity in the image of the saggital sinus) is present, but this finding is not especially reliable. at
Magnetic resonance imaging MRI has been used routinely in other areas of neurology for several years but has not yet become part of routine stroke management in most countries. MRI has several advantages over CT, the most important being clear identification of structures in the posterior fossa. Fig 1 shows how a posterior fossa haematoma was much more obvious with MRI than with CT. Brainstem infarcts, especially lacunes,4are likewise better seen with MRI, as are cerebral hemisphere lacunes, especially if they are studied on T weighted images; even distant effects such as wallerian degeneration have been documented.5 (T images are determined by the loss of phase coherence of precessing
a
left cerebellar
protons after the administration of a radiofrequency pulse.) Contrast enhancement with gadopentate-dimeglumine (Gd-DTPA) may increase the sensitivity of MRI in cerebrovascular disease, but this increase is not matched by high specificity. Consequently, interpretation of small intense signals, sometimes called unidentified bright objects, may be difficult-these appearances may represent non-specific changes such as perivascular spaces or gliosis. Other disadvantages of MRI are the longer imaging time (45 minutes), which may introduce movement artifacts; claustrophobic symptoms in up to 5% of patients; and the inability to study patients with magnetic metallic objects such as old aneurysm clips. A big advantage of MRI over CT is the time of appearance of ischaemic changes.6 These changes are best seen on T2 weighted images, and experimental evidence suggests that they may be noted as early as 45 minutes after onset of ischaemia with newer techniques.7 Unfortunately, the specificity of these very early changes is not high and there may be some difficulty in distinguishing haemorrhage from infarction. Conversely, MRI shows sequential changes during the evolution of cerebral haemorrhage that enable infarction to be distinguished from haemorrhage with greater precision than with CT several days or weeks after the event.8 Other advantages of MRI include more reliable detection of saggital sinus thrombosis than with CT and the characteristic MRI appearance of small cavernous haemansiomas.
475
doppler systems and improves accuracy. It is especially useful in cases of pseudo-occlusion, in which high-grade carotid stenosis may be misinterpreted as total occlusion with standard doppler techniques. One great disadvantage of all carotid doppler systems is that they cannot detect additional "tandem" stenotic lesions in the carotid siphon or middle cerebral artery. Transcranial doppler Transcranial doppler measures flow velocity in the basal cerebral arteries. Use of lower ultrasound frequencies (15-20 MHz) at temporal and base of skull bone windows, has overcome the problem of attenuation of ultrasonic waves by bone. Arterial blood velocity and flow direction in the anterior, middle, and sometimes posterior cerebral arteries can be quantified; with a probe placed in the suboccipital region the basilar and vertebral arteries can likewise be studied in this way. However, the technique has not yet gained universal acceptance because of its low sensitivity and specificity in detecting stenoses within these vessels. It is a useful screening procedure for patients with TIA or minor stroke to identify those with moderate to severe intracranial disease. There have been promising reports of the use of transcranial doppler in detection of patent foramen ovale" and in monitoring the entry of embolic material into the cerebral circulation during surgical procedures such as carotid endarterectomy. 12 Fig 2-lntra-arterial digital subtraction angiography (left) and magnetic resonance angiography (right) of internal carotid artery stenosis.
Reprinted with permission from Tsurunda JS,
et al
(reference 19).
Angiography
Angiography remains the gold standard for assessment of cerebrovascular disease. Before the introduction ofdigital subtraction
radiograph, electrocardiogram, urea and electrolytes, full blood count, erythrocyte sedimentation rate, random blood sugar, urinalysis, and serum cholesterol and triglycerides in patients under 65 years. Other haematological tests may be ordered when rarer causes of stroke are suspected.
Imaging of extracranial and intracranial vasculature
Imaging of the extracranial carotid system should be undertaken with specific questions in mind (see table). The main indication for imaging is in patients with TIA, or in those with minor stroke in whom carotid endarterectomy is contemplated. Carotid doppler ultrasonography The doppler principle has been applied to produce either continuous wave or pulsed ultrasound devices. Although continuous wave doppler more accurately predicts the degree of stenosis, pulsed doppler systems may be easily interfaced with B-mode scanning to provide a coincident image of the vessels studied (duplex scan). Both techniques are highly dependent on the experience of the technicians, who need at least 6 months’ training before they produce reliable data. Sensitivity and specificity of continuous wave and duplex systems for carotid stenosis usually exceed 90%. The duplex system may give additional information about plaque morphology, especially early changes such as fibrous and soft plaques,9 but complex lesions such as intraplaque haemorrhage and ulceration are harder to assess. Colour-coded doppler has lately been introduced; flow away from the transducer is displayed as blue and towards the transducer as red, and the velocity of flow is proportional to colour saturation. This technique facilitates the use of
techniques, angiography was associated with a significant but small risk of stroke, and was expensive because patients had to be admitted to hospital. Intravenous digital subtraction angiography was thought to answer the need for a less invasive technique, but the images were of poor quality and complications still occurred.13 The fine catheters now used with intra-arterial digital subtraction angiography allow the procedure to be done in outpatients, although observations should be maintained for 4 hours afterwards. Even this technique is associated with some morbidity,14 so the indications for its use must be highly specific and the result likely to contribute materially to management decisions. The main indication for angiography is detection of symptomatic carotid artery stenosis. The use of doppler ultrasound devices allows angiography to be used more selectively. The most cost-effective approach can be calculated depending on the degree of carotid stenosis one wishes to detect with respect to management. For example, in one study, 14 to detect internal carotid artery stenosis of > 25%, it was most cost-effective to proceed directly to angiography if an ipsilateral carotid bruit was present, but best to screen first with a duplex scan if a bruit was absent. it was safest and most To detect stenosis of >75% cost-effective to screen all patients with duplex ultrasonography. One may not be able to generalise these findings; other centres should develop their own guidelines based on local conditions.
Cardiac
imaging
New techniques of cardiac imaging have shed light on the relation between the heart and the brain in stroke.15 Cardiac imaging should be contemplated in patients with TIA or minor stoke in whom there is reasonable clinical suspicion of
476
Fig 3-Early prediction of vascular territory involved in cerebral infarction with 99mTc- HM PAO -SPET cerebralperfusion scanning. Normal CT of
perfusion defect
76-year-old woman 4 hours after onset of dense right hemiparests and aphasia (left in the left middle cerebral artery territory (middle panel); eventual area of infarction is
a
cardiac source of embolism (see table). In most cases this will be in patients with normal carotid ultrasound and transcranial doppler results and/or clear clinical evidence of cardiac disease. a
Transthoracic echocardiography Transthoracic echocardiography is a two-dimensional technique and the most widely used cardiac imaging procedure in the investigation of cerebral ischaemia. This procedure is readily available in most centres and is non-invasive. The left ventricle is well displayed, so changes such as akinetic segments and filling defects can be detected. However, posteriorly and deeply located atrial structures are difficult to image. Addition of doppler (continuous wave, pulsed wave, and colour flow techniques) has increased the yield of abnormal findings, but these abnormalities are usually found only in patients with clinical evidence of cardiac disease.16 Use of contrast echo with a Valsalva manoeuvre to detect right-to-left shunting through a patent foramen ovale is a useful addition and has unearthed the interesting finding that stroke patients under 55 years have a higher frequency of patent foramen ovale than age-matched controls. This observation raises the possibility that paradoxical venous embolism may be a more important stroke mechanism than previously realised.17
Transoesophageal echocardiography The principles of transoesophageal echocardiography are the same as those of transthoracic echocardiography, except that an oesophageal ultrasound transducer allows detection of the posterior structures mentioned above as well as the ascending aorta. By comparison with transthoracic echocardiography, use of this technique may increase detection of potential sources of embolism two to ten fold. 15 Echocardiographic abnormalities that may be potential of embolism include left atrial spontaneous echo (an echo pattern produced by low swirling blood flow in the left atrium), patent foramen ovale, atrial septal aneurysm, left atrial appendage thrombus, left ventricular dyskinesis with or without apical thrombus, and mitral valve abnormalities.16 It is difficult to interpret the many findings described since no age-matched control group for this technique has been reported. The other disadvantage of sources
contrast
panel); SPET scan (4 hours) shows a large seen on CT at day 9 (right panel)
transoesophageal echocardiography is its invasive naturemany elderly stroke patients are unable to tolerate the procedure and sedation is undesirable. What
are
likely to be routine investigations over
the next decade?
Several factors are likely to change the pattern of acute stroke management. The first is the introduction of thrombolytic and neuroprotective agents in an effort to reduce morbidity and mortality in acute ischaemic stroke. This development has been accompanied by use of noninvasive means of imaging cerebral blood flow (vessel and tissue) and metabolism.
Magnetic resonance angiography Because flowing blood moves through the image plane and so may miss a second radiofrequency pulse, vessel flow registers as a signal void on conventional MRJ.18 This property, among others, has been exploited to produce angiograms that can be displayed in a similar way to conventional angiograms (fig 2).19 There is a reasonable correlation with results of contrast angiography, although the magnetic resonance technique tends to overestimate the degree of stenosis. 20 Apart from the obvious advantages of its non-invasive nature and short study time (8-14 min), the most impressive credential of magnetic resonance angiography is its ability to image both extracerebral and intracerebral vessels. This property will be invaluable in determining the natural history of acute intracerebral vessel occlusion and the response to thrombolytic agents. The ability to do "one-shot" MRI studies when a patient with acute ischaemic stroke undergoes imaging of brain, to document the extent of cerebral ischaemia (45 min) and vessel patency (extra 8-14 min), is very appealing and such studies are likely to become part of routine management. MR spectroscopy MR spectroscopy with nuclei such as 32p, 32 Na, 19F, and 13C can generate physiological data to match those provided by standard MRI with proton imaging. However, the surface coils used allow only small areas to be studied and it may be difficult to quantify and standardise the spectra
477
produced. Impressive reductions in energy stores (phosphocreatine and ATP) with increases in lactate and acidosis
after cerebral infarction,21 and it may be measure cerebral blood flow, oxygen, and
occur
possible to glucose metabolism.
Single photon emission tomography (SPET) This imaging technique relies on the gamma-emitting properties of radioligands such as 99mTchexamethylpropylenamine oxime (HMPAO) or, less commonly, lz3l_iodoamphetamine to generate computer reconstructions of regional cerebral perfusion. 99m-rCHMPAO is readily available in nuclear medicine departments and images can be obtained with standard rotating gamma cameras. 99mTc-HMPAO may be injected up to several hours before imaging since it is trapped within cells in the distribution of cerebral perfusion. SPET scanning in acute ischaemic stroke may help to predict the vascular territory affected (fig 3) and to assess prognosis.22 New radioligands may allow measurement of other haemodynamic and metabolic variables. Positron emission
tomography (PET) The cyclotron-generated radioligands 0, 0502, and C150 are used to create quantitative images of cerebral perfusion, oxygen consumption, oxygen extraction fraction, and cerebral blood volume.23 These compounds have extremely short half-lives (2 min), so a cyclotron/PET be sited close to acute stroke units. This is seldom the case and consequently few large studies have been done. Nevertheless, PET has increased our understanding of the sequence of events that follow acute vessel occlusion.24 PET will probably remain a powerful research tool in the study of cerebrovascular diseae, but is unlikely to contribute to routine management in its present form. camera must
I thank my colleagues who gave advice on the investigative techniques and Dr A. E. Baird and Dr W. J. McKay for collaboration with SPET studies. Dr B. R. Chambers, Dr R. A. Macdonell, and Dr R. A. Ayton kindly reviewed the typescript, which was skilfully prepared by Mrs Barbara Mottau. Amersham Australia Pty Ltd provided a grant to study SPET with ’Ceretec’.
REFERENCES 1. Stroke. Towards better management. Summary and recommendations of a report of the Royal College of Physicians. J R Coll Physicians Lond 1990; 24: 15-17. 2.Bozzao L, Bastianello S, Fantozzi LM, Angeloni U, Argentiono C, Fieschi C. Correlation of angiographic and sequential CT findings in patients with evolving cerebral infarction. Am J Neuroradiol 1989; 10: 1215-22. 3. Kase CS, Williams JP, Wyatt DA, Mohr JP. Lobar intracerebral hematomas: clinical and CT analysis of 22 cases. Neurology 1982; 32:
1146-50.
M, Besson G, Le Bas JF, et al. Prospective study of lacunar infarction using magnetic resonance imaging. Stroke 1990; 21: 546-54. 5. Pujal J, Marti-Vilalta JL, Junquè C, et al. Wallerian degeneration of the pyramidal tract in capsular infarction studied by magnetic resonance imaging. Stroke 1990; 21: 404-09. 6. Kertsez A, Black SE, Nicholson L, Carr T. The sensitivity and specificity of MRI in stroke. Neurology 1987; 37: 1580-85. 7. Moonen CTW, Van Eijl PCM, Frank JA, Le Bihan D, Becker ED. Functional magnetic resonance imaging in medicine and physiology. Science 1990; 250: 53-60. 8. Brooks RA, Di Chiro G, Patronas N. MR imaging of cerebral hematomas at different field strengths: theory and applications. J Comput Asst
4. Hommel
Tomogr 1989; 13:
194-206.
9. Hennerici M. New technical and clinical aspects for cerebrovascular applications of ultrasound methods. J Neurosci Meth 1991; 34: 169-77. 10. Steinke W, Kloetzsch C, Hennerici M. Carotid artery disease assessed by color
doppler flow imaging: correlation with standard doppler sonography and angiography. Am J Neuroradiol 1990; 11: 259-66.
11. Teague SM, Sharma MK. Detection of paradoxical cerebral echo contrast embolization by transcranial doppler ultrasound. Stroke 1991; 22: 740-45.
Spencer MP, Thomas GI, Nicholls SC, Sauvage LR. Detection of middle cerebral artery emboli during carotid endarterectomy using transcranial doppler ultrasonography. Stroke 1990; 21: 415-23. 13. Hankey GJ, Warlow CP, Sellar RJ. Cerebral angiographic risk in mild 12.
cerebrovascular disease. Stroke 1990; 21: 209-22.
Hankey GJ, Warlow CP. Symptomatic carotid ischaemic events: safest and most cost effective way of selecting patients for angiography, before carotid endarterectomy. Br Med J 1990; 300: 1485-91. 15. Tegeler CH, Downes TR. Cardiac imaging in stroke. Curr Concepts
14.
Cerebrovasc Dis Stroke 1991; 26: 13-18. 16. Cujec B, Polasek P, Voll C, Schuaib A. Transesophageal echocardiography in the detection of potential cardiac source of embolism in stroke patients. Stroke 1991; 22: 727-33. 17. Webster MWI, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; ii: 11-12. 18. Ross JS, Masaryk TJ, Modic MT, et al. Magnetic resonance angiography
19. 20.
21.
22.
23. 24.
of the extracranial carotid arteries and intracranial vessels: a review. Neurology 1989; 39: 1369-76. Tsurunda JS, Saloner D, Anderson C. Noninvasive evaluation of cerebral ischemia. Circulation 1991; 83 (suppl 1): 177-89. Litt AW, eidelman EM, Pinto RS, et al. Diagnosis of carotid artery stenosis: comparison of 2DFT time-of-flight MR angiography and contrast angriography in 50 patients. Am J Neuroradiol 1991; 12: 149-54. Lenkinski RE. Clinical magnetic resonance spectroscopy: a critical evaluation. Invest Radiol 1989; 24: 1034-38. Guibilei F, Lenzi GL, di Piero V, et al. Predictive value of brain perfusion single-photon emission computed tomography in acute ischemic stroke. Stroke 1990; 21: 895-900. Baron JC. Pathophysiology of acute ischemia: PET studies in humans. Cerebrovasc Dis 1991; 1 (suppl 1): 22-31. Wise RJS, Bernardi S, Frackowiak RJS, Legg NJ, Jones T. Serial observations on the pathophysiology of acute stroke. Brain 1983; 106: 197-222.
From The Lancet Dampened spirits The dilution of
spirits with
water, and
particularly of malt
whisky, down to the degree demanded by the Defence of the Realm Act has effected some important changes in the characteristics of this alcoholic liquor which are worth notice. It may be remembered that present supplies to the public cannot be sold at a greater alcoholic strength than 30° under proof spirit, which means about 33% alcohol by weight or 40% by volume (70% proof), whereas before any demand for dilution came into force the average strength of the spirit sold was about 40% by weight of alcohol or 48% by volume (84% proof). This means that 20 gallons of water may be added to 100 gallons of the old-strength whisky to produce 120 gallons of a spirit diluted in accordance with the requirements of the Act. The dilution amounts, in fact, to the addition of about a fifth part water, so that a dozen bottles of the old-strength spirit would make about 14 bottles of the diluted spirit. If whisky were pure alcohol this dilution would give no trouble, but, as everyone knows, genuine malt whisky is not pure alcohol; it is a complex containing certain by-products of fermentation and distillation held in solution in the alcohol. Just as with tinctures the addition of water throws out oil and other active substances, so it happens with malt spirit. Fatty substances, resins, and other products contrive to make the spirit opalescent when water is added to the extent demanded and when allowed to stand. The subsequent elimination of these substances by filtration carries out a material portion of the flavouring substances derived from the malt, and the ethers are to some extent destroyed by this process. This is what the merchants have been compelled to do.... The result is that the whisky now supplied to the public is bright and clear and remains so even on further dilution, while much of the characteristic malty flavour has been withdrawn. This change in the character of whisky may have its hygienic advantages, inasmuch as it may not satisfy the taste of the habitual consumer, and may induce him to drink it less frequently or not at all.
(March 17, 1917)
STROKE OCTET Investigation of patients with stroke and transient ischaemic attacks GEOFFREY A. DONNAN
Investigation of patients who present with stroke has undergone a striking change over the past fifteen years, mainly because of new techniques of imaging the brain and cardiovascular system. Until the 1970s "brain imaging" in patients with cerebrovascular disease meant cerebral angiography, structural change in brain tissue being inferred from blood vessel displacement or occlusion. Development of computed tomography (CT) in 1973 enabled direct imaging of brain structure for the first time, and since then there have been numerous technical developments in the areas of ultrasound, magnetic resonance imaging (MRI), and non-invasive studies of cerebral perfusion and metabolism. In this article I will discuss the application of established techniques in the investigation of patients with transient ischaemic attacks (TIAs) and stroke and place recent advances in perspective.
Investigating what? The
term stroke encompasses a heterogeneous of disorders with various pathophysiological mechanisms. Investigations may assist clinicians to subcategorise patients at three specific levels: (a) to separate strokes from non-strokes such as cerebral tumours and subdural haematoma; (b) to distinguish haemorrhage from infarction; and (c) to identify specific pathophysiological subtypes of cerebral infarction, which is especially important since designation of subtype influences decisions concerning therapy and helps to determine prognosis. The ideal investigative technique should be inexpensive, accessible, non-invasive, accurate, and informative. The usefulness of investigative techniques is best appreciated according to the temporal sequence of acute stroke management.
group
generic
What
investigations to
use
and when
Efficient stroke management in the early stages is ultimately cost-effective because it allows more selective application of subsequent investigations (see table). Since most strokes and TIAs are acute events and the greatest risk of recurrence is within the ensuing few hours or days, investigations need to be done promptly so that appropriate therapy can be initiated. Cerebral imaging will provide the maximum information in the shortest time. CT and MRI are used most commonly. CT remains the workhorse of acute stroke management and is available in most centres whereas access to MRI is limited in many countries.
Brain
imaging
Computed tomography All patients who present with the acute onset of a focal neurological deficit should have a CT scan.1 CT scans are simple and quick to do, largely non-invasive, and extremely accurate in distinguishing haemorrhage from infarction even moments after the event. CT is cheaper than MRI. There are two major disadvantages of CT in the assessment of ischaemic stroke. First, CT cannot define the full extent of infarcted tissue for several days after the event: subtle changes may be seen within 4 hours2 but are difficult to interpret; final topographic distribution is best seen at day 7-10. A second plain CT scan is therefore recommended at this time to help determine infarct mechanism and prognosis. Some infarcts pass through a period of isodensity Department of Neurology, Austin Heidelberg 3084, Australia (Dr G. A. Donnan, FRACP).
ADDRESS
INVESTIGATION OF TIA AND STROKE
’Standard investigations may also be arranged at this time (see text) tSometlmes if patient under 55 years or repeated events definition may vary from centre to centre, but usually 50% stenosis and/or evidence of ulceration
Hospital,
474
,w
z
y
cm
..
Ya ii,
C,
.‘y,
.
z ..
.
z
.
ca z
.
,
, x We.... ..F
Fig 1-CT and MRI of 25-year-old CT (unenhanced) m the left panel shows indistinct changes haematoma (day 16).
in
woman
with sudden onset of
nausea.
left cerebellum (day 7). MR I in the right panel clearly shows
around day 3, which can hinder CT detection. Although intravenous contrast agents may help to overcome this difficulty, use of contrast media increases the complexity and risk of the procedure. The systemic reactions encountered with some agents are less common with non-ionic contrast media. The second disadvantage of CT is that brainstem structures are poorly displayed because of bony artifacts; accurate localisation of the site of infarction in the brainstem is unusual, with the possible exception of the cerebellum. Because CT defines the presence of haemorrhage so clearly as an area of hyperdensity, areas of haemorrhagic infarction are also identified (the sensitivity is less than that of necropsy). Distinction between confluent haemorrhagic infarction and primary intracerebral haemorrhage is sometimes difficult.3 CT may help to identify arterial abnormalities such as ectatic or occluded vessels and aneurysms. Saggital sinus thrombosis may be detected if the empty delta sign (a triangular hypodensity in the image of the saggital sinus) is present, but this finding is not especially reliable. at
Magnetic resonance imaging MRI has been used routinely in other areas of neurology for several years but has not yet become part of routine stroke management in most countries. MRI has several advantages over CT, the most important being clear identification of structures in the posterior fossa. Fig 1 shows how a posterior fossa haematoma was much more obvious with MRI than with CT. Brainstem infarcts, especially lacunes,4are likewise better seen with MRI, as are cerebral hemisphere lacunes, especially if they are studied on T weighted images; even distant effects such as wallerian degeneration have been documented.5 (T images are determined by the loss of phase coherence of precessing
a
left cerebellar
protons after the administration of a radiofrequency pulse.) Contrast enhancement with gadopentate-dimeglumine (Gd-DTPA) may increase the sensitivity of MRI in cerebrovascular disease, but this increase is not matched by high specificity. Consequently, interpretation of small intense signals, sometimes called unidentified bright objects, may be difficult-these appearances may represent non-specific changes such as perivascular spaces or gliosis. Other disadvantages of MRI are the longer imaging time (45 minutes), which may introduce movement artifacts; claustrophobic symptoms in up to 5% of patients; and the inability to study patients with magnetic metallic objects such as old aneurysm clips. A big advantage of MRI over CT is the time of appearance of ischaemic changes.6 These changes are best seen on T2 weighted images, and experimental evidence suggests that they may be noted as early as 45 minutes after onset of ischaemia with newer techniques.7 Unfortunately, the specificity of these very early changes is not high and there may be some difficulty in distinguishing haemorrhage from infarction. Conversely, MRI shows sequential changes during the evolution of cerebral haemorrhage that enable infarction to be distinguished from haemorrhage with greater precision than with CT several days or weeks after the event.8 Other advantages of MRI include more reliable detection of saggital sinus thrombosis than with CT and the characteristic MRI appearance of small cavernous haemansiomas.
475
doppler systems and improves accuracy. It is especially useful in cases of pseudo-occlusion, in which high-grade carotid stenosis may be misinterpreted as total occlusion with standard doppler techniques. One great disadvantage of all carotid doppler systems is that they cannot detect additional "tandem" stenotic lesions in the carotid siphon or middle cerebral artery. Transcranial doppler Transcranial doppler measures flow velocity in the basal cerebral arteries. Use of lower ultrasound frequencies (15-20 MHz) at temporal and base of skull bone windows, has overcome the problem of attenuation of ultrasonic waves by bone. Arterial blood velocity and flow direction in the anterior, middle, and sometimes posterior cerebral arteries can be quantified; with a probe placed in the suboccipital region the basilar and vertebral arteries can likewise be studied in this way. However, the technique has not yet gained universal acceptance because of its low sensitivity and specificity in detecting stenoses within these vessels. It is a useful screening procedure for patients with TIA or minor stroke to identify those with moderate to severe intracranial disease. There have been promising reports of the use of transcranial doppler in detection of patent foramen ovale" and in monitoring the entry of embolic material into the cerebral circulation during surgical procedures such as carotid endarterectomy. 12 Fig 2-lntra-arterial digital subtraction angiography (left) and magnetic resonance angiography (right) of internal carotid artery stenosis.
Reprinted with permission from Tsurunda JS,
et al
(reference 19).
Angiography
Angiography remains the gold standard for assessment of cerebrovascular disease. Before the introduction ofdigital subtraction
radiograph, electrocardiogram, urea and electrolytes, full blood count, erythrocyte sedimentation rate, random blood sugar, urinalysis, and serum cholesterol and triglycerides in patients under 65 years. Other haematological tests may be ordered when rarer causes of stroke are suspected.
Imaging of extracranial and intracranial vasculature
Imaging of the extracranial carotid system should be undertaken with specific questions in mind (see table). The main indication for imaging is in patients with TIA, or in those with minor stroke in whom carotid endarterectomy is contemplated. Carotid doppler ultrasonography The doppler principle has been applied to produce either continuous wave or pulsed ultrasound devices. Although continuous wave doppler more accurately predicts the degree of stenosis, pulsed doppler systems may be easily interfaced with B-mode scanning to provide a coincident image of the vessels studied (duplex scan). Both techniques are highly dependent on the experience of the technicians, who need at least 6 months’ training before they produce reliable data. Sensitivity and specificity of continuous wave and duplex systems for carotid stenosis usually exceed 90%. The duplex system may give additional information about plaque morphology, especially early changes such as fibrous and soft plaques,9 but complex lesions such as intraplaque haemorrhage and ulceration are harder to assess. Colour-coded doppler has lately been introduced; flow away from the transducer is displayed as blue and towards the transducer as red, and the velocity of flow is proportional to colour saturation. This technique facilitates the use of
techniques, angiography was associated with a significant but small risk of stroke, and was expensive because patients had to be admitted to hospital. Intravenous digital subtraction angiography was thought to answer the need for a less invasive technique, but the images were of poor quality and complications still occurred.13 The fine catheters now used with intra-arterial digital subtraction angiography allow the procedure to be done in outpatients, although observations should be maintained for 4 hours afterwards. Even this technique is associated with some morbidity,14 so the indications for its use must be highly specific and the result likely to contribute materially to management decisions. The main indication for angiography is detection of symptomatic carotid artery stenosis. The use of doppler ultrasound devices allows angiography to be used more selectively. The most cost-effective approach can be calculated depending on the degree of carotid stenosis one wishes to detect with respect to management. For example, in one study, 14 to detect internal carotid artery stenosis of > 25%, it was most cost-effective to proceed directly to angiography if an ipsilateral carotid bruit was present, but best to screen first with a duplex scan if a bruit was absent. it was safest and most To detect stenosis of >75% cost-effective to screen all patients with duplex ultrasonography. One may not be able to generalise these findings; other centres should develop their own guidelines based on local conditions.
Cardiac
imaging
New techniques of cardiac imaging have shed light on the relation between the heart and the brain in stroke.15 Cardiac imaging should be contemplated in patients with TIA or minor stoke in whom there is reasonable clinical suspicion of
476
Fig 3-Early prediction of vascular territory involved in cerebral infarction with 99mTc- HM PAO -SPET cerebralperfusion scanning. Normal CT of
perfusion defect
76-year-old woman 4 hours after onset of dense right hemiparests and aphasia (left in the left middle cerebral artery territory (middle panel); eventual area of infarction is
a
cardiac source of embolism (see table). In most cases this will be in patients with normal carotid ultrasound and transcranial doppler results and/or clear clinical evidence of cardiac disease. a
Transthoracic echocardiography Transthoracic echocardiography is a two-dimensional technique and the most widely used cardiac imaging procedure in the investigation of cerebral ischaemia. This procedure is readily available in most centres and is non-invasive. The left ventricle is well displayed, so changes such as akinetic segments and filling defects can be detected. However, posteriorly and deeply located atrial structures are difficult to image. Addition of doppler (continuous wave, pulsed wave, and colour flow techniques) has increased the yield of abnormal findings, but these abnormalities are usually found only in patients with clinical evidence of cardiac disease.16 Use of contrast echo with a Valsalva manoeuvre to detect right-to-left shunting through a patent foramen ovale is a useful addition and has unearthed the interesting finding that stroke patients under 55 years have a higher frequency of patent foramen ovale than age-matched controls. This observation raises the possibility that paradoxical venous embolism may be a more important stroke mechanism than previously realised.17
Transoesophageal echocardiography The principles of transoesophageal echocardiography are the same as those of transthoracic echocardiography, except that an oesophageal ultrasound transducer allows detection of the posterior structures mentioned above as well as the ascending aorta. By comparison with transthoracic echocardiography, use of this technique may increase detection of potential sources of embolism two to ten fold. 15 Echocardiographic abnormalities that may be potential of embolism include left atrial spontaneous echo (an echo pattern produced by low swirling blood flow in the left atrium), patent foramen ovale, atrial septal aneurysm, left atrial appendage thrombus, left ventricular dyskinesis with or without apical thrombus, and mitral valve abnormalities.16 It is difficult to interpret the many findings described since no age-matched control group for this technique has been reported. The other disadvantage of sources
contrast
panel); SPET scan (4 hours) shows a large seen on CT at day 9 (right panel)
transoesophageal echocardiography is its invasive naturemany elderly stroke patients are unable to tolerate the procedure and sedation is undesirable. What
are
likely to be routine investigations over
the next decade?
Several factors are likely to change the pattern of acute stroke management. The first is the introduction of thrombolytic and neuroprotective agents in an effort to reduce morbidity and mortality in acute ischaemic stroke. This development has been accompanied by use of noninvasive means of imaging cerebral blood flow (vessel and tissue) and metabolism.
Magnetic resonance angiography Because flowing blood moves through the image plane and so may miss a second radiofrequency pulse, vessel flow registers as a signal void on conventional MRJ.18 This property, among others, has been exploited to produce angiograms that can be displayed in a similar way to conventional angiograms (fig 2).19 There is a reasonable correlation with results of contrast angiography, although the magnetic resonance technique tends to overestimate the degree of stenosis. 20 Apart from the obvious advantages of its non-invasive nature and short study time (8-14 min), the most impressive credential of magnetic resonance angiography is its ability to image both extracerebral and intracerebral vessels. This property will be invaluable in determining the natural history of acute intracerebral vessel occlusion and the response to thrombolytic agents. The ability to do "one-shot" MRI studies when a patient with acute ischaemic stroke undergoes imaging of brain, to document the extent of cerebral ischaemia (45 min) and vessel patency (extra 8-14 min), is very appealing and such studies are likely to become part of routine management. MR spectroscopy MR spectroscopy with nuclei such as 32p, 32 Na, 19F, and 13C can generate physiological data to match those provided by standard MRI with proton imaging. However, the surface coils used allow only small areas to be studied and it may be difficult to quantify and standardise the spectra
477
produced. Impressive reductions in energy stores (phosphocreatine and ATP) with increases in lactate and acidosis
after cerebral infarction,21 and it may be measure cerebral blood flow, oxygen, and
occur
possible to glucose metabolism.
Single photon emission tomography (SPET) This imaging technique relies on the gamma-emitting properties of radioligands such as 99mTchexamethylpropylenamine oxime (HMPAO) or, less commonly, lz3l_iodoamphetamine to generate computer reconstructions of regional cerebral perfusion. 99m-rCHMPAO is readily available in nuclear medicine departments and images can be obtained with standard rotating gamma cameras. 99mTc-HMPAO may be injected up to several hours before imaging since it is trapped within cells in the distribution of cerebral perfusion. SPET scanning in acute ischaemic stroke may help to predict the vascular territory affected (fig 3) and to assess prognosis.22 New radioligands may allow measurement of other haemodynamic and metabolic variables. Positron emission
tomography (PET) The cyclotron-generated radioligands 0, 0502, and C150 are used to create quantitative images of cerebral perfusion, oxygen consumption, oxygen extraction fraction, and cerebral blood volume.23 These compounds have extremely short half-lives (2 min), so a cyclotron/PET be sited close to acute stroke units. This is seldom the case and consequently few large studies have been done. Nevertheless, PET has increased our understanding of the sequence of events that follow acute vessel occlusion.24 PET will probably remain a powerful research tool in the study of cerebrovascular diseae, but is unlikely to contribute to routine management in its present form. camera must
I thank my colleagues who gave advice on the investigative techniques and Dr A. E. Baird and Dr W. J. McKay for collaboration with SPET studies. Dr B. R. Chambers, Dr R. A. Macdonell, and Dr R. A. Ayton kindly reviewed the typescript, which was skilfully prepared by Mrs Barbara Mottau. Amersham Australia Pty Ltd provided a grant to study SPET with ’Ceretec’.
REFERENCES 1. Stroke. Towards better management. Summary and recommendations of a report of the Royal College of Physicians. J R Coll Physicians Lond 1990; 24: 15-17. 2.Bozzao L, Bastianello S, Fantozzi LM, Angeloni U, Argentiono C, Fieschi C. Correlation of angiographic and sequential CT findings in patients with evolving cerebral infarction. Am J Neuroradiol 1989; 10: 1215-22. 3. Kase CS, Williams JP, Wyatt DA, Mohr JP. Lobar intracerebral hematomas: clinical and CT analysis of 22 cases. Neurology 1982; 32:
1146-50.
M, Besson G, Le Bas JF, et al. Prospective study of lacunar infarction using magnetic resonance imaging. Stroke 1990; 21: 546-54. 5. Pujal J, Marti-Vilalta JL, Junquè C, et al. Wallerian degeneration of the pyramidal tract in capsular infarction studied by magnetic resonance imaging. Stroke 1990; 21: 404-09. 6. Kertsez A, Black SE, Nicholson L, Carr T. The sensitivity and specificity of MRI in stroke. Neurology 1987; 37: 1580-85. 7. Moonen CTW, Van Eijl PCM, Frank JA, Le Bihan D, Becker ED. Functional magnetic resonance imaging in medicine and physiology. Science 1990; 250: 53-60. 8. Brooks RA, Di Chiro G, Patronas N. MR imaging of cerebral hematomas at different field strengths: theory and applications. J Comput Asst
4. Hommel
Tomogr 1989; 13:
194-206.
9. Hennerici M. New technical and clinical aspects for cerebrovascular applications of ultrasound methods. J Neurosci Meth 1991; 34: 169-77. 10. Steinke W, Kloetzsch C, Hennerici M. Carotid artery disease assessed by color
doppler flow imaging: correlation with standard doppler sonography and angiography. Am J Neuroradiol 1990; 11: 259-66.
11. Teague SM, Sharma MK. Detection of paradoxical cerebral echo contrast embolization by transcranial doppler ultrasound. Stroke 1991; 22: 740-45.
Spencer MP, Thomas GI, Nicholls SC, Sauvage LR. Detection of middle cerebral artery emboli during carotid endarterectomy using transcranial doppler ultrasonography. Stroke 1990; 21: 415-23. 13. Hankey GJ, Warlow CP, Sellar RJ. Cerebral angiographic risk in mild 12.
cerebrovascular disease. Stroke 1990; 21: 209-22.
Hankey GJ, Warlow CP. Symptomatic carotid ischaemic events: safest and most cost effective way of selecting patients for angiography, before carotid endarterectomy. Br Med J 1990; 300: 1485-91. 15. Tegeler CH, Downes TR. Cardiac imaging in stroke. Curr Concepts
14.
Cerebrovasc Dis Stroke 1991; 26: 13-18. 16. Cujec B, Polasek P, Voll C, Schuaib A. Transesophageal echocardiography in the detection of potential cardiac source of embolism in stroke patients. Stroke 1991; 22: 727-33. 17. Webster MWI, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; ii: 11-12. 18. Ross JS, Masaryk TJ, Modic MT, et al. Magnetic resonance angiography
19. 20.
21.
22.
23. 24.
of the extracranial carotid arteries and intracranial vessels: a review. Neurology 1989; 39: 1369-76. Tsurunda JS, Saloner D, Anderson C. Noninvasive evaluation of cerebral ischemia. Circulation 1991; 83 (suppl 1): 177-89. Litt AW, eidelman EM, Pinto RS, et al. Diagnosis of carotid artery stenosis: comparison of 2DFT time-of-flight MR angiography and contrast angriography in 50 patients. Am J Neuroradiol 1991; 12: 149-54. Lenkinski RE. Clinical magnetic resonance spectroscopy: a critical evaluation. Invest Radiol 1989; 24: 1034-38. Guibilei F, Lenzi GL, di Piero V, et al. Predictive value of brain perfusion single-photon emission computed tomography in acute ischemic stroke. Stroke 1990; 21: 895-900. Baron JC. Pathophysiology of acute ischemia: PET studies in humans. Cerebrovasc Dis 1991; 1 (suppl 1): 22-31. Wise RJS, Bernardi S, Frackowiak RJS, Legg NJ, Jones T. Serial observations on the pathophysiology of acute stroke. Brain 1983; 106: 197-222.
From The Lancet Dampened spirits The dilution of
spirits with
water, and
particularly of malt
whisky, down to the degree demanded by the Defence of the Realm Act has effected some important changes in the characteristics of this alcoholic liquor which are worth notice. It may be remembered that present supplies to the public cannot be sold at a greater alcoholic strength than 30° under proof spirit, which means about 33% alcohol by weight or 40% by volume (70% proof), whereas before any demand for dilution came into force the average strength of the spirit sold was about 40% by weight of alcohol or 48% by volume (84% proof). This means that 20 gallons of water may be added to 100 gallons of the old-strength whisky to produce 120 gallons of a spirit diluted in accordance with the requirements of the Act. The dilution amounts, in fact, to the addition of about a fifth part water, so that a dozen bottles of the old-strength spirit would make about 14 bottles of the diluted spirit. If whisky were pure alcohol this dilution would give no trouble, but, as everyone knows, genuine malt whisky is not pure alcohol; it is a complex containing certain by-products of fermentation and distillation held in solution in the alcohol. Just as with tinctures the addition of water throws out oil and other active substances, so it happens with malt spirit. Fatty substances, resins, and other products contrive to make the spirit opalescent when water is added to the extent demanded and when allowed to stand. The subsequent elimination of these substances by filtration carries out a material portion of the flavouring substances derived from the malt, and the ethers are to some extent destroyed by this process. This is what the merchants have been compelled to do.... The result is that the whisky now supplied to the public is bright and clear and remains so even on further dilution, while much of the characteristic malty flavour has been withdrawn. This change in the character of whisky may have its hygienic advantages, inasmuch as it may not satisfy the taste of the habitual consumer, and may induce him to drink it less frequently or not at all.
(March 17, 1917)
