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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5773_Библиотеки_им_академика_М_И_Перельмана.pdf
Arterial Ischemia 65
In contrast with myocardial ischemia, in which local
vessel wall disease is practically the only underlying
pathomechanism, ischemic stroke requires extensive consideration regarding its potential etiology and pathogenesis. Ischemic stroke can be classified according to a number of different criteria, e. g., by the temporal pattern, by
the infarct pattern, by the affected vascular territory, by its
etiology, and finally by its pathogenesis. Usually all the
above criteria will be incorporated into the final diagnosis,
although an exact classification is not always possible.
Especially in the acute stage of the disease, other differential diagnoses such as migraine with aura, Todd paresis
following focal seizures, peripheral vestibular syndromes,
peripheral neuropathies, and metabolic disorders such as
acute hypoglycemiaor cerebral venous thrombosis have to
be considered. The following paragraph presents the different abovementioned approaches of stroke classification.
Classification of Arterial Stroke
Temporal Pattern
The temporal pattern is an important aspect from both the
clinician’sandthepatient’s point of view. If clinical symp-
toms completely cease within 24 hours from stroke onset
the episode is defined as a transient ischemic attack (TIA),
whereaspersistingsymptomsaredefinedasacompleted
stroke. The entity of a reversible ischemic neurological
deficit (RIND)—symptoms that do not last longer than 7
days—has been widely abandoned as it falsely suggests
transient ischemia without a morphologic correlate. The
definition of a TIA, which was developed at a time without
the currently available imaging methods, is also under
critical review now, as it again suggests that no structural
damage has occurred. Today’s modern high-resolution
MRI sequences, including DWI, show that small structural
lesionscanbefoundinupto50%ofcasesafteraTIA
(Kidwell et al. 1999). In addition, the arbitrary 24-hour
cut-off seems problematic. About half of all TIAs are limited to 30 minutes duration. If the symptoms last longer
than an hour, the probability of a clinical deficit that will
persist beyond the 24-hour cut-off reaches 86 % (Levy
1988).
Nevertheless, as a category, the term TIA is of great
practical importance as it points out the risk of developing
a subsequent completed stroke. This risk seems to be
higher than previously thought. In a metaanalysis of patients with completed stroke, 23 % reported a prior TIA. Of
these, 43 % had their last TIA within the week before and
17 % on the day of the completed stroke. The TIAs and the
subsequent strokes were mostly located within the same
vascular territory (Rothwelland Warlow 2005). The risk of
having a completed stroke after TIA or minor stroke is
especially high in patients with an intracranial vessel occlusion or with a lesion on DWI MRI. Coutts et al. (2005)
found that the 90-day stroke risk in patients without intra-
cranial vessel occlusion and a DWI lesion was 4.3 %, increasing to 10.8 % in those with a positive DWI finding
alone and to 32.6 % in those with an additional intracranial
vessel occlusion. The overall 90-day stroke risk was 11.7%.
In patients with a symptomatic ICA stenosis the 90-day
stroke risk was 20.1% after a hemispheric TIA (Eliasziw et
al.2004).Consideringtheabovedataitbecomesclearwhy
the current concept of TIAs is under active discussion. A
useful proposition might be to limit the diagnosis of TIA to
neurologic deficits persisting <1 hour and in those in
whom DWI MRI does not depict structural lesions (Albers
etal.2002).Regardlessofitsfuturedefinition,aTIAshould
be recognized as a neurologic emergency that requires
urgent etiological clarification.
Infarct Pattern and Vascular Territory
Stroke requires cerebral imaging—in most places in form
of cranial CT (CCT)—andoftenthisneedstobefollowedby
cerebral MRI. CCT is a well-established method to evaluate
intracranial bleeding (e. g., intracerebral hematoma, subarachnoid hemorrhage, subdural and epidural hematoma)
whichcanbefoundinupto15%ofstrokepatients.More
recently, MRI with its blood sensitive (T2* and fluid attenuated inversion recovery [FLAIR]) sequences was shown to
be able to detect intracranial hemorrhage with a sensitivity equal to or even better than that of CCT. Both MRI and
CCT allow classification of ischemic infarcts according to
their pattern and corresponding vascular territory. We
consider territorial infarctions, lacunar infarctions, and
border zone infarctions as independent entities that may
develop within one vascular territory or in between several vascular territories.
Territorial Infarction
The brain comprises circumscribed regions that are supplied with blood via one main artery and its tributaries
(Fig. A4.2). A territorial infarct may either incompletely
(partial territorial infarction) or completely (total territorial infarction) involve the blood supply area of a brainsupplying artery. The underlying pathogenesis in these
cases is an intracranial arterial occlusion of the dedicated
artery. These occlusions are mostly embolic in nature, for
example, from a cardiac source or from upstream macroangiopathic vessel wall alterations. A less frequent finding
is an autochthonal “in-situ” thrombosis on the basis of
preexisting macroangiopathy (Lhermitte et al. 1970).
The infarct size depends on several factors. In cases with
an embolic event the location of the occlusion (proximal or
distal), the duration of the occlusion, and the quality of the
leptomeningeal collaterals determine the dimension of
the induced lesion (for further details about leptomeningeal collaterals, see Chapter 5, “Collateral Pathways,”
p.101). In the following paragraphs, examples are given
of the most commonly affected intracranial artery, the
MCA. In case of a proximal main stem M1-MCA occlusion,
which includes the lenticulostriate arteries (LSAs), total
4 Pathogenesis of Stroke66
Fig. A4.2 Schematic drawing of the arterial territories of the brain.
Left: Axial plane. Right: Coronal plane. (Adapted from Duus et al.
[2005].)
Fig. A4.3 Variants of MCA territorial infarction in proximal M1-MCA
occlusion. Cranial CT, axial plane. A Hyperdense media sign (arrow).
B Complete MCA infarction.
territorial infarction will occur if timely recanalization
does not occur and if the leptomeningeal collateralization
is insufficient (Fig. A4.3). If good leptomeningeal collateralization is present, the infarct may—despite an identical
location of the occlusion—be restricted to the striatum. The
striatum is, in the above constellation, almost always affected as the LSAs supply blood to end zone territories that
are not reached by other vessels (Fig. A4.4). Occasionally,
LSAs may in part arise from a proximal M2-MCA branch in
which case a main stem M1-MCA occlusion might not
affect the basal ganglia. In between these two extremes
different patterns of partial territorial infarctions with
variable sizes, with or without subcortical involvement,
can be observed in patients with a proximal MCA occlusion. Preserved “cortical islands” that derive their blood
supply from leptomeningeal collaterals are a frequent
finding (Fig. A4.5). In case of a M1-MCA occlusion distal
of the LSA origin the basal ganglia will be preserved. In a
“best case scenario” a circumscribed distal M1-MCA occlusion could be endured without infarction—but only in the
case of excellent leptomeningeal blood supply and if embolus fragments have not migrated into the periphery.
Most commonly, however, an inhomogeneous partial territorial infarct is seen, involving a variable amount of the
corresponding cortex (Fig. A4.6). Only subcortical infarction may also occur. If an MCA branch occlusion is present,
large or small, a mainly homogenous infarct will result,
depending on the level of the occlusion (Fig. A4.7). Because
of their mostly clear localization, supratentorial infarctions
are usually named according to the affected vascular territory.
The distribution pattern of the anterior and posterior
circulation roughly resembles the relation of both territories with regard to the total CBF. In a clinically orientated,
community-based study of 675 patients, 68 % of territorial
infarctions affected the anterior and 32 % affected the posterior circulation (Bamford et al. 1991). An identical proportion (68 %) of strokes in the anterior circulation was
found in the hospital-based Lausanne stroke registry,
which included 1000 consecutive stroke patients who
underwent CCT diagnostics. Distribution of infarcts within
the anterior circulation was as follows: 96 % within the
MCA, 3 % within the ACA, and 1% combined MCA and
ACA territory. Vertebrobasilar and PCA territory ischemia
wasseenin26%ofpatients.Hemodynamicinfarctionand
mixed patterns were seen in 3 % of cases. Lacunar infarcts
in this study were attributed to the corresponding vascular
territory (Bogousslavsky et al. 1988). Often, supratentorial
territorial and lacunar or infratentorial ischemia can be
clinically differentiated as the former demonstrates cortical signs such as aphasia, apraxia, hemineglect, visuospatial impairment, and hemianopsia in combination with
motororsensorimotordeficits.
Fig. A4.4 Variants of MCA territorial infarction in proximal M1-MCA
occlusion. Cranial CT, axial plane. A Hyperdense media sign (arrow).
B Partial MCA infarction leading to a large striatum infarct, only.
Arterial Ischemia 67
Fig. A4.5 Variants of MCA territorial infarction in proximal M1-MCA
occlusion. A Cerebral DW MRI, axial plane. Large MCA infarct with a
vital parenchymal “island.” B Cerebral MRI, FLAIR image, axial plane.
Large MCA infarct predominantly within the frontal and parietal
opercula sparing most of the temporal parenchyma.
Fig. A4.7 Variants of territorial MCA infarction in MCA branch occlusion. Cerebral DW MRI, axial plane. A Large left anterior partial
MCA infarction (prerolandic ar tery) leading to Broca’saphasia.
B SmallleftcorticalMCAinfarctionwithintheleftprecentralgyrus
(rolandic artery) leading to right-sided brachiofacial hemiparesis.
Fig. A4.6 Variants of MCA territorial infarction in distal M1-MCA
occlusion. Cerebral DW MRI, axial plane. A Partial, predominantly
subcortical MCA infarct with spots of cortical involvement. B Partial
MCA infarct affecting mainly theinsula and sparing the basal ganglia.
Fig. A4.8 Microcirculation of the brain. A Schematic drawing
(Adapted from Spatz 1939, Fig. 1, with kind permission of Springer
Science and Business Media). B Postmortem angiogram, axial plane:
Note the distinct ramification of small perforatoring arteries in the
basal ganglia. (Adapted from http://www.radnet.ucla.edu/sections/
DINR/Part%2018/Part18B11.htm by courtesy of Professor G. Salamon, Radiology, UCLA, Los Angeles, USA).
Lacunar Infarction
Lacunar infarctions result from occlusion of single perforating arteries which have an average diameter of between
100 µmand400µm, and arise directly from much larger
arterial vessels in a perpendicular direction (Fig. A4.8).
Causes of lacunar stroke may vary and are subject of ongoing debate (Wardlaw 2005). Histopathologic analysis of
the occlusions often reveals nonatherosclerotic subintimal
vessel wall lipohyalinosis and fibrinoid necrosis. Hypertension and, in particular, diabetes mellitus are predisposing factors for this type of vessel affection. Larger perforating arteries may show a proximal intraluminal atheroma
and occasionally an atherosclerotic plaque located at the
origin of the vessel. Even a small embolus may enter and
occlude a LSA as has been demonstrated in a monkey
model (Macdonald et al. 1995). The most frequently affected perforating arteries are the LSA arising from the
MCA and ACA stem, the thalamoperforating arteries arising from the PCA and posterior communicating artery, and
the paramedian branches of the basilar artery (BA). Corresponding lacunar infarcts are usually found within the
basal ganglia, the internal and external capsule, the centrum semiovale, thalamus (Fig. A4.9), and paramedian regions of the brainstem, mainly of the pontine tegmentum
(Fig. A4.10). Lacunar infarcts are small, by definition not
exceeding 15 mm, but most of them will not exceed
10mm.
4 Pathogenesis of Stroke68
Fig. A4.9 Morphologic variants of supratentorial microangiopathy.
Cerebral MR T2-weighted image, axial plane. A Right-sided lacunar
thalamic infarct. Note the prominent perivascular spaces in the basal
ganglia. B Pronounced periventricular confluent white matter
changes (leukoaraiosis), predominantly in the parietooccipital area,
and small lacunar lesions of the basal ganglia
Fig. A4.11 Variants of anterior external BZI. A Cranial CT, axial
plane. Hypodense BZI located between the left MCA and ACA territory. B Cerebral DW MRI, axial plane. Left anterior BZI, larger in size
and located more laterally.
Fig. A4.10 Variants of lacunar pontine stroke. Cerebral MR T2weighted image, axial plane. A Large right-sided pontine infarct.
B Medium-sized right and small left lacunar pontine infarcts.
Fig. A4.12 Vari ants of posterior ex ternal BZI. A Cerebral MR FLAIR
image, axial plane. Subcortical left hyperintense BZI between the
MCA and PCA territory. B Cerebral MR T2-weighted image, axial
plane. Similar infarct location. Note that the wedge-shaped infarct
extends to the cortical area.
Lacunar infarctions, in contrast with embolic events,
often have a stuttering clinical course. Most lacunes will
present as characteristic syndromes as they affect the
above circumscribed brain regions, e. g., pure motor
stroke,foundinupto50%ofcases,thepuresensory
stroke, sensorimotor stroke dysarthria-clumsy hand syndrome, and ataxic hemiparesis. However, the above syndromes are not pathognomonic of lacunar stroke. A study
in 73 patients with clinically typical lacunar syndromes
revealed a different pathomechanism in 23 % of cases, half
of them attributable to a cardiac embolic source, and half
of them due to a relevant proximal arterial stenosis (Wessels et al. 2005).
Border Zone Infarction
Border zone infarction (BZI) is considered to be caused by a
low-flow state in large brain-supplying arteries due to
high-grade stenosis or occlusion of an upstream artery or
profound hypotension. An incomplete circle of Willis is
probably another important risk factor for BZI (for further
details, see Case 30, p. 338). Brain lesions may be located in
the anterior and in the posterior circulation at the boundary of the territorial blood supply from the major intracranial vessels. They are best discussed under the anterior
circulation, but even here there is considerable concern
about the nature and significance of these lesions (Caplan
and Hennerici 1998, Monjian-Mayor and Baron 2005).
Within the supratentorial parenchyma, two categories
Arterial Ischemia 69
Fig. A4.13 Variants of internal BZI. A Cerebral MRI, FLAIR image,
coronal plane: Corona radiata lesion between the superficial and
deep MCA perforators (lower lesion) and between the superficial
perforators of the MCA and ACA (upper lesion). B Post-mortem
angiogram, axial plane. (Adapted from http://www.radnet.ucla.
edu/sections/DINR/Part%2018/Part18B11.htm by courtesy of Professor G. Salamon, Radiology, UCLA, Los Angeles, USA): Corresponding areas with clearly reduced number of small arterial vessels (blue
and red circle).
can be distinguished: external and internal BZIs, the first
also referred to as cortical BZIs. External BZIs are located
between two or all three cortical territories of the MCA,
ACA, and PCA. The lesions affect mainly the cortical area in
a wedge-shaped manner, but they may extend into the
subcortical areas and may vary considerably in size. An
anterior external BZI (Fig. A4.11) between the MCA and
ACA is mainly observed in ICA pathology. A posterior external BZI (Fig. A4.12), located between the MCA and PCA
territory may be present in fetal-type PCA or additional
stenoocclusive disease of the vertebrobasilar circulation.
However, there is no extensive data correlating the distribution of cortical BZI with the vascular status. The internal
border zone involves a subcortical area within the corona
radiata between the superficial and deep perforators of the
MCA or between the superficial perforators of the MCA and
ACA (Fig. A4.13). An internal BZI may have a distinct rosary-like pattern of small inline white matter lesions or a
more prominent cigar-shaped confluent pattern (Fig.
A4.14). Both patterns may occur separately or in combination (Fig. A4.15). The reported proportion of hemodynamic strokes varies. From clinical and autopsy studies it is
assumed that about 10 % of all brain infarctions are of
hemodynamic cause (Bladin and Chambers 1994, Jorgensen and Torvik 1969). In symptomatic high-grade ICA
stenoses or ICA occlusions of atherosclerotic origin ipsilateral hemodynamic lesions have been observed in about
50 % of cases (Szabo et al. 2001).
Cortical BZIs may present as distinct clinical syndromes.
Lesions of the speech-dominant anterior cortical border
zone result in transcortical motor aphasia. Speech production is affected similar to as in Broca aphasia, but patients
retain their ability to repeat words and sentences. Other
Fig. A4.14 Variants of internal BZI. CerebralMRFLAIRimage,axial
plane. A Rosary-like internal BZI pattern in the left hemisphere.
B Confluent cigar-shaped internal BZI pattern in the left hemisphere.
Fig. A4.15 Variants of combined internal and external BZI. Cerebral
MR FLAIR image, axial plane. A Large right anterior external and
small posterior external BZI in combination with a confluent internal
BZI. B Large right posterior externals BZI and small inline white
matter lesions representing an internal BZI.
patients with BZI present with mood disturbances. A bilateral anterior cortical BZI can provoke the “man-in-thebarrel” syndrome, characterized by paresis of both arms
with intact facial and leg strength. Unilateral posterior
cortical BZI of the speech-dominant side maylead to transcortical sensory aphasia. Again, patients can repeat words,
phrases, or sentences but like patients with Wernicke
aphasia their comprehension is impaired. Other cortical
signs such as apraxia or neglect may also be present but do
not help in differentiation from territorial infarctions. Bilateral posterior cortical BZI may produce variable types of
visual agnosia, the most remarkable of which is the Balint
syndrome—a combination of gaze apraxia, optic ataxia,
and simultanagnosia, which restrict the patient’sability
to perceive more than one object at a time.
4 Pathogenesis of Stroke70
Fig. A4.16 Variants of small centrum ovale infarction. Cerebral MR
FLAIR image, axial plane. A Lef t centrum ovale lesion of about 1 cm
near the lateral ventricle. B Similar lesion, located more medially.
Fig. A4.18 Schematic drawing of pontine infarction patterns, sagittal and axial plane. Lacunar stroke type in distal penetrating artery
occlusion (A) and territorial stroke type in branch occlusion or proximal penetrating artery occlusion (B).
Infarctions of Uncertain Classification
Occasionally stroke patterns occur that make exact classification difficult, e. g., small lesions within the centrum
ovale and the basal pons are often misclassified as lacunar
lesions of suspected microangiopathic origin. However,
they may also be territorial infarcts of embolic or local
thrombotic cause. The so-called small centrum ovale infarcts (SCOI) (Fig. A4.16) are sometimes caused by an occlusion of a superficial penetrating artery originating from
the MCA. A comparison of 38 patients with SCOI and 60
patients with lacunar infarctions in the basal ganglia, all
defined as lesions <15mm, showed significantly higher
rates of sudden clinical onset (63% vs. 26%), potential
Fig. A4.17 Variants of large paramedian pontine infarction.
A Cerebral MR FLAIR image, axial plane. Large signal increase within
the right paramedian pons. B Cerebral MR T2-weighted image.
Lesion in similar location.
cardiac embolic sources (34 % vs. 12 %), and occlusive
MCA and/or ICA occlusive process (53 % vs. 19 %) in the
SCOI group. A clinical lacunar syndrome was more frequent in the lacunar stroke group (81 % vs. 50 %) (Yonemura et al. 2002). In clinical practice this implies that SCOIs
require an extensive search for a treatable embolic source.
Paramedian pontine infarctions are also difficult to classify, especially with regard to the question of a micro- or
macroangiopathic cause. Macroangiopathy might occur in
form of an atherosclerotic BA plaque which may block the
origin of a BA perforator (luminal plaque) or of a plaque
continuing into the perforating artery (junctional plaque)
(Fisher and Caplan 1971). Also, a microatheroma may be
found within the proximal segment of a perforating artery.
In the above circumstances the ischemic lesion is usually a
large, longish paramedian pontine infarction, extending to
the basal surface of the pons (Fig.A4.17). A microangiopathic pontine lesion however, originating from a perforator lipohyalinosis is located more centrally within the
tegmentum pontis and has a rather rounded shape
(Fig. A4.18).
Finally, classification may also be difficult when at-
tempting to distinguish between territorial and border
zone infarcts. A clear separation between an external BZI
and a territorial infarct just at the territorial border is often
difficult and one has to bear in mind that the variability of
the physiologic borders between arterial territories is
larger than generally assumed. Variants of the circle of
Willishavebeenshowntobethemainreasonforthis
phenomenon (van Laar et al. 2006). In chronic ICA disease
the border zones may also be shifted, subsequently resultinginasmallerMCAterritory.Insuchacase,aposterior
external BZI may appear as posterior MCA territorial infarct. Internal BZI may cause difficulties in delineation
from lacunar stroke or SCOI when only small lesions are
present. A strictly unilateral appearance is, however, uncommon in microangiopathy and points toward a hemodynamic origin.
Etiology and Pathogenesis
A variety of causes may lead to the development of stroke
(Fig. A4.19). Vascular disease is the overall main cause of
ischemic stroke. We distinguish between involvement of
the aortic arch and other large extra- and intracranial
brain-supplying arteries (macroangiopathy) and the involvement of the small perforating arteries with a size
<400µm (microangiopathy). In macroangiopathy, atherosclerosis is the most common finding. However, vessel
dissection, vasculitis, vasospasm (e. g., following subarachnoid hemorrhage), radiation injury, and etiologically unclear vasculopathies such as fibromuscular dysplasia and
moyamoya can be found affecting large vessels in different
preferential locations. In microangiopathy, lipohyalinosis
is the main cause of disease. However, large perforating
arteries might also develop microatherosclerotic vessel
wall lesions. A rare but important differential diagnosis is
a cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). All
microangiopathic diseases can lead to lacunar lesions, diffuse white matter involvement (leukoaraiosis), or both
(Fig. A4.9). Infarcts of cardioembolic origin are the third
important group. There is a particularly high risk of embolism in atrial fibrillation, valvular heart disease, acute
myocardial infarction, intracardial thrombi, and in paradoxical embolism in cases with a right-left cardiac shunt.
Less frequently observed causes of ischemic stroke include
several hematologic diseases, mitochondropathies, migraine, and cerebral venous thrombosis (CVT) (for further
details of venous-related stroke, see “Microembolic Signals”,p.72).
The pattern of infarction seen on CCTor MRI often allows
one to draw conclusions about the pathogenesis. Territorial infarctions are in the majority of cases embolic in
origin, either from a cardiac source or from a macroangiopathic vessel wall alteration resulting in artery-to-artery
embolism. However, they may also be caused by an in-situ
thrombosis. Lacunar infarctions are mostly of microangiopathic origin, but small embolic events, in particular in the
SCOIs discussed above, also have to be considered
(Fig. A4.16). BZIs result from relevant occlusive processes
within the extra- or intracranial main stem arteries and
concomitant impaired collateralization or occasionally in
cases with a temporary profound hypotension. Finally, the
clinical course of stroke may also point toward its pathogenesis. In embolic stroke the most striking clinical feature
is the sudden onset of symptoms. In hemodynamic ischemia and lacunar stroke fluctuating symptoms are more
typical.
TOAST Classification
Ideally, a stroke classification system should consist of all
the aspects discussed above. However, such aclassification
wouldbetoolongandtimeconsumingforeverydayclinical application, and therefore it could be sensibly only
Arterial Ischemia 71
Fig. A4.19 Schematic drawing of ischemic stroke causes. (Adapted
from Schünke et al. [2006].)
applied in, e. g., stroke studies. A practical classification
that has been developed in the past few years is the TOAST
classification. This classification includes the radiological
infarct pattern as well as etiological aspects. Nevertheless,
it remains compact and manageable, and has a good interobserver agreement (Adams et al. 1993). The classification criteria distinguish between five groups:
1. Macroangiopathy (large vessel disease): the presence
ofastenosis>50%orocclusionofanintra-orextracranially located brain-supplying artery corresponding
to the clinical symptoms and with a territorial cortical
infarction or subcortical infarction > 1.5cm.
2. Microangiopathy(smallvesseldisease): the presence
of atypical lacunar syndrome with normal CT/MRI or an
infarct of < 1.5cm of diameter on CT/MRI without stenosis of an ipsilateral brain-supplying artery > 50 %.
3. Cardioembolism: thepresenceofasourceofcardiac
embolism (in general from atrial fibrillation, valvular
heart disease, acute myocardial infarction, patent foramen ovale and atrial septum aneurysm, and cardiac
masses) with brain infarction in more than one territory or a territorial cortical infarct or subcortical infarct
>1.5cm.
4. Other determined etiologies: e. g., the presence of dissection, vasculitis, coagulopathies, and hematologic
disorders.
5. Undetermined etiologies: iftheetiologycannotbedetermined, or a complete examination has not been
done, or two or more potential causes of stroke have
been found.
Some authors add a subgroup “concurrent etiology” to
point 5, which includes those patients in whom at least
4 Pathogenesis of Stroke72
Unknown
etiology
Concurrent
etiologies
Macroangiopathy
20.9%
22.7%
6.9%
Other
etiologies
Microangiopathy
Fig. A4.20 Etiologic subgroups of ischemic stroke according to the
Stroke Data Bank of the German Stroke Foundation (Grau et al.
2001).
3.5%
20.5%
25.6%
Cardioembolism
two potential causes of stroke are present. Applying these
criteria, the Stroke Data Bank of the German Stroke Foundation—a multicenter hospital-based stroke registry including 5017 patients with ischemic stroke—reported the
following distribution of stroke pathogenesis. Cardiac embolism (25.6 %) was most common, followed by macroangiopathy (20.9 %) and microangiopathy (20.5 %). Other
etiologies were rare. Cervical artery dissection, vasculitis,
coagulation disorders, hematologic diseases, or nonspecified etiologies were found in 3.5 % of cases. No etiology
was found in 22.7 % of cases, in most instances despite
complete and extensive investigations. Concurrent etiologies were observed in 6.9 % of cases. In the macroangiopathy group, territorial infarction was present in 89 %
and BZI in 11 % (Grau et al. 2001) (Fig. A4.20). It has to be
assumed that the TOAST classification tends to underrate
artery-to-artery embolism as such a mechanism seems
likely in all cases of a distinct atherosclerotic macroangiopathy (stenosis < 50 %) if no competing causes are
present. A further restriction is that the original study fails
to give a clear definition for the grading of stenosis. In the
German study, a stenosis was defined if a diameter reduction of at least 50 % was present.
Microembolic Signals
Ultrasound permits the detection of spontaneous as well
as artificially induced microembolic signals (MES) which
appear within the Doppler spectrum in form of high-intensity transient signals. Spontaneous microembolic signals might be derived from embolic sources within the
heart or frommostly atherosclerotic vessel wall changes of
the brain-supplying arteries. Artificial microembolic signals, induced by intravenous injection of an echo-contrast
agent, are used for the detection of right-left cardiac or
pulmonary shunts.
Fig. A4.21 Spontaneous microemboli. TCD, transtemporal approach. Top and bottom: MCA Doppler spectrum analysis at the
carotid-T junction, MCA signal above the zero-line, ACA signal below
the zero line. Unilateral microembolic signals within the Doppler
spectrum. Note the microembolic signals are present in the MCA
spectrum only, which is an important criterion for differentiation
from, e. g., motion artifacts.
Spontaneous Microemboli
Following the introduction of TCD as a routine clinical
diagnostic method about 25 years ago, the phenomenon
of microembolic signals assessed by TCD was quickly discovered. However, Doppler sonography is still the only
diagnostic method that can detect clinically silent emboli
originating from the heart or proximal vessels. This is
achieved by continuous monitoring of the Doppler spectrum of intracranial arteries. For practical reasons and
because of its clinical relevance the MCA is the most frequently studied vessel, however microembolic signals can
be present in any of the detectable intracranial arteries.
The greatest methodologic challenge, which has led to
continuous improvements of the technique, is differentiating between microembolic signals and artifacts which
may be caused by, e. g., movements of the patient. This led
to clear diagnostic criteria (Consensus Committee 1995):
microembolic signals have a characteristic clicking or
chirping noise easy to depict acoustically. The signal intensity, if analyzed, is ≥ 3DB above the background noise
level of the Doppler spectrum, usually lasting less than
300 ms. They occur unidirectionally within the spectrum
and have an irregular temporal pattern without any relation to the cardiac cycle (see Fig. A4.21 and video). Physical, microembolic signals are caused by an impedance
difference between blood and embolus, caused by an increased reflection of ultrasound waves at the embolus
surface. Microembolic signals can be caused by thrombocyte aggregations, small atheroma particles, fat particles,
or small gaseous microbubbles. Signal intensity of a microembolic signal increases with its size but also depends on
its composition. Gaseous emboli cause in higher impedance differences than solid particles. Solid atheromatous
particles result in stronger signals compared with throm-
Microembolic Signals 73
bocyte aggregations (Markus and Brown 1993). As both
aforementioned factors simultaneously influence signal
intensity, no conclusion can be drawn about size and composition from the ultrasound signal.
The number of spontaneous microembolic signals that
can be detected over time varies considerably. In MCA
stenosis up to 102 per 30 minutes have been reported
(Gao et al. 2004). Generally, however, microembolic signal
counts are far lower. In patients with carotid, aortic, or
cardiac embolic sources microembolic signal counts vary
between 0 and 13 per hour. If analyzed over 4 hours, even
more intraindividual variations, e. g., between 0.25 and 8
per hour, can be found (Droste et al. 1996). This makes
standardized evaluations problematic and in particular
expensive, as ideally long-time online observations over
several hours would be required. Furthermore, a number
of approaches including the use of a neuronal network,
multi-channel techniques, and automated embolus detection have been developed. However, their diagnostic reliability does not yet compare with the analytic abilities of
an experienced sonographer. For practical reasons, the
current consensus is a compromise and includes detection
of microembolic signals over a period of 1 hour.
Clinical Applications
A variety of potential clinical applications have been described. Microembolic signals can almost always be identified during cardiac surgery, especially during aortic
clamping as well as during the initial phase of reperfusion
(Barbut et al. 1994). A potential relationship between the
number of microembolic signals and the occurrence of
postoperative cerebral ischemia or of neuropsychological
deficits has been postulated (Barbut et al. 1997, Clark et al.
1999, Sylivris et al. 1998). Microembolic signals can frequently be found in patients with artificial heart valves
which cause cavitation-induced microbubbles. The extent
of these depends strongly on the type of the implanted
valve (Sliwka and Georgiadis 1998). The question of
whether microembolic signals may in addition be caused
by embolizing valvular thrombi is currently being debated.
Microembolic signals have also been observed in other
cardiologicalconditionssuchasinsymptomaticand
asymptomatic atrial fibrillation, in heart failure, in myocardial infarction, or in cases with intracardial thrombi. So
far, however, there is no evidence tha t micro embolic signals are a true predictor of the occurrence of cerebral
ischemia in the above conditions (Cullinane et al. 1998,
Georgiadis et al. 1997). A large number of studies have
been conductedin carotid surgery.Here, a raised incidence
of microembolic signals correlates with the occurrence of
postoperative cerebral ischemia (Ackerstaff et al.1995). In
particular the number of postoperative microembolic signals seems to correlate with the risk of re-ischemia and
local postoperative thrombosis (Ackerstaff et al. 2000, Levi
et al. 1997). Depending on the applied technique, percutaneous angioplasty might lead to the occurrence of microembolic signals. However, a correlation with ischemic
events or clinically silent new DWI lesions on MRI has
not been found. (Jordan et al. 1999, Rosenkranz et al. 2006).
Numerous studies have analyzed the impact of microembolic signals on the stroke risk in carotid stenosis. It has
been found that number and frequency of microembolic
signals are higher in symptomatic than in asymptomatic
patients (Forteza et al. 1996, Markus et al. 1995, Siebler et
al. 1994a). Ulcerating plaques may (Valton et al. 1995) or
may not lead to raised numbers of microembolic signals
(Storketal.2002).Themicroembolicsignalcountrises
with the degree of stenosis (Eicke et al. 1995) and can be
reduced by carotid endarterectomy (Siebler et al. 1994b,
van Zuilen et al. 1995). The above studies suggest that
microembolic signals might be an indicator for recurrent
cerebral ischemia after an initial event. Concerning the
question of asymptomatic stenoses, data are inconsistent.
Some authors have reported a considerably increased risk
of stroke in the respective vascular territory if microembolic signals are present (Molloy and Markus 1999, Siebler
et al. 1995, Spence et al. 2005). However, other authors
who studied larger patient numbers over a period of almost 3 years couldnot confirmthese findings(Abbott et al.
2005). Clarification of this point will therefore require
more and larger, preferably multicentric studies.
Microembolic signals may also be found in intracranial
stenosis. A large study recently analyzed MES in 114 patients with acute symptomatic MCA stenosis. In these, a
large MES count was the only predictor of recurrent stroke
(Gao et al. 2004).
Furthermore, the Doppler spectrum analysis of pre- and
poststenotic MCA segments might facilitate the allocation
of the embolic source in patients with a competing ipsilateral ICA stenosis (Nabavi et al. 1996). Interestingly,
chronic MCA stenoses do not show any microembolic
signals, regardless of the medication taken by the patient
(Seguraetal.2001;Sliwkaetal.1997).
Some authors evaluated the efficiency of medical secondary stroke prevention in symptomatic carotid artery
stenosis by analyzing the microembolic signal count. One
study found that intravenous heparin administration reduced the number of detectable microembolic signals
(Siebler et al. 1994a), but this was not confirmed by a
second study (Georgiadis et al. 1994). Thrombocyte function inhibitors may reduce the number of detectable microembolic signals. Patients who demonstrated a medication-induced reduction of microembolic signals had a notably lower risk of re-ischemia (Görtler et al. 2002). Dual
antiplatelet therapy with clopidogrel and aspirin has been
reported to be more effective than aspirin alone in reducing microembolic signals in patients with recently symptomatic ICA stenosis (Markus et al. 2005). Depending on
the underlying stroke etiology, the number of detectable
microembolic signals changes over time. In many cases
they decrease with increasing time span to the ischemic
event (Forteza et al. 1996, Grosset et al. 1994, Lund et al.
2000).
4 Pathogenesis of Stroke74
In conclusion, microembolic signals analysis is a promising field of research, giving insight into important aspects of stroke pathophysiology. However, it cannot yet be
considered as a standard routine diagnostic procedure in
stroke. This is due to the required resources in time and
personnel attributed to the unsolved question of the resulting therapeutic consequences. Foreseeable potential
future indications for microembolic signal detection could
be the analysis of treatment effectiveness, e. g., of different
antiplatelet agents in secondary stroke prevention after
TIA and stroke, the risk stratification of patients with
asymptomatic ICA stenosis, as well as the monitoring of
surgical interventions in cardiac surgery and surgery or
intervention of the brain-supplying arteries.
Detection of Microemboli in Patent Foramen Ovale
A patent foramen ovale (PFO) can be directly diagnosed by
transthoracic echocardiography (TTE) or by using the current gold standard—transesophageal echocardiography
(TEE). The combination of contrast-enhanced TEE and
color Doppler TTE yields a sensitivity and specificity of
100 % when compared with autopsy findings (Schneider
et al.1996). Indirect patent foramen ovale diagnosis can be
achieved by TCD analysis.
TheTCDtechniqueusesintravenouslyappliedair-containingecho contrast agentsthat are not capable ofpassing
through the pulmonary circulation. In case of a cardiac or
pulmonary right-to-left shunt, these air bubbles pass into
the arterial body circulation and can be detected by TCD in
the form of high-intensity transient signals (Fig. A4.22).
Two contrast agents are currently used: Mechanically agitated saline containing pure air bubbles or D-galactose
based micro air bubbles (Echovist, Schering, Germany). If
applied at rest and in combination with a Valsalva maneu-
ver, both contrast agents have been shown to reach a
sensitivity of 90 % and specificity between 92 % and 100 %
(Jauss et al. 1994, Klötzsch et al. 1994, Mas 1996). Without a
Valsalva maneuver, the sensitivity decreases. The magnitude of the right-to-left shunt can semiquantitatively be
assessed if the number of high-intensity transient signal in
both MCAs are counted. Following the consensus conference on TCD patent foramen ovale diagnostics, four different grades, separately documented at rest and during
Valsalva maneuver, can be distinguished (Jauss and Zanette 2000):
1. No high-intensity transient signal.
2. 1–10 unilateral or 1–20 bilateral high-intensity transient signals.
3. > 10 unilateral or > 20 bilateral high-intensity transient
signal without a curtain phenomenon.
4. Curtain phenomenon.
The magnitude of microembolic signals positively correlates with the risk of stroke (Serena et al. 1998). The above
findings are only valid when a strictly standardized protocol for TCD examination is followed. Patients should be
studied in a supine position, preferably with continuous
bilateral monitoring of both M1-MCA Doppler spectra. The
Valsalva maneuver has to be practiced with the patient
before testing, starting 10 seconds after intravenous contrast injection and lasting for at least 5 seconds. As a
measure of an adequate Valsalva, flow velocities during
the maneuver fall, whereas opening the glottis will result
in ashort flow velocity rise above normal values. If all these
co-factorsareconsidered,themethodisreliablyableto
detect any right-to-left shunt. In comparison to TEE, the
TCD method is more comfortable for the patient and can
also detect pulmonary right-to-left shunts. However, TCD
cannot localize the shunt and should therefore be used as
complementary test to TEE.
Fig. A4.22 PFO detection. A, B Bilateral TCD monitoring of the right
and left MCA Doppler spectrum. Image during Valsalva maneuver.
A Grade 3 PFO (more than 20 high-intensity transient signals, no
curtain phenomenon)according tothe consensuscriteria. B Grade 4
PFO (curtain phenomenon).
Venous Ischemia
Venous stroke differs considerably from arterial ischemia.
It occurs less frequently and often has a subacute temporal
pattern. It is often accompanied by headaches, has a high
incidence of epileptic seizures and intracranial hemorrhage, responds to heparin treatment, and shows a better
potential with regard to regression of clinical symptoms.
Cerebral venous thrombosis (CVT) accounts for less than
1 % of all strokes. It may present suddenly, mimicking
arterial stroke, and in rare instances even result in subarachnoid hemorrhage (Oppenheim et al. 2005). The vast
majority of patients, however, develop symptoms over
days and weeks. Intracranial hemorrhage in arterial ischemic stroke occurs as a reperfusion phenomenon. In CVT,
the venous congestion leads to raised venous and capillary
pressures, which cannot be compensated for and subsequently results in hemorrhage (Villringer et al. 1994). Another difference between arterial and venous stroke is the