Personal View

Cerebral hyperperfusion syndrome

Walther N K A van Mook, Roger J M W Rennenberg, Geert Willem Schurink, Robert Jan van Oostenbrugge, Werner H Mess, Paul A M Hofman,
Peter W de Leeuw

Cerebral hyperperfusion syndrome (CHS) after carotid endarterectomy is characterised by ipsilateral headache, Lancet Neurol 2005; 4: 877–88
hypertension, seizures, and focal neurological deficits. If not treated properly it can result in severe brain oedema, Department of Internal
intracerebral or subarachnoid haemorrhage, and death. Knowledge of CHS among physicians is limited. Most Medicine and Intensive Care
(W N K A van Mook MD),
studies report incidences of CHS of 0–3% after carotid endarterectomy. CHS is most common in patients with
Department of Internal
increases of more than 100% in perfusion compared with baseline after carotid endarterectomy and is rare in Medicine and Vascular Medicine
patients with increases in perfusion less than 100% compared with baseline. The most important risk factors in (R J M W Rennenberg MD,
CHS are diminished cerebrovascular reserve, postoperative hypertension, and hyperperfusion lasting more than P W de Leeuw MD), Department
of Vascular Surgery
several hours after carotid endarterectomy. Impaired autoregulation as a result of endothelial dysfunction mediated
(G W Schurink MD), Department
by generation of free oxygen radicals is implicated in the pathogenesis of CHS. Treatment strategies are directed of Neurology
towards regulation of blood pressure and limitation of rises in cerebral perfusion. Complete recovery happens in (R J van Oostenbrugge MD),
mild cases, but disability and death can occur in more severe cases. More information about CHS and early Department of Clinical
Neurophysiology
institution of adequate treatment are of paramount importance in order to prevent these potentially severe (W H Mess MD), and
complications. Department of Radiology,
University Hospital Maastricht,
Introduction overabundant cerebral blood flow relative to metabolic Maastricht, Netherlands
(P A M Hofman MD)
Carotid endarterectomy is treatment of choice for needs was termed “luxury perfusion syndrome”6 in
Correspondence to:
symptomatic stenosis of the carotid artery. Reanalysis of 1966, and in 1978 the “normal-perfusion-pressure-
Dr Walther N K A van Mook,
data from three large randomised trials on carotid breakthrough” theory7 was published as an explanation University Hospital Maastricht,
endarterectomy showed that surgery is of some benefit for cerebral oedema and haemorrhage after excision of a Department of Internal Medicine
for patients with symptomatic stenosis, and highly cerebral arteriovenous malformation. Sundt and and Intensive Care, P Debeyelaan
25, 6202 AZ Maastricht,
beneficial for those with symptomatic stenosis of 70% colleagues8 described CHS after carotid endarterectomy. Netherlands
or more without near occulsion.1 Recently the CHS has also been described after other procedures that wvm@sint.azm.nl
Asymptomatic Carotid Surgery Trial showed that in cause increased cerebral blood flow (panel 1).8–18 Most
asymptomatic patients younger than age 75 years with reports are on CHS after carotid endarterectomy, but
carotid stenosis of 70% or more, immediate carotid there have been an increasing number of reports on
endarterectomy halved the 5 year stroke risk from 12% CHS after carotid angioplasty with stenting.
to 6%. These benefits only exist when the complication
rate is kept below 3%.2 Carotid angioplasty with stenting Epidemiology
is a promising alternative to carotid endarterectomy,3 but There are asymptomatic increases in ipsilateral cerebral
carotid endarterectomy remains the treatment of choice. blood flow (20–40% over baseline) in most patients
Cerebral hyperfusion syndrome (CHS) can occur after immediately after carotid endarterectomy that last for
carotid endarterectomy or carotid angioplasty with several hours.8,19,20 In some patients, severe long-lasting
stenting, and is characterised by throbbing ipsilateral hyperaemia occurs with increases of cerebral blood flow
frontotemporal or periorbital headache, and sometimes
diffuse headache, eye and face pain, vomiting,
Panel 1: Summary of revascularisation procedures causing CHS
confusion, macular oedema, and visual disturbances,
focal motor seizures with frequent secondary Carotid endarterectomy8
generalisation, focal neurological deficits, and Aorto-carotid surgery9
intracerebral or subarachnoid haemorrhage. Although Extracranial-intracranial bypass10
most patients have mild symptoms and signs, Carotid stenting11
progression to severe and life-threatening symptoms can Carotid percutaneous transluminal angioplasty 9
occur if CHS is not recognised and treated adequately. Percutaneous transluminal angioplasty of the vertebral artery12
Because CHS is a diagnosis based on several non- Percutaneous transluminal angioplasty of the middle cerebral artery13
specific signs and symptoms, patients may be Percutaneous transluminal angioplasty of the brachiocephalic arteries9
misdiagnosed as having one of the better-known causes Percutaneous transluminal angioplasty/stent of the subclavian artery12
of perioperative complications like thromboembolism. Resection right temporo-occipital arteriovenous malformation with ipsilateral middle and
However, knowledge of CHS among physicians is posterior cerebral arterial supply14
limited.4 In this paper we review research on CHS. Clipping of giant internal carotid artery aneurysm15
Carotid-subclavian bypass16
History Innominate endarterectomy17
Reactive hyperaemia was first described in 1925 during Dural arteriovenous fistula embolisation18
reperfusion after vascular occlusion of limbs,5

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 Personal View
to levels of 100–200% over baseline,8 which is often
maximal 3–4 days after surgery, falls to a steady state by
the sixth or seventh postoperative day, but can last
1–2 weeks.20–22 Hyperperfusion (most commonly defined
as 100% increase over baseline) occurs in a subset of
patients after carotid endarterectomy, and a few of these
patients become symptomatic (figure 1).23 Available
epidemiological data on CHS are summarised in the
table.4,8,20,23–50
CHS can occur any time in the first 28 days after
carotid endarterectomy,51 but most studies report onset
of CHS within several hours to several days. The
incidence of CHS after carotid endarterectomy ranges
from 0·2% to 18·9%, and can be explained by
differences in sample size, inclusion criteria, and
different definitions of CHS. Most studies report
incidences between 0–3% (table). The definitions of
CHS used in these different studies are mentioned in
the table. Until recently, almost all other reports on
patients with CHS provide evidence of hyperperfusion
increasing 100% from baseline. One study with
perfusion MRI reported four patients with symptoms
compatible with CHS, but with only moderate increases
in perfusion as documented by transcranial doppler.48
Another study with transcranial colour-coded real-time
sonography with echo contrast agents had similar
results,46 although the incidence of CHS in this report
was exceptionally high. Although CHS is not commonly
reported, it seems possible that in addition to patients
presenting with CHS with evidence of hyperperfusion
180 CHS
Hyperfusion
Criteria for hyperfusion not met
Cerebral blood flow increase after CEA (%)
100
0
20
Preoperative Immediately after CEA 3 days after CEA
Figure 1: Typical pattern of changes in cerebral blood flow after carotid endarterectomy (CEA)
Only a few patients develop CHS. Adapted with permission from the Amercian Association of Neurological
Surgeons.23
878
(100% increase from baseline), a subset of patients can
develop symptoms and signs with moderate increases in
perfusion.48
Normal cerebral autoregulation
The effects of carbon dioxide and cerebral
autoregulation maintain cerebral blood flow at a blood
pressure range of 60–160 mm Hg. The effect of carbon
dioxide on the cerebral arteries is most pronounced in
smaller arteries (diameter 0·5–1·0 mm), whereas
arteries with a diameter of 2·5 mm or more (eg, the
carotid artery) show no substantial change.52 Cerebral
autoregulation has a myogenic and a neurogenic
component. In myogenic autoregulation, increased
intravascular pressure results in depolarisation of
vascular smooth muscle and vasoconstriction of small
arterioles at high systemic blood pressures.53 When
blood pressure exceeds the limit of myogenic
autoregulation, the remaining autoregulation in large
arterioles and small arteries is dependent on
sympathetic autonomic innervation in the adventitia.54
These vascular changes are a result of neural innervation
and are called neurovascular coupling. As a result of
sparse sympathetic innervation, the vertebrobasilar
system is less protected than other regions of the brain.
Pathophysiology of CHS
Three mechanisms may contribute to the
pathophysiology of hyperperfusion and CHS. First,
impaired autoregulation could mean that increases in
cerebral blood flow after carotid endarterectomy are not
counteracted by paralysis of cerebral autoregulatory
mechanisms.8,55 That diminished cerebrovascular
reactivity or reserve capacity (percentage rise in blood
flow velocity in the middle cerebral artery after
acetazolamide) can identify patients at risk for
hyperperfusion supports this theory.23 Ipsilateral middle
cerebral artery mean-flow velocities are pressure
dependent after carotid endarterectomy, and reduction
of arterial pressure normalised flow velocities and
resolved symptoms in these patients.20 These findings
are analogous to the breakthrough (cerebral blood flow
breaks through autoregulation and rapidly increases) in
hypertensive encephalopathy, and because hypertension
sometimes accompanies CHS, some authors speculate
whether CHS is linked to other hypertensive
emergencies.56 In a previously hypoperfused area with
impaired cerebral autoregulation, restoration of perfus-
ion pressure could lead to hyperperfusion.57 Studies with
cats show that the perfusion pressure breakthrough
threshold in chronically ischaemic brain may not be
reduced by the restoration of normal blood flow, but can
be decreased by the addition of new ischaemic insults
or hypertension.58 Cross clamping during carotid
endarterectomy may further impair autoregulation, but
does not predict hyperperfusion immediately after
carotid endarterectomy.23 Experimental damage to the
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Design Intervention Patients/ Definition of hyperperfusion (syndrome) Patients with Patients with
interventions hyperperfusion CHS
Sundt8 Retrospective CEA 1145 Regional cerebral blood flow 100% Not reported 22/1145=1·9%
Reigel24 Restrospective CEA 2439 Unilateral headche, seizures and transient neurological deficit during the Not reported 10/2439=0·4%
postoperative period after CEA
Piepgras25 Retrospective CEA 2362 100% increase in baseline cerebral blood flow 274/2362=11·6% 12/2362=0·5%
Nicholas26 Retrospective CEA 2331 Ocular blood flow ipsilateral to the CEA exceeding a level considered to be within 12/2331=0·5% 5/2331=0·2%
normal limits (=mean3 SD, =4·12 mL/min)
Sbarigia27 Prospective CEA 36 Unilateral head, eye or facepain, contralateral seizures, delayed intracerebral 3/36=8·3% 3/36=8·3%
haemorrhage
Jansen28 Prospective CEA 130 Not reported Not reported 2/130=1·5%
Jorgensen20 Prospective CEA 95 Symptoms related to excessive increases in cerebral blood flow Not reported 18/95=18·9%
Chambers29 Prospective CEA 35/40 Transient increase in velocity of at least 20% relative to steady state 1 month after 16/40=40% 1/35=2·9%
CEA
Jansen30 Retrospective CEA 233 Not reported Not reported 17/233=7·3%
Breen31 Retrospective CEA 184 Not reported Not reported 5/184=2·7%
Spencer32 Retrospective CEA 500 Persistance of MCA velocities 1·5 times values before cross clamping during 73/500=15% 8/500=1·6 %*
shunting or after final release of carotid cross clamps, without adequate corrective (MCAV2pre-
measures clamp MCAV)
Gosetti33 Retrospective CEA 198/178 Mean blood velocity 100% of basal value Not reported 12/198=6·1%
Dalman34 Case cohort CEA 688 100% increase peak blood flow velocities; 100% increase of Gosling pulsatility indices 62/688=9% 7/688=1·1%
Meyers35 Retrospective PTA 140 Clinical and radiographic signs of hyperperfusion Not reported 7/140=5%
craniocervical
arteries
Dunne36 Retrospective CEA 30 Flow exceeding 1000 cm/s, or three times the velocity 24 h before surgery 6/30=20% 1/30=3·3%
Keunen37 Retrospective CEA 55 Change of blood flow velocity 100% of preoperative value 5/55=9·1% 1/55=1·8 %
Beard38 Prospective CEA 300 Cerebral oedema due to increased cerebral perfusion Not reported 4/300=1·3%
Hosoda39 Prospective CEA 26 CBF increase 100% 2/26=7·7% 2/26=7·7%
Nielsen40 Prospective CEA 61 Symptoms occurring some days after surgery accompanied by hypertension and 100% directly 2/61=3·3%
seizures postoperative
Hingoran 41 Retrospective CEA 444 Hypertension, headaches, seizures, intraparechymal bleeding, oedema, herniation Not reported 2/444=0·5%
and death
Ogasawara42 Prospective CEA 50 CBF increase of 100% compared with preoperative values 6/50=12% 1/50=2%
Naylor4 Prospective CEA 949 Not reported 3/8 if MCAV 8/949=0·8%
100% following
clamping and after 3 h
Ogasawara23 Prospective CEA 55 CBF increase of 100% compared with preoperative values 8/55=14·5% 2/55=3·6%
Hosoda43 Prospective CEA 41 CBF increase 100% 5/41=12·2% 4/41=9·8%
Ascher44 Retrospective CEA 404 Severe unilateral postoperative headache ipsilateral to the site of endarterectomy, Not reported 9/404=2·2%
seizures, of stroke, accompanied by increased ipsilateral ICA flow (100%) compared
with intraoperative values
Coutts45 Retrospective CEA/CAS 129/44 Neurological deficit that occurred after cerebral vascularisation and was localised Not reported 4/129=3·1%/
ipsilateral to the treated artery, not related to thromboemolism 3/44=6·8%
Fujimoto46 Prospective CEA 95 Probable hyperperfusion syndrome was diagnosed if the patient demonstrated a Not reported 12/95=12·6 %
focal seizure, temporary deterioration of consciousness level with remarkably
abnormal speech and conduct for 6 h after stopping propofol sedation, development
of focal neurological signs, such as motor weakness, or intracranial haemorrhage, on CT
Yoshimoto47 Prospective CEA 18 Not reported. 7/18=38·9% 2/18=11·1%
Karapanayiotides48 Retrospective CEA 388 Transient neurological deficits associated with a migraine-like headache, seizures, Not reported 5/388=1·3%
and intracerebral haemorrhage
Wagner49 Retrospective CEA 1602 Severe headaches that significantly prolonged the patients hospitalisation, new-onset Not reported 6/1602=0·4%
seizures or intracranial haemorrhage that developed after completion of the
endarterectomy
Ogasawara50 Prospective CEA 67 CBF increase of 100 % compared with preoperative values 7/67=10·4% 2/67 3·0%

*Hyperperfusion sometimes in combination with other causal factors. CEA=carotid endarterectomy; PTA=percutaneous transluminal angioplasty.

Table: Overview of studies on CHS

cerebral endothelium attenuates or abolishes myogenic
autoregulation;59 and small-vessel disease (as a result of
hypertension or diabetes mellitus) may thus impair
autoregulation.60
A possible mediator of impaired autoregulation in
CHS is nitric oxide, which causes vasodilatation and can
increase the permeability of cerebral vessels.61 There is
also direct and indirect evidence that oxygen-derived free
radicals produced during carotid endarterectomy have a
role even after short internal carotid-artery clamping.62–65
These free radicals can cause damage to the
cerebrovascular endothelium, resulting in postoperative
hyperperfusion. Administration of a free-radical
scavenger can prevent cerebral hyperperfusion and
provide support for this mechanism.66 Therefore,
endothelial dysfunction could promote breakthrough
of autoregulation in vessels downstream from arteries
that possess less sympathetic innervation.56 Another

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potentially important factor is blood pH. Some acid-base
management protocols used during cardiopulmonary
bypass result in increased cerebral perfusion, indicative
of disruption of autoregulation.67 Postoperative rises in
concentrations of carbon dioxide could worsen
hyperperfusion as a result of disturbed autoregulation.
Second, baroreceptor-reflex breakdown may have an
association with the development of CHS. The
baroreceptor reflex buffers acute changes in
systemic arterial blood pressure. Baroreceptor-reflex
breakdown might happen after receptor denervation, for
example after carotid endarterectomy.68 Hypertension
accompanying baroreceptor-reflex breakdown might
increase cerebral perfusion.
Third, an axon-like trigeminovascular reflex has been
implicated in the pathophysiology of CHS.69 The
trigeminovascular system has a cerebroprotective
mechanism, which returns vascular tone back to
baseline after exposure to vasoconstrictors, and involves
release of vasoactive neuropeptides resulting in
increased cerebral blood flow, and its response can be
attenuated by trigeminal ganglionectomy.69,70
Pathology
Cerebral hyperperfusion sufficient to produce break-
through of autoregulation results in transudation of
fluid into the pericapillary astrocytes and interstitium.
Permeability increases via pinocytosis (introduction of
fluids into the cytoplasm by enclosing them in
membranous vesicles at the cell surface), in an attempt
to prevent haemorrhage. The resulting oedema is
hydrostatic in nature56 and predominant in the
vertebrobasilar circulation territory in both CHS and
hypertensive encephalopathy,71 perhaps as a result of
regional variation in cerebral sympathetic innervation.56
Pathological postmortem examination after CHS is
consistent with changes seen in malignant
hypertension, including swelling and hyperplasia of
endothelial cells, extravasation of erythrocytes, and
fibrinoid necrosis.72,73
Potential risk factors for CHS
Many conditions may be predisposing factors for
CHS.4,8,23–25,27,29,33,34,37–40,44,46,47,60,72,74–82 Whether all the factors
mentioned are risk factors for CHS, or simply factors
predisposing for atherosclerosis, and therefore
commonly present in patients with CHS is questionable
(panel 2). Diminished cerebrovascular reserve,
postoperative hypertension, and hyperperfusion lasting
more than several hours to days after carotid
endarterectomy seem to be the most important risk
factors.4,8,24,27,31,39,40,43,44,46,82,83 Patients in whom preoperative
cerebral blood flow is reduced and diminished
cerebrovascular reserve is present are most likely to
develop long-lasting postoperative hyperperfusion.23,43
Blood pressure control in the postoperative phase is
essential in the prevention and management of CHS.
880
Panel 2: Potential risk factors for CHS
Comorbidity/medication
● Diabetes mellitus
● Longstanding hypertension
● Pre-existing hypertensive microangiopathy
● Minor stroke in the presenting history
● Age 72 years
● Recent (3 months) contralateral CEA
● High-grade carotid artery stenosis
Flow related
Preoperative
● Poor collateral flow
● Contralateral carotid occlusion
● Incomplete circle of Willis
● Preoperative hypoperfusion
● Diminished cerebrovascular reactivity or reserve
● Intracerebral steal (decrease of CBF after acetozalamide
challenge)
Perioperative or postoperative
● Increased intraoperative CBF after clamp release
● Intraoperative distal carotid pressure of 40 mm Hg
(measured through shunt)
● Persistence of hyperperfusion longer than several days
postoperative
● Systemic hypertension
Miscellaneous
● Use of (high doses of) volatile halogenated hydrocarbon
anaesthetics
● Use of anticoagulants or antiplatelet therapy
● Periprocedural cerebral infarction
Imaging and functional techniques in CHS
There are two approaches used to try to identify patients
at risk for CHS: preoperative demonstration of cerebral
hypoperfusion, or either peroperative or postoperative
demonstration of cerebral hyperperfusion. CT, MRI, and
transcranial doppler are most widely used, but less
commonly used techniques, such as single-photon
emission CT and PET can also be useful in the diagnosis
of CHS. Routine use of electroencephalography for the
purpose of diagnosing hyperperfusion and CHS is not
useful (figure 2).
CT
CT in the preoperative phase is of limited value because
it cannot identify most of the potential risk factors for
CHS (panel 2). CT done early after the onset of
symptoms after carotid endarterectomy can be
completely normal,4,41 even when single-photon-
emission CT shows hyperperfusion.84 CT abnormalities
suggestive of CHS are diffuse or patchy white-matter
oedema, mass effect, and petechial or massive ipsilateral
haemorrhages ipsiateral to CEA.4,41,56,71,85 Because of
sparse sympathetic innervation of the vertebrobasilar
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Suspicion of CHS after carotid

endarectomy

Occlusion and/or thrombosis Echo duplex carotid artery

No occlusion
Consider re-intervention

Re-intervention No re-intervention CT Alternative diagnosis Treat accordingly

No (new) abnormalities

Disappearance of Persistence of
symptoms symptoms Transcranial doppler Perfusion increase 100% Consider alternative
diagnosis

Perfusion increase 100%

CT

Treatment of perfusion No alternative diagnosis (PW/DW)-MRI

Repeat transcranial doppler

Normalisation cerebral
Consider alternative diagnosis
blood flow

Disappearance of symptoms Persistence of symptoms

Diagnosis of CHS

Figure 2: Algorithm for work-up of patient with symptoms suggestive of CHS after carotid endarterectomy (CEA)
PW=perfusion-weighted; DW=diffusion-weighted

system, white-matter oedema predominantly involves endarterectomy) reported no abnormalities on

the posterior parietal-occipital regions.
MRI
MRI is more sensitive to ischaemic changes than CT,
and magnetic resonance angiography allows non-
invasive assessment of the major intracranial and
extracranial vessels. Therefore, MRI could be suitable
for preoperative assessment of possible risk factors
(panel 2). Abnormalities found with postoperative MRI
are not always associated with symptoms after CEA
(including CHS), and normal findings on MRI do not
exclude the presence of symptoms after CEA (including
CHS).42 MRI abnormalities include white-matter
oedema, predominantly involving the posterior parietal-
occipital regions,4 focal infarction, and local or more
overt haemorrhage. The cerebrovascular reactivity can
be identified by use of new magnetic resonance
techniques86 such as dynamic susceptibility contrast
MRI or perfusion-weighted MRI.87–89 Diffusion-weighted
MRI based on differences in diffusion rate of water
molecules—is more sensitive to ischaemic changes
than conventional MRI techniques. One study48 that
used diffusion-weighted and perfusion-weighted MRI
in four patients (with symptoms of CHS after carotid
diffusion-weighted MRI, ruling out acute ischaemia,
whereas perfusion-weighted MRI revealed relative
interhemispheric differences in cerebral blood flow.
Perfusion-weighted MRI calculates the maximum slope
of decrease by pixel-by-pixel analysis of the time series
(and this slope is associated with the relative cerebral
blood flow). The values found are measured in arbitrary
MRI units. Perfusion-weighted MRI is not a
quantitative method, and conclusions on absolute
cerebral blood flow differences cannot be made using
this technique.48
Transcranial doppler
Transcranial doppler measures cerebral blood flow
velocity in the middle cerebral artery with a doppler
probe through a transcranial bone window. Because the
diameter of the middle cerebral artery is not altered by
autoregulation, changes in flow velocity correlate well
with changes in middle cerebral-artery perfusion.
Transcranial-doppler monitoring can provide direct and
real-time information on middle-cerebral-artery flow
indicative of preoperative cerebral hypoperfusion,
cerebrovascular reactivity, postoperative hyperperfusion,
and emboli after carotid endarterectomy.22,32–34,36,37,76,90–92 In

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CHS, transcranial doppler typically shows a 150–300%
increase in the ipsilateral middle-cerebral-artery flow
velocity, and normalisation of hyperperfusion with blood
pressure reduction corresponds with clinical
improvement.20,29,93 Apart from the measurement of
middle-cerebral-artery flow velocities, the pulsatility
index is derived from the difference in the systolic and
diastolic flow velocity divided by the mean flow velocity
according to the method of Gosling.94
Transcranial-doppler data suggest that cerebral
autoregulation takes time to adapt after carotid
endarterectomy,20,81 but stabilises within 6 weeks.55
Reductions in preoperative flow velocity, pulsatility
index, and cerebrovascular reactivity are associated
with postoperative occurrence of hyperperfusion,37,92
and the increase in peak blood-flow velocity and
pulsatility index after clamp release have high
sensitivity (but low specificity) for prediction persisting
hyperperfusion.34,37,95 Ogasawara and colleagues50
reported that use of peak blood increases in flow
velocity immediately after declamping of the internal
carotid artery to predict hyperperfusion after carotid
endarterectomy resulted in 33% false-positive results;
however, the sensitivity and specificity were 100% (for
both transcranial doppler as single-photon-emission
CT). An increase in peak blood-flow velocity or
pulsatility index of 100% after declamping of the
internal carotid artery predicted intracerebral
haemorrhage more accurately than headache or
hypertension did.30 However, 10% of transcranial
doppler assessments fail because of an insufficient
transcranial bone windows,32,34,36 and false negative
results have been reported.84 Nevertheless, transcranial-
doppler monitoring is the most widely available
practical method that can be used in the preoperative,
perioperative, and postoperative phases. In our hospital
transcranial doppler is used occasionally in the
preoperative phase, for continuous measurement
during the perioperative phase, and for 2 h in the
postoperative phase. When cerebral hyperperfusion
persists thereafter, repeated measurements are made
until cerebral hyperperfusion and symptoms have
disappeared.
Electroencephalography
In many clinics, electroencephalography is used during
endarterectomy to assess intraoperative effects and the
need to construct a shunt.96 After endarterectomy, both
normal electroencephalography patterns and diffuse
slowing of waves in patients with reperfusion seizures
have been described.97,98 Patients with CHS, may also
show periodic lateralised epileptiform discharges, even
in the absence of seizures99 or postseizure.100 These
discharges are indicative of localised cerebral foci of
irritability and resolve fully;24 their occurrence is a
sensitive but non-specific sign, and is not helpful in
identifying patients at risk of CHS.24 Subclinical
882
seizure activity on electroencephalography after carotid
endarterectomy could suggest the need for antiepileptic
medication.24
PET
Oxygen-15-labelled H2O PET was used to disclose
hypoperfusion in the preoperative phase and
hyperperfusion in the postoperative phase.101 There are
no studies on the association between increased
perfusion (as detected by PET) and CHS.
Single-photon-emission CT
Single-photon-emission CT can determine preoperative
cerebral blood-flow reserve (after acetazolamide) and
detect postoperative hyperperfusion,23,39,42,43,84,85,102–109 and
increased uptake on single-photon-emission CT
correlates with abnormalities on postoperative CT
scanning.85,110 Persistence of hyperperfusion on single-
photon-emission CT between the first and third
postoperative day may identify patients at risk for CHS.23
Single-photon-emission CT may be valuable in
differentiating ischaemia from hyperperfusion when
other diagnostics fail,24,39,42,81 and may be further
improved by advances in image processing and
analysis.43
Transcranial regional cerebral-oxygen-saturation
monitoring
An increase in regional cerebral oxygen saturation is a
sign of increases in cerebral blood flow—when cerebral
oxygen consumption and arterial oxygen saturation are
stable. Cerebral oxygen concentrations can be measured
with near-infrared spectroscopy. Recently, a strong
linear correlation was reported between increased
transcranial regional cerebral oxygen saturation and
increased cerebral blood flow immediately after carotid
endarterectomy.42 When compared with single-photon-
emission CT findings, sensitivity and specificity of
transcranial regional cerebral oxygen saturation were
100% for detection of hyperperfusion after carotid
endarterectomy.42
Ocular pneumoplethysmography
Ocular blood flow is a good indicator of cerebral blood
flow, and ocular pneumoplethysmography is an easy and
quick examination. A postoperative ocular blood flow
increase of more than 204% carries a high risk of CHS.26
Transcranial colour-coded real-time ultrasonography
with echo contrast
One study assessed transcranial colour-coded real-time
ultrasonography with echo contrast agents for the
diagnosis of hyperperfusion and prediction of CHS
after carotid endarterectomy.46 A middle-cerebral-artery
mean-flow velocity ratio (preoperative to postoperative)
of 1·5 within 4 days postoperative yielded a sensitivity
of 100% and a specificity of 84% for CHS.46
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Prevention of CHS
Timing of surgery, type and dose of anaesthesia,
treatment of hypertension, and adequate instructions for
patients after hospital discharge. Pretreatment with the
free-radical scavenger edaravone could also be
considered.66
Timing of surgery
Operative risk may increase if surgery is done early—
3–4 weeks after cerebral infarction—especially in
patients with major cerebral infarction or stroke in
evolution, and the risk of haemorrhage in the softened
brain parenchyma may increase as a result of
postoperative hyperperfusion.72 However, recent analysis
of data from the European Carotid Surgery Trial and
North American Symptomatic Carotid Endarterectomy
Trial showed that benefit from carotid endarterectomy in
neurologically stable patients is greatest when the
procedure is done within 2 weeks of a patient’s last
ischaemic event.111 However, carotid endarterectomy
within these 2 weeks is in disagreement with the
theoretically possible increased risk of haemorrhage if
there is hyperperfusion. A recent (3 months)
contralateral carotid endarterectomy has been reported
as an additional potential risk factor for CHS and should
also be considered in the timing of surgery.44
Type of anaesthesia
There is not enough evidence from randomised trials
comparing carotid endarterectomy under local
anaesthetic with carotid endarterectomy under general
anaesthetic.112 In some trials specifically addressing
cerebral blood flow, mean middle-cerebral-artery velocity
after clamping was significantly higher in the local
anaesthesia group.113 Whether this means that the
ipsilateral circulation is better preserved and carotid
clamping is better tolerated,113 or that patients have a
high risk of postoperative hyperperfusion after local
anaesthesia remains unknown. When using general
anaesthesia, the type and dose should be carefully
planned, because various anaesthetic drugs have
different effects on cerebral blood flow and
autoregulation. High doses of volatile halogenated
hydrocarbon anaesthetics may lead to the development
of CHS.60 Isoflurane is the volatile anaesthetic of choice
in neurosurgical operations because of its less
pronounced vasodilating effects compared with other
halogenated anaesthetics at equipotent doses. The
effects of isoflurane on cerebral metabolic rate and
autoregulation are dose dependent, with impairment of
cerebral autoregulation at high doses.114 Nitrous oxide
induces a small rise in cerebral blood flow, intracranial
pressure, and cerebral blood volume. A concentration of
less than 70% nitrous oxide probably has no influence
on cerebral autoregulation. However, nitrous oxide
combined with volatile anaesthetics does have
vasodilatory effects that increase with isoflurane
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Personal View
concentration.115 Propofol has been used in patients with
CHS,116 it normalises cerebral blood flow probably
because of effects on cerebral metabolism.117 Further-
more, catecholamine-induced hypertension causing
increased cerebral blood flow may be offset by the use of
propofol, without altering autoregulation or reactivity of
cerebral vessels to carbon dioxide.118
Blood-pressure control
There are no studies of whether patients with a blood
pressure well-regulated by means of less favourable
drugs (with regard to CHS) should be changed to more
favourable drugs before operation.
Instructions and guidelines after discharge
Because most patients are discharged early after carotid
endarterectomy, some patients develop CHS after
hospital discharge. Instructions and guidelines for
patients with risk factors for CHS should be developed.
The current information on CHS supports return to
hospital in the event of symptoms until a month after
discharge. The optimum policy should be studied
further.
Pretreatment with edaravone
Free radicals are produced in the CNS during
reperfusion and can cause postischaemic hyperper-
fusion. Edaravone inhibits lipid peroxidation119 and
vascular endothelial cell injury,120 and it ameliorates
brain oedema121,122 and tissue injury.119 The antioxidant
was beneficial in the treatment of acute stroke in a
randomised controlled trial.123 Recently, pretreatment
with edaravone (60 mg in 100 mL physiological saline
intravenously 30 min immediately before internal
carotid-artery clamping) decreased the incidence of
carotid endarterectomy hyperperfusion as measured by
single-photon-emission CT.66
Work-up of patients with symptoms after
carotid endarterectomy
Apart from identifying patients at risk, the work-up of a
symptomatic patient after carotid endarterectomy is a
challenge. We propose use of an algorithm for the work-
up of patients with symptoms suggestive of CHS after
carotid endarterectomy (figure 2). Once symptoms after
carotid endarterectomy have occurred, differentiation
between surgically treatable causes (for example,
occlusion of the operated vessel), emboli, low-flow state
(ischaemia or infarction), or high-flow state (CHS) is
essential for treatment. Once the diagnosis of CHS has
been made, adequate lowering of blood pressure,
treatment of cerebral oedema, and anticonvulsant
therapy form the basis of therapy. Whether adding
perfusion-weighted and diffusion-weighted MRI to
native MRI increases the sensitivity for CHS or
alternative diagnoses is unknown and should be studied
further.
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 Personal View
Therapy
Because blood flow is pressure dependent in patients
with CHS, and symptoms can disappear immediately
with reduction of the systemic arterial blood pressure,
most researchers recommend strict control of blood
pressure in CHS. Drugs that have no direct effects on
cerebral blood flow, and those that give some degree of
cerebral vasoconstriction could be advantageous on
theoretical grounds. Many drugs commonly used for
treatment of hypertension, such as direct vasodilators
(for example, nitroprusside or glycerol trinitrate)21,27,124,125
and calcium antagonists125,126 are therefore contra-
indicated. Theoretically inhibition of angiotensin II
production or action could increase cerebral perfusion.
Captopril preserves cerebral blood flow after a single
dose and increases cerebral blood flow despite
decreasing mean arterial pressure with chronic treat-
ment in patients with severe congestive heart failure.
Therefore the effect of angiotensin-converting-enzyme
inhibitors is limited.125 Use of angiotensin II receptor
antagonists is limited because they have a long half-life
and cannot be given intravenously.
The 1-adrenergic antagonists (beta-blockers) reduce
arterial blood pressure with little effect on intracranial
pressure within the autoregulatory range, and can be
used to treat hypertension in patients with brain
injury.125 The mixed -adrenergic antagonist and
-adrenergic antagonist labetalol has no direct effects on
cerebral blood flow and decreases the cerebral perfusion
pressure and mean arterial pressure by about 30%
compared with baseline,127 and has successfully been
used in CHS.20,34 Because hypertension after carotid
endarterectomy is associated with raised cranial and
plasma catecholamine concentrations, treatment could
consist of a central-acting sympatholytic agent.128 The
2-adrenergic agonist clonidine is commonly used after
carotid endarterectomy, resulting in vasorelaxation with
decreases of arterial blood pressure, heart rate, and
cardiac output. The drug decreases cerebral blood flow,125
which, because brainstem sensitivity to baroreceptor
control is preserved, is another reason for its use.129
In summary, labetalol and clonidine are the drugs of
choice for management of hyperperfusion in CHS.
Other vasodilating agents can further worsen CHS.
Duration of treatment
Intensive blood-pressure lowering should be
recommended until cerebral autoregulation is restored.
The time taken for autoregulation to be restored varies
among patients,51 and it raises the question of which test
is most sensitive to identify this. Some practitioners
treat patients for 6 months after surgery,34 whereas
others use equalisation of transcranial-doppler signals
in the two hemispheres as a guide for treatment.20 In
our opinion, transcranial doppler is suitable for follow-
up of hyperperfusion. After disappearance of
hyperperfusion, normalisation of blood pressure should
884
be pursued for secondary prevention of cardiovascular
complications.
Local anaesthetics
With regard to the trigeminovascular pathway hypothesis,
topical anaesthetics or neuromuscular blockade may be
used to treat CHS, but may for several reasons be
suboptimum.69
Treatment of cerebral oedema
Cerebral oedema treatment includes adequate sedation,
(short term) hyperventilation, treatment of fever,
administration of mannitol or hypertonic saline, and
barbiturates; however, there are no data to support these
treatments in CHS. Corticosteroids and barbiturates
have been used in CHS.23,41,42,50
Anticonvulsant therapy
No recommendations on prophylactic use of
anticonvulsant therapy can be made on the basis of the
available data. Some authors consider prophylaxis when
periodic lateralised epileptiform discharges are present
on EEG,24 others in symptomatic patients with unilateral
headache or focal neurological deficits caused by
CHS.17,41 When patients do have seizures, treatment with
anticonvulsants is always indicated.
Anticoagulation and antiplatelet therapy
Seizures after carotid endarterectomy are a contra-
indication for anticoagulation therapy.25 However, for
secondary prevention of cardiovascular complications,
antiplatelet therapy is advised.
Prognosis
Prognosis is dependent on the timing and accuracy of
diagnosis and treatment. Conclusions on prognosis are
derived from a few patients with CHS, all of whom were
diagnosed in different postoperative phases and treated
differently. Although most patients—perhaps those
diagnosed and treated early—seem to recover
completely, some studies indicate that nearly 30% of
patients with (severe CHS, or those diagnosed late) CHS
remain partly disabled,35 and mortality rates of 50%
have been reported.25 Thus, although intracerebral
haemorrhage in CHS is rare, it is almost uniformly a
devastating occurrence.
Conclusions and suggestions
Patients with substantial cerebral hypoperfusion
because of carotid stenosis benefit from intervention in
the form of carotid endarterectomy, but they also face
high risk of complications.
One of these complications is CHS, on which
consensus regarding its definition is lacking. To
facilitate future uniform investigations the following
definition is proposed: headache, neurological deficit,
and seizure or haemorrhage after cerebral revascularisa-
http://neurology.thelancet.com Vol 4 December 2005

Search strategy and selection criteria
References for this review were identified using PubMed, with
search terms “hyperperfusion, syndrome”, “carotid
endarterectomy”, “CHS”, “cerebral blood flow”, and
“hypertension”, and analysis of the reference lists of the
articles retrieved. Case reports and case series were not
discarded in the analysis, but it is obvious that
epidemiological data cannot be derived from these
publication types. There were no date limitations, and the
last search was done in August 2005. Some studies of special
interest published thereafter are also mentioned in the
article.
tion, typically ipsilateral to the treated artery with
evidence of hyperperfusion 100% compared with
baseline MRI, transcranial doppler, or single-photon-
emission CT. Alternative diagnoses should be ruled out
by use of conventional imaging technique’s such as CT
or MRI. Applying a time limit to this definition carries
the potential risk of missing late cases of CHS. One
recent study, however, reported CHS with moderate
increases in perfusion, but this seems the exception
rather than the rule. Several risk factors for CHS have
been identified, of which diminished cerebrovascular
reserve, postoperative hypertension, and hyperperfusion
lasting more than several hours to days after carotid
endarterectomy seem to be most important. Selection of
patients at risk for hyperperfusion and CHS solely on
the basis of preoperative risk factors, clinical parameters,
or diagnostic investigations does not have 100%
sensitivity, and thus prevention of CHS requires a high
level of awareness in all patients after carotid
endarterectomy. Despite their limitations several
methods, such as transcranial doppler and single-
photon-emission CT, can contribute to preoperative
identification of patients at risk of hyperperfusion and
postoperative identification of patients with
hyperperfusion at risk for CHS. Transcranial-doppler
monitoring is perhaps, the most widely available,
practical method for repeated observations. Once
hyperperfusion has been established, perioperative and
postoperative blood-pressure treatment is important.
Clonidine and labetalol are the drugs of choice.
Vasodilators like nicardipine and hydralazine are
contraindicated. Treatment can be guided by the results
of repeated cerebral blood flow determination. Many
questions about pathophysiology, risk factors and effects
of different treatment strategies remain. Further
research to clarify these issues is warranted.
Authors’ contributions
WNKAvM initiated and coordinated the article and wrote the initial
version together with RJMWR; GWS, RJvO, WHM, PAMH, and PWdL
participated in writing various sections of the paper.
Conflicts of interest
We have no conflicts of interest.
http://neurology.thelancet.com Vol 4 December 2005
Personal View
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