Neurological complications of acute ischaemic stroke

www.thelancet.com/neurology Vol 10 April 2011 357
Review
Lancet Neurol 2011; 10: 357–71
Published Online
January 18, 2011
DOI:10.1016/S1474-
4422(10)70313-6
Acute Stroke Programme,
Department of Medicine and
Clinical Geratology, Oxford
Radcliffe NHSTrust, Oxford, UK
(J S Balami MRCP); Nuffield
Department of Medicine,
University of Oxford, Oxford,
UK (R-L Chen PhD); Department
of Neuroradiology, Biomedical
Research Centre, John Radcliffe
Hospital, Oxford, UK
(I Q Grunwald PhD,
Prof A M Buchan FMedSci); and
AcuteVascular Imaging Centre,
Biomedical Research Centre,
University of Oxford, John
Radcliffe Hospital, Oxford, UK
(A M Buchan)
*Contributed equally to this
Review.
Correspondence to:
Prof Alastair M Buchan, Acute
Vascular Imaging Centre,
Biomedical Research Centre,
University of Oxford, John
Radcliffe Hospital, Oxford
OX3 9DU, UK
alastair.buchan@medsci.ox.
ac.uk
Neurological complications of acute ischaemic stroke
Joyce S Balami*, Ruo-Li Chen*, Iris Q Grunwald, Alastair M Buchan
Complications after ischaemic stroke, including both neurological and medical complications, are a major cause of
morbidity and mortality. Neurological complications, such as brain oedema or haemorrhagic transformation, occur
earlier than do medical complications and can affect outcomes with potential serious short-term and long-term
consequences. Some of these complications could be prevented or, when this is not possible, early detection and
proper management could be effective in reducing the adverse effects. However, there is little evidence-based data to
guide the management of these neurological complications. There is a clear need for improved surveillance and
specific interventions for the prevention, early diagnosis, and proper management of neurological complications
during the acute phase of stroke to reduce stroke morbidity and mortality.
Introduction
Advances in the diagnosis and treatment of acute stroke
have been made over the past two decades, but mortality
after stroke is still high, with stroke ranked as the
second most common single cause of death in the
developed world after ischaemic heart disease, or third
if all neoplastic diseases are considered as a group.1
A
leading cause of death, accounting for 23–50% of total
deaths in patients with ischaemic stroke, is post-stroke
complications.2
Even if not always life-threatening,
these complications can lead to delay in rehabilitation,
prolonged hospital stays, poor functional outcomes,
and increased costs of care.2–4
Complications after
ischaemic stroke comprise medical and neurological
complications.2,5,6
Neurological complications include
brain oedema, haemorrhagic transformation, seizures
and epilepsy, recurrent stroke, and delirium (table 1).
These complications are less frequent than medical
complications5
but occur earlier in the course of stroke
progression—within 48–72 h of stroke onset rather than
within the first few weeks of stroke.6,7,9,16,20
Results from
some studies have indicated that deaths within the first
few days of stroke are usuallythe direct consequence of
brain damage from neurological complications.21,22
Similarly, autopsy series of early stroke fatalities have
indicated that death within the first week after stroke is
mainly attributable to the direct effects of stroke, such
as brain oedema with transtentorial herniation.22,23
In a
study of neurological worsening during the acute
phase of ischaemic stroke in 1964 patients, 33∙6% of
patients deteriorated because of progressive stroke,
27∙3% as a result of brain swelling, 11∙3% owing to
recurrent ischaemic stroke, and 10∙5% because of
parenchymal haemorrhage. The remaining 17·3%
deteriorated because of pyrexia, hyperglycaemia, and
hypertension, which are abnormal physiological
variables or medical complications.24
Many reviews have focused on medical complications
and their management, with little discussion of
neurological complications.3,25,26
Moreover, there are few
evidence-based data to guide the management of these
neurological complications. For example, a predicament
arises in the prevention and effective management of
brain oedema, which is a leading cause of death.
Treatments aimed at reducing intracranial pressure are
of unproven value. Similarly, there is insufficient evidence
to lend support to the routine use of antiepileptic drugs
for the primary or secondary prevention of seizures after
ischaemic stroke. Additionally, therapeutic dilemmas can
arise as to when to use anticoagulation after recurrent
stroke in patients with atrial fibrillation and possible
hyperthrombotic states.
In this Review, we focus on major neurological compli-
cations with an emphasis mainly on those events that
occur in the acute phase of ischaemic stroke. We discuss
neurological complications both in animals and in clinical
settings. We outline the relevant preventive and manage-
ment strategies based on recent evidence and guidelines
and highlight the paucity of evidence for many important
and prevalent neurological complications. Subacute and
chronic neurological complications (eg, depression and
dementia) and medical complications are beyond the
scope of this Review and have not been included.
Brain oedema
Clinical features
Brain oedema is a leading cause of death after stroke,
especially within the first week.27
Patients with stroke6,24
and
animals with cerebral ischaemia28
often have brain oedema.
The primary cause of brain oedema is ionic imbalance due
to energy depletion in cerebral ischaemia.29
Two types of
oedema—cytotoxic and vasogenic oedema—occur in
patients with ischaemic stroke. Cytotoxic oedema is
characterised by the translocation of interstitial water into
the intracellular compartment and occurs early, when the
blood–brain barrier is still intact.30
At the late stage of
stroke, the blood–brain barrier is compromised, causing
vasogenic oedema, characterised by fluid movement from
vascular to extravascular spaces.31
Vasogenic oedema leads
to an expansion of brain volume with increased intracranial
pressure, herniation, and additional ischaemic injuries.32
Differentiation of cytotoxic and vasogenic brain oedema in
the clinical setting is important for diagnostic and
therapeutic purposes because cytotoxic oedema is
unresponsive to anti-oedematous pharmacological
treatment.33
Recent advances in MRI help to distinguish
the type of oedema. Cytotoxic brain oedema causes a
reduction in overall diffusivity of water molecules and

358 www.thelancet.com/neurology Vol 10 April 2011
Review
shows high signal intensity on diffusion-weighted MRI34
(figure 1A), whereas vasogenic oedema causes increased
water in brain tissues, which can be shown on conventional
T2-weighted images35
and fluid-attenuated inversion
recovery sequences36
(figure 1B, figure 1C).
The extent of swelling highly depends on the extent
and location of the infarcted area37
and the age of the
patients.38
Younger patients are more prone to developing
fatal brain oedema or malignant middle cerebral artery
(MCA) syndrome than are older patients.38,39
Results from
animal studies also show that ageing mice have
significantly less stroke-induced oedema than do young
animals,40
possibly because some cerebral atrophy
protects older people from developing space-occupying
brain swelling.27
Hemispheric oedema
The overall risk of cerebral oedema in patients with
anterior circulation ischaemic stroke is estimated to be
10–20%.41–43
In patients with major anterior circulation
occlusion such as MCA stem occlusion, cerebral oedema
tends to appear within the first 4 days after stroke onset.44,45
Patients with large cerebral infarction, especially when
complicated by brain oedema, often present in coma46,47
(figure 2A and figure 3A). Brain oedema with midline
structure shift or brainstem compression is a major
cause of mortality.47
Malignant MCA infarction is a condition in which the
MCA territory is completely infarcted, with rapidly
developing massive swelling, which can cause brain
herniation as early as 20 h after symptom onset.27
This
type of infarction is life-threatening and is one of the most
devastating neurological complications of ischaemic
stroke, occurring in 1–10% of all supratentorial ischaemic
strokes.27
The overall mortality rate for acute MCA
infarctions caused by cerebral herniation secondary to
brain oedema ranges between 7% and 23%, whereas that
of malignant MCA infarction is estimated to be between
40% and 80%,27,48
and up to 80% in untreated patients.27,33
The development of malignant MCA infarction can be
predicted with high sensitivity (91%) and specificity (94%)
by the appearance of large hypoattenuation (defined as
greater than two-thirds of the MCA territory) on enhanced
CT and large areas of hypoperfusion on CT perfusion
imaging.43,49,50
Other predictive imaging findings are a
large diffusion-weighted imaging lesion volume, severe
perfusion deficits on perfusion-weighted MRI or single
PET scan within 6 h, and a large area showing an apparent
diffusion coefficient decrease within 6 h of stroke.51,52
Cerebral vein and dural sinus thrombosis (CVST) is an
infrequent stroke type but is potentially life-threatening,
with mortality ranging from 4∙3% to 8∙3%.53,54
CVST
causes a wide range of parenchymal changes, including
cytotoxic oedema and substantial vasogenic oedema.
Indredavik
et al7
Navarro
et al8
Hong
et al9
Rocco
et al10
Hung
et al11
Heuschmann
et al12
Cavallini
et al13
Weimar
et al2
Roth
et al14
Grau
et al15
Langhorne
et al16
Johnston
et al6
Pinto
et al17
Davenport
et al18
Kalra
et al19
Dromerick
and Reding5
Studydesign P, SC P, MC P, MC P, SC P, SC R, MC R, SC P, MC P, SC P, MC P, MC R, MC P, SC P, SC R, SC P, SC
Participants (n) 489 1153 1254 261 346 13440 268 3866 1029 5017 311 279 213 607 245 100
Typeof stroke IS, HS IS, HS IS IS, HS IS, HS IS IS IS IS, HS IS IS, HS IS IS IS, HS IS, HS IS, HS
Timing Acute,
subacute
Acute Acute Sub-
acute
Sub-
acute
Acute Acute Acute Sub-
acute
Acute Acute,
subacute
Acute,
subacute
Acute Subacute Sub-
acute
Subacute
Total complication
rate (%)
64 42·9 24·2 60 44 54·4 54 29·2 75 ·· 85 95 41 59 60 ··
Stroke
progression* (%)
18·4 ·· 17·1 7·9 ·· ·· 11·2 ·· ·· ·· ·· ·· 3 ·· 4·5 ··
Brainoedema (%) ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· 8 ·· ·· ·· ··
Increased ICP (%) ·· ·· ·· ·· ·· 2·8 ·· 7·6 ·· 6·3 ·· ·· ·· ·· ·· ··
Brain herniation
(%)
·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· 3 ·· ·· ·· ··
Hydrocephalus (%) ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· 1 ·· 0·5 ·· ··
SHT (%) ·· ·· 3 ·· ·· ·· ·· 0·3 ·· ·· ·· ·· 1·4 ·· ·· ··
ICH (%) ·· ·· ·· ·· ·· ·· ·· 2 ·· 1·7 ·· 4 0·5 ·· ·· ··
Seizures (%) 2·0 1·3 1 1·7 ·· 1·5 3·0 1·4 1·5 1·4 3 3 0·5 4 3·8 3
Recurrent stroke
(%)
1·0 4·9 2·0 ·· 1·5 2·5 ·· 5·1 1·6 4·3 9 18 0·9 ·· ·· ··
Deliriumor
confusion (%)
·· ·· ·· ·· ·· ·· 3·0 ·· ·· ·· 36 ·· ·· 5 ·· ··
Consciousness
disturbance (%)
·· ·· ·· 15·8 ·· ·· ·· ·· ·· ·· ·· 5 ·· ·· ·· ··
··=not reported. R=retrospective. P=prospective. IS=ischaemic stroke. HS=haemorrhagic stroke. SC=single centre. MC=multicentre. ICP=intracranial pressure. SHT=symptomatic haemorrhagic transformation.
ICH=intracerebral haemorrhage. *Stroke progression refers to early neurological deterioration in the acute phase of stroke associated with poor prognosis.
Table 1: Clinical studies with reported frequencies of neurological complications after stroke

Review
Stupor or coma is reported in 15–19% of patients with
CVST, especially in patients with bilateral thalamic
involvement.54
Transtentorial herniation attributable to
multiple lesions, diffuse oedema, and focal mass effect is
the most frequent cause of death.54
The term malignant
CVSTdescribesasubsetofpatientswithrapiddeterioration
from severe CVST with supratentorial parenchymal lesions
and signs of transtentorial herniation and is reported to
occur in about 5% of cases.55
Signs of malignant CVST
might be present at onset or in the first 48 h in about 25%
of patients, but these signs usually occur after a few days of
undiagnosed headache. The deterioration can be extremely
rapid, occurring as early as 22 h after symptom onset.
Frequent seizures, the presence of large, haemorrhagic
parenchymal lesions, and a rapid increase in lesion volume
can be indicative of a malignant course.55
Cerebellar oedema
Cerebellar oedema is a common complication in 17–54%
of patients with cerebellar infarction and can induce
brainstem compression, descending (transforaminal) or
ascending (transtentorial) herniation, and obstructive
hydrocephalus.56–58
Cerebellar oedema usually peaks on
the third day after the infarction, although it can occur
any time after ischaemia.58
The posterior fossa provides
little space for compensation of mass effect, and life-
threatening brainstem compression can develop rapidly.
Gaze palsy and a progressive decline in level of
consciousness are common clinical manifestations.56
Additionally, rapid deterioration from cerebellar oedema
can be associated with sudden apnoea from brainstem
compression and cardiac arrhythmias. Malignant
cerebellar infarction describes a subset of patients with
rapid deterioration from infarct swelling.58–60
Neuro-
imaging can be used to detect severe oedema formation
before transforaminal or transtentorial herniation occurs58
(figure 2B). CT scans can be used to show displacement
of the fourth ventricle, obstructive hydrocephalus, and
obliteration of the basal cisterns.56,61
However, initial CT
scans are normal in up to 25% of patients who then
develop mass effect.58
Coma or loss of consciousness is
commonly associated with brainstem syndromes such as
top-of-the-basilar syndrome62
and locked-in syndrome.63
Hiccoughs can be associated with lateral medullary
infarction (Wallenberg’s syndrome), after lesions in the
pontomedullary area of the brainstem or infarction in the
territory of the posterior inferior cerebellar artery, and
can cause distress, exhaustion, aspiration pneumonia,
and respiratory distress.64,65
Intractable hiccoughs might
lead to the development of irregularities of the respiratory
rhythm culminating in respiratory arrest.65
Management
The initial general management of increased intracranial
pressure after acute ischaemic stroke includes elevation
of the head end of the bedto a 20–30º angle in an attempt
to improve venous drainage. Additionally, factors that
increase intracranial pressure such as hypoxia,
hypercapnia, hyperthermia, hyperglycaemia, and
antihypertensive drugs, particularly those that can cause
cerebral vasodilatation, should be avoided.59
Hemicraniectomy is recommended in selected patients
with substantial brain ischaemic swelling and life-
threatening brain shifts.59,60
The underlying principle of
removing part of the cranium is to create space for the
expanding brain so as to prevent secondary damage to
vital brain tissue and to improve collateral perfusion.66
Figure 1: MRI showing cytotoxic and vasogenic brain oedema after cerebellar infarction (arrows)
(A) Diffusion-weighted MRI showing cytotoxic oedema in the left cerebellum. (B) Axial fluid-attenuated inversion
recovery image showing vasogenic oedema that matches the DWI lesion. (C)T2-weighted MRI showing vasogenic
oedema 2 days after stroke onset.
Figure 3: Brain samples showing cerebral infarction and haemorrhagic transformation
Slices of brain from autopsy showing (A) an area of infarction involving the middle cerebral artery territory (arrow)
and (B) an area of haemorrhagic transformation in the cerebral hemisphere (from a different patient).
Figure 2: CT scans showing cerebral and cerebellar oedema after acute
ischaemic infarct
(A) CT scan showing cerebral oedema (green arrow) with compression of the left
ventricle (red arrow) after infarct of the left middle cerebral artery territory.
(B) CT scan showing posterior circulation stroke (left-sided posterior inferior
cerebellar artery infarct) with involvement of the pons 10 h after onset of stroke
(green arrows).
B CA
BA
BA

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Similarly, decompressive surgery can improve cortical
collateral vein drainage, thus preventing the extension of
thrombosis and possibly favouring the diffusion of
heparin in CVST.55
Table 2 summarises both medical
and surgical management of brain oedema after
ischaemic stroke.
Haemorrhagic transformation
Clinical features
Haemorrhagic transformation of brain infarction is a
common and potentially serious complication of acute
ischaemic stroke occurring in 30–40% of clinical cases.79
The main causes of haemorrhagic conversion are the
loss of microvascular integrity and disruption of
neurovascular homoeostasis.80
The mechanisms for the
disruption are multifactorial, and these factors can
interact with each other. These factors have been
identified as treatment with alteplase, aquaporin, matrix
metalloproteinase, inflammation, vascular endothelial
growth factor, nitric oxide synthase, and free radicals.30
The frequency of symptomatic haemorrhagic
transformation is higher in patients treated with
intravenous alteplase (6%), mechanical embolectomy,
and intra-arterial fibrinolytics (7%) than in those
managed with supportive care (0∙6%).81–83
Although
thrombolysis with alteplase increases the risk of
haemorrhage, which remains the most feared
complication, 100 patients need to be treated with
alteplase for one significant adverse outcome to occur.41
In addition to thrombolytic drugs, the use of other
antithrombotics, especially anticoagulants, can increase
the likelihood of serious haemorrhagic transformation
after ischaemic stroke.84,85
The early use of aspirin could
be associated with a small increase in the risk of clinically
detectable haemorrhage. However, in the International
Stroke Trial (IST),86
aspirin did not have a significant
effect on the risk of haemorrhagic transformation
compared with prophylactic use of medium-dose
heparin, which significantly increased the risk of
haemorrhagic transformation during the first few weeks
afterischaemicstroke.Otherriskfactorsforthrombolysis-
related intracerebral haemorrhage include age older
than 65 years, severe stroke, high glucose concentrations
in the serum, and signs of mass effect on pre-treatment
imaging.87
Elderly patients with stroke are more likely to
develop haemorrhagic transformation owing to factors
such as impaired rate of alteplase clearance, higher
frequency of transformation in cardioembolic than
Description Level of evidence
Medical
General Measures should be taken to reduce risk of oedema, and patients should be closely monitored for signs of neurological worsening during the first
few days after ischaemic stroke59
Level 1B
Osmotherapy Osmotherapy using glycerol, mannitol, corticosteroids, barbiturates, or hyperosmolar saline solutions are recommended for treatment of
deteriorating patients with brain oedema after large cerebral infarction, although these measures are unproven59
Osmotic substances might be harmful in venous outflow obstruction because they are not quickly eliminated from the intracerebral circulation67
Level 3C
Hypothermia Moderate hypothermia between 32°C and 34°C might improve clinical outcome;68
in a small RCT (n=25), mild hypothermia (35°C) in addition to
decompressive surgery led to a better clinical outcome than did decompressive surgery alone69
No recommendation is given about hypothermic therapy in patients with space-occupying infarction60
Level 3C
Anticoagulation Routineuseof anticoagulation for improving neurologicaloutcome in arterial ischaemic stroke has not been proven and is not recommended59
Intravenous anticoagulationwith heparinor subcutaneous anticoagulationwith low-molecular-weight heparin followed byoral anticoagulation isthe
first-linetreatment for symptomaticCVST70
Endovascular chemicalthrombolysisor mechanicalthrombectomy might be neededwhen systemic anticoagulationtherapy failsor is considered
to be high risk in patientswithCVST71
Managementof isolated intracranial hypertensionowingtoCVST might involve a lumbar puncturetodrainCSF before starting heparinwhen patients
develop papilloedemathat mightthreaten visual acuity;this event isusually followed by a rapid improvementof headache and visiondeficits67
Level 3C
Surgical
Decompressive surgery If done early, decompressive hemicraniectomy (<48 h) improves survival and functional outcome in patients (aged < 60 years) with malignant
middle cerebral artery infarction; results from the RCTs DECIMAL, DESTINY, and HAMLET and their pooled analyses of 93 patients indicated that
hemicraniectomy undertaken within 48 h of stroke onset reduces mortality (number needed to treat: 2) and leads to a good functional outcome
with acceptable quality of life (modified Rankin scale ≤ 3)66,72,73
Level 1B
Decompressive surgery Decompressive surgery has been suggested as a life-saving procedure in malignant CVST, even in patients with bilateral dilated pupils, and has
been associated with a good functional outcome55,74
Shunting procedures (lumboperitoneal, ventriculoperitoneal shunts, or optic nerve fenestration) should be considered in patients whose
vision continues to deteriorate despite repeated lumber punctures or treatment with acetazolamide67
Level 3C
External ventricular
drainage
External ventricular drainage is recommended for patients with worsening levels of consciousness and radiologically evident ventricular
enlargement owing to hydrocephalus secondary to an ischaemic stroke affecting the cerebellum75
Level 1B
Suboccipital
decompressive
craniectomy
Suboccipital decompressive craniectomy and insertion of an external ventricular drainage are recommended as the therapy of choice59,60
This procedure is safe and can be life-saving for patients with malignant cerebellar infarction;76
it reduces mortality in malignant cerebellar
infarction77
and long-term outcome among survivors, mostly in the absence of brainstem infarction76
Level 1B
The level of evidence is according to the Oxford Centre for Evidence-based Medicine Level of Evidence.78
CVST=cerebral venous sinus thrombosis. RCT=randomised controlled trial. DECIMAL=Decompressive
Craniectomy in Malignant Middle Cerebral Artery Infarct. HAMLET=Hemicraniectomy after Middle Cerebral with Life-Threatening OedemaTrial. DESTINY=Decompressive Surgery for theTreatment of Malignant
Infarction of Middle Cerebral Artery.
Table 2: Clinical management of brain oedema after ischaemic stroke

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atherosclerotic infarcts, and possible age-associated
microangiopathy (either cerebral amyloid angiopathy or
hypertensive microangiopathy) and leukoaraiosis.88
Haemorrhagic venous infarct is common in CVST,
occurring in about 30–40% of patients.54
Haemorrhage in
cerebral venous thrombosis might be precipitated by
continued arterial perfusion in areas of cell death, as in
reperfusion in arterial ischaemia. Increased venous
pressure beyond the limit of the venous wall is also a
likely mechanism.89
Intracerebral haemorrhage ranges from small
asymptomatic petechiae to large haematoma with possible
pressure effects (figure 3B). On the basis of radiological
appearance or clinical measurements, haemorrhagic
transformation can be graded by use of either the National
Institute of Neurological Disorders and Stroke (NINDS)90
or European Cooperative Acute Stroke Study (ECASS)91
classifications. ECASS classifies haemorrhagic trans-
formation into haemorrhagic infarction and parenchymal
haemorrhages, with each class further divided into two
types (figure 4). H1-1 is defined as small petechiae along
the margins of the infarcted area; HI-2 as confluent
petechiae within the infarcted area, but with no mass
effect; PH-1 as haematoma in less than 30% of the infarcted
area with mild mass effect; and PH-2 as haematoma in
more than 30% of the infarcted area with a notable mass
effect.91
The NINDS system classifies haemorrhagic
transformation into two types: haemorrhagic cerebral
infarction, defined as CT findings of acute infarction with
punctate or variable hypodensity and hyperdensity, with an
indistinct border within the vascular territory; and intra-
cerebral haematoma, defined as CT findings of a typical
homogeneous, hyperdense lesion with a sharp border with
or without oedema or mass effect within the brain.90
Haemorrhagic transformation expands brain oedema
and leads to displacement and disruption of brain
structures, increases intracranial pressure, induces
apoptotic neuronal and glial cell death,92
and is associated
with extremely high rates of mortality. In patients with
cerebellar ischaemia (figure 4), there is also a notably
increased risk of deterioration from mass effect.58
Similarly, haemorrhagic venous infarct in CVST can lead
to death from cerebral herniation.70
Management
There is no intervention available for reducing the risk of
haemorrhagic transformation, although careful selection
of suitable patients for thrombolytic therapy could reduce
this complication. Antithrombotic drugs are not
recommended for use in the first 24 h after thrombolytic
treatment.59
Management of patients with haemorrhagic
transformation depends on the amount of bleeding and
Figure 4: CT and MRI scans showing cerebral and cerebellar haemorrhagic transformation according to the ECASS classification
(A–E) Cerebral haemorrhagic transformation. CT images showing (A) small petechiae (ECASS91
H1-1), (B) confluent petechiae (H1-2), (C) haematoma in <30% of the
infarcted area with a mild mass effect (PH-1), and (D) haematoma in >30% of the infarcted area with a notable mass effect (PH-2). (E) MRI scan showsT2*-weighted
image of haemosiderin within the infarcted area (PH-1, haematoma in <30% of the infarcted area with a mild mass effect). (F–I) Cerebellar haemorrhagic
transformation on MRI scans obtained 7 days after ischaemic stroke. (F)T1-weighted MRI shows disruption of the blood–brain barrier (confluent petechiae; H1-2).
(G)T2*-weighted MRI shows haemosiderin within the infarcted area (haematoma in <30% of the infarcted area with a mild space-occupying effect; PH-1); and
(H)T2-weighted MRI (confluent petechiae; H1-2). (I) CT image shows a haematoma in <30% of the infarcted area with a mild space-occupying effect (PH-1).
ECASS=European Cooperative Acute Stroke Study.
B C DA
F G IH
E

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associated symptoms, which might require neurosurgical
clot evacuation in deteriorating patients.
The decision as to whether or when to restart anti-
thrombotic therapy after haemorrhagic transformation
depends on the risk of subsequent arterial or venous
thromboembolism, the risk of recurrent intracerebral
haemorrhage, and the clinical state of the patient.
Antiplatelet drugs might be a better and safer choice than
warfarin for patients with a relatively lower risk of
cerebral infarction (eg, patients with non-valvular atrial
fibrillation) but with a higher risk of rebleeding (eg,
elderly patients with lobar intracerebral haemorrhage or
possible amyloid angiopathy); conversely, in patients
with a very high risk of thromboembolism in whom
restarting warfarin is likely to be beneficial, warfarin
therapy can be restarted 7–10 days after onset of the
original intracerebral haemorrhage.93
In patients with haemorrhagic venous infarct caused
by CVST, the risk of heparin-induced intracerebral
haemorrhage needs to be weighed against the risk of
haemorrhage caused by additional thrombotic venous
occlusion. However, no new or enlarging haemorrhage
was reported in 40 patients treated with heparin in a
Cochrane review of two clinical trials.94–96
Furthermore,
treatment with an anticoagulant was safe and associated
with a reduced risk of death or dependency.94
Table 3
summarises both medical and surgical management of
haemorrhagic transformation after ischaemic stroke.
Seizures and epilepsy
Clinical features
Seizures can occur soon after the onset of ischaemic
stroke or can be delayed.97
Early seizures are usually
defined as those that occur within 1 or 2 weeks after
stroke and late seizures as those that occur after that.97,98
The reported frequency of early seizures after ischaemic
stroke ranges from 2% to 23% and that of late seizures
is between 3% and 67%, depending on the study design,
sample sizes, and length of follow-up.97–99
Epilepsy
(recurrent seizures) develops in only 2∙5–4% of
patients.98
Although early seizures after stroke are
thought to result from cellular biochemical dysfunction
leading to electrically excitable tissue, late-onset seizures
are thought to be caused by gliosis and the development
of meningocerebral cicatrices.94
Several risk factors have
been identified, such as large cortical infarcts,
involvement of multiple sites, embolic stroke, stroke
severity,98,100
size of the infarct, decreased consciousness,
and haemodynamic and metabolic disturbance.100
Seizures occur more often in patients with cranial sinus
thrombosis than in patients with arterial stroke and
might be the initial form of presentation in CVST.54
In
Level of evidence
Asymptomatic haemorrhagic transformation
General
No specific intervention is recommended for the management of ischaemic stroke patients with asymptomatic haemorrhagic
transformation59
Level 2BC
Symptomatic haemorrhagic transformation
Medical
Initial monitoring and management of patients should take place in an intensive care unit93
Level 1B
For patients with haemorrhagic transformation secondary to thrombolytic therapy, treatment with infusion of platelets and
cryoprecipitate that contains factorVIII to rapidly correct the systemic fibrinolytic state created by alteplase is recommended93
Level 2BC
Protamine sulfate therapy is recommended to reverse heparin-induced intracerebral haemorrhage93
Level 1B
For patients with warfarin-associated intracerebral haemorrhage, intravenous vitamin K to reverse the effects of warfarin and treatment
to replace clotting factors is recommended93
Level 1B
Full-dose anticoagulation (initially full-dose heparin and then warfarin) is recommended in patients with haemorrhagic venous infarct
owing to CVST70
Level 3C
Surgical
For patients presenting with lobar clots >30 mL and within 1 cm of the surface, evacuation of supratentorial intracerebral haemorrhage
by standard craniotomy might be considered93
Level 2BB
For patients with cerebellar haemorrhage >3 cm who are deteriorating neurologically or who have brainstem compression and/or
hydrocephalus from ventricular obstruction, surgical removal of the haemorrhage as soon as possible is recommended93
Level 1B
Antithrombotic therapy after haemorrhagic transformation
General
The decision to restart antithrombotic therapy after haemorrhagic transformation depends on the risk of subsequent arterial or venous
thromboembolism, the risk of recurrent intracerebral haemorrhage, and the clinical state of the patient
··
Anticoagulation should be considered in patients with a very high risk of thromboembolism or when there are definite indications for
these drugs93
Level 2BB
The use of long-term anticoagulation for treatment of non-valvular atrial fibrillation in patients with high risk of rebleeding should be
avoided93
Level 2AB
··=not applicable.The level of evidence is according to the Oxford Centre for Evidence-based Medicine Level of Evidence.78
Table 3: Clinical management of haemorrhagic transformation after ischaemic stroke

Review
one study,101
nearly 40% of patients with CVST had
seizures at presentation and an additional 7% of patients
with CVST had seizures within 2 weeks of diagnosis.
Non-convulsive seizures, which are difficult to detect
clinically because electroencephalography is needed for
diagnosis, might account for deteriorating function in
some cases.102
Patients with early-onset seizures have a
recurrence rate of 16%, whereas patients with late-onset
seizures have a recurrence rate of more than 50%. The
frequency of recurrent seizures is related to the infarct
and associated neuronal death.103
Recurrence of late-
onset seizures or post-stroke epilepsy increases the
disability of patients with stroke and can promote the
occurrence of vascular cognitive impairment.104,105
The
evidence of an effect of post-stroke seizures on stroke
mortality is conflicting. In one study of 1220 patients,106
the overall in-hospital mortality rate in patients who
developed early seizures (within 48 h) after stroke was
37∙9% compared with 14∙4% in patients without
seizures. Conversely, in two other studies, early seizures
were not associated with worse neurological deficits107
or increased in-hospital mortality, but were associated
with better outcome in terms of Scandinavian stroke
scale scores.108
The authors postulated that seizures
were a manifestation of a large ischaemic penumbra
that contributed to better recovery.
Management
By contrast with intracerebral or subarachnoid
haemorrhage, there is no definitive evidence or clear
guidelines for when to initiate anticonvulsant therapy,
for the choice of therapy, or for duration of therapy in
patients with ischaemic stroke. The optimal timing and
type of antiepileptic treatment for patients with post-
stroke seizures and epilepsy are still under debate. No
controlled trials have yet been done to assess the efficacy
of specific antiepileptic drugs in stroke-related
seizures.97
Thus, the choice of an anticonvulsant drug
should be guided by the individual characteristics of
each patient, including medical comorbidities and
concurrent medications.97
It is common practice to treat recurrent early seizures
with short-term antiepileptic drug treatment for about
3–6 months, whereas late seizures require long-term
conventional therapy. However, no study has been done
to assess the advantages and disadvantages of long-term
and short-term therapy.109
In a retrospective study105
that
specifically examined the risk factors for developing
epilepsy, long-term antiepileptic use was not needed to
prevent recurrence of early seizures in comparison to
late-onset seizures. In one uncontrolled study110
of
gabapentin monotherapy in patients with a first, late
post-stroke seizure, gabapentin was associated with 80%
seizure remission after 30 months.
In early-onset seizures and status epilepticus,
intravenous benzodiazepines are the first choice,
eventually followed by phenytoin, sodium valproate, or
carbamazepine.100
However, most first-generation
antiepileptic drugs, particularly phenytoin, might not be
the best choice in patients with stroke because of their
suboptimal pharmacokinetic profile and interaction with
anticoagulants or salicylates, the possibility of poor
tolerance by patients, and the likely detrimental effecton
bone health and functional recovery.97,111
Similarly, results
fromclinicalstudieshaveindicatedthatmostantiepileptic
drugs impair cognition in elderly patients.97,105
These
side-effects are reduced with the new-generation anti-
epileptic drugs, such as lamotrigine, gabapentin, and
levetiracetam.97
Hence, lamotrigine or gabapentin might
be appropriate first-line treatments for post-stroke
seizures and epilepsy in elderly patients or in younger
patients who need anticoagulants, and carbamazepine
for patients with no bone health problems and who do
not need anticoagulation.97
There is insufficient evidence
for prophylactic use of antiepileptic drugs to prevent
seizures after stroke. Prophylactic treatment with
anticonvulsants in patients with recent stroke who have
not had seizures is not recommended.59
Recurrent stroke
Clinical features
Patients with acute ischaemic stroke are at a high risk of
stroke recurrence in the first week, although this risk
declines over time.112,113
The early risk of recurrence is
about 10% at 1 week, between 2% and 4% at 1 month, and
about 5% yearly thereafter.114,115
The risk of recurrent
stroke can vary substantially among patients according to
the underlying pathological changes, lifestyles factors,
and comorbidities. The major risk factors for recurrent
stroke include old age,116
previous stroke,117
diabetes
mellitus,116
hypertension, atrial fibrillation, cardiac
diseases,118
smoking,116,118
and carotid stenosis.119
Data from
some studies have indicated that patients with large
artery atherosclerosis have the highest risk of early
clinical recurrent stroke113
compared with other
aetiological subgroups.120
Transcranial doppler can be
used to detect microembolic signals and can be useful
for identification of patients who are at risk of early
recurrent stroke.121
The prognostic score (recurrence risk
estimator at 90 days [RRE-90 score]), which integrates
clinical and imaging information to predict early risk of
recurrence after ischaemic stroke, could have the
potential to improve stroke management algorithms and
clinical practice in acute stroke care.122
Contrary to earlier
assumptions that the risk of recurrent stroke is lower for
posterior circulation than for anterior circulation, results
from a meta-analysis suggest that the risk is also high for
posterior circulation strokes.123
In a prospective study,124
the presence of vertebrobasilar stenosis was associated
with a greatly increased risk of recurrent stroke, as high
as 33% in the first month after an initial event. CT
angiography and contrast-enhanced magnetic resonance
angiography have a high sensitivity for detection of
vertebrobasilar stenosis and are more sensitive than

Review
ultrasound, which does not allow visualisation of the
whole vertebral artery.125
Early recurrent ischaemia is highly associated with
increased dependency and with early and late mortality,126
with an increasing risk of severe disability or death with
each additional recurrent stroke.112
Recurrent stroke
caused early clinical deterioration in 11∙3% of
1964 patients with stroke24
and 4∙5% of 8291 patients with
transient ischaemic stroke or minor stroke.126
Several
observational studies in human beings have investigated
whether ischaemic preconditioning occurs after transient
ischaemic stroke.127–129
However, this assessment is very
difficult, because of confounding factors, such as small
sample size, high rate of recanalisation, and low
occurrence of cardioembolic infarct in patients with
transient ischaemic stroke.127
Furthermore, whether
differences in underlying pathophysiology and treatment
of those with earlier transient ischaemic stroke could
account for differences in outcome of subsequent strokes
in these studies is unknown.128
One approach to study this factor is to use animal
models. Some animals have an initial, mild transient
stroke, followed by either a second moderate stroke or
global ischaemia.130,131
The short initial transient stroke
had dual effects on the histopathological consequences
of a second ischaemic insult. Proximal to the occlusion,
there was enhanced injury, whereas there was evidence
of neuroprotection more distal to the occlusion.131
Management
The early increased risk of recurrent stroke justifies the
need for early secondary prevention. Therefore,
identification of the cause and treatment of the stroke
when possible is imperative. There is good evidence that
the correction of abnormal physiological variables after
stroke and early mobilisation (when clinical condition
permits) improve clinical outcome and reduce the risk of
stroke recurrence.59
At least 95% of recurrent strokes
might be prevented through a comprehensive and
multifactorial approach involving the use of antiplatelet
therapy, reduction of elevated cholesterol, treatment of
hypertension, blood sugar control, anticoagulation for
atrial fibrillation, carotid endarterectomy, and lifestyle
changes.132
However, blood pressure management in the
setting of acute stroke is still controversial but hopefully
some results from ongoing trials (Efficacy of Nitric Oxide
in Stroke [ENOS]133
and Scandinavian Candesartan Acute
Stroke Trial [SCAST])134
might provide answers to the
predicament about management of blood pressure in
acute stroke.
Surgical and endovascular interventions are options
for the treatment of patients with ischaemic stroke and
symptomatic atherosclerotic narrowing of large
extracranial or intracranial arteries.135,136
The man-
agement of symptomatic intracranial atherosclerotic
disease, unlike extracranial stenosis, is controversial.
Results from the ongoing trial on the use of the
self-expandable Wingspan stent (Boston Scientific, CA,
USA) for the treatment of intracranial atherosclerotic
disease (Stenting versus Aggressive Medical
Management for Preventing Recurrent Stroke in
Intracranial Stenosis [SAMMPRIS]137
) and the Vitesse
Intracranial Stent Study for Ischemic Therapy (VISSIT)
trial138
using a balloon-expandable stent (Pharos Vitesse
Mircus Endovascular Corporation, CA, USA) might
help to provide an evidence-based management
regimen for patients. Table 4 summarises some of the
medical and surgical management approaches for the
prevention of recurrent stroke.
Delirium
Clinical features
Delirium is an acute transient disturbance of
consciousness and a change in cognition with fluctuating
intensity.156
Delirium is a common problem in the acute
stroke setting, with prevalence estimates ranging from
13% to 48%.157–160
In some studies, delirium has been
reported in up to half of patients, especially in the first
week after ischaemic stroke.16,160
The cause of stroke-
related delirium is poorly understood,161
but changes in
neurotransmitter concentrations (eg, acetylcholine and
dopamine,161–163
serotonin, norepinephrine, and GABA),
a non-specific reaction to stress, and activation of the
hypothalamic–pituitary–adrenal axis might have a
role.25,156
Hypoperfusion in the frontal, parietal, and
pontine regions, as indicated by single photon emission
CT scans in patients with delirium and acute brain
injury, might have an important role in the onset of
delirium post-stroke.164
Furthermore, in one study,157
there was an association between delirium and
hypercortisolism in acute stroke; in previous acute
confusionalstates,pre-existingcognitiveimpairment,158,160
poor pre-stroke vision,157
sleep apnoea, earlier treatment
with anticholinergic drugs, old age,156,158
severe stroke,
total anterior circulation infarction,158,160
left-sided brain
lesions,157
lesions in the thalamus and caudate nucleus,163
cardioembolic stroke, intracerebral haemorrhages,158
dysphagia on admission, neglect, and metabolic or
infectious disorders160
have all been identified as
independent risk factors for the development of post-
stroke delirium. Delirium after stroke prolongs hospital
stay and increases risk of dementia and admission to
an institution.156,159,160
Management
Recommendations about treatment of delirium after
stroke are usually similar to those for the management of
delirium in patients with other diseases, because there
are no trials of delirium specifically in acute stroke. In a
clinical trial of 853 patients aged 70 years or older admitted
to general medical wards, a multicomponent intervention
targeting cognitive impairment, sleep deprivation,
immobility, visual and hearing impairment, and
dehydration reduced the occurrence of delirium from

Review
15% in the control group to 9∙9% in the intervention
group. Although the intervention reduced the duration of
the delirious state, there was no effect on the severity of
delirium once it occurred, or on recurrence rates.165
Haloperidol is the drug of choice if sedation is needed,
although the evidence base for use of this drug is weak.166
Central post-stroke pain
Clinical features
Central post-stroke pain, also known as Dejerine-Roussy
syndrome or thalamic pain syndrome, occurs after infarcts
of the ventroposterolateral thalamus,167,168
and after
subcortical, capsular, lower brainstem infarcts,168,169
lateral
Level of evidence
Medical
Antiplatelet drugs
Antiplatelet drugs are effective in secondary stroke prevention after ischaemic stroke andTIA with an overall risk reduction estimated at about 20–25%139
In a pooled analysis140
of the two largest trials of acute aspirin use (the International StrokeTrial86
and the Chinese Acute StrokeTrial141
), aspirin reduced recurrent
ischaemic stroke by seven per 1000 treated (p<0·001) and mortality by a further four per 1000 treated (p=0·05), which outweighed the increased risk of haemorrhagic
conversion (two per 1000 patients)
Level 1A
Current evidence-based treatment guidelines have recommended antiplatelet drugs as a first-line treatment after a non-cardioembolic ischaemic stroke orTIA135,139
Level 1A
Antihypertensive drugs
Treatment of hypertension for the prevention of ischaemic stroke leads to a 30–40% reduction in risk of recurrent stroke135,142
Level 1A
Results from the CHHIPS pilot trial of treatment of blood pressure in patients with arterial ischaemic stroke (excluding alteplase-treated patients and those with
intracranial haemorrhage) indicate that blood pressure can be safely reduced with labetalol or lisinopril after acute stroke; however, there was no significant difference
in primary outcome (death or dependency, with dependency defined as a modified Rankin scale score of >3) between active treatment (labetalol or lisinopril) and
placebo at 2 weeks (61% with active treatment, 59% with placebo)
Similarly,therewas no significantdifference between activetreatment (labetalolor lisinopril)or placebo in early neurologicaldeterioration (NIHSS scoreof ≥4 points at 72 h:
6%with activetreatment vs 5%with placebo); however,therewas a borderlinedecrease in mortality at 3 months (10%with activetreatment vs 20%with placebo)143
Level 3C
Statins
Data from the SPARCL trial indicated that treatment with atorvastatin reduced the risk of recurrent stroke (16% RRR) in patients with recent stroke orTIA but no
history of heart disease144
Level 1B
Anticoagulation
The routine use of anticoagulation for preventing early recurrent stroke in patients with arterial ischaemic stroke has not been proven and is not recommended59
Results from the European Atrial Fibrillation trial indicate that oral anticoagulation prevents recurrent stroke in patients with atrial fibrillation;145
there was a 68%
RRR for a recurrent stroke in patients treated with warfarin vs only 19% for aspirin
Level 1A
A Cochrane analysis concluded that oral anticoagulation is more effective than was aspirin for the prevention of vascular events (odds ratio 0·67; 95% CI 0·50–0·91)
or recurrent stroke (odds ratio 0·49; 95% CI 0·33–0·72);146
risk of major bleeding complication, but not risk of intracranial bleeding, was significantly increased
Level 1A
In theWASID trial, warfarin was associated with significantly higher rates of adverse events and provided no benefits over aspirin against stroke and vascular death in
patients with symptomatic stenosis of a major intracranial artery, which suggests that aspirin should be used in preference to warfarin for patients with intracranial
arterial stenosis147
Level 1A
Glucose regulation
On the basis of subanalysis of the results of three randomised trials (GIST-UK,THIS, and GRASP) and additional studies, aggressive glucose regulation might be
beneficial in hyperglycaemic patients with diabetes who have moderate to severe stroke148
··
Hyperglycaemia (>140 mg/dL) should be treated with insulin in patients with acute ischaemic stroke59
Level 2C
For patients with type 2 diabetes who do not need insulin after stroke, individualised oral antidiabetic therapy is recommended60
Level 3B
Surgical
Carotid endarterectomy
Carotid endarterectomy is the best-studied surgical intervention for symptomatic carotid stenosis, and data from two large trials indicate that early intervention
reduces recurrent stroke risk149,150
The benefit is much greater if patients are operated on within the first 2 weeks after the initial event151
Level 1A
Carotid artery balloon angioplasty and stenting
Owing to a high mortality, carotid angioplasty and stenting are typically reserved for patients who have a contraindication to carotid endarterectomy or who have
re-stenosis after carotid endarterectomy152
Level 2B
Extracranial/intracranial bypass
Extracranial/intracranial bypass is being assessed in the Carotid Occlusion Surgery Study for use in patients with occlusion of the internal carotid artery who cannot be
treated with carotid endarterectomy or endovascular interventions153
··
Vertebral angioplasty and stenting
Vertebral angioplasty and stenting might offer a potential treatment for patients with vertebrobasilar stenosis;154
however, results from the only published randomised
trial of angioplasty and stenting for vertebral artery disease (CAVATAS) have not shown a benefit of endovascular treatment of vertebral artery stenosis, but this was
based on only a small number of patients155
Level 3C
NIHSS=National Institutes of Health stroke scale. RRR=relative risk reduction.TIA=transient ischaemic
attack. CHHIPS=Controlling Hypertension and Hypotension Immediately Post Stroke. SPARCL=Stroke Prevention by Aggressive Reduction in Cholesterol Levels.WASID=Warfarin–Aspirin Symptomatic
Intracranial Disease.The GIST-UK=Glucose Insulin in Stroke–UK.THIS=Treatment of Hyperglycaemia in Ischaemic Stroke. GRASP=Glucose Regulations in Acute Stroke Patients. CAVATAS=Carotid andVertebral
ArteryTransluminal Angioplasty Study.
Table 4: Clinical management for the prevention of recurrent stroke

Review
medullary infarcts (Wallenberg’s syndrome),170
and
anterior spinal artery syndrome.171
The infarcts are
characterised by involvement of the spinothalamic system
anywhere in its course with sparing of the lemniscal
pathways, as indicated by the normal somatosensory-
evoked potentials in patients with central post-stroke
pain.167,170
The prevalence of central post-stroke pain is
estimated to be between 1% and 12% in all patients with
stroke,7,169,172
whereas about 18% of patients with a
somatosensory disturbance develop central post-stroke
pain.169
The onset time for symptoms to develop is variable,
ranging from days to years, but symptoms usually occur
several months later.172
In one study of 180 patients,173
pain
onset occurred within the first week after stroke in 36% of
patients. Central post-stroke pain can interfere with
sleep169,172
and can compromise rehabilitation.168
Management
Differentiation between central post-stroke pain and
other types of post-stroke pain is important because
different treatment strategies might be needed. A new
grading system for central post-stroke pain was proposed
to distinguish patients with central post-stroke pain from
patients with peripheral pain.172
The new proposed
grading system requires the presence of pain with a
distinct convincing distribution, an association between
history and relevant lesion, clinical examination
suggestive of negative or positive sensory signs within
the area, and confirmation by diagnostic tests (eg, CT or
MRI) for the presence of a relevant disease or lesion
affecting the somatosensory system.174
Despite many guidelines for the treatment of
neuropathic pain, there are few guidelines for the
treatment of central post-stroke pain. Amitriptyline and
lamotrigine are recommended as first-line drugs and
mexiletine, fluvoxamine, and gabapentin as second-line
drugs.175,176
Lidocaine and propofol are recommended for
short-term pain relief in patients with central post-stroke
pain.175
Table 5 summarises the recommended drug
therapy for central post-stroke pain.
Headache
Clinical features
Headache is a common accompaniment of acute ischaemic
stroke, occurring before (sentinel headache; 43–60%),
concurrently (onset headache; 25–30%), or after (late-onset
headache; 14–27%) focal neurological signs.177,178
The
International Headache Society has established criteria to
identify headache associated with stroke. These criteria
include requirements for onset of a new type of headache
(ie, not an exacerbation of a pre-existing type of headache)
and a headache that occurs simultaneously or in very close
temporal relation with the onset of other neurological
signs.179
Ischaemic stroke can cause a migraine syndrome
in patients who previously did not have a history of
migraine or can precipitate a migraine attack in patients
who are prone to migraine. Similarly, patients who are
affected with migraine after stroke might continue to have
recurrent attacks of migraine.180
Headache after acute
stroke is usually severe and generally starts on the first day
of stroke, lasts about 3∙8 days, and is most frequently
continuous and of pressure-type in nature.181
Headaches
are more common after major strokes177,182
and significantly
more frequent in patients with vertebrobasilar territory
ischaemia than in patients with anterior circulation
stroke,183
probably because vessels in the posterior
circulation are more densely innervated by nociceptive
afferents than are those in the anterior circulation.177
Most
aspects of onset headache are still debated and there is no
precise definition, although this type of headache might
be an indication of the initial vascular occlusion and
resultant ischaemia.183
In one study,184
onset headache was
a strong predictor of early neurological deterioration in
acute stroke (sensitivity 56%, specificity 99%, positive
predictive value 98%). Delayed headache might be
attributable to various factors, including oedema,
intracranial hypertension, haemorrhagic transformation,
delayed effects of products of thrombosis and ischaemia,
or delayed disturbance to the function of the
trigeminovascular system.183,184
Headache can also be
secondary to treatments (eg, dipyridamole) used for
secondary stroke prevention.135
Management
There are no specific studies that have investigated
definite treatments and their effects in patients with
headache at stroke onset or those with delayed-onset
headache. Post-stroke headache is usually mild and often
resolves spontaneously or might respond to simple
analgesics such as paracetamol, but opiates should be
avoided because they might mask the clinical picture and
can have possible adverse effects such as respiratory
depression and hypotension.185
Level of evidence
Antidepressants
Tricyclic antidepressants are first-line drugs for neuropathic pain with demonstrable
beneficial effect176
··
Amitriptyline is effective, safe, and well tolerated compared with placebo Level 2B
Fluvoxamine is effective175
Level 2B
Anticonvulsants
Lamotrigine is moderately effective and well tolerated175,176
Level 1B
Gabapentin is well tolerated but not effective173
Level 3C
Opiates
Both morphine and naloxone are ineffective and often cause side-effects175
Level 2B
Anaesthetics
Anaesthetics are effective for a short period ··
Lidocaine is effective173
Level 2B
Propofol and pentothal are effective173
Level 3C
Mexiletine is not effective and causes several side-effects173
Level 3C
Table 5: Clinical management of central post-stroke pain

Review
Sleep disorders
Clinical features
Sleep disorders are frequent in the initial stages after
stroke. Sleep disorders in the form of increased sleep
needs (hypersomnia), excessive daytime sleepiness, or
insomnia are present in about 10–50% of patients with
stroke.186,187
Persistent, severe sleep-wake disturbances are
suggestive of bilateral paramedian thalamic, left-sided
thalamic or brainstem infarcts, and large hemispheric
stroke with mass effect.186,187
Sleepiness can also be part of
a terminal brainstem syndrome.188
Other possible
associations or precipitating factors include depression,
anxiety, sleep-disordered breathing, drugs, post-stroke
pain, medical complications (urinary or respiratory
infections, nocturia, dysphagia), and environmental
factors such as noise and light.186
Sleepiness can be
caused by interruption of the arousal systems at the level
of the mesencephalic reticular formation from
ischaemia.188
As the generation and consolidation of non-
rapid eye movement sleep involves sleep spindles, a basic
causative mechanism of sleep-wake disturbances might
be indicated by changes in spindle activity.186
Although
sleep disturbance is not life-threatening, an early
reduction in sleep stage 2 after stroke has been associated
with a poor prognosis188
and this disturbance might
negatively affect rehabilitation and functional outcome.186
Management
Post-stroke sleep-wake disturbance management is a
challenging therapeutic goal. There are no systematic
studies or guidelines on the treatment of sleep disorders
after stroke. Precipitating factors such as medical
complications should be addressed first. Mianserin is
beneficialintheearlytreatmentofpost-strokeinsomnia.186
Bromocriptine, modafinil, and methylphenidate can
improve sleep behaviour in post-stroke hypersomnia.186,187
Treatment of associated depression with antidepressants
can improve post-stroke sleeping problems and might be
preferable for long-term management of post-stroke
insomnia.186
Non-pharmacological management should
include avoidance of precipitating factors.186
Sleep-disordered breathing
Clinical features
Sleep-disordered breathing in patients presenting with
obstructive, central, or mixed apnoeas is common after
stroke, occurring in about 50–72% of patients, and is
both a risk factor and a consequence of stroke.186,187,189
The
most common form of sleep-disordered breathing is
obstructive sleep apnoea, which is caused by cessation of
nasal flow because of collapse of the upper airway.186,187
Sleep-disordered breathing might lead to early neuro-
logical worsening, thus affecting stroke rehabilitation
and leading to poor outcome.186
This breathing disorder
is an independent prognostic factor for increased
mortality after a first episode of stroke190
and for increased
risk of stroke recurrence.186
Management
Sleep-disordered breathing can improve spontaneously
after stroke, but might need treatment. Despite the
conflicting evidence on the use of continuous positive
airway pressure breathing in patients with stroke who
have sleep-disordered breathing,189
these patients, and
those with obstructive sleep apnoea in particular, should
be treated with continuous positive airway pressure
breathing.60
Conclusions
Neurological complications occur early after ischaemic
stroke onset, and can lead to death within the first few
days of stroke. The webappendix lists other neurological
complications of acute ischaemic stroke. Improved
detection and management of neurological compli-
cations in the acute phase after stroke could save
patients’ lives and help to reduce the burden of stroke.
Therefore, we believe that attempts to prevent and treat
neurological complications after ischaemic stroke
should be made swiftly and aggressively. Until enough
evidence is available from more research, some of
the recommendations will be based on empirical or
restricted anecdotal information rather than being
evidence based. We believe that there is a clear need for
further research on the prevention and treatment of
neurological complications in acute ischaemic stroke to
improve the level of evidence of current guidelines and
recommendations.
Contributors
JSB did the clinical literature search and wrote the paper, R-LC did the
laboratory literature search and drafted the paper, IQG contributed
images and reviewed the manuscript, and AMB reviewed and made
critical revisions of this paper.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
We are grateful for funding received from the Dunhill Medical Trust, the
Biomedical Research Centre, the National Institute for Health Research,
the Fondation Leducq, and the Oxford Radcliffe NHS Trust, UK.
Search strategy and selection criteria
Relevant evidence for this Review was identified through
searches of PubMed and the Cochrane Library, and by
searching and cross-referencing the reference lists and main
journal contents pages. Search terms included “stroke”,
“cerebrovascular accident”, “isch(a)emic stroke”, “cerebral
isch(a)emia”, “complications”, “neurological complications”,
“management”, “treatment”, and “outcome”.The search
included both human and animal studies, and was limited to
studies published in English before November, 2010.The final
reference list was selected on the basis of relevance to the
topics covered in the Review. Guidelines for the management
of acute ischaemic and intracerebral haemorrhage by the
American Heart Association and American Stroke Association
and the European Stroke Organisation were also reviewed.
See Online for webappendix

Review
Figure 3 was provided by Margaret Esiri (Department of Clinical
Neurology and Neuropathology, Oxford Radcliffe NHS Trust, UK).
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