Neurological complications of acute ischaemic stroke

Review

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 usually the 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. www.thelancet.com/neurology Vol 10 April 2011

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 complications 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 management 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.

Lancet Neurol 2011; 10: 357–71 Published Online January 18, 2011 DOI:10.1016/S14744422(10)70313-6 Acute Stroke Programme, Department of Medicine and Clinical Geratology, Oxford Radcliffe NHS Trust, 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 Acute Vascular 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 [email protected]. ac.uk

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 357

Review

Indredavik Navarro Hong Rocco Hung et al7 et al8 et al9 et al10 et al11

Heuschmann Cavallini Weimar Roth et al12 et al13 et al2 et al14

Grau Langhorne Johnston Pinto Davenport Kalra et al15 et al16 et al6 et al17 et al18 et al19

Dromerick and Reding5

Study design

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

IS, HS

IS, HS

Type of stroke

IS, HS

IS, HS

IS

IS, HS

IS, HS

IS

IS

IS

IS, HS

IS

IS

IS

IS, HS

IS, HS

Timing

Acute, subacute

Acute

Acute Subacute

Subacute

Acute

Acute

Acute

Subacute

Acute Acute, subacute

Acute, subacute

Acute Subacute

Subacute

Subacute

Total complication 64 rate (%)

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

··

Brain oedema (%)

··

··

··

··

··

··

··

··

··

··

··

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

··

··

··

Delirium or 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

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.47 358

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. www.thelancet.com/neurology Vol 10 April 2011

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 CVST describes a subset of patients with rapid deterioration 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

A

B

C

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.

A

B

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 lifethreatening 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 Neuroimaging 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 bed to a 20–30º angle in an attempt to improve venous drainage. Additionally, factors that www.thelancet.com/neurology Vol 10 April 2011

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).

A

B

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).

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 lifethreatening 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.66 359

Review

Description

Level of evidence

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

Routine use of anticoagulation for improving neurological outcome in arterial ischaemic stroke has not been proven and is not recommended59 Intravenous anticoagulation with heparin or subcutaneous anticoagulation with low-molecular-weight heparin followed by oral anticoagulation is the first-line treatment for symptomatic CVST70 Endovascular chemical thrombolysis or mechanical thrombectomy might be needed when systemic anticoagulation therapy fails or is considered to be high risk in patients with CVST71 Management of isolated intracranial hypertension owing to CVST might involve a lumbar puncture to drain CSF before starting heparin when patients develop papilloedema that might threaten visual acuity; this event is usually followed by a rapid improvement of headache and vision deficits67

Level 3C

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

Medical

Surgical

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 Oedema Trial. DESTINY=Decompressive Surgery for the Treatment of Malignant Infarction of Middle Cerebral Artery.

Table 2: Clinical management of brain oedema after ischaemic stroke

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 360

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 after ischaemic stroke. Other risk factors for thrombolysisrelated 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 www.thelancet.com/neurology Vol 10 April 2011

Review

A

F

B

C

G

D

H

E

I

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 shows T2*-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.

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 transformation 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 www.thelancet.com/neurology Vol 10 April 2011

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 intracerebral 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 361

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associated symptoms, which might require neurosurgical clot evacuation in deteriorating patients. The decision as to whether or when 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. 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 factor VIII 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 Level 1B to replace clotting factors is recommended93 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

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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 lateonset 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 poststroke 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 www.thelancet.com/neurology Vol 10 April 2011

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 effect on bone health and functional recovery.97,111 Similarly, results from clinical studies have indicated that most antiepileptic drugs impair cognition in elderly patients.97,105 These side-effects are reduced with the new-generation antiepileptic 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 363

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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 management of symptomatic intracranial atherosclerotic disease, unlike extracranial stenosis, is controversial. Results from the ongoing trial on the use of the 364

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 strokerelated 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 confusional states, pre-existing cognitive impairment,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 poststroke 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 www.thelancet.com/neurology Vol 10 April 2011

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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 and TIA 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 Stroke Trial86 and the Chinese Acute Stroke Trial141), 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 or TIA135,139

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

Level 3C 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, there was no significant difference between active treatment (labetalol or lisinopril) or placebo in early neurological deterioration (NIHSS score of ≥4 points at 72 h: 6% with active treatment vs 5% with placebo); however, there was a borderline decrease in mortality at 3 months (10% with active treatment vs 20% with placebo)143 Statins Data from the SPARCL trial indicated that treatment with atorvastatin reduced the risk of recurrent stroke (16% RRR) in patients with recent stroke or TIA 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) Level 1A 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 In the WASID 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

The level of evidence is according to the Oxford Centre for Evidence-based Medicine Level of Evidence.78 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 and Vertebral Artery Transluminal Angioplasty Study.

Table 4: Clinical management for the prevention of recurrent stroke

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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

The level of evidence is according to the Oxford Centre for Evidence-based Medicine Level of Evidence.78

Table 5: Clinical management of central post-stroke pain

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 somatosensoryevoked 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 366

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 www.thelancet.com/neurology Vol 10 April 2011

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Sleep disorders Clinical features

Search strategy and selection criteria

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 nonrapid 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

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.

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

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 beneficial in the early treatment of post-stroke insomnia.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 neurological 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 www.thelancet.com/neurology Vol 10 April 2011

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 complications 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.

See Online for webappendix

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.

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