28(4) NEUROLOGÍA€¦ · Neurología. 2013;28(4):236—249 NEUROLOGÍA REVIEW ARTICLE Clinical...

N

R

C

MJBSAETS

RA

2

2

Document downloa

eurología. 2013;28(4):236—249

NEUROLOGÍAwww.elsevier.es/neurologia

EVIEW ARTICLE

linical practice guidelines in intracerebral haemorrhage�

. Rodríguez-Yáñez, M. Castellanos, M.M. Freijo, J.C. López Fernández,. Martí-Fàbregas, F. Nombela, P. Simal, J. Castillo∗, E. Díez-Tejedor (Coordinator),. Fuentes (Secretaria), M. Alonso de Leciñana, J. Álvarez-Sabin, J. Arenillas,. Calleja, I. Casado, A. Dávalos, F. Díaz-Otero, J.A. Egido, J. Gállego, A. García Pastor,. Gil-Núñez, F. Gilo, P. Irimia, A. Lago, J. Maestre, J. Masjuan, P. Martínez-Sánchez,. Martínez-Vila, C. Molina, A. Morales, F. Purroy, M. Ribó, J. Roquer, F. Rubio,. Segura, J. Serena, J. Tejada, J. Vivancos♦, representing the ad hoc committee of theEN Study Group for Cerebrovascular Diseases:

eceived 23 February 2011; accepted 6 March 2011vailable online 4 May 2013

KEYWORDSIntracerebralhaemorrhage;Guidelines;Stroke

Abstract Intracerebral haemorrhage accounts for 10% to 15% of all strokes, however it has apoor prognosis with higher rates of morbidity and mortality. Neurological deterioration is oftenobserved during the first hours from onset, and determines the poor prognosis. Intracerebralhaemorrhage, therefore, is a neurological emergency which must be diagnosed and treatedproperly as soon as possible. In this guide we review the diagnostic procedures and factors thatinfluence the prognosis of patients with intracerebral haemorrhage and we establish recom-mendations for the therapeutic strategy, systematic diagnosis, acute treatment and secondaryprevention for this condition.© 2011 Sociedad Española de Neurología. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVEHemorragiaintracerebral;Guías;

Guías de actuación clínica en la hemorragia intracerebral

Resumen La hemorragia intracerebral sólo representa entre el 10 y el 15% de todos los ictus,sin embargo condiciona un peor pronóstico, con unas tasas más elevadas de morbilidad y mor-

ded from http://www.elsevier.es, day 06/07/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Ictus talidad. Es frecuente que durante las primeras horas tras el inicio de los síntomas se produzca lo cual condiciona un peor pronóstico, por lo que la hemorragia
un empeoramiento clínico,
intracerebral constituye una emergencia neurológica en la que debe realizarse un diagnós-tico y tratamiento adecuado de manera precoz. En esta guía realizamos una revisión de losprocedimientos diagnósticos y los factores que influyen en el pronóstico de los pacientes conhemorragia intracerebral y establecemos unas recomendaciones para la estrategia asistencial,

� Please cite this article as: Rodríguez-Yáñez M, et al. Guías de actuación clínica en la hemorragia intracerebral. Neurología.013;28:236—49.∗ Corresponding author.

E-mail address: [email protected] (J. Castillo).♦ The affiliations of the authors and composition of the committee are listed in Addendum 1.

173-5808/$ – see front matter © 2011 Sociedad Española de Neurología. Published by Elsevier España, S.L. All rights reserved.

dx.doi.org/10.1016/j.nrleng.2011.03.011http://www.elsevier.es/neurologiamailto:[email protected]

Clinical practice guidelines in intracerebral haemorrhage 237

sistemática diagnóstica, tratamiento en fase aguda y prevención secundaria en la hemorragiaintracerebral.© 2011 Sociedad Española de Neurología. Publicado por Elsevier España, S.L. Todos los derechosreservados.

iwsacrruti

C

IsclfshprwI

P

Tcpatrcptst

C

Ohtiaa

Document downloaded from http://www.elsevier.es, day 06/07/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Introduction

Intracerebral haemorrhage (ICH) refers to the collection ofblood within the cerebral parenchyma as the result of vas-cular rupture unrelated to trauma. Although the bleed mayleak into the ventricular system or the subarachnoid space,it always begins in brain tissue. This trait distinguishes ICHfrom subarachnoid haemorrhage and primary intraventricu-lar haemorrhage.

Haemorrhages are categorised as primary or secondarydepending on the cause of the bleed. Primary ICHs arethe most common and they are caused by the rupture ofany blood vessel within the brain’s normal vascular sys-tem after the vascular wall is weakened by degenerativeprocesses secondary to arterial hypertension (AHT) or amy-loid angiopathy. Secondary ICHs are caused by the ruptureof blood vessels that are congenitally abnormal or newlyformed, or of vessels that contain vascular wall abnormali-ties or weaknesses caused by coagulation disorders. They areassociated with such entities as tumours, arteriovenous mal-formations (AVM), coagulation disorders, substance abuse,or haemorrhages inside areas of ischaemia.1

ICH incidence varies by country, race, age, and sex, and itis closely related to AHT prevalence. In Europe, its incidencerate is approximately 15 cases per 100 000 inhabitants.2

While ICH is only present in 10% to 15% of all strokes, it isassociated with a poorer prognosis and higher morbidity andmortality rates. The mortality rate during the first monthafter ICH is 40.4%.3 Most deaths occur in the first 2 days,and only 20% of the total patients are independent 6 monthsafter having had an ICH.4 Mortality at 30 days is related tothe size and location of the ICH. In patients with an ini-tial haemorrhage volume greater than 60 cm3, mortality fordeep haemorrhages is 93%, and for lobar haemorrhages, 72%.If initial volume is less than 30 cm3, mortality rates are 39%for deep haemorrhages, 7% for lobar haemorrhages, and 57%for cerebellar haemorrhages.3

The incidence of ICH is on the rise despite improved con-trol over certain risk factors. This is related to the ageing ofthe population. However, the higher incidence rate amongthe elderly may also contribute to the decrease in mortal-ity recorded in recent years, because of more pronouncedcerebral atrophy.

The most important risk factor for developing ICH inall age groups and both sexes is AHT, whether systolicor diastolic. AHT is present in 60% of all cases. ChronicAHT provokes degenerative changes in arteriole walls thatfavour vascular obstructions. This in turn causes the lacunarinfarcts, leukoaraiosis, and vascular rupture that are respon-sible for the appearance of ICH.5 AHT may also be an acute

cause of ICH by affecting small arterioles that are at risk dueto hypertrophy of their walls. This leads to haemorrhagessuch as those caused by certain drugs or haemorrhagesoccurring after endarterectomy or angioplasty.6 Another

ipms

mportant cause of ICH is cerebral amyloid angiopathy,hich is the leading cause of lobar haemorrhage in elderly

ubjects. This degenerative process affects small arteriesnd arterioles located in the leptomeninges and cerebralortex. Haemorrhages of this type are superficial, oftenecurring and multiple, and tend to be located in poste-ior areas of the brain. They appear in elderly subjects, andp to half of all patients present cognitive decline.7 Lastly,here are other less common causes of ICH which are listedn Table 1.

are strategy and systematic diagnosis

CH is a neurological emergency, and therefore rapid diagno-is and management are fundamental; as mentioned before,linical exacerbation is common in the first few hours fol-owing ICH. This factor is directly associated with a poorerunctional prognosis. A number of observational studieshow that 1 in 3 patients with supratentorial haemorr-age and most patients with a posterior fossa haemorrhageresent an altered level of consciousness.8 Owing to the highisk of early neurological impairment, which is associatedith poor long-term prognosis, care must be provided to

CH patients as quickly as possible.

re-hospital care

he main objective of pre-hospital care is maintainingorrect cardiovascular and respiratory function and trans-orting the patient to the nearest hospital with facilities forcute-phase stroke patients. Additional objectives includeaking the patient’s medical history, especially events occur-ing at symptom onset and information about prior medicalonditions. It is important to alert the receiving hospitalrior to the arrival of a patient with a possible stroke sohat staff can prepare the equipment needed to assess thetroke. This cuts down on delays in completing neuroimagingests in the emergency department.9

are in the emergency department

nce the haemodynamic and cardiorespiratory functionsave been stabilised, further objectives include confirminghe type of stroke to differentiate a haemorrhage fromschaemia or other brain lesions; gathering informationbout ICH aetiology; preventing potential complications;nd starting appropriate treatment.

The clinical course of ICH may not offer data distinguish-

ng that entity from other types of stroke unless there areathognomonic clinical features pointing to a cerebral hae-orrhage. However, certain signs and symptoms are more

uggestive of ICH than of ischaemia. One symptom that

238

Table 1 Causes of non-traumatic intracerebralhaemorrhage.

High blood pressureAmyloid angiopathyEthanolHaematologicaldiseases

Von Willebrand factor deficiencyHaemophiliaAfibrinogenemiaHyperfibrinolysis syndromesIdiopathic thromboticthrombocytopenic purpuraDisseminated intravascularcoagulationCoagulation disorders andthrombocytopenia in liver diseaseThrombocytopeniaThrombocythemiaMultiple myeloma

Anticoagulants andfibrinolytic drugs

Vitamin K antagonistsHeparinStreptokinaseUrokinaseTissue plasminogen activator

Brain tumours Primary tumoursMetastasis

Vascularmalformations

AneurysmsArteriovenous malformationsVenous angiomasCavernomasTelangiectasias

Moyamoya syndromeNon-infectiousinflammatoryvascular disease

Vasculitis

Infectiousinflammatoryvascular disease

Mycotic aneurysms

sympathomimeticdrugs

CocaineAmphetamines

aImvaa

d((asoadaud

a(a

ttgetddfum

L

Icfcpatabu

doa

N

TgAhatibanddoCahsi

aeac


CrackNasal decongestants

ppears frequently is headache, which is present in 40% ofCH cases and only 17% of ischaemic stroke cases. Other com-on symptoms, present in 50% of ICH cases, include nausea,

omiting, and decreased level of consciousness; these signsre exceptional in ischaemic stroke. We also find increasedrterial blood pressure in almost 90% of ICH cases.10

When taking medical histories, doctors must emphasiseata such as time of symptom onset, vascular risk factorsAHT, diabetes, hypercholesterolaemia), substance abusetobacco, alcohol, cocaine, amphetamines), drugs (antico-gulants, antiplatelet drugs, nasal decongestants, diet pills,timulants, sympathomimetic drugs), prior traumatic eventr recent surgery (especially endarterectomy or carotidngioplasty, which may be associated with reperfusion syn-

rome), pre-existing cognitive decline (related to amyloidngiopathy), seizures, systemic illnesses related to coag-lation disorders (liver disease, vasculitis, cancer, bloodyscrasia), and any family history of neurological diseases

Idtt

M. Rodríguez-Yáñez et al.

ssociated with increased risk of cerebral bleedingincluding arteriovenous malformations and intracranialneurysms).

In addition to assessing neurological deficit in the ini-ial examination, doctors must evaluate respiration andhe haemodynamic state. To this end, an electrocardio-ram and chest radiography are needed. A detailed physicalxamination that includes a cardiovascular study and oph-halmoscopy is often helpful for establishing an aetiologicaliagnosis. In cases in which the patient has remained bedrid-en during long periods of time, doctors should checkor potential associated complications, including pressurelcers, compartment syndromes, rhabdomyolysis, and trau-atic lesions.

aboratory tests

t is important to perform blood tests to gather results foromplete blood count, electrolytes, urea, creatinine, liverunction parameters, and glucose. High creatinine and glu-ose levels are associated with haemorrhage growth and aoor functional prognosis.11,12 Doctors should also complete

coagulation study including activated partial thromboplas-in time (APTT) and INR. This is done because haemorrhagesssociated with anticoagulant treatment are accompaniedy increased risk of morbidity and mortality13,14 and requirergent treatment to reverse the coagulation disorder.

Younger patients should undergo urine screening toetect toxic substances such as cocaine and other sympath-mimetic drugs and women of childbearing age will require

pregnancy test.

euroimaging

he presence of sudden-onset focal neurological deficit sug-ests a vascular origin unless there is another proven cause.lthough some of the symptoms described above, such aseadache, vomiting, and decreased level of consciousness,re suggestive of ICH, these findings are not specific andhey do not enable us to differentiate between neurolog-cal deficit caused by cerebral ischaemia and that causedy a haemorrhage. For this reason, neuroimaging studiesre fundamental. Both computed tomography (CT) and mag-etic resonance imaging (MRI) may be used for the initialiagnosis. CT is highly sensitive for identifying haemorrhageuring the acute phase, and it is regarded as the techniquef choice. Gradient echo MRI sequences are as sensitive asT for detecting blood during the acute phase of stroke,nd they are even more sensitive than CT for detecting oldaemorrhages.15 However, the availability, lower costs, andhorter times associated with CT mean that this techniques more commonly used than MRI.

CT allows us to pinpoint the location of the haemorrhagend identify its effects (mass effect, oedema, ventricularxtension, and subarachnoid extension). Furthermore,dministering contrast intravenously lets us diagnoseertain secondary causes of ICH, such as AVMs or tumours.

n the first hours of the process, ICH presents as increasedensity in the cerebral parenchyma, which is explained byhe haemoglobin in the escaped blood. As the days pass,he haemorrhage can be found in the centre of a hypodense

anshottuvctiwf

M

TIccipcmnam


Clinical practice guidelines in intracerebral haemorrhage

ring. At first, this appearance is caused by retraction of theclot; at a later point, it is caused by vasogenic oedema.At the end of several weeks, the high initial density of thehaemorrhage begins to decrease from the perimeter towardthe centre. The final stage of an ICH as viewed by CT istotal reabsorption of haemorrhagic tissue. This produces aresidual cavity that is indistinguishable from that left by anold cerebral infarct.16

Some data on the location and morphology of ICHsdetected using CT may be important to establish an aetio-logical diagnosis. The most common location of hypertensiveICH is the putamen (30%—50%), followed by subcorticalwhite matter (30%) and the cerebellum (16%). If the loca-tion is lobar, the role played by AHT is less significant andamyloid angiopathy is more likely to be the cause. Thisis especially true in patients older than 60 years with acertain level of cognitive decline.17 Other common causesof lobar haemorrhages are arteriovenous malformations(7%—14%), tumours (7%—9%), and blood dyscrasias, includ-ing anticoagulant treatment (5%—20%). In 3% of all patients,the haemorrhage remains limited to the intraventricularsystem.18

Since the haemorrhage often grows during the acutephase, and this phenomenon is associated with neurologi-cal deterioration and increased morbidity and mortality,19

research is being done on techniques that may help us pre-dict haemorrhage growth. The use of CT angiography withcontrast may help identify patients at risk for haemorrhageexpansion based on the presence of isolated contrast in thehaemorrhage (spot sign).20,21 This technique is also usefulfor detecting secondary causes of ICH, such as arteriovenousmalformations, tumours, or venous thrombosis.

MRI scans contribute further information about the stageof development of the ICH. Differences in these scans haveto do with the way that images of haemoglobin changethroughout the catabolism process. In the early stages ofacute-phase ICH (initial hours), oxyhaemoglobin levels in thehaemorrhage are high and the MRI shows hypointensities inT1 and hyperintensities in T2. In later stages of acute-phaseICH (first few days), oxyhaemoglobin converts to deoxy-haemoglobin from the centre of the bleed to its perimeter.In the MR image, this appears as a hypointense area inT2, surrounded by a hyperintense ring corresponding to theoedema. In late stages of ICH (after several weeks), deoxy-haemoglobin is transformed into methaemoglobin from theperimeter to the centre. The change appears as a periph-eral hyperintense signal in T1 which progressively extendsto the entire area of the haemorrhage. In the recoveryphase (months after onset), all of the haemoglobin has beentransformed into haemosiderin, which creates a pronouncedhypointense signal in T2-weighted sequences. MRI gradient-echo sequences are highly sensitive for detecting smallchronic haemorrhages, called microbleeds, which measureless than 5 mm. Microbleeds appear as hypointense pinpointlesions and indicate the presence of chronic haemosiderindeposition.22 Magnetic resonance angiography (MRA) is auseful technique for detecting vascular lesions associatedwith ICH. It has a high sensitivity for detecting aneurysms

and AVMs.23 MRA is also useful during the venous phase whenthere is a suspicion of sinus thrombosis as the cause of thehaemorrhage. The technique is as reliable as CT angiographywith contrast during the venous phase.

iets

239

Conventional arteriography may be useful when there is strong suspicion of a secondary cause and results fromon-invasive studies are negative. Radiological signs thatuggest a secondary cause are presence of subarachnoidaemorrhage, unusual haemorrhage shape (non-circular),edema size not proportional to haemorrhage evolutionime, uncommon location, or presence of abnormal struc-ures. The probability of detecting a secondary cause bysing angiography is higher in these cases.24 For suspectedasculitis, conventional angiography is the technique ofhoice. In some cases, as with cavernous angiomas, conven-ional angiography may yield negative results. Arteriographys not useful, however, in hypertensive patients older than 45ith haemorrhages in the putamen, thalamus, or posterior

ossa.25

Recommendations for the care strategy and system-atic diagnosis

1. An emergency brain CT or MRI scan is recommendedon an emergency basis in order to distinguishbetween ICH and other ischaemic or structurallesions (level of evidence 1, grade A recommenda-tion).

2. CT angiography with contrast may be useful foridentifying patients who are at risk for haemorrhagegrowth (level of evidence 2b, grade B recommenda-tion).

3. CT angiography and/or MRI angiography may beuseful for identifying structural lesions that areaetiologically related to ICH when there is a suspi-cion based on radiological findings (level of evidence2a, grade B recommendation).

4. Conventional angiography must be considered inpatients when the ICH aetiology has not been deter-mined by non-invasive methods and radiologicalsigns are suggestive of a structural lesion (level ofevidence 4, grade C recommendation).

edical treatment

reatment for patients with ICH is fundamentally medical.t is based on maintaining vital functions, neurologi-al monitoring, maintaining homeostasis, and preventingomplications.26 The key objective of all of these activitiess to prevent increases in haemorrhage size, which wouldrovoke a mass effect, increase intracranial pressure, andause secondary neurological impairment. All ICH patientsust be cared for in hospitals that include a neurologist,

eurosurgeon, CT, stroke unit, and intensive care units thatre available 24 hours a day. If the patient does not requireechanical ventilation, care measures should be carried out

n the stroke unit,27—30 provided that the patient can bexamined by a neurosurgeon and has the option of beingransferred to the intensive care unit at any time of dayhould it become necessary.

2

G

RAsdmthuIrafsi

emwdmopraosacthbaaossiliio

NShofrml

CIapigtP

ingi

bircopdmhphnmdihr

psoathpwelbgowtipcfntttwatfiht

tho2


40

eneral care

esuscitationll patients with ICH must be cared for in hospitals withtroke units and ICUs available 24 hours a day. If the patientoes not require mechanical ventilation, life supporteasures should be applied in the stroke unit, provided

hat the patient can be examined by a neurosurgeon andas the option of being transferred to the intensive carenit at any time of day if necessary. Admission to a generalCU rather than a specialised neurological ICU increasesisk of death by a factor of 3.4.31 Likewise, admission to

stroke unit increases probability of survival and a goodunctional prognosis by 64%.32 Recent population-basedtudies suggest that good medical care has a significantmpact on mortality and morbidity in ICH.33

An initial assessment of the patient will allow us tovaluate the patient’s level of consciousness and ability toaintain spontaneous breathing. However, even in patientsith a high level of consciousness, it is recommended thatoctors know the oxygen saturation level. The simplesteans of measuring oxygen saturation is by using a pulse

ximeter. If arterial oxygen saturation is less than 92%, theatient will require an oxygen mask with a flow that willaise oxygen saturation to above that threshold. Performingn arterial blood gasometry study is optional and dependsn the patient’s condition. Up to a third of the patients withupratentorial haemorrhage and almost all patients with

posterior fossa haemorrhage present decreased level ofonsciousness or bulbar muscle dysfunction that results inhe need for intubation.34 Early intubation in patients whoave suffered from very large haemorrhages accompaniedy decreased level of consciousness may help preventspiration pneumonia. In general, endotracheal intubationnd gastric aspiration are indicated in patients with a scoref less than 8 on the Glasgow coma scale (GCS). Intubationhould be performed after administration of drugs thatuppress the tracheal reflex, since that reflex may causencreased intracranial pressure and exacerbate the neuro-ogical lesion. In any case, the indication for orotrachealntubation is debatable. There may be reason to considert only if doctors plan to apply other treatment measures inrder to improve the patient’s neurological situation.

eurological monitoringince a high number of patients experience a decline in theours following the stroke, periodic monitoring of the levelf consciousness and the neurological deficit should be per-ormed during at least the first 72 hours. The most widelyecommended scales are the NIH stroke scale (NIHSS) foreasuring neurological deficit35 and the GCS for measuring

evel of consciousness due to its simplicity and reliability.36

ontrol over arterial pressuren most patients with an intracerebral haemorrhage,rterial pressure readings are elevated during the acutehase. In fact, values are often higher than those observed

n cases of ischaemic stroke.37 Although blood pressureenerally decreases spontaneously in the days followinghe haemorrhage, high readings persist in many patients.otential pathophysiological mechanisms that promote

oeir


ncreases in arterial pressure include activation of theeuroendocrine system (sympathetic, renin-angiotensin, orlucocorticoid systems) due to stress and the elevation ofntracranial pressure (Cushing effect).

High arterial pressure values in patients with ICH maye associated with increased haemorrhage growth,38 whichs another sign of poor patient prognosis. Arterial pressureeadings in cases of ischaemic stroke follow a U-shapedurve, and both high and low values increase the riskf neurological damage, mortality, and poor functionalrognosis.39 Animal models of ICH have described secondaryamage, possibly caused by mechanical compression oficrovessels, which induces an ischaemic area around the

aemorrhage.40 This leads us to think that decreased arterialressure could contribute to reduced blood flow in the peri-aemorrhagic region, thereby producing more pronouncedeurological impairment. Based on these data, we recom-end maintaining systolic blood pressure below 180 mm Hguring the acute phase of ICH. However, neuroimaging stud-es have been unable to identify ischaemia around theaemorrhage site in human clinical data,41,42 and this aspectemains controversial.

The INTERACT study43 provides new data regarding bloodressure management during the acute phase of ICH. Thistudy was designed in order to evaluate how stricter controlver arterial pressure would affect haemorrhage growthnd the development of peri-lesional oedema. To that end,he study included 404 patients with spontaneous ICHs thatad appeared in the preceding 6 hours. Their systolic bloodressure values were ≥150 mm Hg and ≤220 mm Hg. Patientsere randomly assigned to receive blood pressure treatmentither according to recommendations in international guide-ines or according to stricter standards. In patients whoselood pressure was controlled according to internationaluidelines, systolic pressure was kept below 180 mm Hg. Thebjective in the group of patients under stricter standardsas to reach a systolic blood pressure of 140 mm Hg during

he first hour and maintain levels below that threshold dur-ng the following 7 days. Results from the study show thatatients assigned to the group with stricter blood pressureontrol presented less haemorrhage growth and a tendencyor the peri-haemorrhagic oedema to decrease. There wereo signs of increased neurological decline or poorer func-ional prognosis, but the study was not designed to evaluatehese parameters. Data from the study seem to indicatehat strict control over blood pressure is safe. However,e have yet to determine the most appropriate level ofrterial pressure, the correct duration for antihypertensivereatment, and the effect of these parameters on theunctional prognosis of ICH patients. The study INTERACT 2s currently underway44 and its main objective is to evaluateow maintaining strict control over blood pressure duringhe acute phase affects functional prognosis in ICH patients.

The drugs recommended for blood pressure control arehose that do not induce cerebral vasodilation or suddenypotension, such as intravenous labetalol (loading dosesf 10 to 20 mg in 1 to 2 minutes, repeated every 1 to0 minutes until the blood pressure reaches the desired levelr the maximum dose of 200 mg has been given); intravenousnalapril (1 mg bolus); or intravenous urapidil (25 mg bolus

n 20 s, repeating procedure after 5 minutes in absence of aesponse).

sh

gpVtt3fdpabpac

twahptntptn

P

DPbsdmihdp

STdwwewior

MC



Glycaemic controlHigh glycaemic levels upon admission are associated withincreased risk of mortality and poor prognosis in patientswith intracerebral haemorrhage.45,46 One clinical trial incritical care patients with or without acute stroke shows thatmaintaining glucose levels between 80 and 110 mg/dL usingintravenous insulin has been associated with higher inci-dence rates of hypoglycaemia episodes, whether systemicor cerebral. It may also be linked to an even higher risk ofmortality among the patients receiving this treatment.47,48

There are no intervention studies designed specificallyfor ICH, and as a result, the target level for glycaemic con-trol in ICH patients is not completely clear. However, glucoselevels above 155 mg/dL in ischaemic stroke have been asso-ciated with poor prognosis,49 and it is therefore appropriateto correct levels above this threshold. Hypoglycaemia mustbe prevented by administering a 10% to 20% dextrose solu-tion.

Temperature controlFever owing to any cause is associated with neurologicalimpairment and poor prognosis.50 Although there is noevidence that treatment decreases this risk, symptomatictreatment with antipyretic drugs such as paracetamol is rec-ommended. For patients with fever, we recommend orderinga chest radiography, cultures of blood, sputum, and urine,and urine sediment analysis in order to identify and treatassociated infectious processes. Peripheral blood vesselsshould be systematically checked to rule out phlebitis.

Some recent studies have demonstrated benefits of mod-erate hypothermia in certain conditions including headtrauma. However, its effects have not been explored in casesof patients with ICH.

Mana ging haemostasisHaemostatic alterations, such as treatment with oral anti-coagulants, coagulation factor deficiencies, or plateletabnormalities, can contribute to haemorrhage growth,which in turn leads to neurological impairment. It is there-fore important to correct these factors as quickly aspossible.

In cases in which the patient is being treated with oralanticoagulants, the INR must be corrected to reach nor-mal values as soon as possible.51 This should be done usingintravenous vitamin K and/or fresh frozen plasma and/orprothrombin complex concentrate.52,53 The effectiveness offresh frozen plasma is limited by the risk of allergic reac-tions and infections, as well as by the considerations ofprocessing time and hypervolaemia. Prothrombin complexconcentrates also contain factors II, VII, IX, and X, and theyare able to normalise INR values quickly. On this basis, theyconstitute the treatment of choice for cases of ICH related tooral anticoagulants.54 However, they must be combined withvitamin K, since the half-life of oral anticoagulants is muchlonger than those of vitamin K-dependent clotting factors.In cases in which patients have received intravenous hep-arin and display prolonged APTT, doctors should administer

protamine sulphate. If ICH has occurred due to fibrinolytictreatment, it may be necessary to administer fresh frozenplasma, platelets, or antifibrinolytics such as aminocaproicacid or tranexamic acid. Recombinant activated factor VII

tdom

241

hould be administered to patients with both ICH andaemophilia.

Recombinant activated factor VII has also been investi-ated in ICH patients without disorders of haemostasis. Ahase 2 study has shown that recombinant activated factorII limits haemorrhage growth and improves patients’ func-ional prognosis compared to a placebo, despite increasinghe frequency of thromboembolic complications.55 A phase

study confirmed that delivering recombinant activatedactor VII limits haemorrhage growth, but no significantifferences in prognosis could be found with respect to alacebo.56 It has not yet been shown whether recombinantctivated factor VII can deliver benefits in selected patients,ut in any case, administering this treatment to all ICHatients indiscriminately does not improve their prognosisnd furthermore, it increases the risk of thromboembolicomplications.

Patients with ICH and thrombocytopenia must receiveransfusions of platelet concentrate. Data from patientsithout thrombocytopenia who are being treated withntiplatelet drugs are contradictory. Platelet dysfunctionas been linked to increased haemorrhage volume and aoor functional result57; however, one clinical trial inves-igating neuroprotection in cerebral haemorrhages58 foundo differences between patients receiving a placebo andhose previously treated with antiplatelet drugs. Therefore,latelet replacement therapy is not indicated for patientsaking antiplatelet drugs and those whose platelet count isormal.

reventing complications

eep vein thrombosis and pulmonary embolismatients with ICH are at an increased risk of suffering throm-oembolic complications.59 Sporadic use of compressiontockings has not been shown to be effective for preventingeep vein thrombosis.60 However, the combination of inter-ittent mechanical compression and compression stockings

s much more effective.61 The use of low molecular weighteparin beginning on day 1 after a cerebral haemorrhageecreases the risk of thromboembolic complications in ICHatients and does not increase the risk of bleeding.62

eizureshe presence of seizures increases the brain’s metabolicemand and exacerbates neurological damage in patientsith ICH. If seizures appear, they should initially be treatedith benzodiazepine, followed by antiepileptic drugs. How-ver, administering antiepileptic drugs to ICH patientsho have not experienced a seizure is associated with

ncreased morbidity and mortality, especially in the casef phenytoin.63,64 Prophylactic treatment for seizures is notecommended.

anaging intracranial pressureontrol over intracranial pressure (ICP) is one of the specific

reatment objectives in ICH, and the approach should beirected at the underlying cause. The most common causesf high ICP are hydrocephalus due to intraventricular hae-orrhage and the mass effect of the haemorrhage.

2

hbnnDdid

mtriciltMpoo

oPocpsiosumvaohmaffTt2oicbnbna

tpmaresh

IMbavhmsCil

dation).


42

Placing devices that measure ICP increases the risk ofaemorrhage and infection, and such devices should note used as routine treatment. However, there are alsoon-invasive techniques that allow us to estimate intracra-ial pressure in patients with ICH, such as the transcranialoppler test. An increase in the pulsatility index in the mid-le cerebral artery of the unaffected hemisphere indicatesntracranial hypertension, and this has been shown to pre-ict mortality.65

Data on managing ICP in ICH are limited; recom-endations have been extrapolated from those used in

he management of patients with head trauma.66 Doctorsecommend considering ICP treatment and managementn patients with ICH with a Glasgow scale score ≤8,linical evidence of transtentorial herniation, significantntraventricular haemorrhage, or hydrocephalus. Neverthe-ess, we must be aware that very few studies attempto show the utility of ICP monitoring in ICH patients.ost such studies were unable to discriminate betweenatients who might be candidates for surgical evacuationf the haemorrhage and candidates for medical treatmentnly.

Centring the head and raising the headboard to an anglef 20◦ to 30◦ improves venous return and may decreaseIC slightly. Hyperventilation decreases partial pressure ofxygen in arterial blood, which leads to cerebral vaso-onstriction and a lowered ICP. The target is to reachartial pressure of CO2 between 28 and 35 mm Hg andubsequently maintain pressure between 25 and 30 mm Hgf the ICP remains high. This results in rapid decreasef ICP, although the effect is temporary and other mea-ures will have to be taken in order for ICP to remainnder control. Conditions that can cause increased ICPust be avoided, including fever, Valsalva-like manoeu-

res (coughing or vomiting), seizures, stress, pain, AHT,nd hyponatraemia. Osmotherapy reduces ICP by increasingsmolarity in plasma, which in turn displaces water fromealthy brain tissue into the vascular compartment. Theost commonly employed drugs of this type are mannitol

nd loop diuretics such as furosemide. Recommendationsor dosing 20% mannitol range from 0.7 to 1 g/kg (250 mL)ollowed by 0.3 to 0.5 g/kg (125 mL) every 3 to 8 hours.reatment should not be extended beyond 5 days so aso avoid the rebound effect. Furosemide (10 mg every—8 hours) may be used simultaneously to maintain thesmotic gradient. Using corticosteroids for this purposes not effective and may even increase the number ofomplications.67 Sedation with intravenous drugs, such asenzodiazepines, barbiturates, narcotics, and butyrophe-ones, reduces brain metabolism and decreases cerebrallood flow and ICP. In contrast, sedation also gives rise toumerous complications which include arterial hypotensionnd respiratory infections.

Hydrocephalus caused by the presence of an intraven-ricular bleed is one of the factors associated with aoor prognosis and increased mortality.68,69 Ventriculostomyust be considered in cases in which hydrocephalus and

decreased level of consciousness are both present. Aandomised study named CLEAR III, currently underway, isvaluating the efficacy and safety of intraventricular infu-

ion of thrombolytic drugs in patients with intraparenchymalaemorrhage and ventricular invasion.


CH prognosisany different studies have turned up factors that maye related to patient prognosis. These variables includege, scores on the GCS and NIHSS scales, haemorrhageolume and location, and the presence of intraventricularaemorrhage.70 Data which may reflect a poor prognosisay be interpreted as a reason for limiting care. This deci-

ion affects mortality, and early mortality in particular.71—73

urrent evidence suggests that establishing a sure prognosiss impossible. We therefore do not recommend deciding toimit care in early stages.

Recommendations in medical treatment

General care

Life support and oxygen saturation1. If arterial oxygen saturation is less than 92%, the

patient will require an oxygen mask with a flowsufficient to maintain oxygen saturation above thatthreshold.

2. Early intubation is recommended in patients with amassive ICH and low level of consciousness (GCS < 8)if the patient’s prior functional state is good, butnot if all brainstem signs have disappeared (level ofevidence 5, grade C recommendation).

Neurological monitoring1. Level of consciousness and neurological deficit must

be evaluated periodically during at least the first72 hours after the stroke. Neurological impairmentshould be measured using the NIHSS scale; level ofconsciousness is monitored using the Glasgow comascale (level of evidence 5, grade C recommenda-tion).

Arterial pressure1. The current recommendation, as we await results

from new clinical trials, is to treat patients whosesystolic blood pressure exceeds 180 mm Hg (level ofevidence 2b, grade C recommendation).

2. Rapid reduction of systolic blood pressure to thelimit of 140 mm Hg is safe in patients whose sys-tolic blood pressure readings fall between 150 and220 mm Hg (level of evidence 2a, grade B recom-mendation).

Glycaemia1. Blood glucose levels must be checked regularly and

hyperglycaemia above 155 mg/dL is to be avoided(level of evidence 2c, grade C recommendation).If the glucose level exceeds that threshold, itshould be corrected with insulin. Glucose levelsbelow 70 mg/dL must be corrected with 10% to 20%dextrose (level of evidence 5, grade C recommen-

Clinical practice guidelines in intracerebral haemorrhage 243

Temperature1. Doctors recommend treating hyperthermia above

37.5 ◦C with intravenous paracetamol (level of evi-dence 5, grade C recommendation).

Managing haemostasis

1. Patients with coagulation factor deficiency orsevere thrombocytopenia should be treated withthe lacking coagulation factors or platelets,respectively (level of evidence 1, grade B recom-mendation).

2. Patients on anticoagulant treatment with ICH andelevated INR should receive intravenous prothrom-bin complex concentrate and vitamin K, plus freshplasma if necessary, to replace vitamin K-dependentfactors until INR level is normalised (level of evi-dence 1, grade B recommendation).

3. Patients who have undergone intravenous hep-arin treatment and have a prolonged APTT shouldreceive treatment with protamine sulphate (levelof evidence 5, grade C recommendation).

4. Patients with ICH who have undergone thrombolytictreatment should receive a transfusion of freshplasma and platelets or antifibrinolytic drugs suchas aminocaproic acid or tranexamic acid (level ofevidence 5, grade C recommendation).

Preventing complications

Deep vein thrombosis and pulmonary embolism

1. A combination of intermittent mechanical compres-sion and compression stockings should be used toprevent deep vein thrombosis (level of evidence 1,recommendation level B). Beginning on day 1, it ispossible to administer prophylactic treatment withlow molecular weight heparin (level of evidence 2b,grade B recommendation).

Seizures

1. If seizures appear, the patient will requireantiepileptic drugs (level of evidence 1, grade Arecommendation).

2. Prophylactic treatment with antiepileptic drugs isnot indicated (level of evidence 3, grade B recom-mendation).

Managing intracranial pressure

1. ICP must be monitored in patients with aGCS ≤ 8 and signs of transtentorial herniation orhydrocephalus (level of evidence 2b, grade C rec-ommendation).

2. Placing a ventricular shunt should be considered forpatients with hydrocephalus (level of evidence 2a,grade B recommendation).

3. Although osmotic diuretics are recommended as thefirst treatment option, they are not indicated forprophylactic use (level of evidence 5, grade C rec-ommendation).

4. Doctors recommend hyperventilation in cases thatdo not respond to treatment with osmotic diuret-ics, provided that the patient has a good functionalprognosis (level of evidence 5, grade C recommen-dation).

5. Corticosteroids are not recommended as treatmentfor primary ICH (level of evidence 2, grade B rec-

S

Ttteebo

Iobschailh

lbtdbatocw

gmhss

paahwTafi


ommendation).

urgical treatment

he question of whether or not an ICH patient should bereated surgically is controversial. While surgery may reducehe effects stemming from the mechanical compressionxerted by the haemorrhage and also decrease the toxicffect of blood on nearby brain tissue, surgical risks maye high. In most patients, the benefits of surgery do notutweigh the procedure’s potential for harm.

One important factor in the decision of whether to treatCH surgically is the haemorrhage location. Cerebellar haem-rrhages larger than 3 cm in diameter, those compressing therainstem, or those with hydrocephalus respond better tourgical treatment than to medical treatment.74,75 In theseases, placing a ventricular shunt without evacuating theaemorrhage is insufficient, and shunt placement with nodditional actions is not recommended. In contrast, surgerys not indicated for cerebellar haemorrhages that measureess than 3 cm and do not compress the brainstem or involveydrocephalus.

The clinical trial STICH observed that patients with aobar haemorrhage located less than 1 cm from the cere-ral cortex tended to benefit from surgical treatment, buthe tendency was not statistically significant.76 They alsoiscovered a non-statistically significant tendency towardenefiting from surgery in patients with lobar haemorrhagend GCS scores between 9 and 12. However, further clinicalrials will be needed to demonstrate this benefit. In casesf haemorrhages located more than 1 cm from the cerebralortex and a GCS score ≤8, prognosis is poorer in patientsho undergo surgical treatment.77

Related studies on haemorrhages located in basal gan-lia do not show better results with surgical treatment. Weust also be mindful of the fact that gaining access to the

aemorrhage will involve passing through healthy brain tis-ue, meaning that the procedure will produce more severeequelae.77,78

Recommended surgical treatment techniques includeerforming a craniectomy with decompression and evacu-tion of the haemorrhage, but attempts have been madet developing less invasive techniques. Certain projectsave studied the benefits of stereotactic surgery combined

78,80 81,82

ith local thrombolysis or endoscopic aspiration.hese techniques eliminate the haemorrhage more fullynd decrease mortality when they are performed in therst 72 hours. Nevertheless, they have not been shown to

2

icwrtp

hphwn

S

T3auaM

opptarmb

teIwdds

dfmWd1namr(

csayhspAytaaogEthpRmatNc


44

mprove patients’ functional prognosis. One clinical trialompared surgery using minimally invasive craniopunctureith medical treatment in cases of small-volume haemor-

hages in the basal ganglia. The report observes that theechnique is safe and may improve functional prognosis inatients with this type of haemorrhage.79

The optimal moment in which to surgically evacuate theaemorrhage is also a matter of debate. Studies of surgicalrocedures performed within 24, 48, 72, or 96 hours of theaemorrhage have found no differences in outcome exceptith regard to patients treated with minimally invasive tech-iques, as indicated above.

Recommendations for surgical treatment

1. Surgical treatment is recommended as soon as pos-sible for patients with cerebellar haemorrhages whopresent with neurological impairment, brainstemcompression, or hydrocephalus (level of evidence1, grade B recommendation).

2. In patients with neurological impairment and alobar haemorrhage exceeding 30 mL in volume andlocated less than 1 cm from the cerebral cortex, sur-gical treatment should also be considered (level ofevidence 2b, grade B recommendation).

3. Evacuation procedures are not recommended fordeep haemorrhages (level of evidence 2, gradeB recommendation). Although minimally invasivesurgery may be an alternative in the future, data arenot sufficient to recommend stereotactic surgery toevacuate haemorrhages at the present time (levelof evidence 2, grade B recommendation).

econdary prevention

he risk of recurrence after a first ICH is between 2.1% and.7% yearly.83,84 In addition, lobar haemorrhages related tomyloid angiopathy,85 haemorrhages secondary to anticoag-lant treatment,84 history of prior cerebral haemorrhage,86

dvanced age,84 and microbleeds detected by gradient echoRI87 increase the risk of recurrence.

AHT is the modifiable factor with the most influencen risk of ICH recurrence, which is why proper bloodressure control is so important. Good control over bloodressure lowers risk of ICH recurrence, whether for hyper-ensive haemorrhages or for bleeds secondary to amyloidngiopathy.88 Although the optimal blood pressure value foreducing risk of ICH recurrence is unknown, maintaining nor-al blood pressure values (below 120/80 mm Hg) seems toe a reasonable choice.89

Oral anticoagulants increase risk of ICH recurrence,84 andhe benefits of anticoagulation to prevent thromboembolicvents must therefore be weighed against the risk of futureCHs. Risk of recurrence is higher in lobar haemorrhages,

hich is why anticoagulant treatment should be suspendedefinitively in patients with atrial fibrillation.90 In cases ofeep haemorrhages, risk of recurrence is lower. Generallypeaking, doctors should consider suspending anticoagulants


uring the acute phase except in patients at high riskor thromboembolic events (for example, those fitted withechanical valves) and at low risk for a haemorrhage.90

hen thromboembolic risk is high (CHA2DS2-VASc score ≥2),octors recommend recommencing oral anticoagulants 7 to0 days after the stroke.91 Antiplatelet drugs have a less pro-ounced effect on haemorrhage risk and severity than oralnticoagulants do.92 They may therefore constitute a treat-ent alternative in patients who have a moderate level of

isk (CHA2DS2-VASc ≤1) or who are functionally dependentmodified Rankin scale 4—5).91

In haemorrhages secondary to an underlying lesion, spe-ific treatment decreases risk of recurrence. For example,urgery may be recommended for cavernous angiomas thatre surgically accessible and have a bleed rate of 0.7% perear per lesion,93 depending on the risk of a new haemorr-age. A better approach for deep lesions is close monitoring;urgery should be reserved for cases in which impairment isrogressive or bleeding is recurrent. Risk of rebleeding inVMs is high at 18% the first year94 and 2% per year in laterears.95 Treatment that excludes the AVM from the circula-ory system is recommended where possible. In this case,lternatives include surgical treatment, endovascular ther-py, and radiosurgery. Surgical treatment of ICH dependsn the location. Haemorrhages located in the basal gan-lia, diencephalon, or brainstem are typically inoperable.ndovascular treatment was initially developed to facili-ate resection of very large AVMs, or as an alternative toigh-risk surgery.96 However, when lesions are small, com-lete occlusion may be achieved with endovascular therapy.adiosurgery is more effective in small AVMs (


4. Recommended treatments for AVMs may be surgi-cal, endovascular, and/or radiosurgical dependingon the surgical risk and the size and location of the

MpJGCCHVMAaPAVtRpHeCpU

A

JBSUUHUtHR

Ae

L

1

1

1

2

2

2ecological studies


lesion (level of evidence 5, grade D recommenda-tion).

These clinical guidelines are rewritten periodicallybecause they must reflect a continuous series of advancesin clinical trials. They therefore draw from previous SENrecommendations, as well as from current recommenda-tions by the European Stroke Initiative98 and the AmericanHeart Association Stroke Council.99 These recommenda-tions were taken into account in the process of elaboratingthe guidelines we present here. Likewise, in order toprepare guidelines according to the standard set by inter-national publications, we used the levels of evidenceand grades of recommendation published by the Centrefor Evidence-Based Medicine at the University of Oxford(Addenda 2 and 3).100

Conflict of interest

The authors have no conflicts of interest to declare.

Addendum 1. Ad hoc committee of the SENStudy Group for Cerebrovascular Diseasesconstituted to draw up clinical practiceguidelines for stroke.

Coordinator: Exuperio Díez-Tejedor, Hospital UniversitarioLa Paz, Madrid.

A.1. Drafting committee

Exuperio Díez-Tejedor (Coord), Hospital Universitario LaPaz, Madrid; Blanca Fuentes (Secretary), Hospital Uni-versitario La Paz, Madrid; María Alonso de Leciñana,Hospital Universitario Ramón y Cajal, Madrid; José Álvarez-Sabin, Hospital Universitari Vall d’Hebron, Barcelona; JuanArenillas, Hospital Universitario Clínico de Valladolid; Ser-gio Calleja, Hospital Universitario Central de Asturias,Oviedo; Ignacio Casado, Hospital San Pedro, Cáceres; MarCastellanos, Hospital Josep Trueta, Girona; José Castillo,Hospital Clínico Universitario, Santiago de Compostela;Antonio Dávalos, Hospital Universitari Germans Trias i Pujol,Badalona; Fernando Díaz-Otero, Hospital Universitario Gre-gorio Marañón, Madrid; Exuperio Díez-Tejedor, HospitalUniversitario La Paz, Madrid; José Antonio Egido, HospitalClínico Universitario San Carlos, Madrid; Juan Carlos Fer-nández, Hospital Universitario Dr. Negrín, Las Palmas; MarFreijo, Hospital Universitario de Basurto, Bilbao; BlancaFuentes, Hospital Universitario La Paz, Madrid; Jaime Gál-

lego, Hospital General de Navarra, Pamplona; Andrés GarcíaPastor, Hospital Universitario Gregorio Marañón, Madrid;Antonio Gil-Núñez, Hospital Universitario Gregorio Marañón,Madrid; Francisco Gilo, Hospital Universitario La Princesa,

3

3

245

adrid; Pablo Irimia, Clínica Universitaria de Navarra, Pam-lona; Aida Lago, Hospital Universitario La Fe, Valencia;osé Maestre, Hospital Universitario Virgen de las Nieves,ranada; Jaime Masjuan, Hospital Universitario Ramón yajal, Madrid; Joan Martí-Fábregas, Hospital de la Santareu i Sant Pau, Barcelona; Patricia Martínez-Sánchez,ospital Universitario La Paz, Madrid; Eduardo Martínez-ila, Clínica Universitaria de Navarra, Pamplona; Carlosolina, Hospital Universitario Vall d’Hebron, Barcelona;na Morales, Hospital Universitario Virgen de la Arrix-ca, Murcia; Florentino Nombela, Hospital Universitario Larincesa, Madrid; Francisco Purroy, Hospital Universitariornau de Vilanova, Lérida; Marc Ribó, Hospital Universitariall d’Hebron, Barcelona; Manuel Rodríguez-Yáñez, Hospi-al Clínico Universitario, Santiago de Compostela; Jaimeoquer, Hospital del Mar, Barcelona; Francisco Rubio, Hos-ital Universitario de Bellvitge, Barcelona; Tomás Segura,ospital Universitario de Albacete, Albacete; Joaquín Ser-na, Hospital Josep Trueta, Gerona; Patricia Simal, Hospitallínico Universitario San Carlos, Madrid; Javier Tejada, Hos-ital Universitario de León, León; José Vivancos, Hospitalniversitario La Princesa, Madrid.

.2. Review or institutional committee

osé Álvarez-Sabín, Hospital Universitari Vall d’Hebron,arcelona; José Castillo, Hospital Clínico Universitario,antiago de Compostela; Exuperio Díez-Tejedor, Hospitalniversitario La Paz, Madrid; Antonio Gil-Núñez, Hospitalniversitario Gregorio Marañón, Madrid; José Larracoechea,ospital de Cruces, Bilbao; Eduardo Martínez-Vila, Clínicaniversitaria de Navarra, Pamplona; Jaime Masjuan, Hospi-al Universitario Ramón y Cajal, Madrid; Jorge Matías-Guiu,ospital Clínico Universitario San Carlos, Madrid; Franciscoubio, Hospital de Bellvitge, Barcelona.

ddendum 2. Classification of levels ofvidence

evel of evidence Type of study

a Systematic review ofrandomised clinical trials(with homogeneity)

b Randomised clinical trialwith narrow confidenceinterval

c Clinical practice (all ornone)a

a Systematic review of cohortstudies (with homogeneity)

b Cohort study or low qualityrandomised clinical trialb

c ‘‘Outcomes’’ research,c

a Systematic reviews ofcase—control studies (withhomogeneity)

b Case—control studies

2

L

4

5

apr

wt

aafpcec

c

A

Go

AB

C

D

R


46

evel of evidence Type of study

Case series and poor-qualitycohort and case—controlstudiesd

Experts’ opinion withoutexplicit critical appraisal orbased on physiology, benchresearch or ‘‘firstprinciples’’e

a When all patients died before a certain treatment became avail-ble, and some who received the treatment survived; or if someatients died before the treatment existed, and none of thoseeceiving the treatment died.b For example, follow-up rates below 80%.c The term ‘outcomes research’ refers to cohort studies in patientsith the same diagnosis in which the events that occur are related

o treatments delivered to the patients.d Cohort study: no clear definition of the groups being comparednd/or no objective measurement of treatments and events (prefer-bly blinded) and/or without properly identifying or controllingor known confounders and/or complete and sufficient follow-uperiod. Case—control study: no clear definition of the groups beingompared and/or no objective measurement of treatments andvents (preferably blinded) and/or without properly identifying orontrolling for known confounders.e The term ‘first principles’ refers to the adoption of a specificlinical practice based on pathophysiological evidence.

ddendum 3. Grades of recommendation

rade of rec-mmendation

Level of evidence

Level 1 studies Level 2 or 3 studies, or extrapolations

from level 1 studies Level 4 studies, or extrapolations from

level 2 or 3 studies Level 5 studies, or inconclusive studies

of any level

eferences

1. Kase CS, Caplan LR. Intracerebral hemorrhage. Boston:Butterworth-Heineman; 1994. p. 1.

2. Giroud M, Gras P, Chadan N, Beuriat P, Milan C, ArveuxP, et al. Cerebral haemorrhage in a French prospectivepopulation study. J Neurol Neurosurg Psychiatry. 1991;54:595—8.

3. Van Asch CJ, Luitse MJ, Rinkel GJ, Van der Tweel I, Algra A, KlijnCJ. Incidence, case fatality, and functional outcome of intra-cerebral haemorrhage over time, according to age, sex, andethnic origin: a systematic review and meta-analysis. LancetNeurol. 2010;9:167—76.

4. Broderick J. Intracerebral hemorrhage. In: Gorelick PB, AlterM, editors. Handbook of neuroepidemiology. New York, NY:

Marcek Dekker Inc.; 1994. p. 141—67.

5. Castillo J, Marínez F, Corredera E, Leira R, Prieto JM, Noya M.Hemorragias intracerebrales espontáneas hipertensivas y nohipertensivas. Rev Neurol. 1994;22:549—52.


6. Brott T, Thalinger K, Hertzberg V. Hypertension as a riskfactor for spontaneous intracerebral hemorrhage. Stroke.1986;17:1078—83.

7. Gilbert JJ, Vinters HV. Cerebral amyloid angiopathy: incidenceand complications in the aging brain I. Cerebral hemorrhage.Stroke. 1983;14:915—23.

8. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorr-hage. Lancet. 2009;373:1632—44.

9. Belvis R, Cocho D, Marti-Fabregas J, Pagonabarraga J, AleuA, Garcia-Bargo MD, et al. Benefits of a prehospital strokecode system. Feasibility and efficacy in the first year of clin-ical practice in Barcelona, Spain. Cerebrovasc Dis. 2005;19:96—101.

10. Caplan LR. General symptoms and signs. In: Kase C, CaplanL, editors. Intracerebral hemorrhage. Boston: Butterworth-Heinemann; 1994. p. 31—43.

11. Tetri S, Juvela S, Saloheimo P, Pyhtinen J, Hillbom M.Hypertension and diabetes as predictors of early deathafter spontaneous intracerebral hemorrhage. J Neurosurg.2009;110:411—7.

12. Broderick JP, Diringer MN, Hill MD, Brun NC, Mayer SA, SteinerT, et al. Determinants of intracerebral hemorrhage growth: anexploratory analysis. Stroke. 2007;38:1072—5.

13. Cucchiara B, Messe S, Sansing L, Kasner S, Lyden P. Hematomagrowth in oral anticoagulant related intracerebral hemor-rhage. Stroke. 2008;39:2993—6.

14. Zubkov AY, Mandrekar JN, Claassen DO, Manno EM, WijdicksEF, Rabinstein AA. Predictors of outcome in warfarin-relatedintracerebral hemorrhage. Arch Neurol. 2008;65:1320—5.

15. Chalela JA, Kidwell CS, Nentwich LM, Luby M, Butman JA,Demchuk AM, et al. Magnetic resonance imaging and com-puted tomography in emergency assessment of patients withsuspected acute stroke: a prospective comparison. Lancet.2007;369:293—8.

16. Herold S, Von Kummer R, Jaeger C. Follow-up of spontaneousintracerebral haemorrhage by computed tomography. J Neu-rol. 1982;228:267—76.

17. Broderick J, Brott T, Tomsick T, Leach A. Lobar hemorrhagein the elderly. The undiminishing importance of hypertension.Stroke. 1993;24:49—51.

18. Marti-Fabregas J, Piles S, Guardia E, Marti-Vilalta JL.Spontaneous primary intraventricular hemorrhage: clini-cal data, etiology and outcome. J Neurol. 1999;246:287—91.

19. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN,Mayer SA, et al. Hematoma growth is a determinant ofmortality and poor outcome after intracerebral hemorrhage.Neurology. 2006;66:1175—81.

20. Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tom-linson G, et al. CT angiography ‘‘spot sign’’ predictshematoma expansion in acute intracerebral hemorrhage.Stroke. 2007;38:1257—62.

21. Kim J, Smith A, Hemphill III JC, Smith WS, Lu Y, et al.Contrast extravasation on CT predicts mortality in pri-mary intracerebral hemorrhage. Am J Neuroradiol. 2008;29:520—5.

22. Kidwell CS, Saver JL, Villablanca JP, Duckwiler G, FredieuA, Gough K, et al. Magnetic resonance imaging detection ofmicrobleeds before thrombolysis: an emerging application.Stroke. 2002;33:95—8.

23. Nussel F, Wegmuller H, Huber P. Comparison of magneticresonance angiography, magnetic resonance imaging and con-ventional angiography in cerebral arteriovenous malformation.Neuroradiology. 1991;33:56—61.

24. Halpin SF, Britton JA, Byrne JV, Clifton A, Hart G, Moore A.

Prospective evaluation of cerebral angiography and computedtomography in cerebral haematoma. J Neurol Neurosurg Psy-chiatry. 1994;57:1180—6.

http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0005http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0010http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0015http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0020http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0025http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0030http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0035http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0040http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0045http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0050http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0055http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0060http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0065http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0070http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0070http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0070http://refhub.elsevier.com/S2173-5808(13)00051-5/sbref0070http://r

28(4) NEUROLOGÍA€¦ · Neurología. 2013;28(4):236—249 NEUROLOGÍA REVIEW ARTICLE Clinical...

Documents

Transcript of 28(4) NEUROLOGÍA€¦ · Neurología. 2013;28(4):236—249 NEUROLOGÍA REVIEW ARTICLE Clinical...