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ENDORSEMENT PAGE

Case Report

Non-Haemorrhagic Stroke

Presented by:

Agus Salim

04101401015

Ardiyanto

04101401032

Has been accepted as one of requirements in undergoing senior clinical clerkship period of

April 21 th May 28 st 2014 in Department of Neurology Faculty of Medicine Sriwijaya

University Mohammad Hoesin General Hospital Palembang.

Palembang, 10 th May 2014

Advisor

Dr. H. A. Rachman Toyo, Sp.S(K)


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CHAPTER I

NEUROLOGY MEDICAL RECORDS

IDENTIFICATION

Name : Mr. HD

Age : 67 years

Sex : Laki-laki

Occupation : -

Address : Perum Azhar Blok AX 06 No 17 Rt/Rw: 27/03 Kel.Kenten Laut,

Kab. Banyuasin.

Date of Admission : 07 Mei 2014Registry Number : RI14012432

ANAMNESIS

Patient was admitted to Neurology Department of RSMH due to sudden loss of

consciousness.

+ 12 hours before admission, patient was found unconscious by his neighbours inside

of his house, nothings certain about the process, but they said to seeing him doing someworks outside before the incident. On the onset, whether there is or not headache was

unkown, nauseas (-), vomitting (-), generalized tonic-clonic seizures (-), weakness on right

side of the body (+), drooping mouth (+), slurred speech (could not be assessed), sensibility

(could not be assesed).

History of hypertension (-), history of stroke (-), history of heart diseases (-), history

of head trauma (-), history of fever of unkown origin (-), history of a long time cough (-),

history of previous loss of consciousness (-).

This is the first time patient suffered these conditions and no family history of the same

loss of consciousness.

PHYSICAL EXAMINATION

PRESENT STATEInternal State

Conciousness : E 4M6Vglobal aphasia Nutrition : Overweight Temperature : 37 oC

Heart : No abnormalityLungs : No abnormalityLiver : No abnormality


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Pulse : 56 beats/minRespiratory rate : 16 times/minBlood pressure : 140/80 mmHg

Psychiatric state

Attitude : uncooperativeAttention : unattended

Neurological stateHeadShape : Brachiocephali Size : Normocephalic Symmetric : SymmetricHematome : NoTumor : No

NeckPosition : Straight Torticolis : No

Nape of neck stiffness : yes

Spleen : No abnormality Extremities : see neurological state Genital : Not examined

Facial Expression : FlatPsychological contact : None

Deformity : NoFracture : NoFracture pain : NoVessel : No wideningPulsation : No disorder

Deformity : NoTumor : NoVessels : No widening

CRANIAL NERVES N.I: Olfaktorius nerveSmellingAnosmiaHyposmiaParosmia

N.II: Opticus nerveVisual acuityCampus visi

Anopsia

HemianopsiaOculi fundus Edema papil Atrophy papil Retina bleeding

N.III: Occulomotorius, N.IV: Trochlearis, and N.VI: Abducens nervesDiplopiaEyes gap

PtosisEyes position

Right Not examined Not examined Not examined Not examined

Right6/6

V.O.D

No

No

No No No

Right No

Symmetric

No

Left Not examined Not examined Not examined Not examined

Left6/6

V.O.S

No

No

No No No

Left No

Symmetric

No


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Strabismus Exophtalmus Enophtalmus Deviation conjugae

Eyes movement

Pupil Shape Size Isochor/anisochor Midriasis/miosis

Light reflex direct consensuil accommodation

N.V: Trigeminus nerveMotoric

Biting Trismus Corneal reflex

Sensory Forehead Cheek Chin

N.VII: Facialis nerveMotoricFrowningEyes closingGiggling

Nasolabial foldFacial shape

rest Speaking/whistling

Sensory 2/3 anterior tounge

Autonomy Salivation Lacrimation Chvosteks sign

N.VIII: Statoacusticus nerveCochlearis nerveWhisperingHour tickingWeber test

Rinne testVestibularis nerve

No No No No

No abnormality

Round 3 mmIsochor

No

Positive, NormalPositivePositive

Right No disorder

NoYes

Not examined Not examined Not examined

Right Normal Normal

Not examinedFlat

Drooping mouth No disorder

Not examined

No disorder No disorder No disorder

Right Not examined Not examined Not examined

Not examined

No No No No

No abnormality

Round 3 mmIsochor

No

Positive, NormalPositivePositive

Left No disorder

NoYes

Not examined Not examined Not examined

Left Normal Normal

Not examined Normal

No disorder No disorder

Not examined

No disorder No disorder No disorder

Left Not examined Not examined Not examined

Not examined


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NystagmusVertigo

N.IX: Glossopharingeus, and N.X: Vagus nerves

Pharyngeal archUvulaSwallowing disorderHoarsing/nasalisingHeart beatReflex

Vomiting Coughing Occulocardiac Caroticus sinus

Sensory 1/3 posterior tounge

No No

Right

SymmetricSymmetric

No No

Normal

YesYes


Not examined

No No

Left

SymmetricSymmetric

No No

Normal

YesYes


Not examined

N.XI: Accessorius NerveShoulder RaisingHead Twisting

N.XII: Hypoglossus NerveTounge ShowingFasciculationPapil AthrophyDysarthria

MOTORICArmsMotionStrengthTonesPhysiological Reflex

Biceps Triceps

Radius UlnaPathological Reflex

Hoffman Trommer Leri Meyer

LEGMotionPowerTones

Clonus Thigh

Right No disorder No disorder

Right Not examined Not examined Not examined Not examined

Right

Decreased

DecreasedDecreased

DecreasedDecreased

Negative Negative Negative

Right

Decreased

Negative

Left No disorder No disorder

Left Not examined Not examined Not examined Not examined

Left

Normal

Normal Normal

Normal Normal

Negative Negative Negative

Left

Normal

Negative

Lateralisation to the right

Lateralisation to the right


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FootPhysiological reflex

K P R A P R

Pathological reflex

Babinsky Chaddock Oppenheim Gordon Schaeffer Rossolimo Mendel Bechterew

Abdominal skin reflex Upper Middle Lower

Tropik

Negative

DecreasedDecreased

YesYes

Negative Negative Negative Negative Negative

Negative Negative Negative Negative

Negative

Normal Normal

Negative Negative Negative Negative Negative Negative Negative

Negative Negative Negative Negative

SENSORY Not Examined

PICTURE

VERTEBRAL COLUMN

Kyphosis : No Tumor : NoLordosis : No Meningocele : NoGibbus : No Hematome : NoDeformity : No Tenderness : No


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SYMPTOMS OF MENINGEAL IRRITATION

Nuchal rigidityKerniq

LassequeBrudzinsky

Neck Cheek Symphisis Leg I Leg II

Right No No

No

No No No No No

Left No No

No

No No No No No

GAIT AND BALANCE Not examined

ABNORMAL MOVEMENTSTremor : NoChorea : NoAthetosis : NoBallismus : NoDystoni : NoMyoclonus : No

VEGETATIVE FUNCTIONMicturition : CatheterizedDefecation : No abnormality

LIMBIC FUNCTIONGlobal aphasia

SPECIFIC EXAMINATIONCranium X- Ray : Not performedVertebral column X- Ray : Not PerformedThorax X-Ray : PerformedElectroencephalography : Not performed

Electroneuromyography : Not performedElectrocardiography : Not performedArteriography : Not performedPneumography : Not performedHead CT-Scan : PerformedHead MRI : Not PerformedLumbal Puncture : Not Performed


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Thorax Rontgen Mr.


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Laboratory Findings07 t May 2014 09 t May 2014 Normal value

Haemoglobin - 13,3 12,6-17,4 mg/dLRBCs - 4,21 4,20-4,87 x 10 /mm

WBCs - 8,7 4,5-11,0 x 103

/mm3

Haematocrits - 37 43-49 %

CT Scan Mr HD


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PLT - 260 150-450 x 10 /uLBasophils - 0 0-1 %Eosinophil - 1 1-6 %Rod Neutrophils - 0 2-6 %Segment Neutrophils - 63 50-70 %Lymphocytes - 30 25-40 %Monocytes - 6 2-8 %Prothrombin Time 11.7 - 12-18 detikINR 0.89 -APTT 27,7 - 27-42 detikFibrinogen 362 - 200-400 mg/dLTotal Protein 7,5 6,9 6,4 8,3 g/dLAlbumin 4,1 3,7 3,5 5,0 g/dLGlobulin - 3,2 2,6-3,6 mg/dLTotal Cholesterol 174 177 65 mg/dLLDL 115 120


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CHAPTER II

CASE ANALYSIS

RESUME

IDENTIFICATION:

Name : Mr. Hayun Darwis

Age : 67 years

Sex : Laki-laki

Nationality : Indonesia

Occupation : -Address : Perum Azhar Blok AX 06 No 17 Rt/Rw: 27/03 Kel.Kenten

Laut, Kab. Banyuasin.

Date of Admission : 07 Mei 2014

Registry Number : RI14012432

ANAMNESISPatient was admitted to Neurology Department of RSMH due to sudden loss of

consciousness.+ 12 hours before admission, patient was found unconscious by his neighbours inside

of his house, nothings certain about the process, but they said to seeing him doing some

works outside before the incident. During the onset, the presence of headache was unkown,

nauseas (-), vomitting (-), generalized tonic-clonic seizures (-), weakness on right side of the

body (+), drooping mouth (+), slurred speech (could not be assessed), sensibility (could not

be assesed).

History of hypertension (-), history of diabetes melitus (-), history of stroke (-),history of heart diseases (-), history of head trauma (-), history of fever (unknown patient

lives alone), history of a long time cough (-), history of previous loss of consciousness (-).

This is the first time patient suffered these conditions and no family history of the same

conditions.

PHYSICAL EXAMINATIONConsciousness (GCS score) : E 4M6Vglobal aphasia

Blood pressure : 140/80 mmHgPulse rate : 56 x/m


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Respiration rate : 16 x/m

Temperature : 37 C

Neurological examination:

N III : round pupil, isocoria, Light reflex +/+, diameter 3 mm

N VII : flattening of right plica nasolabialis

Right side drooping of mouth

N XII : not examined (patient held his mouth shut)

Motoric function Right trunk Left trunk Right arm Left arm

Movement

Strength

Tonus decreased n decreased n

Clonus - -

Physiological ref. decreased n decreased n

Pathological ref. - - +B, C -

Sensory function : not examined

Limbic function : global aphasia

Vegetative function : catheterized

Meningeal signs : -

Abnormal movements : -

Gait dan balance : not examined

DIAGNOSIS

Clinical Diagnosis : - Hemiparese dextra flaccid

- Parese N.VII dextra tipe sentral

- Global aphasia

Topical Diagnosis : Partial Anterior Circulation Infact (PACI)

Etiology Diagnosis : Cerebral Embolism

MANAGEMENT

Non-pharmacology : Head elevation 30 0 O2 2 L via nasal cannula

Lateralisation to the ri ht


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2. Posterior Circulation Infarct (POCI)Posterior Circulation Infarct Clinical

Findings:Patients Clinical Findings:

Ipsilateral cranial nerve(s) disfunctionand contralateral sensoric/motoric

deficits

Flaccid right side hemiparesis

Bilateral sensoric or motoric function No

Conjugate eye movement disturbance(horizontal and vertical)

No

Isolated Hemianopia or cortical blind No

Conclusion: POCI as topical diagnosis can be eliminated.

B. Etiology Differential DiagnosisSiriraj Stroke Score

Siriraj Stroke Score :

= (2,5 x level of consciousness) + (2 x vomiting) + (2 x headache) + (0,1 x diastolic blood

pressure) (3 x atheroma markers) 12

= (2,5 X 0) + (2 X 0) + (2 X 1) + (0.1 X 80) (3X0) 12 = -2

Results:

0 : Look at CT Scan findings. -1 : Non Hemorrhagic 1 : HemorrhagicConclusion: Non hemorrhagic stroke

Gajah Mada Algorithm


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There was only Babinsky pathological reflex found in Mr. HD. According to Gajah MadaAlgorithm, the etiology of Mr HD condition was infarctions.

Etiology differential diagnosis based on anamnesis:

1. Hemorrhagic StrokeAnamnesis: In patient:

- Loss of consciousnees > 30

minutes

- There was loss of consciousness

- Occured during/after physical

activities

- Patient was said to be doing

some works before losing his

conscious

- Preceded by headache, nausea,

and vomiting

- History of hipertension

- Headache was unknown, no

nause, no vomiting

- No history of hipertension

So, hemorrhagic as the cause can be eliminated.

2. Cerebral ThrombosisAnamnesis: In patient

- No loss of consciousness - There was loss ofconsciousness

- Occured during rest - Occured after activity

So, cerebral thrombosis as the cause can be eliminated.

3. cerebral embolismAnamnesis: In patient

- Loss of consciousness < 30

minutes

- There was loss of consciousness


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- Arterial fibrillation - No arterial fibrillation- Occur during activity - Occured after activity

So, cerebral embolism as the cause cant be eliminated yet.

Conclusion:Etiology Diagnosis: Cerebral Embolism.

CHAPTER III

LITERATURE RIVIEW

ISCHEMIC STROKE

Acute ischemic stroke is characterized by abrupt neurologic dysfunction due to focal brain

ischemia resulting in persistent neurologic deficit or accompanied by characteristic

abnormalities on brain imaging.

Until recently, stroke was defined using clinical criteria alone, based on duration of

symptoms lasting 24 hours or longer. If the symptoms persisted for less than 24 hours, the

condition was termed transient ischemic attack (TIA) However, modern neuroimaging

techniques, especially diffusion MRI, have shown that defining stroke or TIA based only on

duration of symptoms may not be accurate, since permanent brain damage can occur even

when symptoms last only minutes. Therefore, recently proposed definitions of TIA take into

account both the duration of symptoms (typically less than an hour) and lack of acuteinfarction on brain imaging .Ovbiagele and colleagues estimated that adopting a definition of

TIA based on the above criteria would reduce estimates of the annual incidence of TIA by

33% (currently estimated to be 180,000 annually) and increase annual number of strokes by

7% (currently estimated at 820,000 per year).

ETI OLOGI C AND PATH OLOGI C ASPECTS

It is important to recognize that ischemic stroke results from a heterogeneous group of

disorders whose final common pathway leading to clinical manifestations is interruption of


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blood flow through vascular occlusion. This results in an infarct of which the size is

dependent on extent, duration, and severity of ischemia. Brain infarcts resulting from arterial

occlusion are divided based on their macroscopic appearance into white (bland) and red

(hemorrhagic) infarcts. By gross anatomy, the former are composed of few or no petechiae

while the latter are characterized by grossly visible blood. This latter term is equivalent to

hemorrhagic transformation, which refers to leaking of red blood cells into a dying and

ischemic brain tissue, and should not be confused with parenchymal hematoma, which

represents a homogenous collection of blood usually resulting from a ruptured blood vessel.

Serial brain imaging studies in patients with acute stroke have demonstrated that hemorrhagic

transformation of an initially bland infarct can occur in up to 80% of patients. The risk of

early hemorrhagic transformation and parenchymal hematoma is greatly increased by

administration of thrombolytics or anticoagulants in acute ischemic stroke.

Gross anatomy studies reveal that arterial infarcts evolve over several stages. In the first 12 to

24 hours after the ictus, the lesion is barely visible to the naked eye. Swelling reaches its

zenith at days 3 to 5; in large strokes this can become life threatening due to displacement

and compression of neighboring structures. Between days 5 and 10, the infarcted brain

becomes sharply demarcated from the unaffected brain tissue. The chronic stage, occurring

weeks or months after the ictus, features a fluid-filled cavity that results from reabsorption ofnecrotic debris, hence the name liquefaction necrosis.

STROKE M ECHANI SM S

Two major mechanisms are responsible for ischemia in acute stroke: thromboembolism and

hemodynamic failure. The former usually occurs as a result of embolism or in situ thrombosis

and leads to an abrupt fall in regional cerebral blood flow (CBF). The latter usually occurs

with arterial occlusion or stenosis, when collateral blood supply maintains CBF at levels that

are sufficient for preservation of brain function under normal circumstances. In these cases,

cerebral ischemia may be triggered by conditions that decrease perfusion proximally to the

arterial lesion (systemic hypotension or low cardiac output) and increase metabolic demands

(fever, acidosis) or conditions that lead to "steal" of blood from affected to unaffected areas

in the brain (carbon dioxide retention). Strokes occurring through these mechanisms are

located predominantly in the so-called borderzones or watershed regions, which are areas in

the brain bordering major vascular territories such as the middle cerebral artery

(MCA)/internal carotid artery or MCA/posterior cerebral artery interface. Caplan and


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TABLE High Risk Versus Low or Uncertain Risk Conditions for Cardioembolic Stroke

Artery-to-artery embolism. Emboli occluding brain arteries can also originate from large

vessels situated more proximally, such as the aorta, extracranial carotid, or vertebral arteries

or intracranial arteries. In these circumstances, the embolic material is composed of clot,

platelet aggregates or plaque debris that usually breaks off from atherosclerotic plaques. This

is a major mechanism responsible for stroke due to large vessel atherosclerosis, which

accounts for 15% to 20% of all ischemic strokes.

Thrombosis

Thrombosis represents an obstruction of flow with thrombus formation resulting from an

occlusive process initiated within the vessel wall. In the vast majority of cases this is caused

by atherosclerotic disease, hence the name atherothrombosis. Less common vascular

pathologies leading to vessel stenosis or occlusion include arterial dissection (intracranial or

extracranial), fibromuscular dysplasia, vasospasm (drug induced, inflammatory, or

infectious), radiation-induced vasculopathy, extrinsic compression such as tumor or other

mass lesion, or moyamoya disease.

Small vessel disease. Thrombotic occlusion of the small penetrating arteries in the brain is

another important cause of strokes, accounting for another approximately 20% to 30% of all

ischemic strokes. This type of vascular lesion is strongly associated with hypertension and is

characterized pathologically by lipohyalinosis, microatheroma, fibrinoid necrosis, and

Charcot-Bouchard aneurysms. Lipohyalinosis is characterized by replacement of the normal

vessel wall with fibrin and collagen and is specifically associated with hypertension.

Microatheroma represents an atheromatous plaque of the small vessel that may involve the

origin of a penetrating artery. This latter mechanism is believed to be responsible for larger

subcortical infarcts. Fibrinoid necrosis is usually associated with extremely high blood

pressure, leading to necrosis of smooth muscle cells and extravasation of plasma proteins,

which appear microscopically as fine granular eosinophilic deposits in the connective tissue

of the vessel wall. Charcot-Bouchard aneurysms are areas of focal dilatation in the small

vessel wall, which may thrombose, leading to vessel occlusion.


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CEREBRAL BLOOD F LOW CHAN GES

Following vessel occlusion, the main factors ultimately determining tissue outcome are

regional CBF and duration of vessel occlusion. A decrease in regional CBF leads to

diminished tissue perfusion. In persistent large vessel occlusion, local perfusion pressure,

which is the main factor influencing the eventual outcome of tissue, depends on several

factors such as the presence and extent of collaterals and systemic arterial pressure (due to

loss of the ischemic brain's autoregulatory capacity). It is inversely correlated to the local

tissue pressure (which is increased by ischemic edema).

Cerebral Blood Flow Thresholds in Acute Cerebral Ischemia

The difference in tissue outcome following arterial occlusion is based on the concept that

CBF thresholds exist, below which neuronal integrity and function are differentially affected.

Early human studies performed in the 1950s during carotid artery clamping for carotid

endarterectomy using intracarotid xenon 133 injections reported that hemiparesis occurred

when regional CBF fell below 50% to 30% of normal, and permanent neurologic deficit

occurred if mean CBF fell below 30% of normal. Evidence also indicated that development

of permanent neurologic sequelae is a time-dependent process; for any given blood flow

level, low CBF values are tolerated only for a short period of time, while higher CBF values

require longer time for infarction to occur. Several investigators have studied the relationship

between EEG changes and regional CBF during carotid clamping. EEG would slow down

when mean CBF fell below 23 mL/100 g/min, while at values below 15 mL/100 g/min the

EEG would become flat.

Figure 1 Schematic drawing of the different cerebral blood flow thresholds in man. aFurlan M,

Marchal G, Viader F, et al. Spontaneous neurological recovery after stroke and the fate of the


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ischemic penumbra. Ann Neurol 1996;40(2):216-226.Marchal G, Beaudouin V, Rioux P, et

al. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke.

Stroke 1996;27(4):599-606.Marchal G, Benali K, Iglsias S, et al. Voxel-based mapping of

irreversible ischaemic damage with PET in acute stroke. Brain 1999;122(pt 12):2387-

2400. bHeiss WD, Grond M, Thiel A, et al. Tissue at risk of infarction rescued by early

reperfusion: A positron emission tomography study in systemic recombinant tissue

plasminogen activator thrombolysis of acute stroke. J Cereb Blood Flow Metab

1998;18(12):1298-1307.Heiss WD, Thiel A, Grond M, Graf R. Which targets are relevant for

therapy of acute ischemic stroke? Stroke 1999;30(7):1486-1489.Baron JC. Perfusion

thresholds in human cerebral ischemia: historical perspective and therapeutic implications.

Cerebrovasc Dis 2001;11(suppl 1):2-8. Reprinted with permission from S. Karger, AG,

Basel.

The concept of CBF threshold in focal cerebral ischemia proposed by these early human

studies was then reinforced by landmark studies performed by Symon and colleagues (1977),

who investigated the relationship between severity of local CBF impairment and degree of

neurologic dysfunction at various durations of ischemia in a baboon model of MCA

occlusion. Symon and colleagues (1977) demonstrated that brain tissue perfuses between

certain CBF values (22 mL/100 mg/min to 8 mL/100 mg/min) even when prolongedhypoperfusion stops functioning, but maintains its structural integrity and, most importantly,

can be salvaged with reperfusion. Figure 2 depicts a summary of metabolic and

electrophysiologic disturbances according to reductions of cortical blood flow at different

thresholds.


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Figure 2 Thresholds of metabolic ( left ) and electrophysiologic ( right ) disturbances during

gradual reduction of cortical blood flow.SEP = somatosensory evoked potentials; EEG =

electroencephalogram; ATP = adenosine triphosphate.Hossmann KA. Pathophysiology and

therapy of experimental stroke. Cell Mol Neurobiol 2006;26(7-8):1057-1083. Reprinted with

permission from Springer Science and Business Media.

The time dependence of ischemic thresholds in producing permanent or transient neurologic

damage has been demonstrated by Jones and colleagues (1981) in primate studies using a

temporary or permanent MCA occlusion model. These experiments demonstrated that the

CBF values below which brain tissue becomes infarcted are dependent on the duration of

vessel occlusion. Two hours of continuous MCA occlusion in awake macaque monkeys

required CBF values of 5 mL/100 g/min to produce infarction, while 3 hours of continuous

occlusion resulted in infarction if CBF values were 12 mL/100 mg/min or less. Permanent

occlusion resulted in infarction if flows were 18 mL/100 mg/min or less. It should be noted

that 30 minutes of occlusion did not result in infarction even at CBF values below 5 mL/100mg/min.

It is important to understand that the blood flow thresholds studied in most animal and human

experiments refer to ischemic tolerance of the brain cortex. Thresholds for deep white matter

or basal ganglia have not been studied rigorously and are simply unknown. It is believed,

however, that gray matter is more susceptible to infarction than white matter, and that within

the gray matter the basal ganglia have a lower ischemic tolerance than the cortex.


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Concept of Ischemic Core and Ischemic Penumbra

The notion that in acute stroke, depending on the extent and duration of hypoperfusion, the

tissue supplied by the occluded artery is compartmentalized into areas of irreversibly

damaged brain tissue and areas of brain tissue that are hypoperfused but viable led to the

concept of ischemic core and ischemic penumbra proposed by Astrup and colleagues (1981).

The ischemic core represents tissue that is irreversibly damaged. PET studies in humans

suggest that beyond a certain time limit (probably no longer than an hour) the ischemic core

corresponds to CBF values of less than 7 mL/100 mg/min to 12 mL/100 mg/min. The

ischemic penumbrar presents tissue that is functionally impaired but structurally intact and, as

such, potentially salvageable. It corresponds to a high CBF limit of 17 mL/100 mg/min to 22

mL/100 mg/min and a low CBF limit of 7 mL/100 mg/min to 12 mL/100 mg/min. Salvaging

this tissue by restoring its flow to nonischemic levels is the aim of acute stroke therapy.

Another compartment, termed by Symon and colleagues (1977) oligemia , represents mildly

hypoperfused tissue from the normal range down to around 22 mL/100 mg/min. It is believed

that under normal circumstances this tissue is not at risk of infarction. It is conceivable,

however, that under certain circumstances, such as hypotension, fever, or acidosis, oligemic

tissue can be incorporated into penumbra and subsequently undergo infarction.

Evidence in the literature suggests that there is temporal evolution of the core, which growsat the expense of penumbra (Figure 3). This process occurs because of the interaction of a

multitude of complex factors acting concomitantly or sequentially. It is known that the

ischemic penumbra represents a dynamic phenomenon that evolves in space and time. If

vessel occlusion persists, the penumbra may shrink because of progressive recruitment into

the core. Alternatively, it may return to a normal state following vessel recanalization or

possibly neuroprotective interventions. It thus appears that the ischemic penumbra represents

a transitional state between evolution into permanent ischemia as one possibility and

transformation into normal tissue as the other possibility. On the basis of a rat model of MCA

occlusion studied in a multimodal fashion assessing CBF, metabolism, and gene expression,

Ginsberg (2003) concluded that the penumbra lies within a narrow range of perfusion and

thus is precariously dependent on small perfusion pressure changes; that the penumbra is

electrophysiologically dynamic and undergoes recurrent depolarizations; and that it is

metabolically unstable, being the site of severe metabolism/flow dissociation.


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Figure 3 Experimental model of middle cerebral artery occlusion in rats. Serial MRIs

(coronal sections) at three levels in the brain depicting the apparent diffusion coefficient ofwater (ADC) ( blue ) demonstrating the time-dependent growth of the ischemic

core.Hossmann KA. Pathophysiology and therapy of experimental stroke. Cell Mol

Neurobiol 2006;26(7-8):1057-1083. Reprinted with permission from Springer Science and

Business Media.

Restriction of acute stroke therapy aimed at vessel recanalization to 3 hours from onset of

symptoms for IV thrombolysis and 6 hours for intraarterial thrombolysis is based on the

concept that the ischemic penumbra has a short lifespan, being rapidly incorporated into the

core within hours of the ictus. Recent evidence suggests, however, that penumbral brain

tissue of significant extent is present even beyond 6 hours of stroke onset. PET studies using

quantitative CBF assessment or markers of tissue hypoxia such as 18F fluoromisonidazole to

assess penumbra, included ptients studied within 6 hours to as late as 51 hours after stroke

onset and reported the existence of penumbra comprising 30% to 45% of the total ischemic

tissue at risk. Several investigators have estimated the penumbra based on diffusion/perfusion

MRI (diffusion-weighted imaging [DWI]/perfusion-weighted imaging [PWI]) mismatch in


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acute stroke. Since the diffusion abnormalities are presumed to represent an approximation of

the irreversible ischemic lesion and the perfusion abnormalities are presumed to represent the

brain territory at risk, the area of mismatch between DWI and PWI is considered a territory

still viable but at risk of undergoing infarction and corresponds theoretically to the concept of

ischemic penumbra. The major shortcoming of this concept derives from the lack of

quantitative data provided by MRI imaging. It has been shown that the DWI lesion is not

precise in distinguishing between irreversible and reversible. It incorporates both types of

ischemia and therefore cannot be considered equivalent to the ischemic core. Additionally,

the PWI lesion has been shown to incorporate both imminently threatened brain and brain

that will not undergo infarction as a consequence of persistent vessel occlusion. Since, by

definition, penumbra represents tissue that will undergo infarction with continuous vessel

occlusion, assessment of penumbral extent based on perfusion MRI is also not precise.

Using MRI technology, Schlaug and colleagues (1999) demonstrated that penumbra

comprises about 40% of the total ischemic territory in a cohort of patients that was studied

within 24 hours of symptom onset. Similar extent of penumbral volumes has been reported

by numerous other investigators. These reports have also described that the presence of

diffusion/perfusion mismatch is highly correlated with the presence of large vessel (internal

carotid artery, MCA, or major division) occlusion. SPECT studies performed acutely in patients with large vessel occlusion have confirmed these findings. Insights into the

pathophysiology of acute stroke as it relates to reversible versus irreversible brain tissue are

provided by a study in which a homogenous group of patients with stroke due to

angiographically proven M1 MCA occlusion were studied within 6 hours of symptom onset

with xenon-CT-CBF technology. This study, in which core and penumbra were determined

based on established perfusion thresholds, indicated that within this time frame, irrespective

of the point in time at which the patients were studied, the ischemic penumbra was

consistently present and relatively constant, comprising approximately one-third of the MCA

territory. In contrast to the penumbra, the ischemic core was highly variable, ranging from

20% to 70% of cortical MCA territory. The authors found that both in patients who

recanalized and in those who did not recanalize, the extent of core and not that of penumbra

was correlated with clinical outcome.

Treatment


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After the clinical diagnosis of stroke is made, an orderly process of evaluation and treatment

should follow.

The first goal is to prevent or reverse brain injury. After initial stabilization, an emergency

noncontrast head CT scan should be performed to differentiate ischemic from hemorrhagic

stroke; there are no reliable clinical findings that conclusively separate ischemia fromhemorrhage, although a more depressed level of consciousness and higher initial blood

pressure favor hemorrhage, and a deficit that remits suggests ischemia. Treatments designed

to reverse or lessen the amount of tissue infarction fall within five categories: (1) medical

support, (2) thrombolysis, (3) anticoagulation, (4) antiplatelet agents, and (5)

neuroprotection.

MEDICAL SUPPORT When cerebral infarction occurs, the immediate goal is to optimize

cerebral perfusion in the surrounding ischemic penumbra. Attention is also directed toward


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preventing the common complications of bedridden patients infections (pneumonia,

urinary tract, and skin) and deep venous thrombosis (DVT) with pulmonary embolism. Many

physicians use pneumatic compression stockings to prevent DVT; subcutaneous heparin

appears to be safe as well.

Because collateral blood flow within the ischemic brain is blood pressure dependent, there is

controversy about whether blood pressure should be lowered acutely. Blood pressure should

be lowered if there is malignant hypertension or concomitant myocardial ischemia or if blood

pressure is > 185/110 mmHg and thrombolytic therapy is anticipated. When faced with the

competing demands of myocardium and brain, lowering the heart rate with a 1-adrenergic

blocker (such as esmolol or labetolol) can be a first step to decrease cardiac work and

maintain blood pressure. Fever is detrimental and should be treated with antipyretics. Serum

glucose should be monitored and kept at


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increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous

rtPA within 3 h of the onset of ischemic stroke improved clinical outcome.

Results of other trials of rtPA have been negative, perhaps because of the dose of rtPA and

timing of its delivery. The European Coop- erative Acute Stroke Study (ECASS) I used a

higher dose of rtPA (1.2 mg/kg), and ECASS-II tested the NINDS dose of rtPA (0.9 mg/kg;

maximum dose, 90 mg) but allowed patients to receive drug up to the sixth hour. No

significant benefit was found, but improvement was found in post hoc analyses. ATLANTIS

tested the NINDS dosing of rtPA between 3 and 5 h and found no benefit. Three major trials

using streptokinase reported increased mortality for patients receiving streptokinase. Early

administration of the fibrinolytic agent ancrod appears to improve outcomes for patients with

acute ischemic stroke; although the drug has not been approved for clinical use, its efficacy provides further evidence that thrombolytics should have a role in treatment of acute

ischemic stroke.

Because of the marked differences in trial design, including drug and dose used, time to

thrombolysis, and severity of stroke, the precise efficacy of intravenous thrombolytics for

acute ischemic stroke re- mains unclear. The risk of intracranial hemorrhage appears to rise

with larger strokes, longer times from onset of symptoms, and higher doses of rtPA

administered. The established dose of 0.9 mg/kg administered intravenously within 3 h of

stroke onset appears safe. Many hospitals have developed expert stroke teams to facilitate

this treatment. The drug is now approved in the United States, Canada, and Europe for acute

stroke when given within 3 h from the time the stroke symptoms began, and efforts should be

made to give it as early in this 3-h window as possible. The time of stroke onset is defined as

the time the patients symptoms began or the time the patient was last seen as normal. A

patient who awakens with stroke has the onset defined as when they went to bed. Table 349-2

summarizes eligibility criteria and instruc- tions for administration of rtPA.

There is growing interest in using thrombolytics via an intraarterial route to increase the

concentration of drug at the clot and minimize systemic bleeding complications. The Prolyse

in Acute Cerebral Thromboembolism (PROACT) II trial found benefit for intraarterial pro-

urokinase for acute middle cerebral artery (MCA) occlusions up to the sixth hour following

onset of stroke. Intraarterial treatment of basilar artery occlusions may also be beneficial for

selected patients. Intraarterial administration of a thrombolytic agent for acute ischemic

stroke is not approved by the U.S. Food and Drug Administration (FDA); however, many


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stroke centers offer this treatment based on these data.

ANTIPLATELET AGENTS Aspirin is the only antiplatelet agent that has been prospectively

studied for the treatment of acute ischemic stroke. The recent large trials, the International

Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST), found that the use of aspirin

within 48 h of stroke onset reduced both stroke recurrence risk and mortality min- imally.

Among 19,435 patients in IST, those allocated to aspirin, 300 mg/d, had slightly fewer deaths

within 14 days (9.0 vs. 9.4%), significantly fewer recurrent ischemic strokes (2.8 vs. 3.9%),

no excess of hemorrhagic strokes (0.9 vs. 0.8%), and a trend towards a reduction in death or

dependence at 6 months (61.2 vs. 63.5%). In CAST, 21,106 patients with ischemic stroke

received 160 mg/d of aspirin or a placebo for up to 4 weeks. There were very small

reductions in the aspirin group in early mortality (3.3 vs. 3.9%), recurrent ischemic strokes(1.6 vs. 2.1%), and dependency at discharge or death (30.5 vs. 31.6%). These trials

demonstrate that the use of aspirin in the treatment of acute ischemic stroke is safe and

produces a small net benefit. For every 1000 acute strokes treated with aspirin, about 9 deaths

or non- fatal stroke recurrences will be prevented in the first few weeks and 13 fewer

patients will be dead or dependent at 6 months.

Agents that act at the glycoprotein IIb/IIIa receptor are undergoing clinical trials in acute

stroke treatment. Early results show that intravenous abciximab can be used safely within 6

h of stroke onset and suggest that it may be effective.

ANTICOAGULATION The role of anticoagulation in atherothrombotic cerebral ischemia

is uncertain. Several trials have investigated antiplatelet versus anticoagulant medications

given within 12 to 24 h of the initial event. The U.S. Trial of Organon 10172 in Acute Stroke

Treatment (TOAST), an investigational low-molecular-weight heparin, failed to show any

benefit over aspirin. Use of subcutaneous unfractionated heparin versus aspirin was tested inIST. Heparin given subcutaneously afforded no additional benefit over aspirin and increased

bleeding rates. Several trials of low-molecular-weight heparins have also shown no consistent

benefit in acute ischemic stroke. Therefore, trials do not support the use of heparin or other

anticoagulants for patients with atherothrombotic stroke.

In spite of the absence of evidence, heparin is still used frequently to treat stroke and TIA,

primarily based on beliefs about its impact on pathophysiology. Theoretically, heparin may

prevent propagation of clot within a thrombosed vessel or may prevent more emboli from


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Barber PA, Demchuk AM, Hirt L, Buchan AM. Biochemistry of ischemic stroke. In: BarnettHJM, Bogousslavsky J, Meldrum H, eds. Advances in neurology: ischemic stroke.Philadelphia: Lippincott Williams & Willkins, 2003:151.

Baron JC. Perfusion thresholds in human cerebral ischemia: historical perspective andtherapeutic implications. Cerebrovasc Dis 2001;11(suppl 1):2-8.

Baudry M, Bundman MC, Smith EK, Lynch GS. Micromolar calcium stimulates proteolysisand glutamate binding in rat brain synaptic membranes. Science 1981;212(4497):937-938.

Bhardwaj A, Alkayed NJ, Kirsch JR, Hurn PD. Mechanisms of ischemic brain damage. CurrCardiol Rep 2003;5(2):160-167.

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