CASE REPORT

NON-HAEMORRHAGIC STROKE

SENIOR CLINICAL CLERKSHIP
Period of April 21
th
May 27
st
, 2014








By :
Agus Salim, S.Ked 04101401015
Ardiyanto, S.Ked 04101401032


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



DEPARTMENT OF NEUROLOGY
FACULTY OF MEDICINE SRIWIJAYA UNIVERSITY
MOHAMMAD HOESIN GENERAL HOSPITAL
PALEMBANG
2014

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)

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 2014
Registry 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 some
works 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 STATE
Internal State

Conciousness : E
4
M
6
V
global aphasia
Nutrition : Overweight
Temperature : 37
o
C


Heart : No abnormality
Lungs : No abnormality
Liver : No abnormality
Pulse : 56 beats/min
Respiratory rate : 16 times/min
Blood pressure : 140/80 mmHg

Psychiatric state
Attitude : uncooperative
Attention : unattended

Neurological state
Head
Shape : Brachiocephali
Size : Normocephalic
Symmetric : Symmetric
Hematome : No
Tumor : No
Neck
Position : Straight
Torticolis : No
Nape of neck stiffness : yes
Spleen : No abnormality
Extremities : see neurological state
Genital : Not examined


Facial Expression : Flat
Psychological contact : None



Deformity : No
Fracture : No
Fracture pain : No
Vessel : No widening
Pulsation : No disorder

Deformity : No
Tumor : No
Vessels : No widening


CRANIAL NERVES
N.I: Olfaktorius nerve
Smelling
Anosmia
Hyposmia
Parosmia

N.II: Opticus nerve
Visual acuity
Campus visi





Anopsia
Hemianopsia
Oculi fundus
Edema papil
Atrophy papil
Retina bleeding

N.III: Occulomotorius,
N.IV: Trochlearis, and
N.VI: Abducens nerves
Diplopia
Eyes gap
Ptosis
Eyes position

Right
Not examined
Not examined
Not examined
Not examined

Right
6/6
V.O.D





No
No

No
No
No



Right
No
Symmetric
No


Left
Not examined
Not examined
Not examined
Not examined

Left
6/6
V.O.S





No
No

No
No
No



Left
No
Symmetric
No

Strabismus
Exophtalmus
Enophtalmus
Deviation conjugae
Eyes movement
Pupil
Shape
Size
Isochor/anisochor
Midriasis/miosis
Light reflex
direct
consensuil
accommodation


N.V: Trigeminus nerve
Motoric
Biting
Trismus
Corneal reflex
Sensory
Forehead
Cheek
Chin

N.VII: Facialis nerve
Motoric
Frowning
Eyes closing
Giggling
Nasolabial fold
Facial shape
rest
Speaking/whistling
Sensory
2/3 anterior tounge

Autonomy
Salivation
Lacrimation
Chvosteks sign

N.VIII: Statoacusticus nerve
Cochlearis nerve
Whispering
Hour ticking
Weber test
Rinne test
Vestibularis nerve
No
No
No
No
No abnormality

Round
3 mm
Isochor
No

Positive, Normal
Positive
Positive



Right
No disorder
No
Yes

Not examined
Not examined
Not examined


Right
Normal
Normal
Not examined
Flat

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 mm
Isochor
No

Positive, Normal
Positive
Positive



Left
No disorder
No
Yes

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

Nystagmus
Vertigo

N.IX: Glossopharingeus, and
N.X: Vagus nerves
Pharyngeal arch
Uvula
Swallowing disorder
Hoarsing/nasalising
Heart beat
Reflex
Vomiting
Coughing
Occulocardiac
Caroticus sinus
Sensory
1/3 posterior tounge
No
No


Right
Symmetric
Symmetric
No
No
Normal

Yes
Yes
No disorder
No disorder

Not examined
No
No


Left
Symmetric
Symmetric
No
No
Normal

Yes
Yes
No disorder
No disorder

Not examined

N.XI: Accessorius Nerve
Shoulder Raising
Head Twisting

N.XII: Hypoglossus Nerve
Tounge Showing
Fasciculation
Papil Athrophy
Dysarthria


MOTORIC
Arms
Motion
Strength
Tones
Physiological Reflex
Biceps
Triceps
Radius
Ulna
Pathological Reflex
Hoffman Trommer
Leri
Meyer

LEG
Motion
Power
Tones
Clonus
Thigh
Right
No disorder
No disorder

Right
Not examined
Not examined
Not examined
Not examined



Right


Decreased

Decreased
Decreased
Decreased
Decreased

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
Foot
Physiological 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

Decreased
Decreased

Yes
Yes
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 : No
Lordosis : No Meningocele : No
Gibbus : No Hematome : No
Deformity : No Tenderness : No



SYMPTOMS OF MENINGEAL IRRITATION

Nuchal rigidity
Kerniq
Lasseque
Brudzinsky
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 MOVEMENTS
Tremor : No
Chorea : No
Athetosis : No
Ballismus : No
Dystoni : No
Myoclonus : No

VEGETATIVE FUNCTION
Micturition : Catheterized
Defecation : No abnormality

LIMBIC FUNCTION
Global aphasia


SPECIFIC EXAMINATION
Cranium X- Ray : Not performed
Vertebral column X- Ray : Not Performed
Thorax X-Ray : Performed
Electroencephalography : Not performed
Electroneuromyography : Not performed
Electrocardiography : Not performed
Arteriography : Not performed
Pneumography : Not performed
Head CT-Scan : Performed
Head MRI : Not Performed
Lumbal Puncture : Not Performed













Thorax Rontgen Mr.
HD





Laboratory Findings
07
th
May 2014 09
th
May 2014 Normal value
Haemoglobin - 13,3 12,6-17,4 mg/dL
RBCs - 4,21 4,20-4,87 x 10
3
/mm
3

WBCs - 8,7 4,5-11,0 x 10
3
/mm
3
Haematocrits - 37 43-49 %
CT Scan Mr HD
PLT - 260 150-450 x 10
3
/uL
Basophils - 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 detik
INR 0.89 -
APTT 27,7 - 27-42 detik
Fibrinogen 362 - 200-400 mg/dL
Total Protein 7,5 6,9 6,4 8,3 g/dL
Albumin 4,1 3,7 3,5 5,0 g/dL
Globulin - 3,2 2,6-3,6 mg/dL
Total Cholesterol 174 177 <200 mg/dL
HDL 26 29 >65 mg/dL
LDL 115 120 <100 mg/dL
Triglyceride 179 133 <150 mg/dL
Urea - 42 16,6-48,5 mg/dL
Creatinine - 0,72 0,70-1,20 mg/dL
Calcium - 8,6 8,4-9,7 mg/dL
Phosphor - 3,0 2,5-5,0 mg/dL
Magnesium - 2,16 1,4-2,1 mEq/dL
Sodium - 146 135-155 mEq/dL
Potassium - 2,5 3,6-5,5 mEq/dL
Chloride - 106 96-106 mmol/L
















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

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 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 EXAMINATION
Consciousness (GCS score) : E
4
M
6
V
global aphasia

Blood pressure : 140/80 mmHg
Pulse rate : 56 x/m
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

O
2
2 L via nasal cannula
Lateralisation to the right
Liquid diet

Pharmacology : - IVFD NaCl 0,9% gtt XX
- Aspillet 2x80 mg tab
- Inj Citicholin 2x250 mg IV
- Inj OMZ 2x40 mg IV
- Sukralfat syr 3x1 c
- Amlodipine 1x10 mg
- Sohobion tab 1x5000 mcg

Planning : Repeat lab exam
CT Scan expertizing

PROGNOSIS
Quo ad vitam : dubia ad malam
Quo ad functionam : dubia ad malam


DISCUSSION
A. Topical Differential Diagnosis

Banford Classification:
1.Anterior Circulation Infarct
Anterior Circulation Infarct Clinical
Findings:
Patients Clinical Findings:
Contralateral hemiparesis with or without
sensoric deficits
Flaccid right side hemiparesis
Contralateral hemianopsia No
Limbic function impairments: aphasia,
visuospatial impairment, hemineglct,
agnosia, apraxia
Global aphasia
3 of 3 criterias : Total Anterior Circulation Infarct (TACI)
2 of 3 criterias : Partial Anterior Circulation Infarct (PACI)
Hemiparesis only or sensoric function disturbances: Lacunar Anterior Circulation Infarct
(LACI)
Conclusion: Partial Anterior Circulation Infarct (PACI)








2. Posterior Circulation Infarct (POCI)
Posterior Circulation Infarct Clinical
Findings:
Patients Clinical Findings:
Ipsilateral cranial nerve(s) disfunction
and 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 Diagnosis
Siriraj 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 : Hemorrhagic
Conclusion: Non hemorrhagic stroke

Gajah Mada Algorithm

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

Etiology differential diagnosis based on anamnesis:

1. Hemorrhagic Stroke
Anamnesis: 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 Thrombosis
Anamnesis: In patient
- No loss of consciousness - There was loss of
consciousness
- Occured during rest - Occured after activity
So, cerebral thrombosis as the cause can be eliminated.

3. cerebral embolism
Anamnesis: In patient
- Loss of consciousness < 30
minutes
- There was loss of consciousness
- 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 acute
infarction 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 PATHOLOGI 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
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 of
necrotic debris, hence the name liquefaction necrosis.
STROKE MECHANI SMS
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
Hennerici (1998) postulated that embolism and hypoperfusion oftentimes coexist and
potentiate each other. They proposed impaired clearance of emboli due to low flow states as a
link between these two factors in the pathophysiology of brain infarction.
Embolism
Embolic material formed within the heart or vascular system travels through the arterial
system, lodging in a vessel and partially or completely occluding it. The most common
sources of emboli are the heart and large arteries. Other rare sources of emboli are air, fat,
cholesterol, bacteria, tumor cells, and particulate matter from injected drugs.
Cardioembolism. Cardioembolism accounts for 20% to 30% of all ischemic stroke. Table
below outlines the high risk versus low or uncertain risk conditions for cardioembolic stroke.
Conditions considered at high risk for embolization to the brain are atrial fibrillation,
sustained atrial flutter, sick sinus syndrome, left atrial thrombus, left atrial appendage
thrombus, left atrial myxoma, mitral stenosis, prosthetic valve, infective endocarditis,
noninfective endocarditis, left ventricular thrombus, left ventricular myxoma, recent anterior
myocardial infarct, and dilated cardiomyopathy. Conditions considered at low or uncertain
risk for brain embolization include patent foramen ovale, atrial septal aneurysm, spontaneous
atrial contrast, mitral annulus calcification, mitral valve prolapse, calcified aortic stenosis,
fibroelastoma, giant Lambl excrescences, akinetic or dyskinetic ventricular wall segment,
subaortic hypertrophic cardiomyopathy, and congestive heart failure.


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.

CEREBRAL BLOOD FLOW CHANGES
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.
a
Furlan M,
Marchal G, Viader F, et al. Spontaneous neurological recovery after stroke and the fate of the
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.
b
Heiss 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 prolonged
hypoperfusion 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.

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/100
mg/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.
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 grows
at 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.

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 of
water (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
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
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 per- formed to differentiate ischemic from hemorrhagic
stroke; there are no reliable clinical findings that conclusively separate ischemia from
hemorrhage, 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
sup- port, (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
preventing the common com- plications of bedridden patients infections (pneumonia,
urinary tract, and skin) and deep venous thrombosis (DVT) with pulmonary embolism. Many
physicians use pneumatic compression stockings to pre- vent 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 <11.1 mmol/L (200 mg/dL).
Between 5 and 10% of patients develop enough cerebral edema to cause obtundation or brain
herniation. Edema peaks on the second or third day but can cause mass effect for ~10 days.
The larger the infarct, the greater the likelihood that clinically significant edema will develop.
Special vigilance is warranted for patients with cerebellar infarction. Even small amounts of
cerebellar edema can acutely increase intra- cranial pressure (ICP) in the posterior fossa or
directly compress the brainstem. The resulting brainstem compression can result in coma and
respiratory arrest and require emergency surgical decompression. Water restriction and
intravenous mannitol may be used to raise the serum osmolarity, but hypovolemia should be
avoided as this may contribute to hypotension and worsening infarction. Trials are under way
to test the clinical benefits of craniotomy and temporary removal of part of the skull
(hemicraniectomy) for large hemispheric infarcts with marked cerebral edema.
THROMBOLYSIS The National Institute of Neurological Disorders and Stroke (NINDS)
recombinant tPA (rtPA) Stroke Study showed a clear benefit for intravenous rtPA in selected
patients with acute stroke. The NINDS study used intravenous rtPA (0.9mg/kgtoa90-
mgmax;10% as a bolus, then the remainder over 60 min) vs. placebo in patients with
ischemic stroke within 3 h of onset. Half of the patients were treated within 90 min.
Symptomatic intracerebral hemorrhage occurred in 6.4% of patients on rtPA and 0.6% on
placebo. There was a nonsignificant 4% reduction in mortality in patients on rtPA (21% on
placebo and 17% on rtPA); there was a significant 12% absolute in- crease in the number of
patients with only minimal disability (32% on placebo and 44% on rtPA.) Thus, despite an
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 strep- tokinase. 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
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 intra- venous 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 cere- bral 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 in
IST. 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
occurring. Heparin is widely used for crescendo TIAs (TIAs that in- crease in frequency),
despite the absence of data from controlled studies regarding this indication. In 20% of
patients with acute stroke, deficits will progress over several hours to 1 to 2 days. Some
physicians heparinize all patients with recent mild ischemic stroke in order to prevent some
of this worsening, but this practice is discouraged. The bleeding complication rate for 7 days
of heparin is about 10%, with a serious bleed rate of 2%. Clearly the value of this approach
must be clarified. Heparinization is generally accomplished by beginning an in- fusion
without bolus and is monitored to maintain the activated partial thromboplastin time (PTT) at
approximately twice normal.
NEUROPROTECTION Neuroprotection is the concept of providing a treat- ment that
prolongs the brains tolerance to ischemia. Hypothermia is a powerful neuroprotective
treatment in patients with cardiac arrest, but it has not been adequately studied in patients
with stroke. Drugs that block the excitatory amino acid pathways have been shown to protect
neurons and glia in animals, but despite multiple clinical trials, they have not yet been proven
to be beneficial in humans. Even so, interest in neuroprotection continues because of the
potential for agents to have limited risk, even when administered in the pre-hospital setting or
in conjunction with thrombolytic agents.



CHAPTER III
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