CEREBROVASCULAR

SYSTEM

YUSTIANI DIKOT
How does blood flow inform us about
brain function?

Cerebrovascular anatomy & neural regulation of CNS

blood flow
Cerebral blood flow: intro
Cerebrovascular anatomy
Neurotransmitter systems & neural regulation
Blood flow and the organ of thought
18F-2-Deoxyglucose

Brain Facts:
1. The brain is 2% of the body
weight.

2. The brain receives 11% of the

cardiac output.

3. The brain consumes 20% of the

bodyÕs energy.

Question:
Can ÒactivationsÓaccount for this
high energy consumption?
Alavi, A. & Reivich, M.
Seminars in Nuclear Medicine
XXXII: 2-5, 2002
Blood flow and the organ of thought

•The brain requires blood for:

•General support of maintenance functions, like
every organ - requires energy (ATP)
•Specific localized support of functional activity
related to neural activity - requires energy (ATP)

•Blood supplies substrates for energy production:

Glucose and oxygen
•~750 ml/min
The route of blood to the head
The route of blood within the head
The route of blood within the head
 Scale of the circulatory system
Aorta: 2.5 cm (~1 in)
Large arteries (e.g., carotid): .5 - 1 cm
Arterioles: 10 - 50 um
Capillaries: 5 - 10 um (RBC)
The route of blood within the head
The route of blood within the head
The route of blood within the head
The route of blood within the head
Cortical neural structure

5 mm
 Cortical capillary vasculature

Grey
matter
has 2-4
times the
capillary
density
of white
matter

5 mm
Cerebellar
Histology

Blue = myelin

Pink = neuropil

1 mm
From Duvernoy, 1995
Flow of CSF
CSF return to venous blood
Large vessels in subarachnoid space
 Blood Brain Barrier
• What cerebral capillaries have:
– Tight continuous quintuple-layered intercellular
junctions
– low wall thickness (0.2 um)
– higher mitochondrial content
– thick basement membrane
• What cerebral capillaries don’t have:
– fenestrations
– lots of vesicles
– fluid-filled bulk transport channels
 Blood Brain Barrier
• Allows passage/transport of small
molecules (H2O, O2, CO2), lipophilic
molecules (EtOH, heroin), passive transport
of glucose, active transport of amino
acids/NT precursors
• Prevents passage of larger molecules
(dopamine), charged molecules, etc
 Measurement of blood flow to
the brain

• Aorta 90cm/s, ICA 40cm/s, arterioles 10-

250mm/s, capillaries 1mm/s
• Transcranial doppler ultrasound
 Cerebral autoregulation

• CBF remains constant over wide range of

change in arterial pressure
Flow is regulated by arteriolar smooth
muscle
Arterioles: 10 - 50 um
 Sites of CBF Regulation
• Large diameter vessels (ANS)
• Smaller diameter arterioles, venules
(neurogenic)
– Must have smooth muscle with appropriate
innervation and receptor site to act upon
– If signaling is at capillary level, message must
move upstream to supplying arteriole
 Changes in cerebral blood flow
can be prompted by
• Change in hemical mileu/blood gases
– Arterial hypercarbia/tissue acidosis/hypoxemia
• Neurotransmitter systems
– Autonomic nervous system
• Sympathetic (NE, Neuropeptide Y)
• Parasympathetic (ACh, VIP)
– Dopamine vs noradrenaline
– Serotonin
• Localized neural activity
Sympathetic innervation of blood vessels

from hypothalamus
and brain stem NE (fast, short acting)
&
NPY (slow, longer lasting)

From Wilson-Pauwels, 1997

Sympathetic innervation of cortical pial vessels

from hypothalamus
and brain stem

Noradrenergic Dopaminergic
Neurotransmitter systems
 Cerebral Vasculature
Arterial Venous
system system
 Mechanisms of Vascular Disease
Arterial (high flow) Venous (low flow)
Embolic occlusion Embolic occlusion
In situ occlusion In situ occlusion
Rupture Rupture
Dissection Dissection
Inflammation Inflammation
Spasm Spasm
 Risk Factors - Modifiable
Medical conditions Behaviors
• Hypertension • Smoking
• Heart disease • Sedentary lifestyle
• Atrial fibrillation • Obesity
• Hypercholesterolemia • Alcohol abuse
• Diabetes mellitus
• Carotid stenosis
• Prior stroke or TIA
• PFO
• Elevated homocysteine,
Lp(a)
• Prothrombotic conditions
• Migraine
• Sleep Apnea
 Cerebrovascular Disease:
Stroke Types
Ischemic Stroke (80%) Hemorrhagic Stroke (20%)
Atherothrombotic
Cerebrovascular Intracerebral
Disease (20%) Cryptogenic (30%) Hemorrhage (70%)

Lacunar (25%)
?
(small vessel disease) Cardioembolic (20%) Subarachnoid Hemorrhage (30%)

Albers GW et al. Chest. 1998;119:683S-698S.

Rosamond WD et al. Stroke. 1999;30:736-743.
Acute Ischaemic Stroke
 Making a diagnosis
• Sudden onset neurological deficits
• Loss of consciousness uncommon
• Involuntary movements uncommon
• Headache common

• Investigations determine:
- effect of stroke i.e. ‘brain damage’
- cause of this stroke
- risk of future strokes
Vascular territories (Anterior)
Vascular territories (Posterior)
Vascular territories- MCA
Vascular territories (Posterior)
Vascular territories- MCA
Vascular territories- MCA
Vascular territories- MCA
Vascular territories- ACA &
PCA
Vascular territories (Posterior)
Vascular territories- MCA
Vascular territories- MCA
Vascular territories- MCA
Vascular territories- ACA &
PCA
Vascular territories- vertebrobasilar
 Investigations
Brain imaging Vessel imaging
• CT Brain • CTA
• MRI Brain ‘Stroke • MRA
protocol’ with • Ultrasound carotids
diffusion sequences

•Cardiac- telemetry, Echocardiography

•Clotting
•Aorta- trans-oesophageal echocardiography
 Head CT

Brain Stroke ‘window’

 Head CT

Brain Stroke ‘window’

T1-weighted Images
Normal SI: CSF < GM < WM

Interpretation:
• Anatomic delineation
• Only a few things are bright:
– Fat
– Protein (colloid cysts,
melanin, methemoglobin)
– Gadolinium
T2-weighted Images
Normal SI: WM < GM < CSF

Interpretation:
• Signal intensity generally
follows water content.
• Vasogenic edema looks bright.
• Many pathologic processes
result in increased water
content.
FLAIR Images
“Fluid Attenuated Inversion Rec
Normal SI: CSF < WM < GM
Interpretation:
• T2-weighted image in which signal
from CSF has been suppressed.
• Distinguishes CSF spaces from T2-
bright lesions.
• Increased conspicuity of T2-bright
lesions next to CSF.
• CSF signal will not suppress if:
– SAH
– Protein (as in
infection/inflammation)
– Hyperoxygenation
– Propofol
– Prior gadolinium
“Susceptibility” images
Gradient Echo images
Normal SI: WM < GM < CSF
Interpretation:
• T2 weighted image.

• Substances that exhibit

susceptibility effect will look
dark and “bloom:”
– Deoxyhemoglobin
– Intracellular methemoglobin
– Hemosiderin
– Calcium (sometimes)
– Air
– Metal (aneurysm clips, earrings,
braces, etc).
Diffusion-Weighted Images (DWI)
Normal SI: CSF < WM < GM
Interpretation:
Normal SI: • T2-weighted image, in which
substances look brighter if
water diffusion is restricted.
• In acute stroke, water diffusion
is restricted, so tissue looks
bright.
 Vessel imaging
• Ultrasound
• CT angiography
• MR angiography
• Conventional catheter angiography
Magnetic Resonance Angiography
(MRA)

Interpretation:
• Moving blood looks bright.
• All other substances dark.
• No contrast necessary (but we
use gadolinium for better neck
MRA images).
• Less spatial resolution than
CTA, more motion-sensitive.
 Treatment of Acute Ischaemic Stroke
• Rapid assessment- NIHSS
• Consider tPA (IV or IA)
• Anti-coagulation
• Anti-platelet agent
• Blood pressure, glucose monitoring, fever control
• Surgery
• Early evaluation- fasting glucose & lipids, brain &
vessel imaging, screen for Atrial Fibrillation, TTE +-
TOE
• Rehabilitation- SALT, PT, OT
 Dissection: management
Management is controversial, no RCT
• Medical
– Short term anticoagulation with heparin / warfarin
followed by long term anti-platelet agents
– CTA, MRA, Carotid duplex useful for follow-up
• Endovascular
– Balloon occlusion or stenting considered if recurrent
symptoms occur despite medical treatment
– Coiling of a ‘pseudo’aneurysm
• Surgical
– Bypass, Surgery for pseudoaneurysm
 Secondary Prevention
of Ischemic Stroke
– Carotid endarterectomy: >50% stenosis

– Anticoagulation therapy: Cardioembolic

stroke

– Antiplatelet therapy: Most common therapy

 Antiplatelet Agents
for Stroke Prevention
– Aspirin

– Ticlopidine

– Clopidogrel

– Dipyridamole
 Carotid and Vertebral Artery Dissection

• 2% of all ischemic strokes

• 25% of stroke in young
• Incidence 2.6 per 100,000
(carotid) and 1.0 per
100,000 (vertebral)
• Peaks in the 5th decade
• Intracranial dissections are
rare, occur at younger ages
Intimal tear  sub intimal
or sub adventitial
hematoma (arterial
occlusion, ‘pseudo’
From Schievink WI, NEJM 2001 aneurysm)
 Dissection: management
Management is controversial, no RCT
• Medical
– Short term anticoagulation with heparin / warfarin
followed by long term anti-platelet agents
– CTA, MRA, Carotid duplex useful for follow-up
• Endovascular
– Balloon occlusion or stenting considered if recurrent
symptoms occur despite medical treatment
– Coiling of a ‘pseudo’aneurysm
• Surgical
– Bypass, Surgery for pseudoaneurysm
 Secondary Prevention
of Ischemic Stroke
– Carotid endarterectomy: >50% stenosis

– Anticoagulation therapy: Cardioembolic

stroke

– Antiplatelet therapy: Most common therapy

 Antiplatelet Agents
for Stroke Prevention
– Aspirin

– Ticlopidine

– Clopidogrel

– Dipyridamole
Aneurysm

1/5/2019© 2009, American Heart

Association. All rights reserved.
 Epidemiology

• SAH incidence varies greatly between countries,

from 2 cases/ 100,000 in China to 22.5/100,000
in Finland
• Many cases of SAH are misdiagnosed
• Thus, the annual incidence of aneurysmal SAH
in the US may exceed 30,000
• Incidence increases with age, occurring most
commonly between 40 and 60 years of age
(mean age > 50 years)
1/5/2019© 2009, American Heart
Association. All rights reserved.
 CT Scan of a 65 yo woman,
Subarachnoid Hemorrhage

Arrow:
Hyperintense signal.
Blood in the
subarachnoid
space

CT Scan courtesy: University of Texas Health Science Center at San Antonio, Department of Neurosurgery
1/5/2019© 2009, American Heart
Association. All rights reserved.
Angiogram - Giant ICA Aneurysm

Angio image courtsey: University of Texas Health Science Center at San Antonio - Department of Neurosurgery

1/5/2019© 2009, American Heart

Association. All rights reserved.
 Acute Evaluation - Diagnosis
• “The worst headache of my life” is described by
~80% of patients
• “Sentinel” headache is described by ~20%
• Nausea/vomiting, stiff neck, loss of consciousness,
or focal neurological deficits may occur
• Misdiagnosis of SAH occurred in as many as 64%
of cases prior to 1985
• Recent data suggest an SAH misdiagnosis rate of
approximately 12%
1/5/2019© 2009, American Heart
Association. All rights reserved.
 Acute Evaluation - Diagnosis

• Importance of recognition of a warning or sentinel

leak cannot be overemphasized
• A high index of suspicion is warranted in the ED
• The diagnostic sensitivity of CT scanning is not
100%, thus diagnostic lumbar puncture should be
performed if the initial CT scan is negative

1/5/2019© 2009, American Heart

Association. All rights reserved.
 Acute Evaluation – Emergency
Evaluation

• Emergency medical services (EMS) is first

medical contact in about 2/3 of SAH patients
• EMS personnel should receive continuing
education regarding signs and symptoms and the
importance of rapid neurological assessment in
cases of possible SAH
• On-scene delays should be avoided
• Rapid transport and advanced notification of the
ED should occur
1/5/2019© 2009, American Heart
Association. All rights reserved.
 Acute Evaluation – Preventing Re-
bleeding
• Up to 14% of SAH patients may experience re-
bleeding within 2 hours of the initial hemorrhage
• Re-bleeding was more common in those with a
systolic blood pressure >160mm Hg
• Anti-fibrinolytic therapy may reduce re-bleeding
but has not been shown to improve outcomes

1/5/2019© 2009, American Heart

Association. All rights reserved.
Surgical and Endovascular Management
of SAH

• Occluding aneurysms using endovascular coils

was described in 1991
• Improved outcomes have been linked to
hospitals that provide endovascular services
• Use of endovascular versus surgical techniques
varies greatly across centers
• Coil embolization is associated with a 2.4% risk
of aneurysmal perforation and an 8.5% risk of
ischemic complications

1/5/2019© 2009, American Heart

Association. All rights reserved.
 Definition of an AVM
• A congenital shunt between the arterial and
venous systems
• A tangle of abnormal vessels (nidus)
• Vary in size and location

http://neuro.wehealny.org/endo/illus/13_01.gif
 Epidemiology and Natural History
(These figures are debated in the literature)
• Incidence: about 1 per 100,000 per year
• Point prevalence: about 18 per 100,000
• AVMs account for:
– 1-2% of all strokes
– 9% of subarachnoid hemorrhages
• Annual risk of hemorrhage from unruptured AVM:
about 2% (poor data)
• Risk of recurrent hemorrhage: up to %18 in the first
year, uncertain thereafter (poor data)
• Annual case fatality: 1-1.5% (poor data)
(Al-Shahi et al.)
 Diagnosis
• Diagnosis is made or confirmed by diagnostic
imaging
• Angiography is considered the “gold standard”
for diagnosis and treatment planning
• However, there is very little data about the
sensitivity and specificity, as well as intra- and
inter-observer variability of imaging
modalities used to diagnose and classify
AVMs
 CT Imaging
• What to look for:
– Vascular tangles that are serpiginous and possibly
hyperdense, due to the pooling of blood
– May contain punctate or curvilinear calcifications
– AVMs will enhance with contrast
– An AVM may present as a hemorrhage
Axial
CT
without
contrast

Al-Shahi et al.
Coronal,
unenhanced,
T1- weighted
MRI

Al-Shahi et al.
Saggital,
T1-weighted
MRI

http://www.hmc.psu.edu/neurosurgery/services/images/LF1.jpg
 Treatment
• Surgical options include:
– Neurosurgery (resect the AVM)
– Sterotactic radiosurgery (ablate the AVM through direct
radiation, which causes thrombosis over time)
– Endovascular embolization (ablate AVM through direct
thrombosis with embolic material)
– A combination of these modalities
• AVMs are graded in an effort to help guide treatment
decisions. The most common grading system is the
Spetzer-Martin Scale:
 Spetzler-Martin AVM Grading Scale
• Size
– 0-3 cm 1
– 3.1-6.0 cm 2
– >6 cm 3
• Location
– Noneloquent 0
– Eloquent 1
• Deep venous drainage
– Not present 0
– Present 1
* Eloquent brain regions can be defined as “sensorimotor, language, and visual cortex; the hypothalamus
and thalamus; the internal capsule; the brain stem; the cerebellar peduncles; and the deep cerebellar
nuclei.” (Hofmeister et. al)

Grading scale adapted from Ogilvy et al.

CNS VASCULITIS
CNS Vasculitis aka Primary Angiitis
of the CNS (PACNS)
• Inflammation of small and medium sized
arteries only in CNS causing CNS dysfunction
– Unexplained neurologic or psychiatric deficit
– Classic angiographic or histopathologic features
– No evidence of systemic vasculitis
• Difficult to diagnose and study
– Rarity – about 500 cases reported since 1959
– Nonspecific and various presentations
– No useful animal models
 Pathology
• Pathologic findings include Langerhans or foreign
body giant cells, necrotizing vasculitis or
lymphocytic vasculitis
• Inflammation causes vessels to become narrowed,
occluded and thrombosed
• More likely to affect blood vessels in cerebral cortex
and leptomeninges more than subcortical regions
• Cause is unknown
– Infection Mycoplasma gallisepticum, VZV, WNV, HIV
have been proposed
 Clinical Manifestations
• Suspected when in patients with recurrent
strokes with no identifiable cause or other CNS
dysfunction with no cause
• Male 2:1 predominance
• Mean age is 42 but can occur at any age
• Series of 116 patients presented with
– 83% had decreased cognition, 56% headache, 30%
seizure, 14% stroke, 12% cerebral hemorrhage
• Strokes/TIAs occur in 30-50% of patients
 Differential
• Reversible cerebral vasoconstriction syndrome (Call-Fleming)
• Systemic vasculitis involving the brain
– Behcet’s, polyarteritis nodosa, Wegener’s, Churg-Strauss, cryoglobulinemic vasculitis
• Connective tissue diseases
– SLE, NAIM, rheumatoid vasculitis, antiphospholipid syndrome
• Infections
– Varicella zoster, HIV, hepatitis C, CMV,
• Atherosclerotic disease –
– Premature intracranial, Chronic hypertension
• Demyelinating- MS, ADEM, PML
• Embolic disease
– cardiogenic
• Malignancy
– Intravascular lymphoma
• Miscellanous
– PRES, sarcoidosis, Susac, CADASIL, MELAS, moyamoya
 Testing
• ESR and CRP- usually normal
• Complete infectious and rheumatologic
work up
• Drugs of abuse screen- cocaine
• CSF- abnormal in 80-90% of patients but no
specific abnormalities
– Elevated protein and wbc
– important to rule out other diseases
 Imaging
• MRI – used frequently in work up to assess for
stroke, leptomeningeal enchancement, follow
progress of lesions
• Angiography: ectasia and stenosis “beading” usually
in small arteries with involvement of several sites.
– Also has multiple occlusions with sharp cutoffs and
circumferential or eccentric vessel irregularities
– Two series of patients found sensitivity of 60%. Cannot
use negative exam to rule out
• Vessels usually beyond resolution of exam
Differential Diagnosis of
vascular constriction and
ectasia/beading
Vasospasm
Infection
Emboli
Athereosclerosis
Hypercoaguable state
 Treatment
• Initial- with infection excluded
– Glucocorticoids- no trials on route, dose or length
of treatment
• Biopsy confirmed
– Glucocorticoids
– Cyclophosphamide- 600-750mg/m2 qmonth for
three to sixth months
– Once in remission for 3-6 months switch to
alternative agents MMF, Azathioprine and MTX
– Serial MRIs
 Conclusion
• PACNS is a difficult disease to identify and
treat
• Should be entertained in patients who have
new onset neurologic deficits and multifocal
strokes with no other apparent cause
• Diagnosis is arrived at by exclusion of other
causes and a combination of clinical history,
CSF findings, radiologic and pathologic
findings