Transcript CSF Physiology and Cerebral Blood flow

CSF Physiology and
Cerebral Blood Flow
Keith R. Lodhia, MD,MS
Department of Neurosurgery
University of Michigan
12/20/03
CSF Functions
provide mechanical protection
 maintain a stable extracellular
environment for the brain
 Remove some waste products
 nutrition
 Convey messages? (hormones/releasing
factors/neurotransmitters)

Brain Fluid “Balance”
CSF Production
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70 % CSF produced in choroid
plexuses of lateral, third and
fourth ventricles
produced at rate of 500 cc/day
or approximately 20cc/hour
(0.3-0.5 cc/kg/hr)
eliminated by being absorbed
into the arachnoid villi -->
dural sinus --> jugular system
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The secretion of fluid by the
choroid plexus depends on the
active Na+-transport across
the cells into the CSF. The
electrical gradient pulls along
Cl-, and both ions drag water
by osmosis. The CSF has lower
[K+], [glucose], and much
lower [protein] than blood
plasma, and higher
concentrations of Na+ and Cl-.
The production of CSF in the
choroid plexuses is an active
secretory process, and not
directly dependent on the
arterial blood pressure.
CSF Production
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Other sources of CSF production from
capillary ultrafiltrate (Virchow-Robin spaces)
Additionally some produced from metabolic
H2O production
CSF Production
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VirchowRobin
spaces
CSF PRODUCTION- Choroid Plexus
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CSF is produced by
choroid plexus and
secreted at ciliated
cuboidal epithelial cell
surfaces of the
microvilli into the
ventricles
CSF PRODUCTION- Choroid Plexus
Ependymal Cell Membrane
Transport
CSF Production
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CSF secretion
involves the
transport of ions
( Na+, Cl¯ and
HCO3¯) across
the epithelium
from blood to
CSF
Basolateral
H20, Na+, HCO3¯, Cl¯
Apical
Secretion can occur because of the polarized distribution of specific
ion transporters in the apical or basolateral membrane of the
epithelial cells.
CSF Production
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5-HT2C receptors– from 5HT subfamily. {e.g
1) SSRI’s block 5-HT1A receptor presynaptic
uptake of 5HT 2) antimigraine “triptans”
stimulate vasoconstriction- agonists mediating
5HT1B/1D receptors 3) ondansetron/granisetron
are 5-HT3 receptor antagonists - antinaseau
effects}
5-HT2C receptors found in high concentration in
choroid plexus
CSF Production
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ANP receptors found in choroid plexus
ANP decreases CSF production
Choroid plexus epithelial cells express
receptors for atrial natriuretic peptide
that when stimulated increase cGMP
levels and inhibit cerebral spinal fluid
production
Aquaporin-AQP1 channels are thought
to be involved in the production of
cerebral spinal fluid
CSF Constituency
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CSF volume: 25 cc
ventricular, 25cc
intracranial
subarachnoid space,
and 100cc in spinal
subarachnoid spaces
β2 transferrin
CSF Constituency- β2 transferrin
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PROTEIN ELECTROPHORESISon cellulose/PAGE/filter etc
Transferrin is an iron binding
protein used to shuttle iron
stores to cells- marker of severe
malnutrition . Elevations in:
hypothyroidism, biliary cirrhosis,
nephrosis, chronic iron deficient
anemia, and some cases of
diabetes
CSF shows increased β2 peak
c/w mucous. Therefore useful
in evaluating potential CSF
rhinorrhea
CSF Circulation
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lateral ventricles-->
foramen of Monro third
ventricle --> aqueduct
of Sylvius --> fourth
ventricle --> foramina
of Magendie and
Luschka -->
subarachnoid space
over brain and spinal
cord --> reabsorption
into venous sinus blood
via arachnoid
granulations
CSF Circulation
Lundberg Waves
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Lundberg has described 3 wave patterns ICP waves (A, B, and
C waves). A waves are pathological. There is a rapid rise in ICP
up to 50-100 mm Hg followed by a variable period during
which the ICP remains elevated followed by a rapid fall to the
baseline and when they persist for longer periods, they are
called 'plateau' waves which are pathological. 'Truncated' or
atypical ones, that do not exceed an elevation of 50 mm Hg,
are early indicators of neurological deterioration. B & C waves
are related to respiration and 'Traube-Hering-Mayer' waves
(rhythmical variations in blood pressure) respectively and are
part of normal physiology with little clinical significance.
Lundberg
A- waves
A- waves/Plateau Waves
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Steep rises and abrupt falls in ICP, peaking at 50-100 mm
Hg, that last 5- 20 minutes (also known as plateau waves).
May signify intracranial vasomotor decompensation. May or
may not be associated with clinical deterioration.
Pathogenesis related to dilation of resistance vessels,
increased intracranial blood volume, decreased flow, and
increased pressure.
“Loss of Autoregulation”
CSF Absorption
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CSF is reabsorbed into
the blood of the venous
sinuses via the
arachnoidal villi. The
absorption here is directly
related to the CSF
pressure in the cranial
cavity.
Lymphatics/cribiform
plate
Transependymal flow
Route and Absorption of CSF
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Arachnoid villi are microscopic
one-way valves (modified pia and
arachnoid) that penetrate the
meningeal dural layer that line
the sinuses; hence, arachnoid villi
reside within the sinuses
(especially the superior sagittal
sinus).
Clumps of arachnoid villi =
arachnoid granulations =
macroscopic.
Arachnoid Villus
Route and Absorption of CSF
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Hydrostatic pressure in subarachnoid
space > pressure in dural sinuses
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Typical hydrostatic values of CSF are 150 mm
H2O (11 mm Hg) in subarachnoid space vs.
about 70 mm H2O (5 mm Hg) in dural sinuses.
Arach. villi are one-way valves that open
when the hydrostatic pressure of CSF in
the subarachnoid space is about 1.5 mm
Hg greater than venous hydrostatic
pressure in the dural sinuses (i.e., passive
process).
Drugs affecting Rate of
CSF Production
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Drugs
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Carbonic anhydrase inhibitors
(acetozolamide/Diamox)
Cardiac glycosides (digoxin) inhibit ATPase
pump, thereby reducing CSF formation in a
dose-dependent manner.
Steroids- Effects on CSF formation are
inconsistent.
Future- AqP inhibitors?, 5-HT2C receptor inh ?
CSF Pharmacology cont.
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Carbonic Anhydrase
CO2 + H2O <=H2Co3=>
HCO3- + H+
Inhibition of CAII
decreases production of
CSF by 60 % by
decreasing bicarbonate
formation in choroid
plexus
Acute Mountain Sicknessan aside.
CO2 + H2O <=>
HCO3- + H+
VENTRICLE
Acute Mountain Sickness-AMS
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AMS symptoms (HA fatigue
somnolence etc) represent the
effect of early cerebral edema
with increased intracranial
pressure
a loss of cerebral autoregulation
mechanisms leading to vasogenic
edema (also migrainous-like), or
an osmotic swelling of the brain
cells (cytotoxic edema).
Hypoventilation appears to
contribute to development of
AMS. A brisk increase in
ventilation on ascent to altitude is
associated with a lower incidence
of AMS
Acute Mountain Sickness-AMS
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Prophylaxis: slow ascent, Diamox,
Rx: ASA or tylenol for mild HA
Acute therapy for High Altitude Cerebral
Edema (severe form of AMS): decadron,
but descent to a lower altitude is still the
most reliable treatment
CSF Pathology
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In cases of subarachnoid hemorrhage or traumatic spinal
fluid taps, approximately 1 WBC is added to every 700
RBCs (literature range, 1 WBC/500-1,000 RBCs). This
disagreement in values makes formulas (Fisher ratio etc)
unreliable that attempt to differentiate traumatic tap
artifact from true WBC increase. Also, the presence of
subarachnoid blood itself may sometimes cause
meningeal irritation, producing a mild to moderate
increase in PMNs after several hours that occasionally
may be greater than 500 WBCs/ mm3 .
Xanthochromia begins in > 4 hours (literature range, 248 hours) due to hemoglobin pigment from lysed RBCs.
CSF Pathology
Patterns of Cerebrospinal Fluid Abnormality: Cell Type and Glucose Level
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POLYMORPHONUCLEAR: LOW GLUCOSE
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Acute bacterial meningitis
POLYMORPHONUCLEAR: LOW OR NORMAL GLUCOSE
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Some cases of early phase acute bacterial meningitis
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Primary amoebic (Naegleria species) meningoencephalitis
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Early phase Leptospira meningitis
POLYMORPHONUCLEAR: NORMAL GLUCOSE
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Brain abscess
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Early phase coxsackievirus and echovirus meningitis
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CNS syphilis (some patients)
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Acute bacterial meningitis with IV glucose therapy
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Listeria (about 20% of cases)
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LYMPHOCYTIC: LOW GLUCOSE
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Tuberculosis meningitis
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Cryptococcal (Torula) meningitis
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Mumps meningoencephalitis (some cases)
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Meningeal carcinomatosis (some cases)
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Meningeal sarcoidosis (some cases)
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Listeria (about 15% of cases)
LYMPHOCYTIC: NORMAL GLUCOSE
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Viral meningitis
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Viral encephalitis
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Postinfectious encephalitis
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Lead encephalopathy
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CNS syphilis (majority of patients)
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Brain tumor (occasionally)
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Leptospira meningitis (after the early phase)
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Listeria (about 15% of cases)
Cerebral Blood Flow (CBF)
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CBF = CBV/t
750 mL/minute, which is 15% of the
cardiac output
The normal cerebral blood flow is 4550ml/100g/min, ranging from 20ml 100g1 min-1 in white matter to 70ml 100g1 min-1 in grey matter. Highest in
neurohypophysis
CBF
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When CBF falls to less than 1023ml/100g/min, physiological electrical
function of the cell begins to fail“ischemic penumbra”.
Below 8 ml/100g/min irreversible cell
death- ionic membrane transport failure
Cerebral Perfusion Pressure (CPP)
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Cerebral Perfusion Pressure (CPP)
MAP-ICP=CPP
normal CPP is between 50-150 mmHg
 <50 mmHg --> ischemia
 >150 mmHg --> hyperemia
Autoregulation
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CBF is maintained at a constant level in normal
brain in the face of the usual fluctuations in
blood pressure by the process of autoregulation.
It is a poorly understood local vascular
mechanism. Normally autoregulation maintains a
constant blood flow between CPP 50 mmHg and
150 mmHg.
 Poiseuille’s law- flow through a rigid vessel:
Q = ΔPπr4/8Lη
Autoregulation
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Dysregulation can occur in pathologic states
In traumatised or ischaemic brain, or following
vasodilator agents (volatile agents and sodium
nitroprusside) CBF may become blood pressure
dependent. Thus as arterial pressure rises so CBF
will rise causing an increase in cerebral volume.
Similarly as pressure falls so CBF will also fall,
reducing ICP, but also inducing an uncontrolled
reduction in CBF.
Autoregulation
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pressure/myogenic autoregulation
arterioles dilate or constrict in response to changes in BP
and ICP in order to maintain a constant CBF
“myogenic theory”- vascular smooth muscle within
cerebral arterioles intrinsically contract to stretch thereby
regulating pressure
NO- limited role overall, but if completely abolish NO
production then loss of autoregulation; with CBF being
completely BP-dependent
Metabolic Autoregulation
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arterioles dilate in response to potent chemicals
that are by-products of metabolism such as
lactic acid, carbon dioxide and pyruvic acid
CO2 is a potent vasodilator
increased CO2/decreased BP --> vasodilation
decreased CO2/increased BP -->vasoconstriction
Neurogenic Autoregulation
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Autonomic- sympathetic adrenergic
receptors seen in cortical layers IV and V.
Β1, β2, and ą2 (“dilators”), and ą1
(“constrictor”) receptors
Overall sympathetic system plays minor
role unlike in non-cerebral vascular beds.
Neurogenic Autoregulation- cont
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5-HT- potent “constrictor,” antagonized by NO
Neuropeptide Y- “vasoconstriction”, in assoc
with NO and sympathetic system
Vasoactive intestinal polypeptide (VIP) and
peptide histidine isoleucine (PHI)- “vasodilators”
Substance P, neurokinin A, calcitonin generelated peptide histamine H2 -”vasodilatory” esp.
substance P
CCK, neurotensin, somatostatin, vasopressin,
endorphin
Neurogenic Autoregulation-cont
Autonomic system and
neurochemical control of CBF
in general is a minor control
 Overall, pressure and
metabolic autoregulation
most important
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Increasing CBF-Hyperemia
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Low arterial oxygen
tension has profound
effects on cerebral
blood flow. When it
falls below 50 mmHg
(6.7 kPa), there is a
rapid increase in CBF
and arterial blood
volume
CBF and CO2
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Carbon dioxide causes
cerebral vasodilation.
As the arterial tension
of CO2 rises, CBV and
CBF increases and
when it is reduced
vasoconstriction is
induced.
“Cerebrovascular Reserve”
 In functionally activated areas, CBF augmentation
exceeds the small increases in oxygen utilization and
the concentration of deoxyhemoglobin is relatively low.
Thus, this excess supply of oxygen in response to a
demand stimulus reflects the cerebral perfusion reserve
capacity
 Cerebrovascular reserve capacity is impaired by risk
factors such as hypertension and diabetes,
carotid/cerebral vasc. stenosis, and can be an etiologic
factor in ischemic stroke
Cerebrovascular Reserve
 PET, SPECT, Xe-CT, CT-perfusion to assess.
Pre/post diamox challenge.
 acetazolamide challenge and the CO2-loading
(breath-holding) test raise global CBF
 (MRI) of T2-weighted or Blood oxygenation
level–dependent (BOLD)-weighted images
correlate well with changes in the total amount
of oxygenated hemoglobin
Xenon CT
perfusion CT
BOLD-MRI and singlephoton emission
computed tomography
(SPECT)
(SPECT)
CBF AND CSF- TYING
IT TOGETHER
PATHOPHYSIOLOGY CSF/CBF
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1. the intracranial compartment is a rigid
container and consists of three
components
a. brain-80% of total volume
b. blood-10% of total volume
c. CSF-10% of total volume
PATHOPHYSIOLOGY CSF/CBF
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2. Monro-Kellie
Hypothesis
to maintain a normal ICP,
a change in the volume
of one compartment must
be offset by a reciprocal
change in the volume of
another compartment
pressure is normally wellcontrolled through
alterations in the volume
of blood and CSF
Brain P/V curve
P/V CURVE AND COMPLIANCE
 Pressure gradients can develop within the
brain substance and the compliance or
“squishiness” of pathological brain (e.g.
tumor) can be different from that of
normal brain leading to an altered curve
(shift left).
The extent of the change in ICP caused by an alteration in
the volume of intracranial contents is determined by the
compliance or of the brain. In other words if compliance is
low, the brain is stiffer or less "squashable". Therefore, an
increase in brain volume will result in a higher rise in
intracranial pressure than if the compliance were high.
Blood/Brain-Blood/CSF Barriers
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The blood-brain barrier (BBB) is the specialized
system of capillary endothelial cells that protects
the brain from harmful substances in the blood
stream, while supplying the brain with the
required nutrients for proper function.
Formed by the nonfenestrated capillaries and to
much lesser degree, the astrocytic foot
processes—keeps out most macromolecules
Blood/Brain Barrier
Blood-CSF
Barrier
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“Tight”
junctions at
the
ependymal
level
Fenestrated
junctions at
the choroidal
capillaries
The choroid plexus is composed of fenestrated
capillaries and an epithelial (ependymal) covering,
which reverts from "tight" to moderately "open"
at the base -–not as strenuous of barrier as
blood/brain
Blood/Brain Barrier and
Circumventricular organs
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The circumventricular organs (CVO) are midline
structures bordering the 3rd and 4th ventricles. These
barrier-deficient areas are recognized as important sites
for communicating with the CSF and between the brain
and peripheral organs via blood-borne products. CVO's
include the pineal gland, median eminence,
neurohypophysis, subfornical organ, area postrema,
subcommissural organ, organum vasculosum of the
lamina terminalis, and the choroid plexus. The
intermediate and neural lobes of the pituitary are
sometimes included
Causes of an increased ICP
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Conditions Increasing Brain Volume
intracranial mass (tumor, hematoma,
aneurysm, AVM)
cerebral edema
CNS infection (abscess, inflammatory
process)
Causes of an increased ICP
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Conditions Increasing Blood Volume
obstruction of venous outflow
hyperemia – decreased pO2- inc. CBF
hypercapnea – >pCO2 increases
vasodilation inc CBV , CBF, and ICP
Causes of an increased ICP
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Conditions Increasing CSF Volume
increased production(Ch plexus papilloma)
decreased reabsorption of CSF
(meningitis, SAH)
Obstruction to flow of CSF (e.g. aq
stenosis)
THE END