PHYSIOLOGY OF CSF PRODUCTION AND CIRCULATION, ALTERATIONS

IN VARIOUS PATHOLOGY

Dr Unnikrishnan P

First few drops…

Emanuel Swedenborg who discovered CSF, referred to it as “highly gifted juice” that is dispensed from the roof of the fourth ventricle to the medulla oblongata, and the spinal cord.Albrecht von Haller found that that the “water” in the brain, in case of excess secretion, descends to the base of the skull resulting in hydrocephalus

OUTLINE

CSF SPACES

CSF FORMATION-CIRCULATION-REABSORPTION

METHODS OF DETERMINING Vf and Ra

EFFECTS OF DRUGS

REGULATION

ALTERATION IN CSF DYNAMICS IN PATHOLOGIES

Introduction

CSF flows via macroscopic & ECF spacesPRESSURES AND VOLUMES

CSF PRESSURE [mm of Hg]

CHILDREN 3.0-7.5

ADULTS 4.5-13.5

CSF VOLUME [mL]

INFANTS 40-60

YOUNG CHILDREN 60-100

OLDER CHILDREN 80-120

ADULTS 100-160

CHOROID PLEXUS

Invagination of blood vessels & leptomeninges

covered by a layer of modified ependyma

Epithelium is the blood-CSF barrier

Carbonic anhydrase present in the epithelium

& Na-K pump in luminal plasma membrane

play major role in CSF formation

Anatomy

• Choroid plexus projects into• The temporal horn of each lateral ventricle,• the posterior portion of the third ventricle &• the roof of the fourth ventricle.

CHOROID PLEXUS BLOOD SUPPLY

. Body of lateral ventricle Posterior choroidal artery

Body of third ventricle Anterior choroidal artery

Temporal horns Superior cerebellar artery

Fourth ventricles Posterior inferior cerebellar artery

NERVE SUPPLY:IX,X, Sympathetic nerves

MACROSCOPIC SPACES

Two lateral ventriclesThird ventricleAqueduct of sylviusFourth ventricleCentral canal of spinal cordSubarachnoid spaces

MICROSCOPIC SPACES- BRAIN &SPINAL CORD ECF SPACES

are smallCapillary – ECF exchange is l i m i t e dBlood brain barrier Whats your diameter?

………<20 A⁰ ?

COMPOSITION

L

Plasma CSF

Na+(mM) 140 141

K+(mM) 4.6 2.9

Mg2+(mM) 1.7 2.4

Ca2+(mM) 5.0 2.5

Cl-(mM) 101 124

HCO3-(mM) 23 21

Glucose (mM) 92 61

Amino acids (mM) 2.3 0.8

pH 7.41 7.31

Osmolality (mosmol.Kg H2O-1) 289 289

Protein (mg 100 g-1) 7000 28

Specific gravity 1.025 1.007

COMPOSITION

Na,Cl,Mg

Glucose,Protein,AA,K,HCO3,Ca,P

Vary according to sampling site

Altered during neuroendoscopy

CSF FORMATION

CSF FORMATION

Rate [Vƒ] 0.35-0.40 mL/min OR 500-600 mL/day0.25% of total vol replaced each minuteTurn over time for total CSF vol 5-7 hours= 4 times / day40%-70% enters macroscopic spaces via CP30%-60% enters across ependyma and pia

@ CHOROID PLEXUS

L

@ CHOROID PLEXUS

Blood filtered protein rich fluid similar to ISF

Hydrostatic pressure & bulk flow-> enter cleft between cells

Ultra filtration & secretion

@EXTRA CHOROIDAL SITES

Oxidation of glucose by brain [60%]Ultra filtration from cerebral capillaries [40%]

TIGHT JUNCTIONS

Glucose/electrolyte/water

Large polar/protein

MOVEMENT OF GLUCOSE

Glucose concentration is 60% that of plasmaRemains constant, unless blood glucose >270-360Enters CSF quickly by facilitated transportRate ∝ Serum glucose [not on gradient]

MOVEMENT OF PROTEIN

CSF protein concentrations are 0.5% or less than that of plasma protein concentration [60% @ CP / 40%@ extrachoroidal sites]If structural barrier between ECF & CSF spaces are not intact, it enters, but then also cleared from CSF spaces into dural sinuses - because of the sink effect of flowing CSF

VENTRICLES 26MG/100ML

CISTERNA MAGNA 32MG/100ML

LUMBAR SAC 42MG/100ML

Vƒ & ICP/CPP

↑ ICP

Vƒ

Vƒ

↓CPP

Vƒ and ICP/CPP

As long as CPP remains >70 mm of Hg, increase of ICP [upto 20 mm of Hg] has no major impact on VƒWhen CPP is significantly lowered CBF↓ CPBF↓, Vƒ↓But Rate of reabsorption(Va); @ ICPs > 7 cms of H2O, Va ↑ directly as ICP ↑[relation linear upto ICP of 30 cms of H2O]

CIRCULATION OF CSF

Hydrostatic pressure of CSF formationCilia of ependymal cellsRespiratory variationsVascular pulsations of cerebral arteries,CP

15 cm H2O @ formation

9 cm H2O @SSS

Choroid plexus of the lateral ventricle

Site of formation

1. Lateral ventricle

2. Third ventricle

Interventricular foramina

3. Fourth ventricle

Cerebral aqueduct

3.2 Lateral foramina (Luschka)

3.1 Median foramen (Magendie)

3.2 Lateral foramina (Luschka)

4. Subarachnoid space

Inferiorly

Superiorly

Absorbed

Superiorly

Absorbed

Choroid plexus of the 4th ventricle

Choroid plexus of the 3rd ventricle

12

3

5

3.2

3.1

4

Superiorly = lateral aspect of each cerebral hemisphere

Inferiorly = subarachnoid space around the brain & spinal cord

Choroid plexus of the lateral ventricle

Median sagittal section to show the subarachnoid cisterns & circulation of CSF

Superior cistern

Interpeduncular cistern

Cerebellomedullary cistern

Chiasmatic cistern

Pontine cistern

Circulation of CSF in subarachnoid space :

Median foramen of 4th ventricle

REABSORPTION

Subarachnoid spaceArachnoid villi & granulation venous bloodare protrusion of the arachnoid matter through perforations in the dura into the lumina of venous sinusesIntracranial-Superior sagittal sinus[85%-90%]Spinal-dural sinusoids on dorsal nerve roots[15%]

Reabsorption

High velocity of blood flow through the fixed diameter of the sinuses & the low intraluminal pressure that develops @ the circumference of the sinus wall where the arachnoid villi enter, cause a suction –pump action circulation continues over a wide range of postural pressures…

Arachnoid villus

L

‘Traced’ journey Radio labelled CSF enters

Low Cx-High Tx @ 10-20’

Tx-lumbar @ 30-40’

L-S cul de sac @60-90’

Basal cisterns @ 2-2.5 hrs

SSS @12-24 hrs

Determinants of reabsorption

Endothelium covering the villus acts as a CSF-blood barrierTrans villous hydrostatic pressure gradient

[CSF pressure-Venous sinus pressure]Pressure sensitive resistance to CSF outflow at the arachnoid villusIf through endothelium:(1)pinocytic vesicles

(2)transcellular openings

Determinants of reabsorption

Rate of rebsorption of CSF (Va)Resistance to reabsorption (Ra)

(Va) increase as the pressure gradient increase(Ra) remains normal upto a CSF pressure of 30 cm of H2O; above this it decreases

CSF drainage & cerebral edema

vasogenic edema resolves partly by drainage of fluid into ventricular CSFFactors influencing:

(1) pressure gradient between brain tissue and CSF (2) sink action of CSF

Brain ECF proteins cleared by glial uptake

FUNCTIONS OF CSF-support,nutrition

The low specific gravity of CSF (1.007) relative to that of the brain(1.040) reduces the effective mass of a 1400g brain to only 47gStable supply of nutrients ,primarily glucose; also vitamins /eicosanoids/monosaccharides/neutral & basic Amino acids

Control of the chemical environment

Exchange between neural tissue & CSF is easy diffusion distance 15mm (max) & ISF space and CSF spaces are continuous

CSF

CBF

CBF-AR

Respiration

CMR

Control of the chemical environment

CSF Ca/K/Mg

HR

BP

VASOMOTOR

RESPIRATION

MUSCLE TONE

EMOTIONAL

Control of the chemical environment

L •K/HCO3•Ca/Mg

PRIMARY PUMPS

•H+•Cl-

SECONDARYPUMPS

Excretion

Removes metabolic products,unwanted drugsBBB excludes out toxic large,polar and lipid insoluble drugs, humoral agents etc

Intracerebral transport

CSF

Neurohormone releasing factors formed in hypothalamus

neuron.

ependyma

MEDIAN EMINENCE

METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION

• Plasm• CSF

VENTRICULO CISTERNAL PERFUSION

Heisey and colleagues & Pappenheimer and associatesCannula placed in one or both lateral ventricle and in cisterna magnaLabeled mock CSF into ventriclesLabeled mock + Native CSF collected from cisternal cannula & volume determined

VENTRICULO CISTERNAL PERFUSION

Vf = Vi {Ci –C0/C0}

Vi= mock CSF inflow rate

Ci= concentration of label in mock CSF

C0=concentration of label in the mixed outflow solution

VENTRICULO CISTERNAL PERFUSION

Vf = Vi {Ci –C0/C0}

Vi= mock CSF inflow rate

Ci= concentration of label in mock CSF

C0=concentration of label in the mixed outflow solutionVa= ViCi - V0C0/C0

V0=outflow rate of CSF from cisternal cannula

Ra= reciprocal measure of the slope relating Va to CSF pressure

MANOMETRIC INFUSION

Maffeo and colleagues & Mann and associatesManometric infusion device inserted into the spinal/supracortical SubArachnoid Space[SAS]Mock CSF into the SASCSF pressure measured @ same site of infusionEach steady state CSF pressure[Ps] is paired with its associated Vi

Vi vs Ps semilog plot is made; Vf and Ra are derived from this plot; compliance also can be derived

VOLUME INJECTION OR WITHDRAWAL

Marmarou and colleagues and MillerVentricular or spinal subarachnoid catheter for injection or withdrawal of CSF and for measurement of accompanying CSF pressure change Resting CSF pressure [P0] is determined and a known volume of CSF is injected/withdrawn with timed recording of CSF pressurePressure Volume Index[PVI] calculated & Vf and Ra from it.

METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION

• Plasm• CSF

VENTRICULOCISTERNAL PERFUSION

Outflow catheter in lumbar subarachnoid spaceVentricular & spinal CSF pressures are closely monitored to ensure that obstructed perfusion do not ↑ CSF pressure very highNeeds >1 hourMock CSF

MANOMETRIC INFUSION

Number of infusions are reducedInfusion rate 1.5-15 times Vf [.01-.1mL/sec]

Infusions restricted to20-60 secDiscontinued @ CSF pressures of 60-70 cm H2O/ rapid riseNeeds multiple infusionsMock CSF

VOLUME INJECTION OR WITHDRAWAL

No hazard associated with mock CSFHence more commonly usedCSF withdrawal can be therapeuticClosed system- hence risk of infection lessMore suitable for repeated testingCalculation needs only a single change of CSF volume and pressure lasting for minutes

.

ANESTHETIC AND DRUG INDUCED CHANGES IN CSF FORMATION RATE AND RESISTANCE TO CSF ABSORPTION AND TRANSPORT OF VARIOUS MOLECULES INTO CSF AND THE CNS

INHALED ANESTHETICS

ENFLURANE Vf Ra ICPLOW [0.9% &1.8%] 0 + +

HIGH [2.65 &3.5 end expired]

+ 0 +

ENFLURANE INDUCE INCREASED CP METABOLISM

INHALED ANESTHETICS

HALOTHANE Vf Ra ICP1 MAC -- + +

INCREASE GLUCOSE TRANSPORT INTO BRAININCREASE Na/Cl/H2O/Albumin TRANSPORT INTO CSFHALOTHANE INDUCED STIMULATION OF VASOPRESSIN RECEPTORSDECREASE Vf

INHALED ANESTHETICS

ISOFLURANE Vf Ra ICPLOW[0.6]LOW[1.1%]HIGH[1.7,2.2%]

000

0+--

0+--

GLUTAMATE CONCENTRATION IN CSF IS MORE WHEN ISOFLURANE IS USED THAN IN PROPOFOL BASED ANESTHESIA

INHALED ANESTHETICS

SEVOFLURANE Vf Ra ICP1MAC -- + ?

INHALED ANESTHETICS

DESFLURANE Vf Ra ICPHYPOCAPNIA & ↑CSF PRESSUREOTHER SITUATIONS

+

0

+

0

+

0

ONLY FRUSEMIDE 2MG/KG DECREASED Vf IN THE FIRST SITUATION.

INHALED ANESTHETICS

NITROUS OXIDE Vf Ra ICP66% 0 0 0

DECREASE BRAIN GLUCOSE INFLUX AND EFFLUX

I.V. ANESTHETICS

KETAMINE Vf Ra ICP40MG/KG/HR 0 + +

DECREASE TRANSPORT OF SMALL HYDROPHILIC MOLECULES ACROSS BBB

I.V. ANESTHETICS

ETOMIDATE Vf Ra ICPLOW [.86MG/KG.86MG/KG/HR]HIGH[2.58MG/KG/HR]

0--

0--

0--

I.V. ANESTHETICS

PROPOFOL Vf Ra ICP6MG/KG12,24 & 48 MG/KG/HR 0 0 0

PENTOBARBITAL Vf Ra ICP40MG/KG 0 0 0

CSF CONCENTRATION OF PROPOFOL IS APPROX 60% OF THAT OF PLASMA CONCENTRATION

I.V. ANESTHETICS

THIOPENTAL Vf Ra ICPLOW DOSE[6MG/KG F/B 6-12MG/KG/HR]HIGH DOSE[18-24MG/KG/HR]

0--

+/0--

+/0--

INCREASE

I.V. ANESTHETICS

MIDAZOLAM Vf Ra ICPLOW[1.6MG/KG.5MG/KG/HR]INTERMEDIATE[1-1.5MG/KG/HR]HIGH [2MG/KG/HR]

00--

+0+

+0--/?

FLUMAZENIL Vf Ra ICPLOW[.0025MG/KG]HIGH [.16MG/KG]LOW[DOGS GETTING MIDAZOLAM]HIGH[ “ ]

0000

0--+0

0--

OPIOIDS

FENTANYL Vf Ra ICPLOW DOSEHIGH DOSE

0--

--0/+

----/?

SUFENTANIL Vf Ra ICPLOW DOSEHIGH DOSE

00

--0/+

--0/+

ALFENTANIL Vf Ra ICPLOW DOSEHIGH DOSE

00

--0

--0

I.V. DRUGS

LIDOCAINE Vf Ra ICP.5MG/KG1μG/KG/MIN1.5 34.5 9

-- 0 0/--

I.V. DRUGS

IV acetaminophen permeate readily and attain peak concentration in 1 hour in CSF rapid central analgesia and antipyretic effectsIbuprofen :peak @ 30-40 mins

DIURETICS

Vf MECHANISMS

ACETAZOLAMIDEMETHAZOLAMIDE

-- BY 50% INHIBITION OF CARBONIC ANHYDRASEINDIRECT ACTION ON ION TRANSPORT [VIA HCO3]CONSTRICT CP ARTERIOLES & ↓ CPBF

ACETAZOLAMIDE +OUABAIN↓Vf BY 95% = ADDITIVE

OTHERS

L DRUG Vf MECHANISM

DIGOXIN , OUABAIN -- INHIBIT Na-K PUMP OF CP

THEOPHYLLIN + PHOSPHODIESTERASE INHIBITION↑cAMP STIMULATE CP Na-K PUMP

VASOPRESSIN -- CONSTRICT CP BLOOD VESSELS

3% HYPERTONIC SALINE -- ↓OSMOLALITY GRADIENT FOR MOVEMENT OF FLUID PLASMACP OR BRAIN TISSUECSF

DINITROPHENOL -- UNCOUPLE OXIDATIVE PHOSPHORYLATION DECREASE ENERGY AVAILABLE FOR MEMBRANE PUMP

ANP -- ↑cGMP

DIURETICS

Vf MECHANISMS

FUROSEMIDEMANNITOL

----

DECREASE Na+ OR Cl- TRANSPORTDECREASED CP OUTPUT AND ECF FLOW FROM BRAIN TO CSF COMPARTMENT

MUSCLE RELAXANTS

RELAXANTS Vf Ra

SCOLINE, VECURONIUM INFUSIONS 0 0

STEROIDS

Decrease Ra

M.prednisolone/prednisone/cortisone/dexaProbable mechanisms postulated:Improved CSF flow in subarachnoid spaces/ A. villiReversal of metabolically induced changes in the structure of the villi, action @ CPDexamethasone ↓Vf by 50% [inhibition of Na-K ATPase]

REGULATION OF Vf /Ra

NEUROGENIC REGULATION

Adrenergic nerves from superior and lower cervical ganglia innervate CPLateral ventricle– U/LMidline ventricle– B/L3rd ventricle rich in cholinergic innervation, whereas 4th ventricle devoid of itPeptidergic nerves contain VIP and substance-P : both are potent vasodilators

Adrenergic system

α constriction βdilatationDecrease carbonic anhydrase activityNorepinephrine:↓ Vf

high α mediated vasoconstrictionLow β1 mediated inhibitory action on CP

Cholinergic system

Also ↓ Vf

Receptors presumably muscarinicAct on CP epithelium, rather than on vasculature

METABOLIC REGULATION

HYPOTHERMIA: ↓ Vf – By decreasing secretory and transport process and by ↓ing CBF between 41310 C: each 10 C↓in temperature, ↓ Vf by 11%

HYPOCAPNIA: acutely ↓ Vf [mechanism : ↓ CBF, ↓ H+ for exchange with Na]

METABOLIC REGULATION

Metabolic alkalosis ↓ Vf due to pH effect

Metabolic acidosis: no change

↓ Vf in change of osmolarity/ Wald & associates

↓/↑ in Vf caused by change in serum osmolarity 4 times higher

↑osmolarity of serum

↓osmolarity of ventricular CSF

ALTERATIONS IN VARIOUS PATHOLOGIES

.

Intracranial volume change

Volume of intracranial blood/gas/tissue ↑ CSF volume ↓

Volume of intracranial blood/gas/tissue ↓ CSF volume ↑

MECHANISM: >TRANSLOCATION INTO SPINAL SPACES >INCREASED REABSORPTION

MECHANISM: >CEPHALAD TRANSLOCATION >DECREASED REABSORPTION

SUBDURAL HEMATOMA

Adds volume ↑ ICP driving force for reabsorption Va > Vf CSF volume contracts ICP↓ Va starts returning to normal Va & Vf in a new equillibrium–

Here ICP & total intracranial volume are same as before SDH, but CBV is ↑ed and CSF volume ↓ed

SURGICAL REMOVAL OF TUMOR

Sx ↓ intracranial volume ↓ed ICP a weak driving force for reabsorption Va ↓, Vf same CSF accumulates and volume expand ICP↑ and reach pre surgical valuesstimulate Va Va

↑ Va = Vf

here,ICP same; brain volume ↓;

CSF volume↑

INTRACRANIAL MASS

ANIMAL STUDY IN 3 GROUPS OF DOGS

Hypocapnia ↓ed an increased ICP initially by decreasing CBV but with sustained hypocapnia,CBV reexpanded but H.C. improved access of I.C CSF to spinal sites of reabsorption so CSF vol ↓ed ICP remained lower than initial values

GROUP 1 HYPOCAPNIA

GROUP2 I.C. MASS

GROUP3 I.C.MASS + HYPOCAPNIA

EFFECT OF ANESTHETICS

FIVE GROUP OF DOGS

Vf Ra ICP REASON

ENFLURANE ↑ ↑ ↑ CSF VOL DIDN’T↓TO THE EXTENT OF CBV REEXPANSION

HALOTHANE ↑ ↑ ↑

ISOFLURANE N N N CSF VOL CONTRACTION= CBV REEXPANSION

FENTANYL N N N REEXPANSION MINIMAL

THIOPENTAL N N N CSF VOL CONTRACTION= CBV REEXPANSION

ACUTE SAH

Itrathecal injection: W.Blood / plasma /dialysate of plasma/serum/saline

Whole blood and plasma raised ICP and caused a 3 to 10 fold rise in Ra respectively

C/C CHANGES AFTER SAH

Extensive fibrosis leptomeningeal scarring functional narrowing or blockage of CSF outflow tracts [Ra is increased] hydrocephalus

Bacterial meningitis

Animal study with 1.S pneumoniae 2.E coli↓ is increased

Even with antibiotics it remained high for 2 weeks post RxMethyl prednisolone ↓ed Ra to a value between control and infected

PSEUDOTUMOR CEREBRI

Increased Ra , Vf ,water movement into brain, CBF & CBVincreased ICPImpaired reabsorption is the principal causePrednisone decreased Ra

Head Injury

20% of the raised ICP derived from changes in Ra &Vf

It means…

Vf changes: changes ICP

Ra changes: changes ICP, alters pressure buffering capacity of brainAnesthetics induced changes in both, significantly alters Rx to reduce ICP

So……

We demand more attention from you..

HEAD INJURY

THANK YOU