PHYSIOLOGY OF CSF PRODUCTION AND CIRCULATION, ALTERATIONS IN VARIOUS PATHOLOGY

Physiology of CSF dynamics with an anaesthesia eye!

1. PHYSIOLOGY OF CSF PRODUCTION AND CIRCULATION, ALTERATIONS IN VARIOUS PATHOLOGY Dr Unnikrishnan P

2. 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

3. OUTLINE CSF SPACES CSF FORMATION-CIRCULATION-REABSORPTION METHODS OF DETERMINING V f and R a EFFECTS OF DRUGS REGULATION ALTERATION IN CSF DYNAMICS IN PATHOLOGIES

4. Introduction CSF  flows via macroscopic & ECF spaces PRESSURES 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

5. 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

6. 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.

7. 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 i nferior cerebellar artery NERVE SUPPLY:IX,X, Sympathetic nerves

8. MACROSCOPIC SPACES Two lateral ventricles Third ventricle Aqueduct of sylvius Fourth ventricle Central canal of spinal cord Subarachnoid spaces

9. MICROSCOPIC SPACES- BRAIN & SPINAL CORD ECF SPACES are small Capillary – ECF exchange is limited Blood brain barrier Whats your diameter ? ………<20 A ⁰ ?

10. COMPOSITION L Plasma CSF Na + ( mM ) 140 141 K + ( mM ) 4.6 2.9 Mg 2+ ( mM ) 1.7 2.4 Ca 2+ ( mM ) 5.0 2.5 Cl - ( mM ) 101 124 HCO 3 - ( mM ) 23 21 Glucose ( mM ) 92 61 Amino acids ( mM ) 2.3 0.8 pH 7.41 7.31 Osmolality (mosmol.Kg H 2 O -1 ) 289 289 Protein (mg 100 g -1 ) 7000 28 Specific gravity 1.025 1.007

11. COMPOSITION Vary according to sampling site Altered during neuroendoscopy

12. CSF FORMATION

13. CSF FORMATION Rate [ V ƒ ] 0.35-0.40 mL/min OR 500-600 mL/ day 0.25% of total vol replaced each minute Turn over time for total CSF vol  5-7 hours = 4 times / day 40%-70% enters macroscopic spaces via CP 30%-60% enters across ependyma and pia

14. @ CHOROID PLEXUS L

15. @ CHOROID PLEXUS

16. @EXTRA CHOROIDAL SITES Oxidation of glucose by brain [60%] Ultra filtration from cerebral capillaries [40%] TIGHT JUNCTIONS Glucose/ electrolyte /water Large polar/ protein

17. MOVEMENT OF GLUCOSE Glucose concentration is 60% that of plasma Remains constant, unless blood glucose > 270-360 Enters CSF quickly by facilitated transport Rate ∝ Serum glucose [not on gradient]

18. 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

19. V ƒ & ICP/CPP

20. V ƒ 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 Vƒ When CPP is significantly lowered  CBF ↓ CPBF↓, Vƒ ↓ But Rate of reabsorption (V a ); @ ICPs > 7 cms of H2O, V a ↑ directly as ICP ↑[relation linear upto ICP of 30 cms of H2O]

21. CIRCULATION OF CSF Hydrostatic pressure of CSF formation Cilia of ependymal cells Respiratory variations Vascular pulsations of cerebral arteries,CP

22. 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

23. Choroid plexus of the 4 th ventricle Choroid plexus of the 3 rd ventricle 1 2 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

24. 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 4 th ventricle

25. REABSORPTION Subarachnoid space  Arachnoid villi & granulation venous blood are protrusion of the arachnoid matter through perforations in the dura into the lumina of venous sinuses Intracranial -Superior sagittal sinus[85%-90%] Spinal -dural sinusoids on dorsal nerve roots [15%]

26. 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…

27. Arachnoid villus L

28. ‘ Traced ’ journey Radio labelled CSF enters

29. Determinants of reabsorption Endothelium covering the villus acts as a CSF- blood barrier Trans villous hydrostatic pressure gradient [CSF pressure- Venous sinus pressure] Pressure sensitive resistance to CSF outflow at the arachnoid villus If through endothelium :(1) pinocytic vesicles (2) transcellular openings

30. Determinants of reabsorption Rate of rebsorption of CSF (V a) Resistance to reabsorption (R a ) (Va) increase as the pressure gradient increase (R a ) remains normal upto a CSF pressure of 30 cm of H2O; above this it decreases

31. CSF drainage & cerebral edema vasogenic edema resolves partly by drainage of fluid into ventricular CSF Factors influencing : (1) pressure gradient between brain tissue and CSF (2) sink action of CSF Brain ECF proteins cleared by glial uptake

32. 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 47g Stable supply of nutrients , primarily glucose; also vitamins / eicosanoids /monosaccharides/ neutral & basic Amino acids

33. Control of the chemical environment Exchange between neural tissue & CSF is easy diffusion distance 15mm (max) & ISF space and CSF spaces are continuous

34. Control of the chemical environment

35. Control of the chemical environment L

36. Excretion Removes metabolic products,unwanted drugs BBB excludes out toxic large,polar and lipid insoluble drugs , humoral agents etc

37. Intracerebral transport CSF Neurohormone releasing factors formed in hypothalamus MEDIAN EMINENCE

38. METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION Plasm CSF

39. VENTRICULO CISTERNAL PERFUSION Heisey and colleagues & Pappenheimer and associates Cannula placed in one or both lateral ventricle and in cisterna magna Labeled mock CSF into ventricles Labeled mock + Native CSF  collected from cisternal cannula & volume determined

40. VENTRICULO CISTERNAL PERFUSION V f = V i {C i –C /C } V i = mock CSF inflow rate C i = concentration of label in mock CSF C =concentration of label in the mixed outflow solution

41. VENTRICULO CISTERNAL PERFUSION V f = V i {C i –C /C } V i = mock CSF inflow rate C i = concentration of label in mock CSF C =concentration of label in the mixed outflow solution V a = V i C i - V C /C V = outflow rate of CSF from cisternal cannula R a = reciprocal measure of the slope relating V a to CSF pressure

42. MANOMETRIC INFUSION Maffeo and colleagues & Mann and associates Manometric infusion device inserted into the spinal/ supracortical S ubArachnoid S pace [SAS] Mock CSF into the SAS CSF pressure measured @ same site of infusion Each steady state CSF pressure[P s ] is paired with its associated V i V i vs P s semilog plot is made; V f and R a are derived from this plot; compliance also can be derived

43. VOLUME INJECTION OR WITHDRAWAL Marmarou and colleagues and Miller Ventricular or spinal subarachnoid catheter for injection or withdrawal of CSF and for measurement of accompanying CSF pressure change Resting CSF pressure [P ] is determined and a known volume of CSF is injected / withdrawn with timed recording of CSF pressure Pressure Volume Index[PVI] calculated & V f and R a from it .

44. METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION Plasm CSF

45. VENTRICULOCISTERNAL PERFUSION Outflow catheter in lumbar subarachnoid space Ventricular & spinal CSF pressures are closely monitored to ensure that obstructed perfusion do not ↑ CSF pressure very high Needs >1 hour Mock CSF

46. MANOMETRIC INFUSION Number of infusions are reduced Infusion rate 1.5-15 times V f [.01-.1mL/sec] Infusions restricted to20-60 sec Discontinued @ CSF pressures of 60-70 cm H2O/ rapid rise Needs multiple infusions Mock CSF

47. VOLUME INJECTION OR WITHDRAWAL No hazard associated with mock CSF Hence more commonly used CSF withdrawal can be therapeutic Closed system- hence risk of infection less More suitable for repeated testing Calculation needs only a single change of CSF volume and pressure lasting for minutes

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

49. INHALED ANESTHETICS ENFLURANE V f R a ICP LOW [0.9% &1.8%] + + HIGH [2.65 &3.5 end expired] + + ENFLURANE INDUCE INCREASED CP METABOLISM

50. INHALED ANESTHETICS HALOTHANE V f R a ICP 1 MAC -- + + INCREASE GLUCOSE TRANSPORT INTO BRAIN INCREASE Na/ Cl /H2O/Albumin TRANSPORT INTO CSF HALOTHANE INDUCED STIMULATION OF VASOPRESSIN RECEPTORS DECREASE V f

51. INHALED ANESTHETICS ISOFLURANE V f R a ICP LOW[0.6] LOW[1.1%] HIGH[1.7,2.2%] + -- + -- GLUTAMATE CONCENTRATION IN CSF IS MORE WHEN ISOFLURANE IS USED THAN IN PROPOFOL BASED ANESTHESIA

52. INHALED ANESTHETICS SEVOFLURANE V f R a ICP 1MAC -- + ?

53. INHALED ANESTHETICS DESFLURANE V f R a ICP HYPOCAPNIA & ↑CSF PRESSURE OTHER SITUATIONS + + + ONLY FRUSEMIDE 2MG/KG DECREASED V f IN THE FIRST SITUATION.

54. INHALED ANESTHETICS NITROUS OXIDE V f R a ICP 66% DECREASE BRAIN GLUCOSE INFLUX AND EFFLUX

55. I.V. ANESTHETICS KETAMINE V f R a ICP 40MG/KG/HR + + DECREASE TRANSPORT OF SMALL HYDROPHILIC MOLECULES ACROSS BBB

56. I.V. ANESTHETICS ETOMIDATE V f R a ICP LOW [.86MG/KG  .86MG/KG/HR] HIGH[2.58MG/KG/HR] -- -- --

57. I.V. ANESTHETICS PROPOFOL V f R a ICP 6MG/KG 12,24 & 48 MG/KG/HR PENTOBARBITAL V f R a ICP 40MG/KG CSF CONCENTRATION OF PROPOFOL IS APPROX 60% OF THAT OF PLASMA CONCENTRATION

58. I.V. ANESTHETICS THIOPENTAL V f R a ICP LOW DOSE[6MG/KG F/B 6-12MG/KG/HR] HIGH DOSE[18-24MG/KG/HR] -- +/0 -- +/0 -- INCREASE

59. I.V. ANESTHETICS MIDAZOLAM V f R a ICP LOW[1.6MG/KG .5MG/KG/HR] INTERMEDIATE[1-1.5MG/KG/HR] HIGH [2MG/KG/HR] -- + + + --/? FLUMAZENIL V f R a ICP LOW[.0025MG/KG ] HIGH [.16MG/KG] LOW[DOGS GETTING MIDAZOLAM] HIGH[ “ ] -- + --

60. OPIOIDS FENTANYL V f R a ICP LOW DOSE HIGH DOSE -- -- 0/+ -- --/? SUFENTANIL V f R a ICP LOW DOSE HIGH DOSE -- 0/+ -- 0/+ ALFENTANIL V f R a ICP LOW DOSE HIGH DOSE -- --

61. I.V. DRUGS LIDOCAINE V f R a ICP .5MG/KG 1 μ G/KG/MIN 1.5 3 4.5 9 -- 0/--

62. I.V. DRUGS IV acetaminophen permeate readily and attain peak concentration in 1 hour in CSF  rapid central analgesia and antipyretic effects Ibuprofen : peak @ 30-40 mins

63. DIURETICS V f MECHANISMS ACETAZOLAMIDE METHAZOLAMIDE -- BY 50% INHIBITION OF CARBONIC ANHYDRASE INDIRECT ACTION ON ION TRANSPORT [VIA HCO3] CONSTRICT CP ARTERIOLES & ↓ CPBF ACETAZOLAMIDE +OUABAIN  ↓ V f BY 95% = ADDITIVE

64. OTHERS L DRUG V f 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 PLASMA CP OR BRAIN TISSUECSF DINITROPHENOL -- UNCOUPLE OXIDATIVE PHOSPHORYLATION  DECREASE ENERGY AVAILABLE FOR MEMBRANE PUMP ANP -- ↑ cGMP

65. DIURETICS V f MECHANISMS FUROSEMIDE MANNITOL -- -- DECREASE Na+ OR Cl - TRANSPORT DECREASED CP OUTPUT AND ECF FLOW FROM BRAIN TO CSF COMPARTMENT

66. MUSCLE RELAXANTS RELAXANTS V f R a SCOLINE, VECURONIUM INFUSIONS

67. STEROIDS Decrease R a M.prednisolone / prednisone /cortisone/ dexa Probable mechanisms postulated : Improved CSF flow in subarachnoid spaces / A. villi Reversal of metabolically induced changes in the structure of the villi , action @ CP Dexamethasone ↓ V f by 50% [inhibition of Na-K ATPase ]

68. REGULATION OF V f /R a

69. NEUROGENIC REGULATION Adrenergic nerves from superior and lower cervical ganglia innervate CP Lateral ventricle – U/L Midline ventricle – B/L 3rd ventricle rich in cholinergic innervation, whereas 4th ventricle devoid of it Peptidergic nerves contain VIP and substance-P : both are potent vasodilators

70. Adrenergic system α  constriction β dilatation Decrease carbonic anhydrase activity Norepinephrine :↓ V f high  α mediated vasoconstriction Low  β 1 mediated inhibitory action on CP

71. Cholinergic system Also ↓ V f Receptors presumably muscarinic Act on CP epithelium , rather than on vasculature

72. METABOLIC REGULATION HYPOTHERMIA: ↓ V f – By decreasing secretory and transport process and by ↓ ing CBF between 41 31 C: each 1 C ↓in temperature , ↓ V f by 11% HYPOCAPNIA: acutely ↓ V f [ mechanism : ↓ CBF, ↓ H+ for exchange with Na]

73. METABOLIC REGULATION Metabolic alkalosis ↓ V f due to pH effect Metabolic acidosis : no change

74. ↓ V f in change of osmolarity / Wald & associates ↓/↑ in V f caused by change in serum osmolarity 4 times higher

75. ALTERATIONS IN VARIOUS PATHOLOGIES .

76. 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

77. SUBDURAL HEMATOMA Adds volume  ↑ ICP  driving force for reabsorption  V a > V f  CSF volume contracts  ICP ↓ V a starts returning to normal V a & V f in a new equillibrium – Here ICP & total intracranial volume are same as before SDH, but CBV is ↑ ed and CSF volume ↓ ed

78. SURGICAL REMOVAL OF TUMOR Sx  ↓ intracranial volume ↓ ed ICP a weak driving force for reabsorption  V a ↓, V f same  CSF accumulates and volume expand  ICP ↑ and reach pre surgical values stimulate V a  V a ↑ V a = V f here ,ICP same ; brain volume ↓; CSF volume↑

79. 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

80. EFFECT OF ANESTHETICS FIVE GROUP OF DOGS V f R a 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

81. 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 R a respectively

82. C/C CHANGES AFTER SAH Extensive fibrosis  leptomeningeal scarring  functional narrowing or blockage of CSF outflow tracts [R a is increased ]  hydrocephalus

83. Bacterial meningitis Animal study with 1.S pneumoniae 2.E coli ↓ is increased Even with antibiotics it remained high for 2 weeks post Rx Methyl prednisolone ↓ ed R a to a value between control and infected

84. PSEUDOTUMOR CEREBRI Increased R a , V f ,water movement into brain , CBF & CBV  increased ICP Impaired reabsorption is the principal cause Prednisone decreased R a

85. Head Injury 20% of the raised ICP derived from changes in R a & V f

86. It means … V f changes: changes ICP R a changes: changes ICP, alters pressure buffering capacity of brain Anesthetics induced changes in both , significantly alters Rx to reduce ICP

87. So…… We demand more attention from you ..

88. HEAD INJURY THANK YOU