CSF Physiology and Cerebral Blood Flow

1. CSF Physiology and Cerebral Blood Flow Keith R. Lodhia, MD,MS Department of Neurosurgery University of Michigan 12/20/03

2. CSF Functions • provide mechanical protection • maintain a stable extracellular environment for the brain • Remove some waste products • nutrition • Convey messages? (hormones/releasing factors/neurotransmitters)

3. Brain Fluid “Balance”

4. 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 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

5. CSF Production • Other sources of CSF production from capillary ultrafiltrate (Virchow-Robin spaces) • Additionally some produced from metabolic H2O production

6. CSF Production • Virchow-Robin spaces

7. CSF PRODUCTION- Choroid Plexus • CSF is produced by choroid plexus and secreted at ciliated cuboidal epithelial cell surfaces of the microvilli into the ventricles

8. CSF PRODUCTION- Choroid Plexus

9. Ependymal Cell Membrane Transport

10. CSF Production H20, Na+, HCO3¯, Cl¯ • CSF secretion involves the transport of ions ( Na+, Cl¯ and HCO3¯) across the epithelium from blood to CSF Basolateral Apical Secretion can occur because of the polarized distribution of specific ion transporters in the apical or basolateral membrane of the epithelial cells.

11. CSF Production • 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

12. CSF Production • 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

13. CSF Constituency • CSF volume: 25 cc ventricular, 25cc intracranial subarachnoid space, and 100cc in spinal subarachnoid spaces • β2 transferrin

14. CSF Constituency- β2 transferrin • PROTEIN ELECTROPHORESIS-on 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

15. CSF Circulation • 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

16. CSF Circulation

17. Lundberg Waves • 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.  LundbergA- waves

18. A- waves/Plateau Waves • 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”

19. CSF Absorption • 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

20. Route and Absorption of CSF • 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.

21. Arachnoid Villus

22. Route and Absorption of CSF • Hydrostatic pressure in subarachnoid space > pressure in dural sinuses • 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).

23. Drugs affecting Rate ofCSF Production • Drugs • 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 ?

24. CSF Pharmacology cont. • 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 Sickness- an aside. CO2 + H2O <=> HCO3- + H+ VENTRICLE

25. Acute Mountain Sickness-AMS • 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

26. Acute Mountain Sickness-AMS • 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

27. CSF Pathology • 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, 2-48 hours) due to hemoglobin pigment from lysed RBCs.

28. CSF Pathology Patterns of Cerebrospinal Fluid Abnormality: Cell Type and Glucose Level • POLYMORPHONUCLEAR: LOW GLUCOSE • Acute bacterial meningitis • POLYMORPHONUCLEAR: LOW OR NORMAL GLUCOSE • Some cases of early phase acute bacterial meningitis • Primary amoebic (Naegleria species) meningoencephalitis • Early phase Leptospira meningitis • POLYMORPHONUCLEAR: NORMAL GLUCOSE • Brain abscess • Early phase coxsackievirus and echovirus meningitis • CNS syphilis (some patients) • Acute bacterial meningitis with IV glucose therapy • Listeria (about 20% of cases)

29. LYMPHOCYTIC: LOW GLUCOSE • Tuberculosis meningitis • Cryptococcal (Torula) meningitis • Mumps meningoencephalitis (some cases) • Meningeal carcinomatosis (some cases) • Meningeal sarcoidosis (some cases) • Listeria (about 15% of cases) • LYMPHOCYTIC: NORMAL GLUCOSE • Viral meningitis • Viral encephalitis • Postinfectious encephalitis • Lead encephalopathy • CNS syphilis (majority of patients) • Brain tumor (occasionally) • Leptospira meningitis (after the early phase) • Listeria (about 15% of cases)

30. Cerebral Blood Flow (CBF) • CBF = CBV/t • 750 mL/minute, which is 15% of the cardiac output • The normal cerebral blood flow is 45-50ml/100g/min, ranging from 20ml 100g-1 min-1 in white matter to 70ml 100g-1 min-1 in grey matter. Highest in neurohypophysis

31. CBF • When CBF falls to less than 10-23ml/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

32. Cerebral Perfusion Pressure (CPP) • Cerebral Perfusion Pressure (CPP) MAP-ICP=CPP normal CPP is between 50-150 mmHg • <50 mmHg --> ischemia • >150 mmHg --> hyperemia

33. Autoregulation • 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

35. Autoregulation • 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.

36. Autoregulation • 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

37. Metabolic Autoregulation • 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

38. Neurogenic Autoregulation • 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.

39. Neurogenic Autoregulation- cont • 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 gene-related peptide histamine H2 -”vasodilatory” esp. substance P • CCK, neurotensin, somatostatin, vasopressin, endorphin

40. Neurogenic Autoregulation-cont • Autonomic system and neurochemical control of CBF in general is a minor control • Overall, pressure and metabolic autoregulation most important

41. Increasing CBF-Hyperemia • 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

42. CBF and CO2 • Carbon dioxide causes cerebral vasodilation. As the arterial tension of CO2 rises, CBV and CBF increases and when it is reduced vasoconstriction is induced.

43. “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

44. 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

45. Xenon CT perfusion CT BOLD-MRI and single-photon emission computed tomography (SPECT) (SPECT)

46. CBF AND CSF- TYING IT TOGETHER

47. PATHOPHYSIOLOGY CSF/CBF • 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

48. PATHOPHYSIOLOGY CSF/CBF • 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 well-controlled through alterations in the volume of blood and CSF

49. Brain P/V curve

50. 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.