Cerebrospinal Fluid (CSF) & Blood-Brain Barrier Physiology

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Fundamentals

What is cerebrospinal fluid (CSF)?

  • Specialized transcellular fluid that surrounds the brain and spinal cord 
  • Circulates within the cerebral ventricular system and the subarachnoid space

What are the functions of cerebrospinal fluid (CSF)? 

Mechanical Protection
Maintenance of Constant Environment
Regulation of ICP
Control of Respiration
Clearance of Waste Products
  • Provides buoyancy and cushioning
  • Reduces the effective weight of the brain
  • Protects against deformation caused by acceleration and deceleration
  • Maintains a constant ionic and osmotic environment for neuronal cells
  • Essential for the functioning of normal neuronal activity
  • Displacement of CSF into spinal canal provides important, though limited, compensation for increases in ICP ('Spatial compensation')
  • Central chemoreceptors detect changes in CSF pH caused by variations in CO2 levels resulting in the respiratory centre adjusting respiratory rate and tidal volumes
  • CO2 freely dissolves in CSF from blood given its lipid solubility and low molecular weight
  • Comparatively low protein levels in CSF reduce buffering capacity making CSF pH very sensitive to changes in blood pCO2
  • The brain lacks a lymphatic system to cleat waste products (extracellular proteins excess fluid and metabolic waste)
  • A specialised 'glymphatic system' circulates CSF in paravascular channels where waste products are removed

What is the normal volume of cerebrospinal fluid (CSF)?

  • Overall volume is between 100-150ml
    • 23 within the ventricles
    • 13 within the subarachnoid space around the spinal cord (35ml)
  • Equates to ~10% of intracranial volume

What is the pressure of cerebrospinal fluid (CSF)? 

  • CSF pressure is gravitational and varies with position
    • In the lateral position normal pressure is 5-20 cm of H2O
    • In the sitting position:
      • Pressure in the lumbar region rises to 20-50 cmH20
      • Pressure in the cervical region may be sub-atmospheric

Production & Reabsorption

Where is CSF produced and through which processes?

  • Produced by the four choroid plexuses:
    • Located in the two lateral, third, and fourth ventricles
    • Highly vascular invaginations of pia mater
    • Covered by specialised ciliated ependymal cells
Location of the choroid plexuses
  • Produced by a combination of:
    • Filtration of plasma through the fenestrated capillaries
    • Active transport of solutes
  • Control of substances entering is regulated by the blood-CSF barrier (distinct from the BBB)
Structure of the choroid plexus

How much CSF is normally produced?

  • Normal rate of production is 0.3-0.4ml/min or 20ml/hour or 500ml/day
  • Results in effective replacement of CSF volume 3x daily
  • Production is largely independent of ICP:
    • Raised ICP is compensated by increased absorption of CSF reducing total volume
    • Decreased when CPP <70 mmHg due to reduction in choroid plexus blood flow

How and where is CSF reabsorbed?

  • Reabsorbed by the arachnoid granulations:
    • Villi arising from the arachnoid mater
    • Project into venous sinuses and veins
  • Reabsorption occurs throughout the brain and spine
    • 90% by villi of the sagittal and sigmoid Dural sinuses
    • 10% by spinal villi
  • Reabsorption due to differences in pressure between CSF and veins
    • Pressure of CSF typically 15 cm H2O and venous blood typical 8cm H2O
    • Removal of CSF increases with rising intracranial pressure.
Structure of the arachnoid granulations

Composition

How does the makeup of CSF compare with plasma?

  • Despite their common origin, CSF and plasma have a number of important differences:
    • Na+, Cl and Mg2+concentrations are higher
    • K+ and Ca2+ concentrations are lower than plasma
    • Protein is <1% of plasma resulting in reduced buffering capability and a lower pH
Sodium
(mmol/L)
Calcium
(mmol/L)
Potassium
(mmol/L)
Chloride
(mmol/L)
Bicarbonate
(mmol/L)
Glucose
(mmol/L)
pCO2 (kPa)
pH
Protein
(g/L)
Specific Gravity
WCC
(per mm3)
CSF
140
1.2
(∼50% that of plasma)
3.0
120
24
Equal
4
(∼60% that of plasma)
6.6
7.32
(0.08 lower than plasm)
0.2-0.4
(<1% that of plasma)
1.004-1.007
0-5
(usually lymphocytes and monocytes)
Normal
140
2.2-2.6
4.0-5.0
96-106
24
6
5.2
7.40
70
1.010
4,000-11,000

Ventricular System & CSF Flow

What is the structure of the ventricular system?

Structure of the ventricular system

How does CSF flow through the ventricular system?

  • Cerebrospinal fluid (CSF) is produced by the choroid plexuses of the lateral, third and fourth ventricles
  • Passes from the lateral ventricles to the third ventricle through the two interventricular foramina (foramen of Monro)
  • passes from the third ventricle to the fourth ventricle via the Sylvian aqueduct
  • Escapes into the cerebellar subarachnoid space through the:
    • Foramen of Magendie (Medial)
    • Foramen of Lushka (Lateral)
  • CSF then flows around the cerebral hemispheres and spinal cord
    • Flow is aided by the ciliary movement of ependymal cells
  • Reabsorbed primarily by the arachnoid villi of the dural venous sinuses
Circulation of CSF between the ventricles and foramina

Structure

What is the blood brain barrier?

The unique anatomical and physiological properties of the central nervous system microvasculature that allows it to tightly regulate the movement of molecules, ions, and cells between the blood and the CNS

Which structures make up the blood-brain barrier?

  • Comprises of 3 cellular layers and a basement membrane
  • Together these form a barrier virtually impenetrable barrier to lipophobic molecules
Structure of the blood brain barrier
Capillary Endothelium
Basement Memebrane
Pericytes
Astrocytes
  • Interconnected by tight junctions (50-100x 'tighter' than peripheral capillaries) restricting the passage of substances from the capillaries to the brain ECF
  • Differ from extracerebral capillaries in having a high density of mitochondria
  • Have a relative paucity of pinocytic vesicles for vesicular transport
  • Surrounds the endothelium
  • 40-50nm thick
  • Rich in proteoglycans, heparin sulphate, collagen type IV and laminin
  • Reside next to capillaries
  • Possesses smooth muscle like action
  • A type of supportive glial cell
  • Projections called foot processes ensheath >95% of vessel surface
  • Secrete chemicals that reduce the permeability of the capillary endothelial cells

How does the endothelium of the blood brain barrier compare other with that at other sites?

Continuous Non-Fenestrated (General)
Muscle, thymus, bone, lung
  • Continuous endothelial cytoplasm without fenestrae and continuous basement membrane which restricts passage of substances across the endothelium
  • Tight junctions between cells limiting paracellular movement of, ions, solutes, and water - regulation of transport varies across endothelium and influenced by both physiological and pathophysiological stimuli
  • Vesicles transport substances through cytoplasm in a bidirectional pathway (transcytosis)
Continuous Non-Fenestrated (Blood-Brain Barrier)
Brain
  • Similar baseline characteristics to general non-fenestrated endothelium
  • Possess very 'restrictive' tight junctions between cells to prevent paracellular transport
  • Close contact with pericytes and astroctyes which aid barrier function
Continuous Fenestrated
Kidney
  • Circular pores of fenestrae that penetrate the endothelium
  • Thick continuous basement membrane
  • Allows the passage of small macromolecules through the endothelium
Non-continuous (Sinusoidal)
Liver
  • Does not form a continuous lining between the lumen and surrounding tissues
  • Gaps between adjacent cells and absent basement membrane
  • Poses no barrier to blood and constituents

Which structure in the brain lie outside the blood-brain barrier?

  • Certain areas of the brain have a reduced blood-brain barrier and retain a direct connection with the systemic circulation in order to
    • Detect alterations in composition of the blood
    • Allow secretion of hormones
  • Areas that are outside the BBB are known as ‘circumventricular organs’:
Hypothalamus
Area postrema
Anterior & posterior pituitary gland
Choroid plexus
Pineal gland
Subfornical organ
  • Hypothalamic osmoreceptors monitor the osmolarity of systemic blood
  • Contains a chemoreceptor trigger zone
  • In the presence of noxious substances, sends afferent signals to the vomiting centre triggering vomiting
  • Secretes eight pituitary hormones directly into the systemic circulation
  • Uses plasma from systemic blood to produce CSF
  • Secretes melatonin directly into the systemic circulation.
  • Contains a chemoreceptor area
  • Monitors blood angiotension II leveI as part of the regulation of body fluids

Function

What are the functions of the blood-brain barrier?

Barrier Functions
  • Protects against potentially harmful molecules from entering the brain
  • Provided through 4 main mechanisms:
    • Paracellular barrier: endothelial tight junction restrict free movement of water
    • Transcellular barrier: Low level of inherent endocytosis and transcytosis prevents transport of substances to the cytoplasm
    • Enzymatic barrier: Complex set of enzymes capable of metabolising compounds before crossing the BBB
    • Efflux barrier: Large number of efflux transporters present which can remove molecules from cells of the BBB
Carrier Functions
  • Transports nutrients, metabolites and essential ions to ensure the maintenance of a constant environment for the functioning of neurons
  • Provided through a number of mechanisms:
    • Passive and facilitated diffusion: Allows small lipid soluble molecules, water and gases to pass through the membrane
    • Specific transport proteins: Provides a supply of essential nutrients such as glucose and amino acids
    • Transcytosis: Ensures important metabolic molecules such as insulin can reach the brain

Which substances does the blood-brain barrier prevent from entering the brain?

Catecholamines
Amino acids
Ammonia (NH3)
Macromolecules
Charged Ions
  • A number of catecholamines (such as noradrenaline and dopamine) act as neurotransmitters in the central nervous system
  • Unregulated entry across the blood brain barrier can result in permanent neuroexcitatory damage
  • Similarly to catecholamines a number of amino-acids (such as glycine and glutamic acid) act as neurotransmitters in the central nervous system
  • Unregulated entry across the blood brain barrier can result in permanent neuroexcitatory damage
  • Ammonia is potentially neurotoxic in significant concentrations
  • It is a small lipophilic molecule which may be expected to cross the BBB
  • It is rapidly metabolised by the enzymatic barrier to glutamine, preventing passage across the BBB in relevant quantities
  • Plasma proteins such as albumin and plasminogen are damaging to nervous tissue and can lead to apoptosis
  • The BBB prevents passage of such molecules leading to low CSF levels
  • Results in a lower ability to buffer changes in pH
  • The BBB is impermeable to H+ and HCO3- ions due to their charge
  • However it is permeable to CO2 which can pass freely through into the CSF
  • In this way CO2 from arterial blood can become converted in to H+ and HCO3- ions which become trapped lowering the pH of CSF

How do substances cross the blood-brain barrier and which substances pass by each route?

Route
Free Membrane Diffusion
Membrane Channels
Carrier-Mediated Transport
Receptor-Mediated Transport (via transcytosis)
Adsorption mediated transport (via transcytosis)
Examples
Small Lipophilic molecules and gases:
  • O2, CO2
  • Anaesthetics
  • Ethanol, nicotine
Small ions and water:
  • H2O
  • Na, K+, Cl-
  • Energy transport systems:
    • Glucose (GLUT-1)
    • Lactate, pyruvate (MCT1)
    • Creatine (CrT)
  • Amino acid transport systems
    • Large neural amino acids (LAT1)
    • Neurotransmitter precursors
  • Insulin
  • Leptin
  • IgG
  • TNFa
  • Histone
  • Albumin

Which important drugs pass freely through the blood-brain barrier?

Opioid Analgesics
Anaesthetic Agents
Anetiepileptics
Antidepressants
CNS Stimulants
Antibiotics
  • Morphine
  • Codeine
  • Fentanyl
  • Propofol
  • Fentanyl
  • Ketamine
  • Volatile anaesthetics
  • Benzoziazepines
  • Barbiturates
  • Phenytoin
  • Triciylic antidepressants
  • SSRIs
  • MOAs
  • Cocaine
  • Amphetamines
  • MDMA
  • Carbapenems
  • 3rd & 4th generation cephalosporins
  • Fluoroquinolones
  • Aciclovir

How can the passage of drugs to the CNS across BBB be enhanced?

Route
Bypass the BBB
Increase the lipophilicity of drug
Increase permeability of BBB
'Prodrug' to Utilise BBB Transport Mechanisms
'Trojan Horse' Delivery to Utilise BBB Transport Mechanisms
Explanation
  • Direct administration into the CSF bypasses the BBB to reach structures within the CNS
  • Increased lipophilicity of aids passive diffusion across lipid membranes of the BBB
  • Increased permeability my be due to disease or induced by vasoactive compounds (such as bradykinin and histamine) to enhance drug delivery
  • Prodrugs which cross the BBB may be used which are subsequently metabolised in the brain to active compounds
  • A monoclonal Ab (Mab) acts as a molecular Trojan horse to deliver drugs across the BBB
  • A drug pharmaceutical is genetically fused to the MAb
  • The MAb acts against receptors on cells of the BB such as the insulin receptor leading to transport across the cell via transcytosis
Example
  • Intrathecal antibiotics to treat meningitis or ventriculitis
  • Intrathecal chemotherapy agents to treat CNS malignancy
  • Heroin has to acetyl groups added to morphine molecule making it 100x more lipid soluble - produces more rapid onset of action
  • Once within the brain metabolised to morphine, which only slowly leaves the brain
  • Delivery of chemotherapeutic agents into the brain
  • Delivery of certain antibiotics enhanced by inflammation in meningitis
  • The neurotransmitter dopamine cannot cross the BBB
  • The precursor L-DOPA is transported across the BBB by facilitated diffusion where it is subsequently converted to dopamine
  • It is used in Patients with Parkinson’s disease, in which there is a dopamine deficiency of the substantia nigra
  • Early clinical trials for specialist treatments

Author

The Guidewire
Trainee in ICM & Anaesthesia

Reviewer

The Guidewire
Trainee in ICM & Anaesthesia