CNS Physiology

CNS Physiology

Describe the physiology of CSF

CSF is the fluid that bathes the brain and spinal cord and is contained in the ventricles and subarachnoid space. The total volume of CSF is approximately 150mls but there is very regular turn over so the daily production is  500-600mls/.

Formation:

• CSF is formed mainly by the choroid plexus which is a rich network of blood vessels that project into the ventricles. The choroid plexus is made up of highly specialised cuboidal epithelium which is continuous with ependymal cells that line the ventricles. The epithelium surrounds clusters of fenestrated capillaries. The epithelial cells of the choroid plexus are interconnected via tight junctions which creates a blood-CSF barrier.
• The remainder of CSF is formed directly from the walls of the ventricles
• CSF is produced by selective ultrafiltration of plasma through fenestrated capillaries of the choroid plexus and by active secretion
• Sodium is transported by active transport, chloride is transported with sodium due to the electrical gradient and water is transported via osmosis. Bicarbonate can enter via ion channels or via conversion from carbon dioxide and water under the influence of carbonic anhydrase.
• CSF formation is relatively constant but reduces when CPP falls below 70mmHg. Increases in ICP have minimal influence on the rate of CSF production as long as the CPP remains > 70mmHg

Composition: (compared to plasma)

• Higher pco2 (50mmHg) and thus lower pH (7.33)
• The protein content is normally very low due to the blood-CSF barrier. The protein level is normally 0.2 – 0.4g/L which is at least 100 – 200 times less than serum protein levels. CSF is therefore a poor buffer solution. Beta 2 transferrin is a protein that is exclusively found in CSF and is sometimes used as a test to distinguish CSF from other secretions.
• Potassium and calcium levels are lower
• Glucose concentration is lower, approximately 60 – 80% of plasma levels
• Chloride levels are higher, about 124mmol/L
• Magnesium levels are higher
• CSF normally has no or just a trace amount of cells

Flow:

• CSF flows unidirectionally rostrally to caudally. It is initially secreted into the lateral ventricles then passes into the third ventricle via the foramen of Monro, where a small amount of fluid is added. It then flows down the aqueduct of Sylvius into the fourth ventricle where further fluid is added and then passes out of the 4^th ventricle through the foramen of Magendie and the foramina of Luschka into the subarachnoid space. The CSF flows over the surface of the brain and down the length of the spinal cord. It is then absorbed mostly by arachnoid villi along the superior sagittal sinus and transverse sinus into the bloodstream. A small amount of CSF can also be absorbed through the cribiform plate into lymphatic channels, and from the spinal canal.
• The rate of CSF absorption correlates with CSF pressure. Absorption of CSF increases linearly as ICP rises above 7cmH20

List the functions of CSF

Functions:

• Mechanical protection
  • The brain weighs approximately 1.4kg, however due to the CSF bathing the brain it reduces the effective weight of the brain to 47g. This recues the force applied to the brain parenchyma and vessels during injury.
  • The CSF also acts as a shock absorber as it cushions the brain against the skull
• ICP buffering
  • CSF absorption can increase and it can be translocated from within the cranial vault to the extra-cranial compartment in situations of raised ICP. This buffering capacity obviously has limits
• Homeostasis
  • Neurons are highly sensitive to ionic changes and CSF provides a constant chemical environment for neuronal activity.
  • CSF pH plays a critical role in the regulation of respiration
• Transport medium
  • For nutrients for the CNS
  • Transports hormones, metabolites and some neurotransmitters
  • Can remove metabolic waste products such as excess neurotransmitters, pathogens, drugs and glycosylated proteins.

Outline the physiological factors that influence cerebral blood flow

The normal brain is approximately 1.4kg and receives about 750ml/minute blood flow or 15% of total cardiac output despite comprising only 2% of body weight. This translates to about 50ml/100g/minute of blood flow. Cerebral blood flow is supplied by the carotid (about 70%) and the vertebral (remaining 30%) arteries.

The brain also has a high oxygen requirement, consuming 3 – 3.5ml of oxygen/100g/minute or about 50ml/minute which is about 20% of total basal oxygen consumption. It has an oxygen extraction ratio of 33%.

Cerebral blood flow is dependent on a number of factors which can be described by the Hagen Poiseuille law. This states that blood flow is proportional to the change in pressure (in this case the cerebral perfusion pressure) x pi x radius to the power of 4 divided by 8 x viscosity of the fluid x length of the vessel. Put another way this is the change in pressure divided by resistance.

Factors affecting blood flow can therefore be thought of in terms of factors affecting cerebral perfusion pressure and factors affecting cerebral vascular resistance.

Cerebral perfusion pressure: this is the difference between the mean arterial pressure and the intra-cranial pressure or CVP (whichever is higher). CPP is normally around 80mmHg. Factors affecting cerebral perfusion pressure:

• MAP
  • Cerebral blood flow is normally autoregulated between a range of cerebral perfusion pressures and mean arterial pressures. This range is thought to be between around 60 – 150mmHg but may be left-shifted in children and right shifted in chronic hypertension. Furthermore, cerebral autoregulatory mechanisms are thought to compromised in certain pathologies such as traumatic brain injuries and therefore changes in MAP may result in similar changes in cerebral perfusion pressure and therefore cerebral blood flow.
• ICP (or CVP whichever is higher)
  • Changes in ICP may cause opposing changes in cerebral perfusion pressure and therefore cerebral blood flow if the MAP remains constant

Factors affecting cerebral vascular resistance include:

• Carbon dioxide concentration
  • Increased paco2 results in vasodilatation which decreases cerebral vascular resistance and causes an almost linear increase in cerebral blood flow. This effect probably plateaus at a paco2 of over 80mmHg or less than 20mmHg
  • Hypoxia and hypercapnoea have a synergistic effect on cerebral blood flow
• Oxygen concentration
  • A pa02 of below about 60mmHg results is vasodilatation through release of adenosine which decreases cerebral vascular resistance and causes increased cerebral blood flow
  • Above this partial pressure, oxygen has minimal effect on cerebral blood flow
• Cerebral metabolic demand
  • Cerebral blood flow undergoes flow metabolic coupling where an increase in activity, either regional or general, causes an increase in cerebral metabolic rate and then an increase in cerebral blood flow
  • This ensures matching of oxygen and glucose to metabolic requirements and is thought to be mediated by substances such as hydrogen, adenosine, nitric oxide and carbon dioxide.
  • Cerebral metabolic demand can be influenced by external factors such as
    • Temperature: CMRO2 decreases by 7% per degree celcius reduction in temperature
    • Drugs: for example, thiopentone causes a decrease in CMRO2 whereas amphetamines increase CMRO2
    • Diseases: seizures, fevers increase CMRO2 whereas hepatic encephalopathy decreases CMRO2
  • Blood viscosity
    • Decreased haematocrit decreases blood viscosity and resistance therefore increases CBF. However decreased haematocrit may reduce the oxygen-carrying capacity of the blood.
  • Sympathetic nerves
    • The sympathetic nervous system normally has little influence on cerebral blood flow except during conditions of acute rises in MAP such as during strenuous exercise. In this case, the sympathetic nervous system constricts large and intermediate size arteries and acutely shifts the autoregulation curve to the right. This prevents sudden increases in cerebral blood flow.

 What are the factors that determine ICP?

Intracranial pressure is determined by the total volume of substance within the skull. This consists of 3 substances:

• Brain tissue: comprises the majority, 80 – 85%
• CSF: 7 – 10%
• Cerebral blood volume: 5 – 8%

The normal ICP is 5 – 14mmHg and has rhythmic variations associated with respiration and blood pressure.

The Monroe Kellie Doctrine states that the skull is a rigid box and that the sum of volumes of the constituents within the skull, that is the brain, CSF and intracerebral blood, is constant. Consequently, for ICP to remain normal, an increase in the volume of any one of the constituents should result in a reciprocal decrease in either one or both of the remaining two constituents. Therefore, the volume of brain tissue, CSF and cerebral blood are the main determinants of ICP.

• Brain
  • Increase in brain tissue volume such as with oedema and space-occupying lesions
• CSF
  • As mentioned earlier, the rate of CSF production is not affected by ICP however increases in ICP can increase CSF absorption
  • Any barriers to CSF absorption such as with obstructive hydrocephalus can increase ICP
• Cerebral blood volume:
  • This is affected by cerebral blood flow: anything that increases cerebral blood flow can increase ICP. These factors were discussed earlier.

Increases in intracranial constituent volume can initially be compensated by:

• Changes in blood flow: the cerebral venous volume can be changed quickly by compressing the vascular bed, venoconstriction and displacement of blood into the jugular veins.
• CSF displaced into the spinal canal
• Increased CSF absorption

After these compensatory mechanisms are exhausted, an increase in volume will cause an almost linear increase in ICP.

What are the consequences of increased ICP?

An increase in ICP can  have the following effects:

• Decreased cerebral perfusion pressure which can result in ischemia
• Temporal lobe herniation beneath tentorium cerebelli (uncal herniation)
  • Cranial nerve 3 palsy: dilation of pupil followed by a movement of the eye down and out
  • The uncus can put pressure on the cerebral peduncles resulting in hemiparesis and then abnormal posturing
  • It can also compress the posterior cerebral artery causing cortical blindness
  • Will have decreased level of consciousness
• Herniation of cerebellar peduncles through the foramen magnum (tonsillar herniation)
  • Pressure on brainstem causes Cushing triad (hypertension, bradycardia, abnormal respiratory pattern)
• Subfalcine herniation: cingulate gyrus of medial aspect of frontal lobe displaced across the midline and the free edge of falx cerebrii
  • may compress the anterior cerebral artery and cause leg weakness
• Lateral displacement of the diencephalon or ‘midline shift’
  • Clinical features will depend on the degree and speed of displacement and may cause a decreased level of consciousness
• Central transtentorial herniation
  • Symmetric or severe mass effect causing downward displacement of the thalami and midbrain
  • Results in a coma, diabetes insipidus, abnormal posturing and downward gaze
• ECG changes can result widespread giant T wave inversion, QT prolongation and bradycardia.

 Outline the structure and function of the blood-brain barrier

 The blood-brain barrier is a selectively permeable membrane which regulates the passage of substances to and from the brain. The primary function of the blood-brain barrier is to maintain the homeostasis of the CNS environment. It regulates the uptake of electrolytes and nutrients into the brain, it buffers the brain from changes in blood composition, and it helps prevents toxins and pathogens from entering the brain. The blood-brain barrier consists of endothelial cells, pericytes, and astrocyte endfeet.

• Endothelial cells: these form the endothelial walls of the capillaries but have special characteristics that allow them to perform their function. These characteristics are
  • Tight junctions between adjacent cells which prevent paracellular movement of substances
  • Do not have fenestrations
  • They lack vesicles or other transcellular pathways
  • Contain some transporters which enable them to shuttle essential nutrients and metabolites across the BBB
  • Contains enzymes which can metabolise certain substances
  • Contains efflux pumps such as ABC transporter and P-glycoprotein which can pump substances back into the capillary lumen
  • Impermeable to large, polar or lipid insoluble substances which help to protect the brain
• Pericytes: encircle endothelial cells and are able to contract in order to regulate capillary blood flow
  • May also promote the formation of tight junction and inhibit chemicals that promote vascular permeability
• Astrocyte end feet: surround the capillaries
  • Play a supportive role and also regulates aquaporin

Certain areas of the brain are not protected by the blood-brain barrier including the posterior pituitary gland, pineal gland, the median eminence of the hypothalamus, and the area postrema.