Flashcards in Neurology I Deck (38)
Cerebral blood flow
1) The brain is the least tolerant of ischaemia, >3 mins results in irreversible brain damage.
2) Interruption of the cerebral blood flow for 5 s will cause loss of consciousness
3) The brain receives approx. 12% of the cardiac output.
Regulation of cerebral blood flow: Myogenic autoregulation I
1) Arteriolar smooth muscle in the brain spontaneously contracts when the arteriolar wall tension is passively increased by an increase in arterial blood pressure.
2) Conversely, the arterioles relax when the pressure decreases.
3) The reduction in radius caused by contraction matches the increase in perfusion pressure such that there is no change in blood flow over a certain pressure range.
Myogenic autoregulation II
1) If mean arterial pressure falls below 50mmHg, the vasodilatation is no longer sufficient to maintain flow.
2) Conversely there is an upper limit to autoregulation above which the cerebral blood flow (CBF) rises sharply with arterial hypertension – the cerebral vessels becoming abnormally permeable, resulting in cerebral oedema.
3) The normal upper limit of mean arterial blood pressure is around 150mmHg. The range of mean arterial blood pressure is 50–150 mmHg.
1) Changes in systemic arterial blood pressure can control CBF
2) This is caused by stimulation of the vasomotor centre in the medulla by ischaemia.
3) This is known as Cushing’s phenomenon and aids in maintaining CBF in certain cerebral conditions, e.g. expanding intracranial tumours.
1) This leads to alteration of local blood flow to maintain a constant supply of oxygen to individual regions of the brain according to their level of activity.
2) During increased organ metabolism there is local decrease in PaO2, an increase in PaCO2, and increase in H concentration.
3) These changes result in arteriolar smooth muscle relaxation, ensuring an increase in flow with little or no change in perfusion pressure, to meet the needs of increased metabolism.
1) The cerebral vessels are innervated by cervical sympathetic nerve fibres which accompany the internal carotid and vertebral arteries.
2) Neural regulation of the cerebral circulation is considered weak and the contractile state of the smooth muscle of cerebral vessels depends mainly on local metabolic factors, i.e. metabolic autoregulation, and cannot be overridden by nervous control of arterioles.
Local factors: PaCO2
1) CBF is altered when partial pressures of O2 and CO2 change throughout the body. CBF is extremely sensitive to changes in arteriolar partial pressure of CO2.
2) Increases in PaCO2 causes marked cerebral vasodilatation. CBF doubles as PaCO2 rises from 40 to 100 mmHg (hypercapnia) and halves as PaCO2 falls to 20mmHg (hypocapnia).
3) The cerebral vasoconstriction caused by hypocapnia can cause mild cerebral ischaemia. Hyperventilation is used as a means of reducing raised intracranial pressure by inducing hypocapnic vasoconstriction with a reduction in CBF and cerebral blood volume. This type of therapy needs to be used with care to avoid ischaemic brain damage.
Local factors: PaO2
1) The relationship between CBF and PaO2 is not as marked as in the case of PaCO2. CBF remains constant over a wide range of PaO2 values until PaO2 falls below 60mmHg.
2) There is then a rise in CBF which is progressive and may be as high as three-fold at PaO2 of 30mmHg. Since a reduced O2 supply is usually accompanied by an increase in PaCO2, CBF is regulated by hypercapnia rather than hypoxia to maintain a constant O2 supply.
3) Increased PaO2 causes mild cerebral vasoconstriction only. Indeed, hyperbaric oxygen therapy reduces CBF by only 25%.
These vascular responses to change in arterial blood gas tensions may become impaired in the following states:
• head injury;
• cerebral haemorrhage;
Under such circumstances the protective autoregulatory mechanisms ensuring adequate CBF and oxygen delivery are lacking.
CSF is produced by the choroid plexuses of the
C) Fourth ventricles
Flow of CSF through the ventricles
1) Lateral ventricles -->
2) Interventricular foramina -->
3) The third ventricle (more CSF is produced)-->
4) The cerebral aqueduct into the fourth ventricle--> (further CSF is formed).
5) From the fourth ventricle-->sub- arachnoid space either via the lateral foramina (of Luschka) or the midline foramen (of Magendie).
CSF then circulates through the subarachnoid space that surrounds the brain and spinal cord. In certain areas the subarachnoid spaces are dilated and are called cisterns.
CSF is reabsorbed into the arachnoid villi
The cisterna magna (See diagram)
The cisterna magna (cerebellomedullary cistern) lies posterior to the medulla and below the cerebellum, is continuous inferiorly with the subarachnoid space around the spinal cord.
It is possible to pass a needle through the foramen magnum into the cisterna magna to obtain a specimen of CSF.
The lumbar cistern (See diagram)
The lumbar cistern, which surrounds the lumbar and sacrospinal routes below the level of termination of the spinal cord, is the usual target for a lumbar puncture.
Final CSF absorption
The CSF is finally reabsorbed through the arachnoid villi into the sinuses of the venous system.
The arachnoid villi may become aggregated into arachnoid granulations. These may grow quite large in the adult, producing hollows on the inner surface of the parietal bone in particular.
Some CSF (approximately 15%) is absorbed in the lumbar area through spinal villi similar to arachnoid villi, or along nerve sheaths into the lymphatics.
CSF absorption is passive, depending on its hydrostatic pressure being higher than that of venous blood.
CSF volume breakdown
The volume of CSF in the adult is about 140mL
1) 40 mL in the cerebral ventricles
2) 100 mL in the subarachnoid spaces.
CSF is produced at a constant rate of about 0.35 mL/min, i.e. 500 mL/day. This rate allows for the CSF to be turned over approximately four times daily.
The pressure in the CSF column measured with the patient recumbent in the lateral position is between 120 and 180 mmH2O.
The rate at which CSF is produced is relatively independent of the pressure in the ventricles and subarachnoid space and of the systemic blood pressure. However, absorption of CSF is a direct function of CSF pressure. CSF pressure transiently increases during coughing and straining as a result of increase in central venous pressure.
Blood brain barrier
In the cerebral microcirculation the junctions between endothelial cells are very tight. They do not permit the passage of substances which would normally pass between the endothelial cells of capillaries in other tissues.
Also, the capillaries of the brain are surrounded by the end-feet of astrocytes which are closely applied to the basal membrane of the capillaries. The astrocyte end-feet and the tight junctions between the endothelial cells constitute a blood-brain barrier.
This barrier is quite permeable at birth, demonstrated by the fact that bilirubin passes into the brain interstitial fluid if its concentration in plasma rises. However, during infancy and childhood, permea- bility of the barrier decreases considerably.
Substances crossing the blood brain barrier
Substances are still able to cross the barrier, e.g.
1) Respiratory gases
3) Fat-soluble drugs like volatile anaesthetic agents
Hydrogen ions do not usually cross the barrier but can do so in chronic acidotic conditions. The existence of the barrier maintains a constancy of interstitial environment around the neurons, for these are sensitive to changes in K+, Ca2+ and H+ concentrations in the fluids surrounding them.
Neurons are also protected from toxins which may be present in the systemic circulation. The barrier works in both directions, preventing the entry into the systemic circulation of large quantities of neurotransmitter substances released from the synapses of the CNS.
Absence of the blood brain barrier
Posterior lobe of the pituitary gland
Median eminence of the hypothalamus
•Circumventricular organs which abut on the third and fourth ventricles.
At the area postrema, drugs such as morphine and digoxin, creatinine and ketones in diabetes mellitus pass through the capillaries to stimulate the chemoreceptor trigger area in the floor of the fourth ventricle, which is connected to the vomiting centre.
Angiotensin II also passes through capillaries in this region to stimulate the vasomotor centre to increase sympathetic outflow, thus causing vasoconstriction and increasing peripheral resistance.
• the posterior lobe of the pituitary gland. ADH and oxytocin are released from axon terminals in the posterior pituitary and pass into the circulation; and
• the median eminence of the hypothalamus. Here neurons within the hypothalamus pass releasing or inhibitory hormones into the capillaries of
the hypothalamic–pituitary portal system. These control the secretion of hormones by the anterior pituitary.
Circumventricular organs: POSS MAN
Organ vasculosum of the lamina terminalis
Nerve conduction: Peripheral nerves
A typical peripheral nerve consists of a number of fasciculi surrounded by the epineurium. Changes in electrical potential recorded from a peripheral nerve represent the sum of all potential changes in each individual axon. Stimulation thresholds and conduction velocities differ in different types of neuron.
No action potential is recorded if a subthreshold stimulus is applied to a nerve. As the intensity of the stimulus increases, nerve fibres are recruited and action potentials are recorded. The stimulus that recruits all nerve fibres within an individual nerve is called the maximal stimulus. A supramaximal stimulus produces no increase in recorded potential changes, as all the nerve fibres have already been recruited and the action potential is an ‘all or none’ phenomenon.
Compound action potential
Different nerve groups have different stimulation thresholds and different conduction velocities. The recorded action potential from a peripheral nerve, therefore, has a number of peaks, and this is termed the compound action potential.
The compound action potential differs for different nerves and varies with stimulus strength until the maximal stimulus is applied and all nerve fibres are recruited.
Nerve fibres can be divided into different groups based on their morphology and function. Large myelinated fibres have faster conduction velocities than smaller non-myelinated fibres.
Types of nerve fibres and conduction velocity
Aalpha: Motor proprioception 100m/s
ABeta: Touch pressure 50m/s
AGamma: Muscle spindles (Motor) 30m/s
ADelta: Pain, temperature, touch 20m/s
B: Autonomic (Preganglionic) 10m/s
C: Pain 1m/s
Local anaesthetics act on nerve fibres by altering the ionic permeability of the cell membrane. This is brought about by alterations in the membrane-binding of calcium, which prevent sodium influx which is necessary for production of an action potential.
C-fibres, i.e. small unmyelinated patent fibres, are affected before A-fibres, i.e. large myelinated motor fibres.
Pain is the sensation resulting from stimuli which are intensive enough to threaten or cause tissue injury. Painful stimuli may be:
• Mechanical, e.g. pinprick
• Chemical, e.g. acid, corrosive
• Thermal, e.g. burn.
The specific sense organs for pain, i.e. the peripheral pain detectors, are called nociceptors. In the skin they are probably free nerve endings. They are supplied by either small myelinated (Aà) fibres or unmyelinated (C) fibres.
The endings of A fibres register high intensity mechanical stimuli (mechanical nociceptors), whilst the endings of C fibres register high intensity mechanical or heat stimuli (mechanothermal nociceptors).
The latter are probably less selective in responding to mechanical, thermal, or noxious chemical stimuli. Nerves supplying mechanical nociceptors conduct at velocities as high as 30m/s, while nerves supplying mechanothermal nociceptors conduct at velocities of less than 5 m/s.
Stimulation of both types of fibres may give rise to a double sensation: an initial sharp pain caused by the fast-acting A fibres, followed by a longer lasting aching pain due to activity in C fibres.
Visceral nociceptors are thought to be free nerve endings which occur in the walls of most hollow viscera and mesenteries. They are supplied by small myelinated and unmyelinated afferent fibres.
Stimuli exciting a response in these nerves are usually stretching, distension, or ischaemia. Afferents have been identified in the ureter which respond specifically to overdisten- sion, while afferents in the heart have been identified which respond to reduction in coronary blood flow.
Excessive stretching or distension of many viscera give rise to colicky or intermittent pain, e.g. intestinal, biliary, or ureteric colic. Visceral pain can also occur with ischaemia, e.g. angina pectoris, or the colicky abdominal pain associated with mesenteric ischaemia.
Visceral pains are commonly poorly localised and may be referred to other parts of the body. Most viscera are insensitive to stimuli which would cause intense pain if applied to the skin. Visceral perito- neum does not have pain receptors, whereas parietal peritoneum does.
In the unanaesthetised patient, the viscera are:
• insensitive to the pain of cutting;
• insensitive of the pain of burning;
• sensitive to factors distending or stretching the
• sensitive to inflammation, probably due to spasm of the associated muscle.
Character of visceral pain
Visceral pain is diffuse, poorly localised and may vary in intensity from a mild pain (the early stages of acute appendicitis where there is a mild central abdominal pain) to severe (biliary colic, ureteric colic).
Localisation of visceral pain
The localisation of visceral pain in the abdomen depends upon the embryological derivation of the viscus involved:
• foregut-derived structures – poorly localised upper abdominal pain (e.g. biliary colic)
• midgut-derived structures – poorly localised across the central abdomen (e.g. early stages of acute appendicitis)
• hindgut-derived structures – poorly localised across the lower abdomen (e.g. left-sided obstructive colonic carcinoma).
Pain arising from a viscus is carried back to the CNS by visceral afferents of the autonomic nervous system.
Visceral afferents enter the spinal cord at the dorsal root entry zone after entering the spinal canal in the white rami communicantes.
Visceral afferents enter the dorsal root entry zone with other sensory fibres passing back from sensory areas, i.e. the dermatome supplied by a spinal nerve.
The pain experienced by the individual is referred to the skin surface within the associated dermatome of the spinal nerve.
A classical example of referred pain is that from the irritation of the under- surface of the diaphragm (nerve supply C4) referred to the cutaneous distribution of C4 (shoulder tip).
Pain control pathways
There are two physiological mechanisms by which pain can be controlled:
• A peripheral afferent input system
• A central descending system
Both of these systems act at a common site, i.e. the cells of the substantia gelatinosa in the grey matter of the dorsal horn.
A peripheral spinal gate control theory
The theory that antagonism exists between large cutaneous afferents and small pain fibres was based on the observation that counterirritation, e.g. heat or massage, will alleviate pain. Impulses in large fibres inhibit cells in the substantia gelatinosa of the dorsal grey matter, thus shutting the ‘gate’ to the ascent of impulses from the smaller pain fibres.
Transcutaneous electrical nerve stimulation (TENS) is based on this theory. Skin electrodes activate the large fibres in peripheral nerves. This selective activation reduces the ability of nocicep- tive fibres (Aà and C) to activate spinal neurons which transmit the pain signals to higher centres.
The central descending system
Analgesia can be produced by electrical stimulation of the periaqueductal grey matter in the midbrain or in the limbic system or thalamus.
Descending fibres lie in the dorsolateral funiculus of the spinal cord, where control is exerted selectively on the pain input. Part of the descending control of pain may be due to release of endorphins or enkephalins. On the basis of these pathways a more invasive approach to neuromodulation of pain has been devised.
Direct or percutaneous implantation of electrodes into the spinal canal to electrically stimulate the dorsal columns has been advocated. This is most effective for pain of the extremities, e.g. after nerve injuries or for peripheral neuropathies. In patients with ischaemic pain, spinal cord stimulation not only reduces pain but may also improve blood flow.
Electrodes may also be placed stereotactically either into the periaqueductal grey matter or into the thalamus. Thalamic stimulation is useful for neuropathic pains, while periaqueductal grey matter stimulation is beneficial for nociceptive pain such as severe spinal pain.
Drug modulation of pain: paracetamol
Paracetamol inhibits prostaglandin synthesis by a different action to that of NSAIDs.
1) Its action is related to local peroxide concentrations which act as a cofactor in prostaglandin synthesis.
2) Paracetamol reduces peroxide levels. This effectively prevents prostaglandin biosynthesis where the peroxide concentration is low, e.g in brain, but not where it is high, e.g. in sites of inflammation or pus.
Drug modulation of pain: NSAIDs
1) Tissue injury results in the breakdown of cell wall lipid to arachidonic acid.
2) Release of histamine and bradykinin initiates inflammation and stimulates nociceptors, a process sensitised by prostaglandins.
3) Non-steroidal anti-inflammatory drugs (NSAIDs) limit the conversion of arachidonic acid to PGG2, an intermediary in prostaglandin production, by inhibiting cyclo-oxygenase.
4) This inhibition of production of prostaglandins by NSAIDs is responsible for their analgesic action.
Drug modulation of pain: Opioids
Opiates are drugs derived from the juice of the opium poppy. They exert their analgesic effects by binding to specific opiate receptors. This binding is stereospecifically inhibited by a morphine derivative called naloxone.
Compounds not derived from the opium poppy, but that exert direct effects by binding to opiate receptors, are called opioids. In practice, opioids are defined as directly acting compounds whose effects are stereospecifically antagonised by naloxone.
Opiates such as morphine, heroin and codeine are the most powerful analgesics known. They act by com- bining with the receptors in many areas of the CNS, including the periaqueductal grey matter, parts of the limbic system, and the substantia gelatinosa of the spi- nal cord. Certain endogenous analgesic peptides bind to these receptors. These may be divided into three groups:
Opioid peptides I
Opioid peptides are not effective when injected intravenously but are more potent than opiates when applied directly to certain areas of the brain and the spinal cord.
Opioid peptides may play a role in the effects of acupuncture, as some of the effects of acupuncture can be blocked by the opioid antagonist naloxone.
It has also been suggested that opioid peptides may be decreased in chronic pain states. As has been seen above, they can be increased by electrical stimulation of the periaqueductal grey matter.
Opioid peptides II
Opioid peptides may act at the level of the spinal cord and in peripheral tissues.
Substance P, a peptide present in the terminals of afferent fibres, has been suggested as the transmitter for nociceptive stimuli in the dorsal horn.
Opioids may block the release of substance P presynaptically from these afferent fibres, thus reducing pain.
There are several types of opioid receptors: these are μ, kappa, delta, O.
Conventional opioids (e.g. morphine, pethidine) are agonists attaching to the μ receptors and produce:
• Analgesia at a supraspinal level
• Drug-induced euphoria
• Respiratory depression
• Drug dependency