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11
Inflammation
oedema
Cell swelling
Functional impact
Time after ischaemic attack
ATP pumps
+/K+
) fail
(Na
Membrane
depolarisation
Activation of
voltage-gated
2+
Ca
channels
Ischaemia
Decreased blood flow
( O
)
2
Depletion of energy stores
Energy failure
Acidosis
(lactate accumulation)
Glutamate
release
Activate NMDA
and AMPA receptors
Increase intracellular
2+
Ca
levels
Enzyme induction
2+
Ca
buffering system
2+
and Ca
pumps fail
Mitochondrial
damage
Reperfusion of
anoxic tissue with O
STROKE AND HEAD INJURY
2
Apoptosis
Cell death
Free radical productionMembrane
Lipid
peroxidation
Microglia
activation
Cytokine
production
(oedema)
Cytotoxic
Fig. 11.16 Mechanisms contributing to neurotoxicity in ischaemia. Disruption of normal blood flow results in activation of multiple and complex
signal cascades that ultimately result in cell death. The key event is excitotoxicity, leading to increased intracellular Ca2+ levels, which result in the
generation and activation of free radicals that damage the cells and cause further inflammatory responses. Paradoxically, reperfusion of ischaemic
tissue with oxygen can also lead to neuronal damage—reperfusion injury—by causing free radical formation. AMPA, 4-amino-3-hydroxy-5-methyl4-isoxazole propionic acid; NMDA, N-methyl-D-aspartate. (Adapted from De Kayser J, et al. (1999) Trends in Neuroscience 22:535–539.)
degradation
by proteases
and lipases
Activation of the N- methyl- D- aspartate (NMDA)
Excitotoxicity
Inflammation
and oedema
Apoptosis
(amount of cell death)
glutamate receptor leads to Ca2+ influx into neurons. A
number of factors normally tightly regulate this receptor, so that Ca2+ entry into neurons is closely controlled.
Excessive extracellular glutamate levels lead to prolonged neuronal depolarization via 4- amino- 3- hydroxy
- 5- methyl- 4- isoxazole propionic acid (AMPA) receptors,
which in itself is not harmful. However, the depolarization of the postsynaptic cell also activates the NMDA
Minutes Hours Days
receptor (which is held inactive at normal resting potentials by the Mg2+ block of the receptor) and this in turn
Fig. 11.17 Time course of pathophysiological changes occurring
in ischaemic stroke. In the earliest stages, excitotoxic mechanisms
damage both neurons and glial cells and contribute to the genesis of
inflammation and cell death. (Adapted from Dirnagl U, et al. (1999)
Trends in Neuroscience 22:391–397.)
leads to further Ca2+ entry. This is where critical processes are triggered, due to Ca2+ overload, as the Ca2+
buffering systems of neurons, mitochondria and the
endoplasmic reticulum fail. The rise in internal Ca2+ level
activates many second messenger systems, which all
239THE NERVOUS SYSTEM
11
Box
11.5
Nitric oxide (NO) is produced from arginine via the enzyme
nitric oxide synthase (NOS). There are several isoforms
of NOS, and NO can also be produced through a NOSindependent mechanism. NO is a gaseous compound with
powerful vasodilator properties. The well- known therapeutic actions of nitrates or nitrites given to angina sufferers
are likely due to formation of NO and the strong vasodilator action on coronary arteries. NO is also a vasodilator of
STROKE AND HEAD INJURY
cerebral blood vessels; NOS is expressed in the endothelial
cells lining cerebral blood vessels. Blockade of NO synthesis reduces cerebral blood flow and attenuates the response
of cerebral vessels to hypercapnia. However, there are
problems with the hypothesis that NO is the intrinsic cerebral vasodilator control substance. If this were the case,
NO levels would be expected to increase during cerebral
hypoxia, as this is known to be a powerful stimulant of cerebral vasodilatation. However, blockade of NO synthesis
does not block hypoxia- induced vasodilatation in the brain.
In fact, rather than NO production being part of a protective mechanism against hypoxia, there is considerable evidence that the opposite may be true: release of NO in some
cases appears to be a fundamental step in the excitotoxic
response. Following cerebral hypoxia, NO reacts with the
superoxide anion to form peroxynitrite, which destroys cell
membranes. NO also decreases the activity of superoxide
dismutase (which inactivates the superoxide anion).
delivery in neurons, why is it also involved in the excitotoxic mechanisms of cell death? There are three different
isoforms of NOS—neuronal, endothelial and inducible
The role of nitric oxide in stroke
If NO is part of a mechanism that supports oxygen
(found in macrophages)—and they have different functions. Endothelial NOS normally functions as a vasodilator.
Increases in endothelial NOS levels that occur in stroke may
contribute to reperfusion- induced cell death through production of NO, which can interact with free radical ions.
Neuronal NOS is found in a small proportion of neurons
and is upregulated in cells after stroke. Glutamate activates
neuronal NOS via Ca2+ influx. Here, NOS can act as a death
mediator. Interestingly, NOS- expressing neurons appear to
be unusually resistant to hypoxic damage, and so the NO
released by these cells during extreme hypoxia may cause
the death of others. Could the excess NO released during
hypoxia act as a selective ‘culling’ process, so that when
life- threatening levels of hypoxia occur, some neurons are
actively sacrificed before others? Not all cells in any one
brain area may have the same importance to the organism. Cells that have a history of high levels of activity might
have high levels of intracellular reducing agents such as
vitamin C or glutathione, which would initially protect
them from the consequences of NO attack. In contrast, cells
that had been relatively inactive before the hypoxia would
have less biochemical protection and might be the first
to die. In such a way, the brain could attempt a ‘damage
limitation exercise’ to protect the cells that have been most
active in the past from the effects of a hypoxic crisis.
NOS inhibitors show neuroprotective effects in animal
models of ischaemia, and thus offer a therapeutic option
for stroke treatment. However, none of the few clinical trials that have assessed these inhibitors so far has shown a
beneficial outcome.
demand energy in the form of ATP or other substrates.
However, because of hypoxia, this energy is not available. Disruption of neuronal Ca2+- induced processes
leads to the formation of free radicals, such as the superoxide anion (O
–
), via the activation of NO production
2
(Box 11.5). These free radicals are very reactive and initi-
ate cell damage by reacting with many cell components
(e.g. a lipid peroxidation reaction). This eventually damages the cell so badly that it undergoes necrosis (see Fig.
11.17). Thus, glutamate toxicity is a prominent cause of
necrotic cell death.
The brain has a number of natural defence molecules
to protect against free radical damage. These molecules
are reducing agents. They prevent other molecules
being oxidized and react with free radicals or oxidizing
agents to form inert products. Three of the most important protectors are vitamin C (ascorbic acid), vitamin E
(α- tocopherol) and glutathione. Vitamin C is a powerful water- soluble reducing agent that is present in high
levels in the CNS, in both neurons and glial cells, and
is also found in the CSF. Vitamin C is released into the
CSF by neuronal depolarization, and also by increases
in neuronal activity. Its CSF levels rise sharply following
240 SYSTEMS OF THE BODY
ischaemic hypoxia, and this may be a protective measure
to ‘mop up’ free radicals produced by hypoxic metabolism. Vitamin E is a lipid- soluble reducing agent that
eliminates free radicals in cell membranes and other
lipid- rich structures and acts synergistically with vitamin
C. Glutathione is a tripeptide that can exist as a reduced
or oxidized form (the latter is a dimer molecule). The
enzyme glutathione peroxidase catalyses the reaction
that produces oxidised glutathione.
Healthy cells have a ratio of reduced/oxidised glutathione of >100, whereas during oxidative stress the ratio
can drop to 0.1.
Increased intracellular Ca2+ levels can trigger the formation of cytokines such as tumour necrosis factor- α,
interleukin- 1β and platelet- activating factor. It also leads
to increased activity of the enzyme cyclo- oxygenase 2
(COX- 2), which contributes to postischaemic inflammation. The cytokines activate microglia, which then
release more cytokines, glutamate and other neurotoxins and attract immune cells that express inducible nitric
oxide synthase (iNOS). High intracellular Ca2+ levels also
damage mitochondria (with subsequent disruption of
energy metabolism) and induce apoptosis (cell suicide
11
programmes) via activation of caspases, particularly
within the penumbra region. The apoptotic mechanism
operates on a slower time scale, occurring over a period
of hours to days after the initial focal ischaemic event
(see Fig. 11.16). Apoptotic cells do not swell and burst;
in this mode of cell death, they shrivel and implode. The
initial necrosis and the more delayed apoptosis are only
two examples of the various types of cell death associated with injury.
Stroke management: the acute phase,
neuroprotection and prevention
There are various dimensions linked to the management
of a stroke patient: (1) acute intervention after a stroke
and neuroprotection, (2) support during the recovery
period and (3) prevention against recurrence of stroke.
Prevention can also be implemented from the perspective of reducing the risk of stroke occurring in the first
instance, that is, primary prevention.
The acute management of haemorrhagic stroke
involves control of the bleeding and limitation of the risk
of dangerously high intracranial pressure, because of the
pooling of fluid. Surgery may be required to evacuate the
blood, control the intracranial pressure and also repair
the damaged vessel at the origin of the haemorrhage.
In the acute phase of an ischaemic stroke there are
two main approaches: thrombolysis and thrombectomy.
Intravenous thrombolysis is the first intervention, based
on the use of a recombinant tissue plasminogen activator (alteplase; t- PA), which is the only available compound that can be used at present in the acute phase
and that has been shown to improve outcome. The drug
cleaves plasminogen and produces plasmin, a fibrinolytic enzyme that breaks down the blood clot. The intravascular infusion of t- PA must start generally within
4.5 h of the stroke onset and presentation of symptoms
(although in patients where there is demonstrable evidence of salvageable tissue beyond this time, it could be
used up to 9 h after onset). Thrombolysis intervention
attempts to reperfuse tissue, as severely compromised
tissue in the penumbra, which is still viable, could be
rescued by fast reperfusion. However, due to its limited therapeutic time frame, it is only used in a minority
of stroke patients, as the majority of stroke patients do
not have fast access to a specialist team. Only approximately 15%–60% of acute stroke patients arrive at the
hospital within 3 hours after the onset of symptoms.
The other approach for acute intervention is thrombectomy, a mechanical removal of the clot. During this
procedure, a clot- removing device is inserted through
a catheter (usually in the groin) into the affected vessel, to pull out the clot. This procedure is only used to
treat patients with clots in large vessels. Most patients
are treated within 6 h of symptoms onset, although
in some cases thrombectomy can be carried out up to
24 h after onset. Thrombectomy does not significantly
reduce overall mortality but reduces disability in stroke
survivors. Patients can return home earlier and there are
reduced hospital and social care costs. A new interesting development in the stroke field is the introduction
of mobile stroke units, which are modified ambulances
where a CT scan can be performed and thromboplasty
can be implemented. This expedites the process of diagnosis and treatment, improves the triage decision making and increases the overall efficiency of management;
it also reduces the pressure on admissions to emergency
services.
For both thromboplasty and thrombectomy, it is important to note that reperfusion of the ischaemic tissue may
lead to a phenomenon known as ‘reperfusion injury’ – a
paradoxical triggering of processes which can further
injure tissue. One of the most critical consequences of
introducing oxygen in tissue by restoring blood flow
is the enhanced generation of reactive oxygen species
(ROS). These can directly damage cells and also activate an inflammatory reaction, increase leucocyte adhesion and activate platelets, which can then aggregate.
Neuroprotective drugs are aimed at preventing or reducing secondary cell death in the penumbra region. Such
drugs might also be valuable against reperfusion- linked
injury. Although much is now known about the molecular
pathways of apoptosis, excitotoxicity, neuroinflammation
and oxidative stress, clinically effective neuroprotective
treatments remain elusive. Numerous drugs that were
shown in animal models of stroke to be neuroprotective have failed to achieve their preclinical promise in
phase III clinical trials (Box 11.6 and Table 11.6) in terms
of improving neurological and functional deficits, therefore no neuroprotective agents are used at present in the
acute management of stroke patients. Some of the reasons
for the repeated failures are probably that the trials often
used drugs to target one specific pathway of the pathophysiology cascade, which may be insufficient, and/or
the intervention time window was not optimized. It is
possible that using combinations of clot- lysing drugs and
neuroprotective drugs could achieve synergistic effects
in the salvage of the penumbra. Therefore, the search for
new drugs that offer neuroprotection acutely after stroke
continues.
For prevention, drugs that treat accessory conditions, such as angiotensin- converting enzyme (ACE)
inhibitors and diuretics, for the management of hypertension, reduce the risk of stroke. Statins (HMG- CoA
reductase inhibitors) are a family of drugs that reduce
cholesterol levels by blocking its synthesis. They do
have a very rare and important side effect, in that they
cause myopathy, resulting in muscle pain and weakness. Statins reduce the risk of stroke by 20%–30%. For
people who have already suffered a stroke, secondary prevention measures are required. Individuals are
strongly advised to change their lifestyle in order to
reduce the relevant risk factors (see Table 11.2). Other
preventive measures include administration of agents
that prevent platelet aggregation and blood coagulation. Oral anti-coagulation is the therapy of choice for
primary and secondary stroke prevention in patients
STROKE AND HEAD INJURY
241THE NERVOUS SYSTEM
11
Box
11.6
Neuroprotection of the penumbra and also of the tissue
affected by reperfusion- linked injury, is a worthwhile goal
in stroke. However, several decades of work in experimental models of stroke have failed to deliver neuroprotectants that could be used in the clinic in the acute phase of
stroke. The question often asked is why? Is it the drug,
the trial design or the experimental models used, that led
to failure? The answer is probably all three. Animal mod-
STROKE AND HEAD INJURY
els of ischaemia generally fall into one of two categories:
reversible or permanent. In stroke patients, both types
occur, so that animal models never really mimic the clinical
situation. Preclinical models use standardized methods to
evoke reproducible ischaemic lesions in healthy young animals, whereas the typical stroke patient is usually elderly,
with numerous risk factors and complicating diseases such
as hypertension or heart disease. Therefore, animal models need to reflect the human condition more accurately.
Additionally, in clinical trials, young and old patients are
often grouped together, as are the types of stroke that
they present with. Thus it is not surprising that no benefit is demonstrated when a drug designed to target a
very specific pathophysiological mechanisms is given to
such a heterogeneous population of patients. It is becoming increasingly apparent that a drug treatment targeting
a single mechanism may not be applicable to all stroke
types; the relative weighting of the various components of
the pathophysiology cascade may differ between patients.
Doses of drugs that are neuroprotective in animal models
often have adverse effects in humans. Good examples of
these are anti-excitotoxicity drugs such as the NMDA receptor antagonists. These induce psychotomimetic effects such
as delirium, hallucinations, paranoia, catatonia and sedation, which preclude their use. In some instances the dose
is reduced to suboptimal levels because of overemphasis on
safety aspects and this may lead to compromising efficacy.
Additionally, the time window for intervention is often very
hard to define and extrapolate from animals to humans,
therefore it is not known how long neuroprotective therapies should be continued for. Most preclinical observations also indicate that combinations of clot- lysing drugs
and neuroprotective drugs have synergistic effects. Thus,
drug combinations that promote cell survival and target
Neuroprotection: an elusive goal
multiple pathways, in combination with thrombolysis or
thrombectomy, may prove to be the way forward in treating stroke in the acute phase. Some of the most promising recent trials with potentially neuroprotective agents in
stroke, such as the immunomodulator fingolimod or statins
such as atorvastatin, consider the use of thrombolysis and
thrombectomy, thus providing a more integrated analysis
of efficacy in a real pragmatic clinical context.
It is also important to note that the analysis of outcomes
in animal and human studies is different. In animal models, infarct size is most often quantified histologically so
that the effect of a drug can be evaluated, usually over a
short time span. Behavioural improvement is often not
assessed in the chronic phase after experimental stroke. In
contrast, in humans, neurological and functional scores are
very important. The National Institutes of Health Stroke
Scale (NIHSS, Table 11.5) and the Barthel index or the modified Rankin scale, are commonly used at 3 or 6 months
after stroke. Recent evidence suggests that the NIHSS score
strongly predicts outcome; patients who score 6 or less at 3
months have a good outcome, whilst those that score 16 or
more are likely to die or have severe disability. These scores
and scales may be less amenable to statistical analysis and
may be less sensitive than anatomical markers of infarct
size. The latter can be assessed with the use of sophisticated imaging methods such as positron emission tomography and diffusion- weighted and perfusion magnetic
resonance imaging, to measure the penumbra and infarct
size before and after treatment.
Finally, recent clinical trials which are reporting encouraging results for neuroprotection in stroke are reconsidering old targets, but from a new perspective. For example,
the NMDA receptor is targeted not using a classical antagonist approach but using a very specific disruption of the
connection of the NMDA receptor subunit GluN2B, to the
formation of nitric oxide (NO) (a mechanism which exacerbates toxicity after activation of the NMDA receptor).
This disruption, achieved through a small peptide—nerinetide—appears to have beneficial effects, according to
the first exploratory clinical trials. Such novel approaches,
with more specificity, may lead to much more success in the
future.
with atrial fibrillation. Heparin, warfarin or newer
drugs such as apixaban (an inhibitor of Factor Xa in
the coagulation cascade) can be given to such patients.
Aspirin inhibits the enzyme COX and chronic treatment with low dose aspirin (e.g. 75–300 mg/day)
reduces the relative risk of stroke by 25% in those
who have already had a TIA or stroke. For the prevention of non-cardioembolic ischaemic stroke, antiplatelet agents rather than oral anti-coagulation are
recommended to reduce the risk of recurrent stroke.
Aspirin monotherapy, the combination of aspirin and
242 SYSTEMS OF THE BODY
extended- release dipyridamole (a nucleoside transport
inhibitor and a phosphodiesterase inhibitor) and clopidogrel (a drug that leads to inhibition of the purinergic
receptors P2Y12 involved in the activation of platelets),
used as monotherapy, are acceptable options.
Stroke remains a major public health problem worldwide, and its impact will increase in the decades to come,
because of the change in demographics and the increasing ageing population. Better preventive treatment and a
much- improved management in the acute phase remain
important goals.
11
Table 11.6 Examples of drugs explored for acute neuroprotection
in clinical studies in stroke
Target or Mechanism Drug
Ca2+ channels Nimodipine (L- type channel blocker)
Glutamate receptors (NMDA
type)
GABAA receptors Clomethiazole (GABAA positive
Free radical scavenging Tirilazad
Cell membrane
stabilisation
Neurotrophic effects Cerebrolysin (mixture of peptides)
Anti- inflammatory effects Minocycline
NMDA, N- methyl- D- aspartate; GABA, γ- aminobutyric acid;
IL- 1, interleukin- 1
Selfotel (competitive receptor
antagonist)
allosteric modulator)
Ebselen
Citicholine
Anakinra (IL- 1 receptor antagonist)
Rehabilitation of stroke patients
At least one- third of stroke patients who survive the initial
event are left with considerable disability. Recovery from
disabling stroke can take at least 3–12 months. The length
of time varies widely from person to person. Some of this
is due to spontaneous resolution of acute problems such
as oedema, compensatory brain plasticity and the effects
of drugs that rescue cells in the penumbra. It is now recognized that patients recovering in specialist stroke units,
as opposed to general wards, make a better recovery. This
is because of the availability of specialist multidisciplinary
teams that aim to optimize each patient’s recovery and
maximize the plasticity of the intact brain.
The purpose of rehabilitation is to help people re- learn
skills that they have lost (reablement), learn new skills
and find ways to manage any permanent disabilities that
they may have been left with.
Medical rehabilitation involves a problem- solving
process focused upon disability and handicap by:
1. Assessment, which aims to discover the level of
disability, prognostic factors and the patient’s goals.
2. Goal planning, which covers the areas of
accommodation, personal support and social
role of the patient. This is an essential part of the
rehabilitation process and should be discussed by the
patient, family and carers.
3. Intervention, which tries to reduce the risk of
subsequent attacks by addressing potentially treatable
risk factors (see Table 11.2).
4. Evaluation by neurological examination.
A rehabilitation programme includes methods
designed to help with posture, balance and movement,
together with specialist help for specific difficulties such
as speech and language. Many different professionals
may be involved in this, but the patient’s motivation and
efforts are equally important. Key experts include doctors and nurses (specialist stroke nurses or community
nurses) to oversee medical management; physiotherapists to help with problems of posture and movement;
occupational therapists to help with everyday activities
at home, leisure and work; speech and language therapists to help with communication problems and clinical
psychologists to help with problems affecting mental
processes and emotions. As well as reablement, the
patient needs resettlement, which may involve adaptation or alteration of their environment (housing and
social lifestyles) and involve other professionals such as
social workers and dieticians.
Prognosis for recovery
It is imperative that patients receive medical treatment
as soon as possible after stroke. Time is of the essence, as
the faster the treatment initiation, the better the probability of saving more brain tissue and reducing functional
deficits. The initial aim is to stabilize the condition, control blood pressure and prevent the acute complications
of stroke, such as aspiration pneumonia or immobility;
these account for 35% of acute deaths. The doctor may
prescribe drugs designed to prevent a further stroke and
to treat any underlying conditions such as high blood
pressure or high cholesterol levels.
The brain is capable of great plasticity. In the weeks
and months following a stroke, many partially damaged
cells recover and start to work again. Meanwhile, other
unaffected parts of the brain take over tasks previously
performed by the brain cells that are destroyed. This is
part of the aim of rehabilitation. The length of time it
takes to recover varies widely from person to person. It
is common to have an initial spurt of recovery in the first
few weeks after the stroke. In general, most of the recovery takes place during the first year to 18 months, but
many people continue to improve over a much longer
period, especially with sustained rehabilitation.
It is now recognized that patients who suffer small
haemorrhagic strokes often make a better recovery than
those with ischaemic stroke. Haematomas more often
irritate brain tissue rather than physically damage it.
The brain absorbs some of the blood from these haemorrhages and, as it does so, the affected area heals and
begins to function again, making it possible for normal
function to be completely regained after small haemorrhagic strokes.
Head injury
Traumatic head injuries can occur over a wide range
of severities. Very severe head injuries involve forces
incompatible with life and death is immediate. With
most severe head injuries, however, there is a variable
STROKE AND HEAD INJURY
243THE NERVOUS SYSTEM
11
Box
11.7
Cerebral swelling after head injury may be caused by either
cerebral oedema or vascular haemorrhage. There are three
types of cerebral oedema:
1. Vasogenic. This is due to accumulation of water outside
STROKE AND HEAD INJURY
2. Cytotoxic. As the brain swells due to vasogenic oedema,
3. Interstitial. This is a consequence of an increase in the
oedema are important.
brospinal fluid and the vascular supply, within a fixed
Brain swelling and raised intracranial pressure
cells, as a result of disruption of the blood–brain barrier.
After trauma, damaged plasma constituents move into the
extracellular space, causing the extracellular compartment
to increase in volume, leading to brain swelling.
the tissue becomes ischaemic, cell membranes become
damaged and Na+/K+ pumps fail to maintain the
membrane ionic gradient. Intracellular Na+ accumulation
leads to cell swelling, resulting in cytotoxic oedema.
volume of the extracellular fluid in the absence of
disruption to the blood–brain barrier, for example, due
to insufficient antidiuretic hormone secretion.
In the context of head trauma, vasogenic and cytotoxic
The cranial vault contains the brain and meninges, cere-
volume. Any increase in volume of one of these must occur
at the expense of the others, if the pressure is to remain
unchanged. Any uncompensated increase in volume of
any of the constituents causes raised intracranial pressure.
While raised intracranial pressure is always seen with spaceoccupying lesions, pressure may rise in the absence of a mass
lesion. Brain swelling and hydrocephalus are the two most
common generalized causes of raised intracranial pressure.
The brain is only perfused because systemic arterial pressure is higher than intracranial pressure. As intracranial
pressure rises, blood flow to the brain decreases, unless the
arterial pressure rises in compensation. This compensatory
rise does occur when intracranial pressure starts to rise, but
cerebral perfusion rapidly falls off as intracranial pressure
rises still higher. Tissue ischaemia then leads to cytotoxic
oedema and therefore more swelling.
Rising intracranial pressure causes a number of nonspecific symptoms, including headache (from stretching
and distortion of dura and blood vessels), vomiting (from
pressure on the floor of the fourth ventricle), papilloedema
(from pressure on the optic nerve sheath) and falling consciousness levels (from pressure on the diencephalon and
upper brainstem).
period of survival and the usual cause of death is raised
intracranial pressure (Box 11.7) as a result of either brain
swelling or a haemorrhage accumulating inside the skull,
which distorts the brain and damages vital structures
(see Box 11.7). Posttraumatic disability depends on the
location and amount of brain damage; the most usual
neuropathological causes of long- term disability after a
head injury are damage to axons and hypoxic–ischaemic
damage sustained at the time of injury.
There are two important mechanisms involved in head
injury which have significant consequences for brain tissue: the impact to the head and the movement of the
brain, resulting in slightly different patterns of injury. In
the human situation, of course, there is almost always
impact, with variable amounts of brain movement.
Because excessive movement alone can damage the brain,
it is important to remember that it is not necessary for the
head to hit anything for a severe brain injury to occur.
As a function of the severity of the injury, the patients
may present a wide variety of symptoms, for example,
nausea and vomiting, headache, confusion, paralysis,
dilated pupils, vision changes, dizziness and balance
problems, breathing problems, body numbness, seizures
and loss of consciousness. The symptoms associated with
traumatic brain injury can appear immediately following
injury or develop days to weeks later; as a result of the
injury, patients can develop a wide range of physical and
psychological deficits including major motor impairment,
secondary epilepsy, personality change and cognition and
memory impairment. It is also now well established that
even a single brain injury can significantly increase the
risk of developing neurodegenerative diseases later in
life, such as Alzheimer’s disease. Traumatic brain injury is
thus one of the strongest risk factors for dementia.
The severity of head injury is assessed in several ways:
by the level of consciousness (Box 11.8), by pupil reactions to light and by neurological and radiological investigations. The Glasgow Coma Scale (GCS) is an important
indicator of head injury severity and is used to clinically
assess the degree of coma (Table 11.7). This method is eas-
ily reproducible and very useful for monitoring changes
in the level of consciousness. The GCS score is calculated
based on the patient’s eye- opening and verbal and best
motor responses. Scores in each category range from 1 (no
response) to a maximum of between 4 and 6 (for a normal response) and are summed to give a score ranging
between 3 and 15. Patients with a score of <8 are in coma
and have a severe head injury. A score of 9–12 indicates
a moderate head injury and a score >12 indicates a mild
head injury. The GCS has prognostic value, as the scores
both immediately after the injury and 24 hours later correlate with the degree of long- term impairment.
The brain tissue damage seen in head injury is classified in a number of ways. Clinically, the most useful is as
focal or diffuse injury (Table 11.8). Focal injury indicates
pathology that can be seen on a CT or magnetic resonance imaging (MRI) scan and which may be neurosurgically treatable. Diffuse brain injury refers to microscopic
244 SYSTEMS OF THE BODY
Box
11.8
Basic mechanisms of consciousness
and coma
11
STROKE AND HEAD INJURY
Table 11.7 The Glasgow Coma Scale
Category Score
There are two separate components to consciousness:
being awake or alert, and being aware. In order to be fully
conscious, a person needs to have both an intact ascending
reticular activating system in the brainstem and a functioning cerebral cortex.
Coma is a state of unrousable unresponsiveness, caused
by damage to either the diencephalon/midbrain or the
hemispheres. After head injury, it may be due to:
• generalized brain swelling causing pressure on the
reticular formation
• temporal lobe herniation through the tentorial notch
that compresses or distorts the midbrain
• traumatic damage to axons (which effectively leads to
deafferentation of the cortex)
• severe hypoxic damage to neurons in the cortex (e.g.
from cardiac arrest or impaired cerebral perfusion).
Concussion, in contrast, is a reversible state of unconsciousness of brief duration. Recent research has shown that concussion, as a single episode or repetitive occurrence, although
apparently rather innocuous in the acute phase, can have significant consequences in terms of tissue changes and increased
risk of developing neurodegenerative disease (see main text).
Eye- opening response
Spontaneous 4
On command 3
In response to pain 2
None 1
Verbal response
Speaks freely, coherently and purposefully 5
Speaks in a confused, disoriented fashion 4
Uses inappropriate words 3
Makes incomprehensible sounds 2
No response 1
Best motor response
Obeys commands freely 6
Makes purposeful movements in response to noxious
stimuli
Withdraws from noxious stimuli 4
Shows flexion after noxious stimuli (decorticate
posturing)
Shows extension after noxious stimuli (decerebrate
posturing)
No response 1
5
3
2
damage that cannot be demonstrated with standard imaging techniques, but which clinicians diagnose because
they have an unconscious patient whose scan shows very
little obvious damage. A CT scan is the gold standard for
the first assessment after admission. It is easy to perform
and detects fractures and the presence of blood. MRI is not
commonly used for acute head injury since it takes longer to perform, is logistically more complicated and more
impractical. However, once a patient is stabilized, it can
reveal lesions that were not detected on the CT scan.
The response of the brain to injury and the quality of
the recovery may be at least partly influenced by certain
genetic variations. Genes of interest in traumatic brain
injury include genes encoding cytokines such as interleukin (IL)- 6, the neurotrophin brain- derived neurotrophic
factor (BDNF) or the lipid- binding protein apolipoprotein E (ApoE) and also mitochondrial genes or genes
associated with specific neurotransmitter pathways
(e.g. dopamine and serotonin). Much attention has been
focused on apoE because of its link with Alzheimer’s
disease. In the nervous system, ApoE acts as a carrier
for cholesterol, and it has been reported that the ɛ4 allele
of the gene may confer a less favourable recovery after
brain injury. Overall, there is still a clear need for large,
adequately powered genome- wide association studies,
with appropriate corrections for non-genetic covariates
that may influence outcome, before drawing firm conclusions as to the critical role of specific genes.
Table 11.8 Patterns of damage during head injury
Damage Example
Focal damage
Scalp Contusions (bruises)
Lacerations
Skull Fracture
Meninges Extradural and subdural haemorrhages
Brain Contusions and lacerations
Intracerebral (parenchymal) haemorrhage
Axonal damage
Diffuse damage
Brain Diffuse axonal injury
Hypoxic–ischaemic damage
Diffuse brain swelling
Focal pathology in relation to vascular injury
Skull fractures
A skull fracture (Fig. 11.18A) is of relevance because it
is an indication of the force of the impact on the head.
245THE NERVOUS SYSTEM
11
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AB
Fig. 11.18 (A) Radiograph showing skull fractures (arrows). (B) Skull base fracture in a baby showing Battle’s sign (bruising behind the ear),
indicating petrous bone skull fracture.
A depressed fracture, in which an area of skull is driven
inwards, needs to be repaired by a neurosurgeon.
Depressed fractures may tear arteries or the meninges,
leading to haemorrhage. Infection is a possible secondary consequence of skull fractures in which the scalp
is torn. Skull base fractures are difficult to see on X- ray
images. They are associated with physical signs such as
CSF bleeding through the nose (as there is communication with the nasal sinuses), bleeding into the middle
ear or Battle’s sign (bruising over the mastoid process,
Fig. 11.18B). Importantly, Battle’s sign takes 1–2 days to
appear, so although it is not helpful in acute diagnosis or
management of head injury it is useful as a clinical sign
for detecting skull base fractures.
Blows around the eyes may fracture the orbit. The
medial and inferior walls are paper- thin, and indirect
injuries that displace the orbital walls produce ‘blow- out
fractures’, which may involve damage to the air sinuses.
Orbital fractures often produce intraorbital bleeding, producing pressure on the eyeball and ‘black eyes’, as the
blood accumulates in the soft tissues around the eye.
Orbital fractures may damage the cavernous sinus and thus
the blood/nerve supply to the eye. The abducens nerve
and ICA run in its substance, and the oculomotor, trochlear, ophthalmic and maxillary nerves run in its lateral wall.
Infection can spread to the cavernous sinus via the ophthalmic vein as a result of such fractures.
Meninges
Bleeding in the spaces around the brain is a common feature of closed head injury. In trauma, bleeding may be
extradural, subdural or subarachnoid. Extradural and
subdural haemorrhages usually need to be evacuated
neurosurgically; if left untreated they are important causes
of death because they act as mass lesions (Box 11.9).
Extradural haemorrhage
Extradural haemorrhage (EDH) occurs in approximately
10% of severe head injuries and in up to 15% of fatal
head injuries. It is important to understand the anatomy
and natural history of EDHs, because if an EDH is not
diagnosed and treated, it will kill the patient. EDH is an
impact phenomenon. It occurs when a blood vessel running between the skull and the dura is torn, in association with a skull fracture. The blood vessel damaged is
either an artery or one of the large venous sinuses (the
veins are thin walled, with little muscle or elastic tissue
and no valves). In many cases, it is the middle meningeal
artery that is torn. This artery lies beneath the pterion,
where the skull is thinnest, and is relatively easily fractured by a blow to the side of the head. Although the
blood flow from the bleed may be rapid, EDHs accumulate slowly, usually over a period of hours, because the
dura strongly adheres to the inner aspect of the calvarium, and the enlarging clot slowly strips the dura from
the bone. The patient may appear to be lucid immediately after the injury and only becomes unconscious as
the haemorrhage enlarges and begins to press on the
brain (Fig. 11.20). Because there is so little reserve volume inside the skull, haematomas of more than 75 mL
are usually fatal; death is caused by a combination of
mass effect and raised intracranial pressure.
On CT or MRI images, EDHs appear convex (Fig. 11.23);
the bone sutures limit their spread because the dura mater
tightly adheres to the sutures and so they expand inward
toward the brain rather than along the skull margin.
246 SYSTEMS OF THE BODY
Box
Falx
Compression and
mass (tumour or
cerebellum
1. Subfalcine herniation.
2. Uncal herniation.
11.9
11
STROKE AND HEAD INJURY
The effects of a mass lesion inside the skull
The cranial cavity is subdivided by the relatively rigid tentorium and falx cerebri into three compartments, with limited
capacity to accommodate accumulations of blood or swelling
due to oedema without an increase in pressure. Differences
in pressure between two adjacent intracranial compartments,
or between an intracranial compartment and the spinal
canal, cause the brain to be displaced into the lower- pressure
compartment (i.e. internal herniation). Raised intracranial
pressure can also lead to external herniation of brain tissue
through a skull fracture or craniotomy.
There are three sites where herniation tends to occur (Fig.
11.19):
1. subfalcine – herniation of the cingulate gyrus under the
falx cerebri
2. tentorial – herniation of the uncus of the temporal lobe
through the tentorial notch
3. tonsillar – herniation of the cerebellar tonsils through the
foramen magnum and onto the respiratory and cardiac
centres of the medulla.
Apart from distorting and causing pressure on the brain,
internal herniation compresses blood vessels, leading to secondary ischaemic damage. Cranial nerves are often also compressed, causing focal neurological signs.
With herniation there is downward displacement of
diencephalic structures and descent of the brainstem,
resulting in buckling of the brainstem, with traction on the
external portions of the arterial supply and compression
of their internal parts. This creates foci of haemorrhagic
necrosis in the midbrain and pons. It is this brainstem
damage, along with the rise in intracranial pressure, that
leads to death.
midline shift of
lateral ventricle
Extradural
haemorrhage
caused by
skull fracture
Expanding
intracerebral
haemorrhage)
2
3. Tonsillar herniation.
Fig. 11.19 Schematic showing the neuroanatomical basis for brain
herniation syndromes. An increase in the volume of the contents in
the skull, such as a brain tumour or intracranial bleed, can cause brain
tissue to be displaced at one of the three sites shown.
cerebrum
Dura
1
Tentorum
CerebellumCerebellar tonsil
3
Subdural haemorrhage
Acute subdural haemorrhage (SDH) is completely different from EDH. It is principally caused by movement of
the brain and not by impact. The movement responsible is
acceleration, with or without deceleration. When the head
undergoes acceleration the inertia of the brain causes its
movement to lag behind that of the skull. This leads to traction on bridging veins running between the brain and dura
mater, which get torn. Blood from the ruptured vessels
spreads slowly and freely through the subdural space (an
artificial region within the dura created by the separation of
the arachnoid mater from the dura mater and not between
the dura mater and arachnoid mater, as its name suggests).
SDH can envelop the entire hemisphere (Fig. 11.21, upper
image) and may spread into the subarachnoid space below.
The bleeding tends to stop spontaneously. Sometimes, the
symptoms (headache, drowsiness and confusion) may take
days to months to become apparent. Because of the forces
involved in producing an SDH, there is very often damage
to axons in the underlying brain as well. This is in contrast
to an EDH, where the underlying brain tissue is not usually
severely damaged. If the blood is not removed, it will compress the brain tissue, leading to infarction.
SDHs are more frequent than EDHs and are common
findings in child abuse cases such as ‘shaken baby syndrome’. Acute subdural bleeds have a mortality rate of
60%–80% if left untreated. They are also common in chronic
alcoholics and the elderly, where cortical atrophy is common, increasing the tension on the bridging veins and thus
increasing the likelihood of damage with shearing forces.
On CT and MRI images, an SDH often appears crescent
shaped, with the concave side facing away from the skull,
and may also track along the dural folds (see Fig. 11.23).
Subarachnoid haemorrhage
Subarachnoid bleeding (SAH) is classified into traumatic
and non-traumatic (spontaneous) categories; the former
is more common than the latter. Traumatic SAH is almost
always insignificant and is seen on the surface of the hemispheres in relation to fracture sites or contusions. It most
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Fig. 11.20 Extradural haematoma (EDH). Top: an example of an EDH
caused by rupture of the middle meningeal artery. Bottom: effects of
an EDH on the underlying brain tissue, showing severe compression of
the left frontal lobe.
248 SYSTEMS OF THE BODY
Fig. 11.21 Two examples of subdural haemorrhage (SDH), where
blood distributes and collects over the surface of the front of the brain
(upper figure) or collects at the base of the brain (lower figure).