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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2817_Библиотеки_им_академика_М_И_Перельмана.pdf
GDP
L
Adenylate
cyclase
phosphatases
A
2
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
1
2
3
4
5
6
R*
L
R*
GDP
L
R*
L
R*
L
R*
L
R*
β
α
γ
GDP
β
α
γ
β
α∗
γ
GTP
β
γ
GTP
β
α
γ
GTP
GDP+P
E
B
E
Ca2+Calmodulin-dependent
protein kinases
E
E*
α
Fig. 2.14 Diagram of second messenger pathways. (A) Pathway
+/−
Second
messengers
E
generating cyclic AMP (cAMP). (B) Pathway generating diacylglycerol
(DAG) and inositol 1,4,5- trisphosphate (IP3). PIP2, Phosphatidylinositol
4,5- bisphosphate; PKA, protein kinase A; PKC, protein kinase C.
subunit is bound, which can lead to a large change in the
concentration of second messengers. This is especially
i
true in the case of PLC- linked systems, as the second
ATP cAMP
Phospholipase C
PIP
2
Calmodulin
(CAM)
Protein
DAG PKC
IP
3
2+
Ca
stores
2+
Ca
PKA
messenger IP3 can itself release large amounts of Ca2+.
This amplification of the neurotransmitter signal can produce significant downstream biochemical changes in the
β
α
γ
E
neuron through the levels of protein phosphorylation by
activated kinases and phosphatases.
After activation of the receptor, the response of the
receptor to the ligand may be reduced. One mecha-
Fig. 2.13 Sequence of events associated with the activation of a
G- protein- coupled receptor. E, Enzyme; GDP, guanosine diphosphate;
GTP, guanosine triphosphate; L, ligand; Pi, phosphate; R, receptor; α, β
and γ, G-protein subunits; *, activated state.
nism that may be linked to this reduced response is the
internalisation of the receptor. Internalisation occurs in
several steps and may have different consequences. As
described in Fig. 2.15, the first step is the phosphoryla-
tion of the receptor by a specialised kinase—GPCRthe release of Ca2+ into the cytoplasm. Ca2+ can activate
both protein kinases such as PKC and protein phosphatases (see Fig. 2.14). It can do this either directly or, in
some cases, via a Ca2+- binding protein called calmodulin; in this case, the resulting Ca2+–calmodulin complex
activates the target protein. cAMP, DAG, IP3 and Ca2+ are
called second messengers, as they act within the cell. In
this context the neurotransmitter (ligand) is called the
first messenger, although this term is very rarely used.
An important aspect of signalling via GPCRs is that an
activated receptor may itself activate multiple G- proteins
before the ligand is removed. Additionally, each α subunit can bind to a single enzyme molecule, although the
enzyme activity is changed for the entire time that the α
associated kinase (GRK). The phosphorylation can lead
to fast desensitisation of the receptor. The phosphorylation can also be followed by the binding of a protein
called β- arrestin, which will trigger internalisation of the
receptor through clathrin- coated membrane pits. The β-
arrestin- bound receptor- ligand complex can trigger intracellular signalling through enzymatic pathways such as
those involving the mitogen- activated protein- kinase
(MAPK) system of phosphorylation cascades. The complex can also be diverted towards the lysosomal compartment, where the receptor and ligand are degraded,
or the receptor is dephosphorylated and recycled back
to the plasma membrane. Signalling can be triggered by
the internalized receptor through the endosome or the
49THE NERVOUS SYSTEM
2
Ligand
GPCR
Recycling
endosome
Lysosome
Recycling
Plasma
membrane
G
δ
AC
st
1
signaling phase
(from cell membrane)
Recycling
GRKs
Arrestin-mediated
MAPK signaling
nd
signaling phase
2
(from endosome)
OR
P
P
β-arrestin
P
P
Internalization
Clathrin-coated
pit
Early
endosome
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
nd
signaling phase
Lysosomal
degradation
Fig. 2.15 The dynamics of GPCR internalization and intracellular signalling. The receptor can be rapidly phosphorylated by a GRK, and β- arrestin
is rapidly recruited. The complex can then be internalized and directed towards the endosomal compartment and towards the trans- Golgi
network. During this internalization, GPCR can continue to be involved in signalling processes. GPCR, G- protein coupled receptor; GRK, GPCR
kinase; MAPK, mitogen- associated protein kinase; TGN, trans- Golgi network. (From Calebiro D, Godbole A. (2018) Internalization of G-proteincoupled receptors: implication in receptor function, physiology and diseases. Best Practice and Research: Clinical Endocrinology and Metabolism
32:83–91.)
trans- Golgi network—a major secretory complex which
directs proteins to various subcellular locations.
One of the consequences of GPCR activation is the
modulation of neuronal excitability. Many of the ion
channels present in neuronal membranes can, like many
intracellular proteins, have their properties changed by
2
(from Golgi/TGN)
Nucleus
altering their state of phosphorylation. This can determine the conditions under which they open and for
how long they open. GPCRs can lead to changes in the
level of channel phosphorylation. Changes in the opening of ion channels then influences whether a neuron
fires in response to the stimulus produced by ionotropic
Trans-Golgi network
(TGN)
Golgi
50 SYSTEMS OF THE BODY
2
receptors and other metabotropic receptors. In this way,
GPCRs affect the overall excitability of neurons and thus
their firing patterns. In some cases, it has been shown
that both α and βγ subunits can interact directly with ion
channels to modulate their activity, without the intervention of an enzyme or second messenger.
Neurotransmitter synthesis
The small ‘classical’ neurotransmitters (amino acids and
amines) are biosynthesized from precursors in reactions
catalyzed by enzymes present in the presynaptic terminal. For example, in the case of glutamate, it is synthesized either from glucose provided by the Krebs cycle or
from glutamine produced by glial cells. It is important to
note that glutamate is present in large amounts in the cell
and has different metabolic and neurotransmitter pools.
After biosynthesis, neurotransmitters are concentrated
in vesicles through an antiport system, for example,
transporting H+ out of the presynaptic storage vesicle in
exchange for the neurotransmitter. The high concentration of H+ in the vesicles is maintained by an H+- ATPase
in the vesicle membrane.
Peptide transmitters are manufactured in the cell body
as larger precursors, by ribosomes in the rough endoplasmic reticulum, and are processed and packaged via the
extensive Golgi system into vesicles that are transported
down the axon via anterograde transport. They appear
in the presynaptic terminal in large dense- core vesicles,
which are found further away from the synaptic cleft
than the small clear vesicles that contain neurotransmitters like the amino acids and amines. They are released
from the synapse when the frequency of action potentials
is high and the intracellular Ca2+ concentration reaches
higher values than under lower- frequency stimulation.
It is possible to trace the neurotransmitter pathways
in the brain by immunocytochemistry, using antibodies for the specific enzymes associated with a particular
neurotransmitter. For example, ACh is made from acetyl coenzyme A (acetyl- CoA) and choline by the enzyme
choline acetyltransferase (ChAT), and the presence of
ChAT can be used to identify neurons that synthesize
and release ACh.
Neurotransmitter inactivation
After release, enzymes present on the postsynaptic side
can inactivate neurotransmitters. ACh is inactivated by
enzymatic degradation within the synapse by acetylcholinesterase (AChE) at the neuromuscular junction or
other cholinergic synapses. The enzyme is found in the
folds of the postsynaptic membrane, located close to
the receptors. The esterase activity cleaves ACh into its
inactive components—choline and acetate. Choline is
then transported back into the presynaptic neuron by
an Na+- dependent choline transporter, where it can be
used to resynthesize ACh in combination with acetyl-
CoA derived from glycolysis. As well as the membranebound AChE, there are two soluble esterase enzymes.
One of these is another type of AChE, found in the
cerebrospinal fluid, and the other, called butyrylcholinesterase (BChE) or pseudocholinesterase, is found in
plasma. It is less substrate- specific than the AChE and
can hydrolyse a wide range of esters. Suxamethonium is
a commonly used, short- acting neuromuscular blocking
agent that is normally inactivated by BChE. However,
approximately 1 in 3000 individuals have an inherited
condition in which they have a modified form of BChE
that fails to metabolize suxamethonium. These mutated
forms are the consequence of various genetic mutations
in the BChE gene that are associated with loss of function. These individuals show neuromuscular paralysis
that lasts for several hours instead of a few minutes, and
hence will need to be ventilated until the suxamethonium is degraded. These variations in BChE may also
underlie increased susceptibility to the toxic effects of
organophosphorus compounds such as nerve agents,
which can be inactivated by non-mutated BChE.
Most classical neurotransmitters are de facto inacti-
vated—their action at their receptors is terminated by
their removal from the synaptic cleft by high- affinity
Na+- dependent uptake systems (also known as sodium
symporters). These transporters are found on neurons
and, in some cases, glial cells. The importance of these
mechanisms is highlighted by the fact that drugs that
inhibit neurotransmitter uptake can have profound
effects on brain function. Cocaine inhibits dopamine
uptake, which at least partly accounts for the euphoria
and addiction associated with the drug. More usefully,
tricyclic antidepressant drugs, which block the uptake of
serotonin and adrenaline (and also in some cases dopamine) and selective serotonin uptake inhibitors such as
fluoxetine (Prozac®) are widely used in the treatment of
depression, although the link between reuptake blockade and the long- term therapeutic effect is rather complex. The signals mediated by glutamate or GABA can
also be terminated by removal of these neurotransmitters through transporters such as the excitatory amino
acid transporter (EAAT) family, and GAT- 1, respectively.
Simple diffusion away from the synaptic cleft may also
be important in the inactivation of transported molecules, and is a mechanism of inactivation for peptide
neurotransmitters, in parallel with the action of specific
peptidases. As diffusion may be slow, this may explain
why peptide actions are more long- lasting that the effects
of transmitters such as ACh or monoamines. Finally,
removal of ligand- bound receptors by internalisation, as
discussed above, is another mechanism of termination of
the synaptic signal.
Summation and neuronal integration
Each neuron in the brain establishes tens of thousands of
synaptic contacts with other neurons. If a given input is
closer to the trigger zone of the neuron, then it is more
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
51THE NERVOUS SYSTEM
2
+5 excitatory inputs
+100
Membrane
A
Single Three (25 /s) Multiple (100 /s)
Force of
potential
(mV)
0
Threshold
contraction
RMP
−100
+
+ +
3 excitatory inputs
B
+100
0
RMP
−100
−
+ + +
1 inhibitory input
C
+100
+3 excitatory inputs
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
0
RMP
−100
−
+ + + + +
1 inhibitory input
Fig. 2.16 Integration of excitatory and inhibitory inputs. (A) Three
closely spaced excitatory inputs cause the neuron to exceed the
threshold and fire an action potential. (B) A single inhibitory input
prior to the three excitatory inputs prevents the neuron from firing. (C)
Increasing the number of excitatory inputs enables the threshold to be
reached and an action potential to fire.
likely to affect the firing of that neuron. This is often the
case with inhibitory inputs. If the firing frequency of the
input is high, then the EPSPs may summate to produce
an action potential (Fig. 2.16A), a process known as tem-
Fig. 2.17 Single twitch and summation of inputs produces tetanus in
skeletal muscle. The force of contraction in a skeletal muscle depends
on the frequency of firing of the motor nerve.
poral summation. If another synapse also contributes,
then the electrical potentials from all inputs summate in
spatial summation. If there is an IPSP, then this may prevent the action potential (see Fig. 2.16B). The number of
EPSPs would have to increase to overcome the inhibition
(see Fig. 2.16C). The density of a given type of receptor at
a given synapse will also affect the subsequent behaviour.
This spatial and temporal summation, along with the current electrical status of the neuron (i.e. how depolarized or
hyperpolarized the neuron is), will all determine whether
it fires or not. In most cases neurons will require the
simultaneous activation of a number of excitatory inputs
in order to fire, thus ensuring integration of signals.
Sometimes, the sum of the inputs will ensure firing
of the postsynaptic cell in all cases, but this seems to be
relatively rare. At the neuromuscular junction, firing of
the motor neuron releases so much neurotransmitter that
muscle contraction is always activated, although for a
large contraction it requires a high frequency of inputs,
as single twitches summate to produce a tetanus (Fig.
2.17). In the cerebellum, inputs from a climbing fibre
always cause the firing of the large PC that it innervates.
The cerebellum is involved in the acquisition and refining of motor patterns, and this climbing fibre/PC signal
is activated when an error of execution occurs.
Finally, beyond the temporal and spatial integration
which is a fundamental characteristic of the function
of local neuronal circuits, there is now awareness of a
higher level of integration of signals between neuronal
populations in different regions of the brain, based on
the ‘connectome’—the whole network of structural connections in the CNS. The present goal of the study of
the connectome is to deepen the understanding of the
dynamics of the cerebral networks that underlie normal
function and neurodevelopment and analyse how these
networks are disrupted very distinctly by pathological
processes that characterize specific diseases.
52 SYSTEMS OF THE BODY
CLINICAL ASSESSMENT
Chapter summary
1. The clinical examination consists of several parts: gaining the
patient’s consent, taking a history (presenting complaint and
medical, drug, family and social histories) and then performing the
relevant component parts—the neurological examination, mental
state examination and clerking the observations.
2. Major common clinical laboratory techniques that can provide
additional or confirmatory information relevant to the clinical
examination include neurophysiological, medical imaging,
biochemical, immunological, microbiological and haematological
tests.
3
3
Introduction
A clinical examination has three components: the history,
the examination and the explanation, where the doctor
discusses the nature and implications of the clinical findings. A patient seeks medical help for three main reasons:
diagnostic purposes, treatment or reassurance or a combination of these factors. The foundation of the patient–
doctor relationship is based on establishing a good
CLINICAL ASSESSMENT
rapport during the history taking and the examination.
Although increasingly sophisticated tests are available to support the diagnostic process in neurology and
psychiatry, the history and clinical examination remain
the core of the assessment of a patient who suffers from
some form of damage to, or dysfunction of, the nervous
system. The important point is to be systematic. This
chapter aims to provide a brief overview of the essential points of the clinical examination and to describe
the main additional laboratory- based investigations that
may help in the formulation of a diagnosis.
The clinical examination is preceded by obtaining
the patient’s consent to perform the assessment. This is
best done by introducing oneself, explaining who you
are and what you do and asking permission to talk with
them and examine them. Additionally, clues as to the
potential issues can be gained by general observation of
the patient as they enter the consulting room or at the
patient’s bedside, for example, the use of aids such as
hearing aids, crutches, walking sticks etc., whether they
appear unwell and observation of any obvious physical
signs, such as muscle atrophy, abnormal gait or scars.
These may provide clues to the experienced clinician of a
preliminary diagnosis.
Next comes the taking of the patient’s history; this
provides essential information about the possible aetiology of the disease. It is the most important part of the
clinical assessment, during which, the following information is obtained about the patient: age, gender, race,
occupation and handedness. It comprises several parts:
history of the present complaint (e.g. onset, is it sudden or gradual; nature and distribution, is it uni- or
bilateral; symptom onset/frequency), past medical history (including past and/or present drug treatment and
associated conditions like diabetes, hypertension), family history and social history. For example, the temporal
evolution of the problems that the patient is experiencing provides important clues as to their nature. An acute
onset is characteristic of trauma or a major vascular accident. Development over days may suggest an inflammatory component. Neoplasms develop, in general, over
months or years. Neurological problems resulting from
an immune mechanism, such as multiple sclerosis, also
have an evolution over months and years, with a pattern
of relapse and remission. Neurodegenerative diseases,
such as Parkinson’s disease, motor neurone disease or
Alzheimer’s disease, develop inexorably over years.
In some cases, if the patient presents with an impaired
state of consciousness, either transient (e.g. seizures)
or chronic (e.g. dementia), a complete history of the
patient’s problems will require involving others, such as
relatives, carers or the general practitioner. Psychiatric
histories are often more detailed, as more detail is
needed about the patient’s personal life, family and
social background (e.g. siblings and ‘family’ illnesses,
home circumstances, diet, smoking status, drug and alcohol history and sexual orientation and history).
A general physical examination is performed. This is
important, as systemic disease may lead to neurological complications (e.g. links exist between atherosclerosis and stroke, cancer and cerebral metastases, diabetes
and peripheral neuropathy and rheumatoid arthritis and
cervical cord compression). The whole of the clinical
examination is performed gently, tactfully and with
consideration for the patient, who may be surprised or
intimidated by some of the questions or procedures that
are part of the examination, or may perceive them as
completely unrelated to the complaint. Avoid using medical jargon, using instead simple explanations and common language, building the patient’s trust and gaining
their confidence, thus making the examination as participatory and interactive as possible.
There is no absolute ‘gold standard’ way to perform
a neurological examination, and methods vary between
clinicians, hospitals and countries. However, any basic
neurological clinical examination includes an evaluation
of the follwoing: (1) mental state, (2) sensory systems,
(3) cranial nerves, (4) motor system and reflexes, (5) coordination, (6) gait and (7) cortical function.
A general practitioner of medicine could carry out
a first assessment of this type before involving a specialist. For diseases in the field of psychiatry, such as
depression or schizophrenia, more specialized tests
and rating systems may be required, as mentioned in
the corresponding case analyses discussed in this book.
It is also important to note that the autonomic nervous
system is not tested directly during the examination.
However, the patient may present with complex indirect
signs and symptoms of dysfunction in the sympathetic
or parasympathetic systems (e.g. postural hypotension, constipation or faecal incontinence, urinary retention or incontinence, pupillary immobility, disturbances
of sweating or erectile failure). If required, the Valsalva
manoeuvre is the gold- standard test used to assess the
integrity of the autonomic nervous system. It requires
the patient to take a deep breath and, while pinching
the nose and keeping the mouth closed, to try to exhale
against a resistance of 40 mmHg for 15 seconds. During
this test, the heart rate increases, and then returns to normal once the subject breaths normally.
After the clinical examination, a series of laboratorybased investigations may be required in order to obtain
information that the clinical examination cannot reveal.
Inconsistencies in the history or examination should
make one think about the possibility of a functional nonorganic disorder.
54
SYSTEMS OF THE BODY
3
Component parts of the clinical
examination
Mental state
The mental state examination is the psychiatric equivalent of the physical examination. It is a thorough and systematic evaluation of the emotional and mental state of a
patient carried out as an interview. The following areas
must be assessed:
• appearanceandbehaviour
• speech
• mood
• thoughtcontent
• abnormalexperiencesandbeliefs
• cognitivestate
The time devoted to each component depends on the
patient’s answers and the diagnostic possibilities; much
of this information is gathered through observation and
interaction with the patient during the history taking and
the initial general physical examination.
The patient’s appearance can often reveal much about
an underlying psychiatric disorder. Important points
to look for include dress, personal hygiene and general
grooming. The general appearance and demeanour of
the patient may suggest self- neglect, depression or anxiety. The latter may also be revealed by hyperventilation
or sweating. The way in which a patient sits also gives
important hints to a possible underlying pathology; are
they relaxed and at ease or sitting tensely and fidgeting?
The agitated depressive or the excited manic or schizophrenic may be so agitated that they get up from the
seat and pace around the room. A demented or confused
patient may leave the chair because they do not understand what is going on. The presence of delusions of persecution may lead the patient to feel threatened by the
proceedings and to become angry or terminate the consultation. Alternatively, patients may appear to drift off
to sleep repeatedly, suggesting either a confusional state,
with fluctuating levels of consciousness or over- sedation
due to existing medication.
The patient’s behaviour during the interview may
be disinhibited, as in the manic patient who strips;
the patient may be manipulative or seductive and
may threaten violence if their wishes are not met.
Alternatively, the patient may appear unduly submissive or self- critical or make little or no eye contact with
the interviewer. They may appear suspicious of questions due to an underlying personality disorder or paranoid illness. The patient may also appear inattentive to
the interviewer or to be listening to someone else when
there is no one else in the room; this suggests that they
are experiencing auditory hallucinations. Undue terror
without any obvious cause or attempts to touch or shoo
away non- existing objects suggests that the patient is
experiencing visual hallucinations.
Gradually, the clinician can also assess whether the
patient is confused or, on the contrary, has good insight
into their condition. Assessment of drug/alcohol use and
social and family circumstances should also be considered. It must be remembered that bizarre behaviour or
inability to relate to the interviewer may reflect subnormal intelligence.
Speech is a form of behaviour, and thus it is important to assess its production, form and content. Does
the patient speak at all or are they mute, and if so, is
this deliberate, organic or part of a depressive stupor?
In a mute patient, it is important to assess all aspects
of speech production, including the ability to produce
sounds and communicate non- verbally. If the patient
does speak, is this spontaneous or only in answer to
questions, with monosyllabic or fuller and more elaborate replies, or is the patient vague and evasive? Is
speech unduly slow, as in depressive illness, or so quick
and continuous that it is impossible to interrupt, as in
hypomania and mania? A sudden change in verbal style
may indicate an emotionally sensitive subject requiring
further questioning. Language production is related to
handedness; dysphasia (difficulty in verbal communication) is a feature of dominant hemisphere dysfunction
(see Chapter 1).
Mood has both a subjective component, which is
reflected in the way the patient describes their emotional
state, and an objective component, that is, what the interviewer sees. The subjective and objective components
of mood are usually, but not always, congruent. Facial
expression is one of the outward signs of the patient’s
mood. For example, tearfulness or poverty of expression in depression, elation in mania, tenseness in anxiety
and perplexity in schizophrenia are observed. The emotional expression may be abnormally labile, as in mania
or organic brain disease. A patient’s mood can be probed
using direct questions, for example, ‘How have you been
feeling lately?’ Psychiatric symptoms (e.g. paranoid
delusions or profound thought disorder) may become
apparent during the conversation with the patient.
Abnormal moods most commonly include depression
and anxiety; they also include elation, irritability, anger
and perplexity. When the mood is abnormal, it should
be evaluated in detail, in the same way as any other presenting symptom. Some severely depressed patients may
see no future, feel despairing and hopeless and have suicidal thoughts. Suicidal ideation must always be sought
for in depressed patients, and it is also appropriate to
ask about suicidality in those with other disorders such
as schizophrenia, alcohol dependence, hypomania and
severe anxiety disorders. Not only is it incorrect to think
that discussing suicide with patients encourages them
to commit suicide, but failure to discuss it may lead to
tragedies that could have been prevented. Intent to commit suicide can be probed with questions such as ‘Is life
worth living nowadays? Have you seriously contemplated ending it all?’
CLINICAL ASSESSMENT
THE NERVOUS SYSTEM
55
3
The patient should be asked what their main worries
are and whether they are preoccupied by any thoughts,
for example, morbid thoughts. Obsessional ruminations
are stereotyped thoughts that the patient recognizes as
their own and realizes are silly but unsuccessfully tries to
resist. They occur in obsessive- compulsive neuroses and
may be associated with obsessional rituals, that is, acts
that the patient feels compelled to carry out, even though
they recognize them as being absurd, for example, compulsive hand washing because they ‘feel dirty’. For
CLINICAL ASSESSMENT
obsessional rituals, the patient realizes that the compulsion comes from within, unlike delusions of influence, in
which the impulse is felt to come from outside forces.
Perceptual abnormalities most often take the form
of hallucinations or delusions. Patients suffering delusions have a false and unshakeable belief that is out of
keeping with the social milieu from which they come.
Hallucinations are apparently normal perceptions that
occur in the absence of an appropriate stimulus. In psychiatric illness, hallucinations occur in organic and functional psychoses, for example, in schizophrenia and
affective illnesses, cases of severely raised levels of anxiety due to hyperventilation, grief reactions and hysterical illnesses. Illusions occur when the object is real but
perception is disturbed. They are usually related, in the
psychiatric sense, to disorders of the perceptual environment of the object, thereby leading to decreased visual
clarity coupled with a state of high emotion in the perceiver. Illusions are common in psychiatric illness, particularly acute confusional states. In affective disorders,
the content of any hallucinations or delusions is generally mood- congruent. Depressed patients may think that
they are evil, while manic patients may believe that they
are God.
Impaired concentration is a characteristic sign of
depression; it also occurs in dementia and acute confusional states. Cognitive function can be assessed using
the Mini Mental State Examination (see Table 14.3). It
includes several components: the level of consciousness,
the orientation in time and place, general appearance,
mood, interaction with the examiner and attention and
memory.
Cranial nerves
Abnormalities in cranial nerves may occur in isolation
and involve one nerve only or may affect several nerves.
Assessment aids lesion localisation and in an unconscious patient can give prognostic information.
Cranial nerve I (olfactory)
The olfactory nerve is tested by exposing the patient to
a range of scents (e.g. cinnamon, cloves, vanilla, tobacco
mint, oranges or coffee). With the patient’s eyes closed,
each nostril is alternately occluded, while the other nostril is tested. Odours that produce irritation are avoided
(e.g. ammonia). It is also important to note that anosmia
(loss of the sense of smell) may not have a neurological
cause but be simply due to a sinus inflammation
(catarrh), which may be linked to an infection. Anosmia
is an important symptom of SARS- CoV- 2 viral infection
(which causes COVID- 19). Olfactory hallucinations may
be associated with epilepsy. Testing of this nerve is not
routinely performed but is carried out when patients
report a decrease in their sense of taste or smell. It is also
performed in patients with suspected dementia and in
patients with tumours or fractures through the cribriform plate of the skull or damage to the nasal passages,
where there may also be associated optic nerve or frontal
lobe damage. Loss of the sense of smell may significantly
affect the sense of taste.
Cranial nerve II (optic)
Testing of the optic nerve starts with an assessment of
the patient’s ability to read printed material with each
eye separately, that is, visual acuity using a Snellen chart.
Testing consists of a series of letters whose sizes are such
that the biggest letter can be seen at a distance of 60 m,
whereas the smallest can be seen with normal vision at
5 m. If the patient wears glasses, the type of lens worn is
determined in order to differentiate between myopia and
hypermetropia. Acuity at the normal reading distance is
also assessed. The visual fields are then tested by moving an object (usually the examiner’s finger) into the four
visual quadrants. The left and right eyes can be tested
together at first (binocular vision), and then monocular
testing can be performed. Any subjective visual sensations are also noted, for example, visual hallucinations
or white flashes in the visual field. Fundoscopic examination of the retina can detect the possible presence of
papilloedema, suggesting raised intracranial pressure,
and retinal haemorrhages, which may occur in diabetics
or hypertensives. Colour blindness, although not regularly tested, is assessed using Ishihara plates, in which
a series of coloured spots contain numerical shapes that
the patient must identify.
Cranial nerves III (oculomotor), IV (trochlear) and
VI (abducens)
The examination of these three nerves assesses eye
movements and pupillary function. The examiner first
notes the position of the eyes during gazing straight
ahead (where a squint or strabismus could become
evident), and then assesses any symmetrical or asymmetrical change in the movement of the eyes when
performing specific tests. Visual tracking is tested by
assessing the convergence response (depth of focussing),
smooth pursuit is tested by observing the conjugate eye
movements in response to drawing an imaginary letter
‘H’ and peripheral fields are tested by confrontation testing. Saccade responses (fast conjugate eye movements
that shift the eyes between different targets) are assessed
by asking the patient to rapidly and alternately fixate on
the examiner’s hands (e.g. thumb of one hand and finger of the other) several times in quick succession. The
patient should be specifically asked for the presence of
56 SYSTEMS OF THE BODY
Looking to the right
Looking to the left
3
CLINICAL ASSESSMENT
Fig. 3.2 Example of Horner’s syndrome (left eye). Note the slight
drooping of the patient’s left eyelid and asymmetry of the pupils; the
left is slightly smaller than the right.
tion. Drugs such as morphine and atropine can also alter
pupillary size. A small pupil can be part of Horner ’s
syndrome (Fig. 3.2), which may be due, for example, to
a carcinoma impinging on the superior cervical ganglion
or to damage to the sympathetic pathways anywhere
along their cranio- cervical course.
Fig. 3.1 Left oculomotor nerve lesion. Note the inability of the
patient’s left eye to adduct on command to look right. It deviates
laterally due to the unopposed action of the lateral rectus muscle
(innervated by cranial nerve six).
any diplopia (double vision) on looking in particular
directions. A lesion to cranial nerve III may lead to deficits of adduction (Fig. 3.1), depression or elevation of the
eye and unilateral ptosis. A lesion of cranial nerve IV will
result in deficient abduction and in the medial deviation
of the eye. A lesion in cranial nerve VI leads to a deficit
in the internal rotation of the eye and failure to abduct.
Examination of the pupils involves assessment of the
size, shape and mobility of the pupils, and the accommodation reflex response (see Chapter 6). Slight asymmetry
between pupillary sizes occurs in up to 20% of people.
The pupillary light response (direct and indirect) is also
performed (see Chapter 6). Painful third nerve palsy
can be a sign of an intracranial aneurysm (enlargement
of an artery due to weakening of the arterial wall) pressing on the third nerve. Diabetic neuropathy and atherosclerosis can also cause pupillary dysfunction. A fixed,
dilated pupil in a person with a mass lesion (e.g. tumour)
can occur when the intracranial pressure has reached the
point where the brain starts herniating to compress the
third nerve. It is a sign of impending death in that situa-
Cranial nerve V (trigeminal)
Examination of this nerve involves assessment of the
normal functioning of each of its three divisions: ophthalmic, maxillary and mandibular. Lesion of the whole
nerve leads to a loss of sensation in the skin and mucous
membranes of the face and nasopharynx. Sensory testing
involves assessing the response to light touch and pinprick. The presence and symmetry of the corneal reflex
(Chapter 6) are also tested. Motor function is assessed by
asking the patient to clench their teeth (to check the masseter muscle), as well as testing the strength of the masticator muscles by asking the patient to open the mouth
against resistance.
Damage to the motor division produces muscle wasting, which is most easily seen in the temporalis muscle
(above the zygomatic arch). In addition, the mandible
deviates to one side (indicating pterygoid muscle weakness on the side of nerve damage) rather than travelling
vertically (normal) on opening and closing the mouth.
The jaw- jerk stretch reflex (see Chapter 6) of the jawclosing muscles (masseter and temporalis muscles) is
weak or absent in normal subjects. Brisk or exaggerated
jaw jerks often indicate bilateral lesions of upper motor
neuron pathways.
Cranial nerve VII (facial)
The patient’s face is inspected, looking for symmetry
of movement—which is a key element in the testing of
the facial nerve—when asked to perform specific movements, for example, eyebrow elevation, smile or show
the upper teeth or blow out the cheeks. Several other
manipulations can also reveal facial nerve dysfunction;
for example, the patient may find it difficult to whistle.
57THE NERVOUS SYSTEM
3
CLINICAL ASSESSMENT
Fig. 3.3 Patient with left facial nerve palsy being asked to shut his
eyes and grimace.
Lesions above the facial motor nucleus (located in the
pons) cause supranuclear palsies, whereas lesions distal
to the nucleus cause infranuclear (nerve) facial palsies.
The ability to wrinkle the forehead is used to distinguish
between upper and lower motor neuron damage to the
facial nerve (Fig. 3.3), since the forehead muscles are
bilaterally innervated by the corticobulbar tract, whereas
the lower facial muscle motoneurons only receive a contralateral bulbar input (see Fig. 9.9). Supranuclear paralysis affects mainly the lower part of the face, whereas
infranuclear palsies affect both parts of the face. The latter, but not the former, cause atrophy of the facial muscles. This is because the upper part of the face receives
bilateral innervation from both facial nerves, unlike
the lower part. The sensory component of this nerve is
examined by assessing the response of the anterior twothirds of the tongue to sweet, salty or sour solutions (on
both sides).
Cranial nerve VIII (auditory and vestibular)
Hearing tests assess the auditory component of cranial nerve VIII. Hearing is tested by blocking one ear
while testing the hearing in the other ear by whispering or varying the intensity of speech. This is followed,
if necessary, by Weber’s and Rinne’s tests, which are
tests of hearing involving the use of a tuning fork (see
Chapter 8). The examiner also notes abnormal sensa-
tions (e.g. hyperacusis or tinnitus, although the former
can indicate a lesion of the facial nerve). Vertigo (a sensation of spinning) and nystagmus (involuntary eye
movements) reflect dysfunction in the vestibular component (although opticokinetic nystagmus in response
to normal object tracking can occur physiologically).
Vertigo can be associated with the patient’s sensation
that objects move around them. Nystagmus and vertigo
can also be induced by sudden changes in head posture.
Caloric testing, Hallpike’s manoeuvre and Romberg’s
test may also be useful in aiding the investigation of
vestibular dysfunction (see Chapter 8). A vestibular
Schwannoma (acoustic neuroma) is a type of VIIIth
nerve tumour that presents initially with only mild
hearing loss.
Cranial nerves IX (glossopharyngeal) and X (vagus)
These nerves are tested functionally by observing the
quality of speech and coughing, and monitoring taste,
swallowing and the position of the palate at rest. The
movement of the palate is also assessed during voluntary
or reflex activity. Damage to the glossopharyngeal nerve
is associated with loss of taste in the posterior part of the
tongue. Lesions of the vagus nerve lead to swallowing
(dysphagia) and voice (dysphonia) problems for example, a hoarse, deep voice, blurred and ineffectual speech
and a displaced uvula. The last of these is assessed by
asking the patient to say ‘Ah’, and observing the movement of the soft palate and uvula. Damage to either
nerve results in loss of the gag reflex.
Cranial nerve XI (spinal part of the accessory
nerve)
These nerves are tested by assessing the weakness or
wasting of the innervated muscles (upper trapezius
and sternocleidomastoid) by asking the patient to shrug
their shoulders and turn their face to each side against
resistance.
Cranial nerve XII (hypoglossal)
This nerve supplies the tongue muscles. If this nerve or
its nucleus is damaged, a deviation of the tongue to the
side of the lesion can be seen, as well as wasting and
fasciculation of the tongue on the same side when the
tongue is protruded (Fig. 3.4).
Motor function
Examination of motor function involves the assessment
of the following:
• musclebulk
• presenceofinvoluntarymovements
• muscletone
• musclepower
• reflexes
• coordination
• gait
58 SYSTEMS OF THE BODY