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13
Figure 13.11, after its release into the synaptic cleft, GABA
is transported into surrounding neurons and glial cells by
high- affinity transporters such as GAT1. It is then broken
down by GABA transaminase (GABA- T) to produce glutamate. Glutamate is metabolized to glutamine, which is
then transported back into the neuron or glia. GABA is
synthesized in neurons from glutamate, by the action of
glutamic acid decarboxylase (GAD). This shunt enables
the carbon skeleton of GABA to be returned to the neuron
via glutamine, which has no neurotransmitter action.
Two anticonvulsant drugs act on elements of this cycle
to increase GABA concentrations. Tiagabine blocks the
reuptake of GABA by the GABA transporter GAT1, while
vigabatrin is a selective irreversible inhibitor of GABA- T
(Fig.13.12). Sodium valproate can also inhibit GABA- T.
Both vigabatrin and tiagabine are used as adjunctive
therapy in partial seizures.
Other drugs
As illustrated above, the pharmacology of epilepsy is
complex and some of the compounds in present use may
have efficacy because of the multiple targets they affect.
For example, the same drug can inhibit voltage- gated ion
channels, act at the benzodiazepine site of the GABAA
receptor and suppress the release of monoamines! Which
component of such a spectrum is the most important
is not always clear and it may be that synergism is an
important concept in the design of new drugs. Some
other new drugs affect entirely new targets, for example,
levetiracetam (and more recently, brivaracetam), which
targets the presynaptic vesicle protein SV2A (blockade of
this protein may reduce the recycling of vesicles during
vesicle endocytosis), and perampanel, which acts as an
antagonist at AMPA receptors. Topiramate is a carbonic
anhydrase inhibitor. Zonisamide is a drug that blocks
sodium channels and also calcium T- type channels but
it may also have modulatory effects on GABAergic and
glutamatergic signalling. Fig. 13.12 summarizes the various types of drugs that modulate excitatory and inhibitory synapses and are used as anti-epileptic medication.
However, many of the diverse new second- generation
anti-epileptic drugs, although in general are better tolerated, have so far failed to show significantly more
efficacy than the established first- generation drugs.
This may be because new drugs are tested preclinically
on the same animal models as the old drugs, and such
models may be inadequate and fail to reveal new targets
with entirely new mechanisms of action. Furthermore, in
some cases, although the rationale for the new target is
sound, the drugs may induce unacceptable side effects.
General comments on anticonvulsant medication
The unwanted effects induced by anticonvulsant drugs
are numerous, and some of the drugs used to treat epilepsy can have significant drug interactions with other
drugs. Some do this by inducing metabolizing liver
enzymes, thus increasing the metabolism of other medications, including warfarin and the contraceptive pill,
as well as other anti-epileptics. Sodium valproate, used
in the case history given in Box 13.1, inhibits the liver
metabolism of some drugs, increasing their half- life.
Many of the drugs used to treat epilepsy are teratogenic, and this may determine the treatment given to
women patients who wish to become pregnant. A lower
dose of a safer drug and, in some cases, folate supplements and early screening for foetal abnormalities, are of
benefit.
Anticonvulsant drug concentrations can be measured
in the blood, and this is particularly useful in optimizing the dose of drugs such as phenytoin, which have a
relatively narrow therapeutic window before reaching
saturation kinetics. Knowledge of drug levels may also
be useful in assessing compliance, particularly in cases
where a patient is brought into hospital unconscious.
To conclude, different drugs are recommended for use
in patients with generalized or focal epilepsies (Table 13.4)
and some drugs are preferred in different age groups.
Characteristics of the ideal drug and strategy for
the treatment of epilepsy
The choice of a drug usually depends upon the patient’s
seizure type (see Table 13.4). The pharmacokinetic char-
acteristics, including absorption, elimination and potential for drug interactions (e.g. through potentiation or
inhibition of common metabolic pathways), are of critical importance for patients who also take medication for
other conditions, and for patients with impaired renal
or hepatic function. The ideal drug would have a rapid
absorption rate, low plasma protein binding, rapid CNS
penetration and be eliminated predominantly by the
kidneys. The new anticonvulsant drugs do not prompt
the same concerns about interactions, because they have
much better pharmacokinetic profiles than the older
drugs (such as phenytoin and carbamazepine) and therefore require less monitoring for potential interactions. The
potential interaction of anticonvulsant therapy with the
contraceptive medication used by a young woman with
epilepsy is illustrated in the case history given in Box 13.1.
The new anti-epileptic drugs, such as vigabatrin, gabapentin, lamotrigine, tiagabine and levetiracetam, do not
affect the metabolism of the contraceptive pill. However,
caution is warranted concerning the effects of these new
drugs on the foetus, as there is insufficient information to
determine whether they are teratogenic or not.
The goal of anti-epileptic therapy is to keep the
patient free of seizures, with no adverse effects on
brain function. However, many of the drugs used to
treat epilepsy have considerable side effects, both on
the CNS and on other organs. In order to ensure patient
compliance over what will probably be an extended
period of time (sometimes a lifetime), it is important
to test different drugs until a satisfactory drug regimen
is established. Usually, a patient will be given a single
EPILEPSY
289THE NERVOUS SYSTEM
13
Propagated
A
Excitatory synapse
Excitatory
EPILEPSY
Gabapentin,
Pregabalin
α2δ subunit of
L-type Ca
channel
Postsynaptic
neuron
presynaptic
terminal
2+
Felbamate
NMDA
receptor
Ca2+, Na
+
K
+
action potential
+
Na
Depolarization
Vesicular
release
Glutamate
Voltage-gated
Na
Na+ (Ca2+)
Phenytoin, carbamazepine,
valproic acid, felbamate,
rufinamide, lamotrigine,
lacosamide, topiramate,
zonisamide, oxcarbazepine
+
channel
SV2A
Topiramate
+
K
AMPA and kainate
receptors
Levetiracetam
Inhibitory synapse
B
Vigabatrin
Succinic
semi-
aldehyde
Postsynaptic
Fig. 13.12 Overview of the A) Excitatory synapse and B) Inhibitory synapse, indicating the mode of action of several major anticonvulsant
drugs. GAT1, GABA transporter; GABA- T, GABA transaminase; GAD, glutamic acid dehydrogenase; SV2A, presynaptic vesicle protein SV2A. (From
Bialer M, White HS. (2010) Key factors in the discovery and development of new anti-epileptic drugs. Nature Reviews Drug Discovery 9:68–82.)
neuron
GABA-T
GABA
Tiagabine
Succinic
semi-
aldehyde
GATI
GABA
receptor
A
Glutamate
GAD
GABA
GABA-T
Benzodiazepines
GABA
Inhibitory
presynaptic
terminal
-
Cl
Felbamate,
topiramate,
zonisamide
Barbiturates
drug (monotherapy) and the dosage varied until either
seizure activity is stopped or there are adverse effects.
Additional drugs should also be tried on a monotherapy basis, before they are added (if monotherapy
is ineffective). It is unusual to give more than three
290 SYSTEMS OF THE BODY
drugs simultaneously. Approximately 60% of patients
are controlled with a single drug. In other patients better results are obtained by adding a second and even
a third drug. If a patient still suffers seizures after
the addition of multiple drugs, this is referred to as
13
refractory epilepsy. Unfortunately, up to 40% of individuals suffer from this intractable, pharmaco- resistant
epilepsy (Box 13.4).
Other treatments for epilepsy
Surgery
In patients with focal epilepsy that cannot be adequately
controlled by drugs, surgical removal of the epileptic
focus may be possible if it is in an area of the brain that
can be removed without leaving a major neurological
Box
13.4
The phenomenon of pharmaco- resistance in epilepsy is
significant. There are at least four different types of drug
resistance: (1) resistance de novo or ab initio, where the
patient never experiences seizure relief, from the beginning of pharmacological management; (2) delayed resistance, when the patient experiences seizure reduction at
the beginning but then the treatment loses efficacy; (3) a
fluctuating pattern, where the treatment efficacy waxes
and wanes; and (4) the epilepsy is initially drug- resistant
but improves with time. More than 30% of patients with
epilepsy are pharmacological treatment- resistant. Fewer
than 5% of patients who are refractory to first- generation
anticonvulsant drugs are free of seizures with the newer
drugs. Intractability of seizures is associated with various factors, such as onset of seizures in the first year of
life, structural brain lesions (e.g. hippocampal sclerosis),
brain tumours and neurodevelopmental abnormalities.
Pharmaco- resistance is frequent in patients with focal seizures. Pharmaco- resistance may be due to genetic factors,
disease- related factors or drug- related factors. Genetic
polymorphisms in the drug target may underlie lack of
response to a drug. On the other hand, the resistance may
be due to the ongoing reorganization of neuronal networks triggered by the seizures. Disruption of the blood–
brain barrier and persistent neuroinflammation may play
a role. Last, but not least, drug uptake into the brain may
be drastically reduced by the overexpression of multidrug transporters in the blood–brain barrier, whose activity leads to significant drug efflux. One such transporter
is the P- glycoprotein, encoded by the MDR1/ABCB1 gene.
If this is the case, inhibitors of these transporters, or drugs
that are not substrates of these transporters, might be the
answer to the problem of resistance. Pharmaco- resistance
has been recently shown in experimental models to be
associated with changes in certain non-coding RNAs such
as specific microRNAs, which indirectly control protein synthesis. Novel oligonucleotide inhibitors targeting microRNAs (antagomirs) might become an innovative therapeutic
option in drug- resistant epilepsy.
Pharmaco- resistance in epilepsy
deficit. The area to be removed can be pinpointed using
MRI and EEG recordings. The aim of the surgery is to
obtain either complete freedom from seizures or amelioration of the seizure frequency. The types of epilepsy
most amenable to this type of treatment are epilepsy due
to MTS or tumours. Other rare surgical interventions
include separating the two hemispheres of the brain
by sectioning of the corpus callosum (callosotomy), in
order to prevent seizures becoming generalized to both
hemispheres.
Nerve stimulation
Vagus nerve stimulation is currently the most widely
used adjunctive therapy in pharmaco- resistant partial
epilepsy. Since its introduction in the late 1990s, it has
been used on thousands of patients worldwide. The left
vagus nerve is stimulated with electrodes that are connected to a pulse generator in the left part of the chest.
Intermittent stimulation of the nerve reduces seizure frequency by 50% in up to 43% of patients with pharmacologically refractory partial- onset seizures. However, in
some patients there is a delay of several months before a
beneficial effect can be seen. Transcranial magnetic stimulation or stimulation through scalp depth electrodes has
also been attempted with some success. A possible mode
of action is disruption of the neural patterns required to
initiate seizure activity, altering neurotransmitter levels
or increasing blood flow to key brain areas.
Closed- loop neurostimulation is a form of neuromodulation that provides therapeutic stimulation only when
necessary. An early application of closed- loop neurostimulation was for the treatment of refractory epilepsy,
when seizures were not adequately controlled by medication alone. Much like a pacemaker stops abnormal
heart rhythms, a closed- loop device aims to halt epileptic seizures by delivering stimulation when it detects the
beginnings of seizure activity. A programmable responsive neurostimulation brain implant for the treatment of
certain types of epilepsy received approval from the FDA
in November 2013. Studies have demonstrated favourable outcomes, with 53% median seizure reduction after
2 years and 70% median seizure reduction after 5 years.
Dietary approaches
The ketogenic diet is one of the oldest available treatments for epilepsy, and one of the most successful treatments for medically intractable epilepsy in children. It is
also effective in adult epileptic patients, but compliance
is less than that seen in children. The principle is based
on the physiology of starvation (fasting). The brain usually uses glucose as its preferred energy source but can
metabolize ketones under starvation. During extended
periods of fasting, ketones cover up to 60% of the human
brain’s energy consumption. In the ketogenic diet, carbohydrate intake is very limited and most of the calorie intake is in the form of fat. The metabolism of fat
EPILEPSY
291THE NERVOUS SYSTEM
13
leads to production of ketone bodies (ketogenesis): β-
hydroxybutyrate (>85% of circulating ketones), acetoacetate and acetone (not circulating, only found inside
EPILEPSY
cells). While on the diet children also receive vitamins
and minerals, in particular, calcium supplementation.
This diet was proposed more than 80 years ago and was
based on observations on the effect of fasting on epilepsy
that date back to the Middle Ages. Prospective and retrospective studies have repeatedly confirmed the efficacy,
tolerability and safety of this diet, but its mechanism of
action remains incompletely understood. Several potential mechanisms may underlie the efficacy of ketones in
epilepsy. Ketones reduce neuronal electrical hyperactivity through various mechanisms that ultimately stabilize
the resting neuronal membrane potential. They increase
ATP production, therefore they support the Na+/K+
ATPase activity and clearance of glutamate from the synaptic cleft. The increased production of ATP leads to a
concurrent increase in adenosine as a breakdown product, which has an inhibitory effect. β- Hydroxybutyrate
can activate certain voltage- gated K+ channels. In addition, acetoacetate can block vesicular glutamate transporters, thus ultimately depleting the presynaptic stores
of glutamate and reducing excitation. There is also some
evidence that ketones could increase the production of
GABA.
Treatment of this medical emergency is in three parts.
First, the patient must be given immediate resuscitation (ABC: Airway, Breathing and Circulation). Drugs
are then given to control the seizures and, finally,
identification and possible treatment of the underlying cause of the status epilepticus are required. Drugs
given initially are usually diazepam (or other benzodiazepines such as lorazepam). If these are ineffective at suppressing seizure activity, the barbiturate
phenobarbitone or the anticonvulsant phenytoin can
be used in large intravenous doses. If seizures continue, general anaesthesia using thiopentone should
be applied, with ventilation and intensive care
treatment.
lepsy. Their condition may be caused by a failure to take
their medication, which can be determined by measuring
drug blood levels. If this is the case, their normal medication should be resumed; otherwise, treatment should
be as for new cases. In patients with no previous history
of epilepsy, status epilepticus may be caused by several
factors, such as trauma, alcohol abuse, drug overdose,
tumours or stroke. Status epilepticus is a major risk factor for developing secondary epilepsy.
Treatment of status epilepticus
Some patients will have a previous diagnosis of epi-
Social consequences of epilepsy
There is still a significant social stigma associated with
a diagnosis of epilepsy. Social stigma is the term given
when a person’s social, physical or mental condition
influences other people’s views of them or their behaviour towards them. Members of the general public may
be uneasy with someone with epilepsy. This may possibly be overcome by informing them exactly what the
seizures entail, but, because of fears of rejection, many
epileptics try to hide their condition.
A diagnosis of epilepsy may have severe consequences
for a person’s present or future employment prospects.
Some jobs are completely inaccessible to people with epilepsy, such as the police and fire services, or the armed
forces. They also cannot fly aircraft or drive trains.
There are strict regulations governing whether a person with epilepsy can hold a driving licence. For example, in the UK, if you have had epileptic seizures with
loss of consciousness, you will lose the right to drive
and the licence will be revoked. You can reapply if you
have not had a seizure for at least a year. Further restrictions apply with regard to heavy goods vehicles and
passenger service vehicles. This directly limits the type
of occupation available to someone with epilepsy, and
depending on where they live and their need for a car as
a means of transport, it may limit their choice to jobs not
requiring a driving licence.
There are occupations that may be difficult for someone with poorly controlled epilepsy, such as teaching young children or working at height. There may be
reluctance among employers to employ someone with
epilepsy, because of fears that their customers or other
employees might be upset by someone having a seizure,
or that they may be held responsible if the epileptic person injures themselves during a seizure.
A person with epilepsy may be advised about the
dangers of certain leisure activities. Water sports and
climbing should not be done unsupervised, and riding a bicycle, particularly on the public highway, may
be dangerous. Simple measures, such as not locking the
bathroom door, may be advisable. Patients with photosensitive epilepsy may be advised to sit further away
from the television than normal and avoid computer
games with flashing lights. Stroboscopic disco lights usually operate at too low a frequency to induce seizures,
but highly sensitive individuals may be affected by
striped objects or Venetian window blinds.
A better future for epilepsy patients will depend on an
improvement in patient stratification and the ability to offer
personalized seizure management based on complex algorithms derived from accurate characterization of the cellular and molecular signature of the individual’s seizures.
This remains an overarching goal for this complex disease.
292 SYSTEMS OF THE BODY
13
Self- assessment case study
A 6- year- old girl has been observed by both her parents
and her teacher to have frequent ‘vacant’ spells during
class, when she stares into space and does not respond to
her name. Her parents take her to the general practitioner,
who immediately refers them to a local paediatrician.
At the hospital, EEG is performed, during which the
doctor asks the girl to hyperventilate for 3 min. This provokes one of the ‘spells’. She is initially prescribed sodium
valproate but this is changed to ethosuximide, which
prevents further seizures. Every few years she stops the
medication, but this provokes a return of her vacant spells
until she is 17 years old, when there is no recurrence.
After studying this chapter you should be able to
answer the following questions:
1. What type of epilepsy does she have?
She is likely to suffer from childhood absence seizures.
2. Why is she asked to hyperventilate during the EEG
procedure, and what will the EEG show?
Hyperventilation can act as a trigger of seizures in more
than 90% of cases of childhood absence seizures. The EEG
can show typical spike- and- wave pattern of discharges.
3. What are the possible reasons for changing her
medication?
She may have shown an incomplete response to
valproate. Ethosuximide is a highly specific drug used
for the management of absence seizures.
4. Why does she periodically stop taking her
medication?
In most cases, childhood absence seizures spontaneously
disappear, often by adolescence. This also proves the case
in this patient. Stopping the medication every now and
then helps to assess whether the condition has resolved
on its own.
EPILEPSY
293THE NERVOUS SYSTEM
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DEMENTIA
Chapter summary
1. Dementia is a term used to describe several conditions that are
associated with major impairment in cognitive function, in the ability
to interact with others and to plan and execute daily activities.
Most forms of dementia are progressive and have some genetic
determinant. This group of diseases includes Alzheimer’s disease
(AD), vascular dementia, dementia with Lewy bodies, frontotemporal
dementia, HIV- related dementia and Creutzfeldt–Jakob disease.
2. Memory is a key cognitive domain impaired in dementia. The cellular
mechanisms underlying learning and memory involve processes
such as long- term potentiation and long- term depression. These
have been characterized in structures such as the hippocampus,
cerebellum and amygdala. They are adaptations in the strength of
synapses, which are linked to significant changes in glutamatergic
signalling involving N-methyl-D-aspartate (NMDA) and 4-amino-3hydroxy-5-methyl-4-isoxazole propionic acid receptors. They underlie
neuronal plasticity.
14
3. AD is the most common form of dementia and is characterized by
major brain atrophy, a decline in brain metabolism and cholinergic
signalling and specific pathological features such as amyloid plaques
and neurofibrillary tau tangles. Symptomatic treatment is based on
acetylcholinesterase inhibitors such as donepezil, and memantine,
an NMDA receptor antagonist. There is intense focus on the
development of disease- modifying treatments that could directly
target amyloid and tau pathology. Such treatments could be based
on the use of vaccines against amyloid and tau aggregates.
4. Biomarkers of dementia have the potential to significantly change the
way conditions such as AD can be managed in the future. Biomarkers
can be based on measurements of specific compounds in cerebrospinal
14
DEMENTIA
fluid or plasma and can also be based on imaging, using ligands that
bind to markers of processes such as those involved with amyloid
and tau pathology. Biomarkers can help monitor disease progression
and response to treatment. As pathological processes in dementias
such as AD may be active for many years before clinical presentation,
biomarkers would enable more effective intervention at earlier stages
of the disease.
Introduction
Dementia is a generic term (from the Latin ‘demens’,
meaning ‘without mind, out of one’s mind’) for a range
of conditions that are characterized by a progressive and
irreversible loss of higher mental functions, general cognitive abilities and, in particular, memory, as reflected
in the presented case (see Box 14.1). As dementia is not
a single disease per se and can be a symptom of various diseases, the DSM- 5 has replaced the term ‘dementia’ with the category ‘major neurocognitive disorder’.
Cognitive decline in dementia is associated with other
significant alterations in mood and behaviour that lead
to complete disintegration of the personality. Dementia
progression can become a terrifying experience for both
patients and carers, although in many cases the patients
may not be as aware of their condition as their carers.
Dementia occurs mainly in the elderly, and patients
become progressively more dependent; it is the main
cause of disability among older adults and affects approximately 50 million people worldwide. Dementia was
a relatively rare occurrence before the 20th century, as
fewer people lived to old age in the preindustrial society.
Changes may be slow and insidious, and may be ignored
initially, so dementia may be at an advanced stage at the
time of diagnosis. There are several major types of dementia. Alzheimer’s disease (AD) is the commonest form of
dementia in the elderly, followed by dementia with Lewy
bodies, frontotemporal dementia and vascular dementia.
Dementia may also occur in younger patients, for example, secondary to other conditions such as in patients
infected with the human immunodeficiency virus (HIV).
Causes and diagnosis of dementia
Dementia leads to a gradual loss of cognitive function, without impairment of consciousness. Pseudo- dementia is a
form of impaired thinking that occurs in some patients with
severe depression. Certain types of dementia are also associated with very specific behavioural and personality changes
(e.g. moral disinhibition in frontotemporal dementia).
Dementia is distinguished from acute confusion by
several criteria (Table 14.1). In acute confusional states
the patient responds to some stimuli in a purposeful manner but is often disoriented, sleepy, inattentive
or agitated (delirium). Furthermore, there are often
Box
14.1
Seventy- eight- year- old Gary P. is seen by his general practitioner after his wife expresses concern about his condition.
He has gradually become very forgetful over the last 1–2
years. She says that he recently got lost when out shopping, even though they had lived in the same place for
years, and that at a recent family gathering he had not
been able to remember the names of some of the younger
family members. He has always managed the household
bills but recently she has taken over, as he complains that
‘things are getting too complicated’. He complains that
he cannot find things around the house because his wife
keeps moving them, which she denies.
and his physical examination is normal. He looks fit and
he takes no medication. He speaks fluently but makes frequent errors, either using incorrect words or substituting
made- up words instead. He can name three objects but
cannot recall them later. When asked the name of the current Prime Minister, he says ‘I’ve never met him’.
husband is developing Alzheimer’s disease, as his mother died
‘senile’ 20 years ago. She wants to know about any treatment
that could help him and slow down his mental decline.
1. How do you test for dementia?
2. Does this man suffer from dementia?
3. How are memories formed and maintained?
4. What is Alzheimer’s disease and what are its causes?
5. What is the treatment for dementia and can its
Case history
Gary has had no significant medical problems in the past
Gary’s wife is very anxious and asks the doctor whether her
This case gives rise to the following questions:
progression be stopped?
296
SYSTEMS OF THE BODY
14
DEMENTIA
Table 14.1 Differences between acute confusional states and
dementia
Criteria Acute confusion Dementia
Level of consciousness Impaired Normal
Course Acute/fluctuating Chronic/progressive
Autonomic dysfunction Present Absent
Prognosis Usually reversible Generally irreversible
autonomic disturbances (fever, tachycardia and sweating) and motor abnormalities (tremor and myoclonus).
A presentation of dementia may emerge in a variety of
diseases and syndromes with very diverse causes (Table
14.2). The degenerative/inherited types of dementia
are non-reversible. Other causes are either reversible
or can be partially reversed or halted with treatment.
Dementia can range in severity from mild, when a
patient may still be independent in a few activities, to
severe, when total dependence occurs. Mild cognitive
impairment is the term that describes the earlier phase
of symptomatic cognitive impairment that precedes
mild dementia, and is described in DSM- 5 as a ‘minor
neurocognitive disorder’.
Irrespective of dementia being of a primary or secondary nature, a key element in the diagnosis is the psychological testing of the patient. The criteria for dementia,
as defined by DSM- 5, include: (1) evidence of significant
cognitive decline from a previous level of performance
in one or more cognitive domains (learning and memory, language, executive function, complex attention,
perceptual- motor and social cognition); (2) the cognitive
deficits interfere with independence in everyday activities (at a minimum, assistance should be required with
complex instrumental activities of daily living, such as
paying bills or managing medications); (3) the cognitive
deficits do not occur exclusively in the context of a delirium; (4) the cognitive deficits are not better explained by
another mental disorder (e.g. major depressive disorder,
schizophrenia). Testing of the higher mental functions of
a patient involves examining their speech abilities and
requires appropriate attention, although some aspects
can be tested without speech. Patients also need to be
able to hear or read instructions.
Cognition is a generic term that defines all mental
processes that allow us to perceive and form a concept
of the world surrounding us. Cognition includes global
consciousness, orientation and attention, various aspects
of memory, executive function, execution of motor
sequences, perception and language. Cognitive function can be examined initially using standard tests such
as the Mini Mental State Examination (MMSE) (Table
14.3). This test is a simple method of scoring mental
performance and the maximum score is 30. However,
this test cannot detect small degrees of impairment and
results depend on the patient’s initial intrinsic cognitive
Table 14.2 Conditions associated with dementia
Degenerative/
inherited diseases Alzheimer’s disease
Frontotemporal dementia (Pick’s disease)
Dementia with Lewy bodies
Huntington’s disease
Wilson’s disease
Parkinson’s disease
Autoimmune disease Multiple sclerosis
Vascular causes Vascular dementia
Cerebral vasculitis
Space- occupying
lesions
Infection HIV- associated dementia
Traumatic Post head trauma
Toxic Cerebral anoxia (due to cardiac arrest,
Metabolic or
nutritional causes
Chronic hydrocephalus
Normal pressure hydrocephalus
Tumour
Chronic subdural haematoma
Creutzfeldt–Jakob disease
Abscess
Syphilis (now rare)
Postmeningitis
Postencephalitis
Punch- drunk syndrome (dementia
pugilistica)
respiratory failure or carbon monoxide
poisoning)
Alcohol and drugs (e.g. barbiturates)
Occupational exposure to toxins
Heavy metal poisoning
Hypothyroidism
Hypocalcaemia
Vitamin B12/folic acid/niacin deficiency
Thiamine deficiency (often in alcoholics)
leading to Korsakoff’s syndrome and
Wernicke’s encephalopathy
abilities. The MMSE is also weighted towards aspects
of memory and attention. Addenbrooke’s Cognitive
Examination (ACE) is a more recent test that addresses
some of the weaknesses of the MMSE. ACE is composed
of tests of attention, orientation, memory, language,
visual perception and visuospatial skills. The Montreal
Cognitive Assessment (MoCA) is another screening
method for the detection of cognition abnormalities. It
assesses short- term memory recall, visuospatial abilities,
executive function, attention, concentration and working memory, orientation to time and place, language and
THE NERVOUS SYSTEM
297
14
lA
Table 14.3 Mini Mental State Examination
Test Maximum score
DEMENTIA
Orientation
What is the year, month, day, date,
season?
Where are you (country, county,
town, hospital, ward)?
Retention
Name three objects and then repeat
these named objects
Calculation and attention
Count up in 7s five times or spell
‘world’ backwards
Recall
Recall the three objects named earlier 3 (1 mark per object)
Language
Show the patients simple objects
(e.g. a pencil and a watch) and
ask the patient to name them
Repeat the phrase ‘No ifs, ands, or
buts’
Give a three- stage command, e.g.
‘Take the paper in your right hand,
fold it in half and put it on the
floor.’
Read and obey the written command
‘Close your eyes’
Write a sensible sentence, with a
subject and a verb
Copy a picture (two intersecting
pentagons)
5 (1 mark per item)
5 (1 mark per item)
3 (1 mark for each object)
5 (1 mark for each correct
addition or correct letter)
2 (1 mark for each object
named)
1
3 (1 mark for each stage)
1
1
1
Box
14.2
Mild cognitive impairment (MCI) is an age- related syndrome that may be the precursor to Alzheimer’s disease
(AD). MCI is characterized by significant memory impairment in the absence of dementia. Patients with MCI have
memory deficits that are at least one and a half standard
deviations below the mean of the population. It is important to look for verbal memory impairment, since this
is one of the primary deficits in patients who progress to
AD. Impaired delayed recall is also a good predictor of progression to AD. MCI as a clinical entity is heterogeneous:
some patients with MCI may have very early AD, whereas
others may never progress to AD. However, in many cases,
MCI is a transitional stage between normal ageing and
AD, the annual conversion rate reaching 15%. It is important to identify which MCI patients will progress to AD. At
present, there is no reliable clinical method to determine
which patients will progress to AD and which patients will
not. In the future, the choice of appropriate AD biomarkers (Box 14.3) will help to identify such patients, who may
already have significant pathological changes in the brain.
MCI patients represent the most promising population of
patients for whom prophylactic treatment could be initiated very early on in order to delay the onset of AD.
Mild cognitive impairment—a
prodrome to Alzheimer’s disease
Contro
D
abstract reasoning. It is valuable for the detection of mild
cognitive impairment, a state that may represent a transition state between normal brain ageing and the development of dementia (Box 14.2).
Dementia is associated with structural changes,
for example, cortical atrophy, enlarged ventricles and
widening of the sulci, which can all be detected using
computed tomography (CT) and magnetic resonance
imaging (MRI) scans (Fig. 14.1)—the former being less
sensitive than the latter. Imaging can add to the specificity of diagnosis of certain subtypes of dementia. At the
same time, these techniques can also show the significant overlap between dementias: for example, AD can
be associated with white matter lesions revealed by MRI,
whereas vascular dementia can be associated with temporal lobe atrophy revealed by CT and MRI. Functional
MRI (fMRI) is a more recent technique that provides
information on blood flow and cerebral metabolism. It
provides better identification rates than MRI, and used
298 SYSTEMS OF THE BODY
expandingcontracting
Fig. 14.1 Neuroimage showing brain atrophy and ventricular
enlargement in a patient with Alzheimer’s disease (AD) compared
with an age- matched control. These are fluid- registered volumetric
MRI scans from a 60- year- old patient with AD (right) and a normal
age- matched control. (From Johns P. (2014) Clinical neuroscience,
Churchill Livingstone, Elsevier Ltd., Oxford.)
in conjunction with psychological testing it can enable
the location of function in the brain, monitor deficiencies and evaluate the effects of treatment. Both restingstate fMRI and task- related fMRI can reveal significant