Clinical Pharmacy and Therapeutics - Book 1

EPILEPSY 31

Table 31.5 Examples of drug interactions involving antiepileptic drugs

Drug affected Effect on serum level Drug implicated Possible mechanism
Carbamazepine Increase Enzyme inhibition
Valproate sodium
Decrease Cimetidine Enzyme induction
Dextropropoxyphene Enzyme inhibition
Erythromycin Enzyme induction
Isoniazid Enzyme inhibition
Troleandomycin Enzyme induction
Danazol Enzyme inhibition
Phenytoin, phenobarbital Enzyme induction
Enzyme inhibition
Ethosuximide Increase Valproate sodium
Decrease Carbamazepine Mechanism unclear
Enzyme induction
Lamotrigine Increase Valproate sodium
Decrease Phenytoin, carbamazepine Decreased responsiveness of renal
tubules. Increased osteomalacia
Phenobarbital Increase Valproate sodium Displacement from protein binding
Decrease Rifampicin sites and possible enzyme inhibition
Enzyme induction
Phenytoin Increase Valproate sodium Enzyme induction
Chloramphenicol Enzyme induction
Decrease Isoniazid
Disulfiram
Fluconazole
Flu vaccine
Amiodarone
Fluoxetine
Phenobarbital
Rifampicin
Carbamazepine
Furosemide
Acetazolamide

Sodium valproate Increase Salicylates

Topiramate Decrease Phenytoin, carbamazepine
Zonisamide Decrease Potential enzyme inducers

Decrease Carbamazepine, phenytoin,
phenobarbital and primidone

Gabapentin Lacosamide

Gabapentin is occasionally used as a second-line treatment Lacosamide, a functionalised amino acid, is a second-line drug for
of focal seizures. Although initially developed as an AED, its
main use currently is for the treatment of neuropathic pain. It focal epilepsy in people older than 16 years. Its putative mode of
exerts its effect through blockage of high-voltage activated cal-
cium channels. In view of its pharmacokinetic proile, a three action is not shared with any other currently available AEDs. It
times daily dosage must be used; the usual dosage is 0.9–3.6 g is said to enhance the slow inactivation of sodium channels and
daily. It should be started with 300 mg once daily on day 1, to modulate collapsing response mediator protein-2. The mainte-
then 300 mg twice daily on day 2 and then 300 mg three times
a day on day 3. To date, no clinically signiicant interactions nance dosage is 100 mg twice daily, and the maximum dosage is
with other AEDs, or other drugs, have been reported. The most 200 mg twice daily. It should be started at 50 mg twice daily and
frequently reported side effects are drowsiness, dizziness, increased by steps of 50 mg twice daily in weekly intervals. No
diplopia, ataxia and headache. Idiosyncratic effects include drug interactions are known. Its commonest side effects are dizzi-
increasing seizures.  ness, headaches, nausea and diplopia. No idiosyncratic side effects

have yet been associated with this drug. The drug should be used
with caution in people with a history of cardiac conduction prob-
lems because it is known to increase PR intervals in some people. 

535

31 THERAPEUTICS

Table 31.6 Side-effect profile of antiepileptic drugs

Drug Dose related (predictable) Non-dose related (idiosyncratic)
Brivaracetam Drowsiness, dizziness, fatigue, nausea, ataxia, irritability Not reported

Carbamazepine Diplopia, drowsiness, headache, nausea, orofacial dyskine- Photosensitivity, Stevens–Johnson syndrome, agranulocy-

sia, arrhythmias tosis, aplastic anaemia, hepatotoxicity, teratogenicity

Clobazam Fatigue, drowsiness, dizziness, ataxia, irritability, hypersali- Rash
vation, weight gain, psychosis

Clonazepam Fatigue, sedation, drowsiness, ataxia Rash, thrombocytopenia

Eslicarbazepine Fatigue, drowsiness, diplopia, hyponatraemia, ataxia, Not reported
nystagmus, tremor

Ethosuximide Nausea, vomiting, drowsiness, headache, lethargy Rash, erythema multiform, Stevens–Johnson syndrome,
aplastic anaemia

Gabapentin Drowsiness, fatigue, diplopia, ataxia, headache Increased seizures

Lacosamide Nausea, vomiting, dizziness, headache, drowsiness, depres- Not reported
sion, diplopia, impaired memory, impaired coordination,
tremor, fatigue, asthenia, pruritus

Lamotrigine Headaches, drowsiness, diplopia, ataxia, tremor, insomnia Rash, liver failure, Stevens–Johnson syndrome, aplastic
anaemia, toxic epidermal necrolysis, pancytopenia

Levetiracetam Dizziness, drowsiness, irritability, behavioural problems, Not reported
insomnia, ataxia headache, nausea

Oxcarbazepine Diplopia, ataxia, fatigue, hyponatraemia, headache, nausea, Rash
confusion, vomiting

Perampanel Drowsiness, ataxia, lethargy, blurred vision, weight gain Not reported

Phenobarbital Fatigue, listlessness, depression, poor memory, impotence, Maculopapular rash, exfoliation, hepatotoxicity, teratoge-
irritability, hypocalcaemia, osteomalacia, folate deficiency nicity, Dupuytren’s contracture, frozen shoulder

Phenytoin Ataxia, nystagmus, drowsiness, diplopia, asterixis, orofacial Blood dyscrasias, rash, Dupuytren’s contracture, hepato-

dyskinesia, folate deficiency toxicity, gingival hyperplasia, acne, coarse facies, hirsutism

Pregabalin Dizziness, ataxia, weight gain, diplopia, tremor, abnormal Not reported
thinking

Piracetam Diarrhoea, weight gain, insomnia, depression, hyperkinesia Not reported

Primidone Fatigue, depression, psychosis, impotence, hyperkinesia, Rash, agranulocytosis, thrombocytopenia, teratogenicity
nausea, nystagmus, ataxia, folate deficiency

Retigabine Drowsiness, slurred speech, ataxia, tremor, diplopia Urinary tract symptoms, skin and retinal discolouration

Sodium valpro- Tremor, weight gain, dyspepsia, nausea, vomiting, hair loss, Acute pancreatitis, thrombocytopenia, hepatotoxicity,

ate drowsiness, peripheral oedema, hyperammonaemia teratogenicity, polycystic ovarian syndrome

Tiagabine Dizziness, nervousness, tremor, concentration difficulties Increased seizures, non-convulsive status

Topiramate Anorexia, weight loss, impaired concentration, impaired Not reported
speech, paraesthesia, kidney stones

Vigabatrin Drowsiness, weight gain, nystagmus, diplopia, ataxia, ir- Visual field defects, increased seizures
ritability, depression, psychosis

Zonisamide Ataxia, dizziness, somnolence, anorexia, memory and con- Rash, blood dyscrasias
centration impairment, confusion
536

EPILEPSY 31

Table 31.7 Practice points Comment
Problem
Hepatic enzyme induction Enzyme induction occurs with carbamazepine, phenytoin, phenobarbital, primidone and
topiramate. Interactions occur with a large number of drugs including oral contraceptives.
Use of progesterone-only contraceptives
with enzyme-inducing AED Best avoided. If no acceptable alternative, women should take at least double usual dose of
Use of combined oral contraceptive with progesterone-only pill.
enzyme-inducing AED
Continuation of AED during pregnancy Preparations containing 50 micrograms of oestrogen should be used.

Use of phenytoin as monotherapy Should be reviewed before attempting pregnancy to determine whether reducing or discon-
tinuing treatment is possible. Avoid use of sodium valproate in childbearing women.
Changing between generic manufacturers
Less frequently considered first- or second-line monotherapy because of poor side-effect
AED, Antiepileptic drugs. profile, narrow therapeutic index and saturation pharmacokinetics.

Because bioavailability or pharmacokinetic profiles may vary between different generic
drugs, it is now recommended to prescribe a consistent brand of AED.

Lamotrigine adverse events are dizziness, irritability, asthenia, insomnia
and ataxia. No idiosyncratic adverse events have yet been
Lamotrigine is a irst-line drug for people with focal and reported. 
generalised seizures. The main action is through blockage of
voltage-gated sodium channel. Lamotrigine does not seem Oxcarbazepine
to interact with other concomitantly administered AEDs.
However, hepatic enzyme inducers increase the metabolism Oxcarbazepine is an analogue of carbamazepine. It is an inactive
of lamotrigine, reducing its half-life. Therefore, higher doses pro-drug that is converted in the liver to the active 10-hydroxy
need to be administered if it is used in conjunction with enzyme metabolite and bypasses the 10,11-epoxide, the primary metab-
inducers such as phenytoin and carbamazepine. Inhibitors of olite of carbamazepine. The usual dosage is between 600 and
hepatic enzymes such as sodium valproate block the metabo- 2400 mg daily in divided doses. The spectrum of eficacy and
lism of lamotrigine, and reduced doses need to be used if both side effects is broadly comparable with carbamazepine, apart
drugs are given in combination. The recommended starting from hyponatraemia which is more pronounced with oxcar-
dosage is 25 mg once daily when used as monotherapy and 25 bazepine. The principal advantage over carbamazepine is the
mg on alternate days in people receiving concomitant sodium lack of induction of hepatic enzymes, with the consequence that
valproate, with a maximum recommended dosage of 500 mg there is no auto-induction of the metabolism of the drug and
daily, but no more than 200 mg daily if concomitant to valpro- fewer pharmacokinetic interactions. In addition, more than two-
ate. It should be increased by 25 mg in 14-day intervals, as too thirds of people who are allergic to carbamazepine can tolerate
rapid titration may be associated with an increased incidence oxcarbazepine. 
of skin rash.
Perampanel
Headaches, drowsiness, ataxia and diplopia are the most com-
monly reported acute adverse effects, particularly during dose Perampanel is licensed for the adjunctive treatment of focal-
escalation. A skin rash is the commonest idiosyncratic side effect onset seizures with or without secondarily generalised seizures
and affects up to 5% of individuals.  in people with epilepsy aged ≥12 years. It is a selective, non-
competitive antagonist of the α-amino-3-hydroxy-5-methyl-4-
Levetiracetam isoxazolepropionic acid glutamate receptor. Effective dosage
is between 4 and 12 mg/day, given in a once-a-day regimen.
Levetiracetam is a broad-spectrum drug, indicated both as a Commonest side effects are drowsiness, ataxia, lethargy, irrita-
irst-line and as an add-on for the treatment of focal and gen- bility, weight gain and blurred vision. 
eralised seizures. Mechanism of action is not fully understood,
but it binds to the synaptic vesicle protein 2A. The usual dos- Phenobarbital 537
age is between 1000 and 3000 mg/day, divided in two daily
doses. It is usually started at 250 mg once daily for 1–2 weeks, Phenobarbital, a barbiturate, may be used for the treatment of
then increased to 250 mg twice daily and then titrated upwards tonic-clonic and focal seizures. It may also be used in other
in incremental steps of 250 mg twice daily every 2 weeks. It
is well tolerated, and the most frequent central nervous system

31 THERAPEUTICS

seizure types. As with other barbiturates, it acts through activa- be the basis of its antiepileptic mechanism. The recommended
tion of the ionotropic GABAA receptor. Its antiepileptic eficacy doses for pregabalin are between 150 and 600 mg divided into
is similar to that of phenytoin or carbamazepine. Adverse effects two doses, although some people may respond to doses outside
on cognitive function, the propensity to produce tolerance and this range. Pregabalin is normally started at 25 mg twice daily
the risk of serious seizure exacerbation on withdrawal make and increased in incremental steps of 50 mg daily every week
it an unattractive option, and it should be used only as a last up to 600 mg daily in two to three divided doses according to
resort. In addition to cognitive effects, barbiturates may cause clinical need.
skin rashes, ataxia, folate deiciency, osteomalacia, behavioural
disturbances (particularly in children) and an increased risk of Overall, pregabalin is well tolerated, and so far no idiosyn-
connective tissue disorders such as Dupuytren’s contracture and cratic side effects have been described. Dizziness, drowsiness,
frozen shoulder. Phenobarbital is a potent enzyme inducer and ataxia, tremor and diplopia are the most common side effects.
is implicated in several clinically important drug interactions Weight gain occurs particularly with higher doses. No pharmaco-
(see Table 31.5).  kinetic interactions have yet been identiied. In addition to its use
in epilepsy, pregabalin has also been indicated for neuropathic
Phenytoin pain and generalised anxiety disorders. 

In current practice, phenytoin is a second-line drug for focal Primidone
seizures, tonic-clonic seizures, as well as atonic seizures and
atypical absences. It is not effective in typical generalised Primidone is principally metabolised to phenobarbital and has
absences and myoclonic seizures, where it may even be delete- similar effects but a more severe side-effect proile than pheno-
rious. It acts through blockage of voltage-gated sodium chan- barbital. There is nothing to recommend primidone as an AED
nel. Tolerance to its antiepileptic action does not usually occur. over phenobarbital. 
Phenytoin has non-linear kinetics and a low therapeutic index,
and in some patients frequent drug serum level measurements Rufinamide
may be necessary. Drug interactions (see Table 31.5) are com-
mon because phenytoin metabolism is very susceptible to inhi- Ruinamide is licensed as an orphan drug for the adjunctive treat-
bition by some drugs, whereas it may enhance the metabolism ment of seizures in Lennox–Gastaut syndrome. It is a triazole
of others (see Table 31.7). Caution should be exercised when derivative and is structurally unrelated to any other AED. Its
other medication is introduced or withdrawn. Effective dos- mode of action is unknown. A serious hypersensitivity syndrome
ages are between 200 and 500 mg/day. that may include rash, fever, lymphadenopathy, hepatic dysfunc-
tion, haematuria and multi-organ dysfunction has been reported
Adverse events may occur in up to a half of those treated with upon initiation of therapy. Individuals should be warned to seek
phenytoin, but only about 10% will necessitate drug withdrawal, immediate medical assistance if signs or symptoms of hypersen-
most commonly because of skin rash. Dose-related adverse sitivity develop. 
reactions including nystagmus, ataxia and lethargy are com-
mon. Cosmetic effects such as gum hypertrophy, hirsutism and Sodium valproate
acne are well-recognised adverse effects and should be taken
into account when prescribing for children and young women. Sodium valproate is a broad-spectrum AED, effective over the
Chronic adverse effects include folate deiciency, osteomalacia, complete range of seizures type, but with particular value in the
Dupuytren’s contractures and cerebellar atrophy. Serious idio- idiopathic generalised epilepsies. This is mainly due to its broad
syncratic adverse events, including hepatic failure and bone mar- mechanism of action, known to act on voltage-gated sodium and
row depression, are extremely uncommon.  calcium channels, and also in the turnover of GABA. Tolerance
to its antiepileptic action does not usually occur. Drug interac-
Piracetam tions with other AEDs may be problematic (see Table 31.5).
Phenobarbital levels increase following co-medication with
Piracetam is indicated only for treatment of refractory myoclo- valproate, and a combination of these two drugs may result in
nus as an add-on drug. Effective dosages are between 12 and 24 severe sedation. Sodium valproate may also inhibit the metabo-
mg/day. The most common side effects are diarrhoea, weight lism of lamotrigine, phenytoin and carbamazepine. Enzyme-
gain, insomnia and depression. There are no known idiosyncratic inducing drugs enhance the metabolism of sodium valproate, so
adverse effects or drug interactions.  caution should be exercised when other AEDs are introduced or
withdrawn.
Pregabalin
Up to a third of people may experience adverse effects, but
Pregabalin has been licensed for the adjunctive treatment of fewer than 5% will require the drug to be stopped. Adverse
refractory focal epilepsy. It is closely related to gabapentin and effects include nausea, diarrhoea, weight gain, alopecia, skin rash
a structural analogue of the neurotransmitter GABA but does not and thrombocytopenia. Confusion, stupor, tremor and hyper-
seem to affect transmitter response. It modulates calcium chan- ammonaemia are usually dose related. Serious adverse events,
nels by binding to a subunit of Ca2+, and this action is thought to including fatal pancreatic and hepatic failure, are extremely
538 uncommon.

EPILEPSY 31

The usual therapeutic range quoted is 1–2 g daily with a Vigabatrin
maximum dosage of 2.5 g/day. Because of the lack of a good
correlation between total valproate concentrations and effect, Vigabatrin inhibits GABA degradation, but because of a poor safety
serum level monitoring of the drug has limited use. TDM proile it is a last resort drug for focal seizures. It is still a irst-line
should only be performed in cases of suspected toxicity, dete- treatment of infantile spasms, particularly if associated with tuber-
rioration in seizure control, to check adherence or to monitor ous sclerosis. Vigabatrin does not interact with other drugs apart
drug interactions. Sodium valproate is more teratogenic than from decreasing phenytoin levels, probably by blocking its absorp-
other commonly used AEDs and should be avoided in women tion. The most common adverse events associated with vigaba-
of childbearing age (see Table 31.7).  trin are behavioural disturbances, ranging from agitation to frank
psychosis and visual ield defects, which had been associated with
Stiripentol long-term treatment in up to 40–50% of patients. Other known
adverse effects include drowsiness, headaches, ataxia, weight gain,
Stiripentol is licensed as an orphan drug for severe myoclonic depression and tremor. Careful monitoring for side effects, particu-
epilepsy of infancy (Dravet syndrome) when used in conjunc- larly ophthalmological, on initiation of therapy is essential. 
tion with sodium valproate and clobazam. It is an aromatic
alcohol and is unrelated to any other AED. Its mode of action is Zonisamide
unknown. 
Zonisamide, a sulfonamide analogue which inhibits carbonic
Tiagabine anhydrase, is a potent blocker of the spread of epileptic dis-
charges. This effect is believed to be mediated through action
Tiagabine is a drug with mild eficacy in seizure control. It is also at voltage-sensitive sodium channels. It is used as a second-
used as a second-line drug in focal seizures with or without sec- line drug for those with focal seizures with or without secondary
ondary generalisation. It prevents the removal of GABA from generalisation. It can be effective in generalised seizures, particu-
the synaptic cleft by blockage of GABA transport. The usual larly myoclonic seizures. Recommended dosages are between
dosage is between 30 and 45 mg daily in two to three divided 200 and 500 mg/day, although some people may derive beneit
doses, and it is normally started at 5–10 mg daily in one to two from dosages outside this range. When used in monotherapy,
divided doses, with incremental steps of 5–10 mg every week. the recommended starting dose is 100 mg once daily, titrating
The most common adverse events are on the central nervous sys- upwards every 2 weeks in 100 mg increments. The usual mainte-
tem and consist of sedation, tremor, headache, mental slowing, nance dosage is 300 mg once daily, and the maximum dosage is
tiredness and dizziness. Confusion, irritability and depression 500 mg/day. When used as adjunctive therapy, the recommended
may occur. Increases in seizure frequency and episodes of non- starting dosage is 50 mg daily in two divided doses for 7 days,
convulsive status have also been reported. Use in pregnancy is then increased to 100 mg daily in two divided doses, and inally
not recommended, although no teratogenicity has been reported increased in steps of 100 mg every week. The usual maintenance
in humans.  dosage is 300–500 mg daily in one to two divided doses. Its long
elimination half-life allows once-daily dosing.
Topiramate
It does not affect levels of carbamazepine, barbiturates or val-
Topiramate is chemically unrelated to other AEDs and is a proate, but may increase the serum concentration of phenytoin
used as a irst-line drug for people with focal seizures with by about 10–15%. Zonisamide metabolism is, however, induced
or without secondary generalisation and for generalised sei- by carbamazepine, barbiturates and phenytoin, and higher
zure. It has multiple mechanism of action: voltage-gated zonisamide doses may be necessary during co-administration
sodium and calcium channels, GABA and glutamate recep- with these AEDs.
tors. Recommended dosages are between 75 and 300 mg/
day. It has to be titrated slowly, starting with a dosage of 25 Side effects include dizziness, drowsiness, headaches,
mg once daily, titrating upwards in 25- to 50 mg increments anorexia, weight loss, skin rashes, irritability, impaired concen-
every 1–2 weeks up to a usual dosage of 100–200 mg daily tration and fatigue. These are mostly transient and seem to be
in two divided doses. The maximum dosage is 500 mg/day in related to the dose and rate of titration. Nephrolithiasis has also
monotherapy or 400 mg/day as adjunctive therapy. It has no been reported, particularly in Caucasians. It is not recommended
clinically signiicant interactions with other AEDs, although for women of childbearing age because there are issues about its
hepatic enzyme inducers accelerate its metabolism and doses teratogenic potential. 
need to be adjusted downwards if the patient is coming off
carbamazepine or phenytoin. Recent and future evidence for
antiepileptic drugs
Side effects include dizziness, drowsiness, irritability, impaired
concentration, paraesthesias, nephrolithiasis and fatigue. People ILAE has published an updated review of AED eficacy and effec-
starting topiramate should increase their luid intake to reduce the tiveness as initial monotherapy for epileptic seizures and syn-
risk of kidney stones. Weight loss is seen in up to 40% of those dromes (Glauser et al., 2013). After a thorough review of published
who are taking topiramate. 

539

31 THERAPEUTICS

reports, they summarised the level of evidence for each seizure type Case 31.2
and epilepsy syndrome. In adults with focal-onset seizures, carba-
mazepine, levetiracetam, phenytoin and zonisamide have level A Mr OB is a 44-year-old man who suffers from focal epilepsy. An
evidence (highest supporting level of clinical trial evidence). Only MRI scan shows a choroid cyst on the right temporal lobe, bilat-
oxcarbazepine has level A for children with focal-onset seizures, eral hippocampal sclerosis and cerebral atrophy. Seizures take the
and gabapentin and lamotrigine have that level for the elderly with form of focal with impaired awareness and at night evolved to
the same seizure type. There is no drug with level A evidence for bilateral tonic-clonic. He has had trials of treatment with every
generalised-onset tonic-clonic seizures in adults or in children. single drug available and almost every combination.
Ethosuximide and valproic acid have level A evidence in children
with childhood absence epilepsy. Six months ago, he was taking 225 mg topiramate, 400 mg
phenytoin and 10 mg clobazam each day. He could not tolerate a
The new AEDs are still not capable of achieving the primary higher dose of topiramate. At this point levetiracetam was added
goal of epilepsy treatment – complete freedom of seizures – and titrated up to 2000 mg/day. This led to a significant improve-
although some may have a more favourable proile, with lesser ment in Mr OB’s seizure control. Indeed, seizures have almost
drug interactions and side effects. As such, this group of drugs completely been abolished and he is only having occasional noc-
will probably continue to expand, with new AEDs appearing in turnal events. He is, however, complaining of drowsiness and peri-
the quest of epilepsy cure.  ods of unsteadiness.

Case studies Question

Case 31.1 What treatment is appropriate for Mr OB? 

Ms JB is a 31-year-old woman with a history of early-morning Answer
myoclonic jerks from age 14 years. When she was 18 years old
she had her first convulsive seizure. A diagnosis of juvenile myo- Mr OB needs his drug regimen optimising. The decision should be made
clonic epilepsy was made, and Ms JB was started on phenytoin to reduce either the dose of topiramate or that of phenytoin. Usually phe-
with no results. She was then switched to topiramate, which also nytoin is reduced first, as it is an enzyme inducer. However, because Mr
did not help her seizures. As a last resort, at age 18 years, she was OB has had a bad experience in the past when an attempt was made to
switched to sodium valproate 1200 mg/day which fully controlled discontinue phenytoin, at which time he had a significant increase in sei-
her seizures. zure frequency, it would, therefore, be more appropriate to discontinue
topiramate. This was done and his improvement has been maintained. 
At the age of 21 years, she delivered a healthy baby and expe-
rienced no problems with epilepsy control. At age 22, she had her Case 31.3
second pregnancy and delivered a healthy baby. Three weeks after
delivery early-morning myoclonic seizures returned. The dose of Ms GD is a 28-year-old woman with a history of early-morning myo-
sodium valproate was increased to 1500 mg/day to control jerks. clonic jerks since age 14 years. At 16 years of age she presented
However, 6 months later she experienced a recurrence of her con- with her first generalised tonic clonic convulsive seizure and was
vulsive attacks with no clear precipitating factor. Sodium valproate referred to a hospital specialist who diagnosed juvenile myoclonic
was increased to 2000 mg/day. Early-morning myoclonic seizures epilepsy. At that time Ms GD was started on sodium valproate
crept back and she had further convulsive seizures. Lamotrigine 1200 mg/day and within a few weeks her seizures were totally
was started and she is now taking 100 mg daily. She has been com- controlled. Ms GD has since remained on the same medication and
pletely seizure-free for the last 2 years and is now driving again. has been well controlled. However, she now wishes to start a fam-
ily and is concerned about the effects of the valproate on her baby.
Ms JB wants to discuss her medication with you and would like
to stop treatment. She has no plans to increase her family. Question

Question What advice would you give Ms GD? 

What advice would you give Ms JB?  Answer

Answer Sodium valproate is teratogenic, with the most common malforma-
tion reported being neural tube defects. Ms GD has had no seizures
Ms JB should be advised to continue on medication. She has juvenile for more than 5 years, and it must, therefore, be determined whether
myoclonic epilepsy, which tends to recur when medication is with- she still needs medication. The risk of recurrence is low because she
drawn. Because Ms JB has no intention of having further children, has been seizure free for well over 5 years. An important consider-
pregnancy need not be a consideration in the choice of her contin- ation is whether she is a driver, because if she is taken off medication
ued drug therapy with valproate. She is generally well, and hence it and has a seizure, she will be unable to hold a license. The other
would be sensible to advise her to continue with the present regimen, issue is the effect of pregnancy on her seizures because some women
because sodium valproate and lamotrigine have a synergistic effect in may experience an increase in seizures during pregnancy. The options
juvenile myoclonic epilepsy. If, however, Ms JB wants to reduce medi- that need to be considered include change of medication. The fol-
cation, then a slow decrease of sodium valproate with optimisation of lowing drugs would be alternatives: lamotrigine, zonisamide and
treatment with lamotrigine should be considered.  levetiracetam. 

540

EPILEPSY 31

Case 31.4 Question

Mr TD is a 41-year-old man who has cryptogenic focal epilepsy. Mr Was Mr FD’s clinical management appropriate, and is there a role for
TD experienced his first seizure at age 14, and this was diagnosed prophylactic anticonvulsant medication? 
as a secondary generalised attack, although discussing his history
revealed he might have had focal with impaired awareness seizures. Answer
Two years ago Mr TD was referred for assessment, but it was deter-
mined that he was not a candidate for surgery. Mr TD was taking Mr FD requires a full neurological review. The long-term use of anti-
carbamazepine 1200 mg/day and could not tolerate higher doses. epileptics following head injury is not indicated unless the person has
Previous trials of valproate, phenytoin, phenobarbital, vigabatrin, a history of seizures, and Mr FD has had no seizures post-discharge. 
lamotrigine, oxcarbazepine and topiramate had demonstrated lit-
tle benefit. Levetiracetam was started and increased to 2500 mg. Case 31.6
Improvement in Mr TD’s seizure control has been noted over the
past 2 years, with only two nocturnal focal with impaired awareness Mr RA is a 75-year-old retired teacher who lives alone. He has long-
seizures recorded. His current medication is levetiracetam 2500 standing epilepsy, and his current medication includes phenytoin
mg/day and carbamazepine 1200 mg/day. 300 mg daily. Mr RA suffered a recent fall and was rushed to hospital
with a suspected fractured neck of femur. On admission he was stabi-
Question lised and found not to have sustained a fracture. His other medication
was furosemide 40 mg in the morning and enalapril 5 mg twice daily.
Should TD’s therapy be reduced to levetiracetam monotherapy?  Routine blood levels of the anticonvulsants revealed a toxic level of
phenytoin of 40 mg/L (normal therapeutic range 10–20 mg/L).
Answer
Question
If a person has been seizure free for 3 years, it is good practice to
review therapy. There is a need to discuss with Mr TD whether he How long will it take for the toxic levels of phenytoin to fall within the
wishes to continue with his medication. Issues of relevance include a therapeutic range? 
long history of epilepsy, the diagnosis and the range of drugs previ-
ously tried which may indicate an increased risk of seizure recurrence Answer
on coming off drugs. It also needs to be clear whether he wishes to
drive, because a recurrence would lead to him having to surrender his Phenytoin exhibits non-linear pharmacokinetics. Usual management
driving license.  will involve withholding phenytoin and monitoring serum levels each
day. One assumption that can be made is that if the hepatic enzymes
Case 31.5 are fully saturated with phenytoin, then at maximum metabolic capacity
approximately 10 mg/L of the drug will be eliminated each day. Initially,
Mr FD is a 23-year-old student who was involved in a road traffic however, the drug will redistribute into serum, so for the first few days
accident and admitted to hospital with a head trauma. He was phenytoin levels will fall slowly. It is usual for the levels to take 6–7
stabilised, but during his admission he had a seizure and was then days to fall within the therapeutic range. Therapy will then need to be
discharged on no medication. Three months later Mr FD attended reviewed. On further investigation it was found that Mr RA had a severe
an outpatient hospital follow-up appointment and was identified chest infection and was prescribed ciprofloxacin. His antibiotic regimen
to have had no further seizures. was completed 5 days ago. Mr RA was suffering from phenytoin toxicity
which may have resulted in ataxia and contributed to his fall.

References National Institute for Health and Care Excellence (NICE), 2012. Epilepsies: di-
agnosis and management. Clinical guideline [CG137]. Available at: https://
Duncan, J.S., Sander, J.W., Sisodiya, S.M., Walker, M.C., 2006. Adult epilepsy. www.nice.org.uk/guidance/cg137.
Lancet 367, 1087–1100.
National Institute for Health and Care Excellence (NICE), 2014. Evidence
Fisher, R.S., Acevedo, C., Arzimanoglou, A., et al., 2014. ILAE oficial update 53: the epilepsies. Available at: http://www.nice.org.uk/guidance/
report: a practical clinical deinition of epilepsy. Epilepsia 55, 475–482. cg137/evidence/evidence-update-544389949.

Fisher, R.S., Cross, J.H., French, J.A., et al., 2017. Operational classiication Sabers, A., Gram, L., 2000. Newer anticonvulsants: comparative review of
of seizure types by the International League Against Epilepsy: position
paper of the ILAE Commission for Classiication and Terminology. drug interactions and adverse effects. Drugs 60, 23–33.
Epilepsia 58 (4), 522–530.
Thurman, D.J., Logroscino, G., Beghi, E., et al., 2017. The burden of
Glauser, T., Ben-Menachem, E., Bourgeois, B., et al., 2013. ILAE Subcom- premature mortality of epilepsy in high-income countries: a systematic
mission on AED Guidelines. ILAE Subcommission on AED Guidelines. review from the Mortality Task Force of the International League Against
Updated ILAE evidence review of antiepileptic drug eficacy and ef- Epilepsy. Epilepsia 58, 17–26.
fectiveness as initial monotherapy for epileptic seizures and syndromes.
Epilepsia 54, 551–563. Tomson, T., Walczak, T., Sillanpaa, M., et al., 2005. Sudden unexpected
death in epilepsy: a review of incidence and risk factors. Epilepsia 46
Medicines and Healthcare products Regulatory Agency (MHRA), 2013. (Suppl. 11), 54–61.
Formulation switching of antiepileptic drugs: a report on the recom-
mendations of the Commission on Human Medicines from July 2013. World Health Organization (WHO), 2015. Epilepsy, key facts. Fact Sheet
Available at: http://webarchive.nationalarchives.gov.uk/20141205150130 Number 999. Available at: http://www.who.int/mediacentre/factsheets/
/http://www.mhra.gov.uk/home/groups/comms-ic/documents/websitereso
urces/con341226.pdf. fs999/en/.

541

31 THERAPEUTICS

Further reading Schmidt, D., Schachter, S.C., 2014. Drug treatment of epilepsy in adults.

Nair, D.R., Nair, R., O’Dyer, R. (Eds.), 2010. Epilepsy. Clinical Publishing, Br. Med. J. 348, g254.
Oxford. Trinka, E., Cock, H., Hesdorffer, D., et al., 2015. A deinition and classiica-

National Institute for Health and Care Excellence (NICE), 2013. Epilepsy in tion of status epilepticus—report of the ILAE Task Force on Classiica-
adults. Available at: http://www.nice.org.uk/guidance/qs26. tion of Status Epilepticus. Epilepsia 56, 1515–1523.
Wyllie, E., 2015. Wyllie’s Treatment of Epilepsy: Principles and Practice,
National Institute for Health and Care Excellence (NICE), 2013. Epilepsy sixth ed. Lippincott Williams and Wilkins, Philadelphia.
in children and young people. Available at: http://www.nice.org.uk/guida
nce/qs27.

Perucca, E., Tomson, T., 2011. The pharmacological treatment of epilepsy in
adults. Lancet Neurol. 10 (5), 446–456.

542

THERAPEUTICS

32 Parkinson’s Disease

Emma Lane and Roger Barker

Key points pigmented neurons in the substantia nigra occurred in the middle
part of the 20th century and was soon followed by the introduction
• Parkinson’s disease is the second most common neurodegenera- of dopamine replacement therapy with levodopa. Although excel-
tive disease, affecting 1% of the population older than 65 years. lent at managing some of the motor features, levodopa is associated
with the development of motor complications after some years in the
• Parkinson’s disease is characterised by bradykinesia, resting form of on–off problems and dyskinesias. Such complications can
tremor, rigidity and, later in the disease course, postural instability. now be treated using a range of other therapeutics including more
invasive approaches such as deep brain stimulation.
• A range of non-motor features including psychiatric, cogni-
tive and autonomic impairments contribute significantly to In addition to these motor features, only some of which respond
an impaired quality of life and are present from early in the to dopaminergic agents, the identiication of a host of non-motor
disease course in many cases. symptoms from disease onset (and in some cases even ahead of
them) is now known to contribute in a major way to the qual-
• Neuronal loss in the brainstem (substantia nigra) leads to a pro- ity of life of patients with PD. This similarly presents a complex
found dopamine deficiency in the striatum. This provides the therapeutic challenge.
rationale for dopaminergic replacement therapies, although
the pathology is not restricted to this site. Background

• Levodopa, coupled with an amino acid decarboxylase inhibitor, PD affects 1% of the population that are more than 65 years of age,
remains the most potent oral treatment for Parkinson’s disease. increasing to 2% over the age of 80 years. One in 20 patients is,
however, diagnosed before their 40th year. It is estimated that PD
• End-of-dose wearing off and on–off fluctuations are motor affects around 127,000 people in the UK, with more than 6 million
complications synonymous with the ongoing use of levodopa. sufferers worldwide. Demographically the disease is believed to
Despite advances in oral pharmacotherapy, the on–off phe- have a small male/female predominance (around 3:2). Prevalence
nomenon can be difficult to treat effectively. is recorded as slightly higher in European and North and South
American populations compared with Arabic, African and Asian
• Other dopaminergic therapies are available for the management countries. The biggest risk factor for the disease is age, which has
of Parkinson’s disease. Dopamine agonists are used, sometimes major implications for public health as the lifespan of the world’s
as first-line therapy, in younger patients, although the increasing population increases.
recognition of the neuropsychiatric problems that can arise with
these agents has reduced their use. It is now therefore recom- Parkinsonism describes the main motor features of the disease
mended that information regarding impulse control disorders is but can also be a feature of other, less common neurodegenera-
explicitly given to patients when such drugs are used. tive conditions (multiple system atrophy [MSA], progressive
supranuclear palsy and corticobasal degeneration), as well as a
• Dopamine agonists can also be given as adjunctive therapies side effect of various medications. 
to levodopa, when the primary aim is to smooth out motor
fluctuations.

• Other interventions including surgical treatments of Parkinson’s
disease, such as deep brain stimulation of the subthalamic nucleus,
are effective in certain patients with marked motor fluctuations.

• Advanced Parkinson’s disease is difficult to manage, particu-
larly the emerging dementia and neuropsychiatric problems.
Reduction of dopaminergic therapy is the first approach, and
rivastigmine and other cholinesterase inhibitors may be useful
for the dementia associated with Parkinson’s disease.

Parkinson’s disease (PD) is the most common cause of Parkinsonism Aetiology
and is the second most common neurodegenerative disease, after
Alzheimer’s disease. Although descriptions of the condition Both genetic and environmental factors are likely to contribute 543
appeared before the 19th century, it was James Parkinson’s eloquent to the risk of development of PD (Fig. 32.1), with environmental
account in 1817 that fully documented the clinical features of the factors precipitating the onset of PD in a genetically susceptible
illness and Charcot in the late 19th century who named the condi- individual.
tion after him. Identiication of the dopamine deiciency and loss of

32 THERAPEUTICS

Ageing Environmental the condition. Since this discovery, duplication and triplica-
factors tion in the α-synuclein gene, as well as further mutations in it
Genetic factors along with mutations in many other genes, have been found
to contribute to familial forms of the disease. However, the
Altered UPS Lysosome-autophagy Mitochondrial phenotypic nature of these forms of Parkinsonism is often
processing pathway dysfunction and different from idiopathic disease, causing atypical or early-
onset forms of the disease, with the exception of the LRRK2
mitophagy families.

Oxidative Protein Inflammation Although these genes form very much the minority of cases,
stress aggregation there is nevertheless clear genetic risk of the development of PD,
as is evidenced by recent large genome-wide associated studies
Prion like Synaptic dysfunction, loss Impaired protein (Bras et al., 2015; Edwards et al., 2011). This has revealed a large
transmission and failed dopamine and membrane number of genetic loci linked to an increased risk of development
neurotransmission of the disorder.
trafficking
More recently, through careful clinical observation in Gaucher’s
CELL DEATH disease families, it was recognised that one of the strongest
genetic risk factors is a heterozygous mutation in the GBA gene.
Fig. 32.1 Summary of pathophysiological processes considered to This is found in between 5% and 10% of patients with so-called
be central to Parkinson’s disease. sporadic disease. 
UPS, Ubiquitin proteasome system.
Pathophysiology
Environment
The two characteristic pathological features of PD are neu-
The relevance of environmental factors came to the fore ronal loss, especially in the pigmented brainstem nuclei,
in the 1980s, when drug addicts attempting to manufac- together with the presence of eosinophilic inclusion bodies,
ture pethidine accidently produced a toxin called MPTP called Lewy bodies, in surviving cells. Dopaminergic neu-
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The severe rones within the substantia nigra pars compacta, projecting
Parkinsonian state induced by inhalation or injection of the to the striatum, are particularly affected by the disease, lead-
toxin produced a clinical syndrome that was indistinguishable ing to a loss of dopamine in the terminal region. There is
from advanced PD. Similarities in the structure of MPTP to considerable reserve in this pathway, and a loss of more than
the commonly used herbicide paraquat opened up explora- 50% of nigral neurones occurs before overt motor features
tion of the role of chemicals used in the agricultural industry. appear. The identification of Lewy bodies in other areas of
Pesticide exposure, rural living, agricultural occupation and the central nervous system (CNS) means that dopamine is
well water drinking alongside head injury are all associated not the only neurotransmitter system affected, and all of this
with an increased risk of development of PD. Conversely, correlates with the increasing recognition of the range of
tobacco smoking, coffee drinking, non-steroidal anti-inflam- other clinical features seen in the course of the disease,
matory drug use, calcium channel blocker use and alcohol some of which even precede the development of the motor
consumption have all been linked to a reduced risk of the phenotype.
disease (Bellou et al., 2016). 
Indeed, neuropathologically, the Braak hypothesis proposes
Genetics that α-synuclein may irst accumulate in the dorsal vagal
nucleus of the lower brainstem and then gradually ascend ros-
Single monogenic causes for PD account for a very small trally to affect critical brain regions including the substantia
number of patients. The irst gene of this nature to be dis- nigra and ultimately the cerebral cortex (Braak et al., 2003).
covered was that encoding a mutation in the synaptic protein If true, this would suggest that prior to the loss of dopamine
α-synuclein (Polymeropoulos et al., 1997). Shortly after its cells, other cell populations should be affected, resulting in
identiication as the causative gene in this familial form of changes in bowel control, mood, sleep and locomotion, all of
PD, it was found to be the major component of the intracellu- which would it with the prodromal features that many patients
lar protein accumulations, Lewy bodies that characterise spo- with PD report. In addition there is early pathology in the olfac-
radic disease (Spillantini et al., 1997). This highlighted that tory bulb which may also account for the loss of sense of smell
this protein was central to what goes wrong in all cases of that many patients experience ahead of them developing overt
PD and was not just the preserve of a rare familial form of motor problems.
544
All of this not only accounts for the features of prodromal PD,
but also the deicits that are reported as the disease evolves and
which typically do not respond to dopaminergic replacement
therapies. 

PARKINSON’S DISEASE 32

Clinical features patient at disease onset. Younger onset patients may show
cognitive impairment but evolve to a dementia at a slower
Motor features rate compared with older patients. Longitudinal community-
based studies indicate that dementia may ultimately develop
A prerequisite feature for a diagnosis of PD is the presence of bra- in 80% of people with PD (Hely et al., 2008). The cognitive
dykinesia. This is the slowness of initiation of voluntary move- impairment that deines the dementia is often associated with
ment, with progressive reduction in speed of repetitive actions. the symptoms of hallucinations that are typically visual with
The other cardinal features of the disease are tremor when at rest delusional misinterpretation, including paranoid ideation, and
(pill-rolling tremor), postural instability and cogwheel rigidity. rapid luctuations in attention.
Cogwheel rigidity describes the jerky resistance when limbs
are moved. These are listed in most diagnostic guidelines for Finally many patients complain of sleep problems, with the
PD. The disease presents asymmetrically and patients continue major one being a REM sleep behavioural disorder that can occur
to report a ‘bad side’ as the disease progresses, although pure ahead of the diagnosis of PD. This condition is characterised by
unilateral disease is rare, and usually raises concerns that some patients acting out their dreams. In addition many patients com-
other disease process is occurring if this is the case. It is impor- plain of a restless leg syndrome and limb pain. 
tant to note, however, that many patients (15–20%) never really
develop a tremor, whereas up to 60% of people with PD may Differential diagnosis
have a dominant postural tremor (tremor-dominant), worse with
the arms held outstretched, which can cause diagnostic confusion Although PD is a common form of Parkinsonism, there are numer-
with essential tremor (ET). Postural instability is an important ous other diseases that present with Parkinsonism. A detailed
milestone in PD, and typically more than half of patients will description of these different causes is beyond the scope of this
reach this stage within 10 years of diagnosis. This problem com- chapter, but a few points should be highlighted. ET is a common
prises an impairment of righting relexes, which leads to impaired condition but does not cause bradykinesia. Nevertheless, it may
gait and increased risk of falling. be very dificult to differentiate from tremor-dominant PD. In
about 50% of cases of ET there is a positive family history and in
Patients typically display a characteristic stooped posture and a similar number a good response to a low dose of alcohol. If there
loss of arm swing when walking, which is often a very helpful are doubts, some form of nuclear medicine imaging looking at
early diagnostic sign when seeing patients for the irst time. There dopamine in the brain can help distinguish tremulous PD from ET.
is reduced blink frequency and facial expression (hypomimia),
which, together with a low-volume (hypophonic), monotonous Several clinical and clinicopathological series have highlighted
speech, may lead to signiicant dificulties in communication. the problems in making a correct diagnosis of PD. If clinical cri-
All of this can easily be misdiagnosed as depression. Writing teria, such as those produced by the UK Parkinson’s Disease
becomes small (micrographia) and barely legible, with the words Brain Bank, are not applied, then the error rate (false-negative
falling off the line as the patient continues to write.  diagnosis) may be as high as 25–30%. These criteria are listed in
Box 32.1. The common conditions misdiagnosed as PD, outside
Non-motor features of ET or dystonic tremor, are other neurodegenerative disorders
such as progressive supranuclear palsy, MSA and corticobasal
A range of non-motor features encompassing autonomic, cognitive degeneration, as well as small vessel disease affecting the brain.
and psychiatric problems are seen in nearly all cases of PD and have
a pronounced effect on quality of life. They can precede disease Drug-induced Parkinsonism
onset and tend to become more prominent as the condition evolves.
Common autonomic problems include postural hypotension (falling An important differential diagnosis to consider when a patient pres-
blood pressure on standing) which may contribute to falls and black- ents with Parkinsonism is whether their symptoms and signs may
outs later in the disease course and is a leading cause of hospitalisa- be drug induced. This is because drug-induced Parkinsonism is
tion for patients with PD. Constipation can be an ongoing problem potentially reversible upon cessation of the drug. Reports linking
that may precede the diagnosis of PD by up to 20 years and relates drug-induced Parkinsonism with the neuroleptic chlorpromazine
possibly to pathology in the enteric nervous system. In terms of psy- were irst published in the 1950s. Since then, numerous other agents
chiatric problems, depression affects approximately 40% of patients have been associated with it. Many of these are widely recognised,
and is a major determinant of both carer stress and nursing home although others are not (Table 32.1). Repeat prescription of vestibu-
placement. Paranoia and hallucinations occur in many patients typi- lar sedatives and antiemetics such as prochlorperazine and cinna-
cally as a prelude of the dementia, but often are provoked and wors- rizine are the most commonly encountered causes of drug-induced
ened by dopaminergic and related drugs used to treat PD. In addition Parkinsonism. The pathogenesis of drug-induced Parkinsonism is
some of the dopaminergic agonists can induce major behavioural likely due to dopamine receptor blockade, but only in part because
problems in some patients, especially young male patients with PD. there is no clear correlation in incidence and severity with the drug
dosage and length of exposure. Sodium valproate is also now recog-
Cognitive impairment at a very mild level is now thought nised to cause an encephalopathy dominated by Parkinsonism and
to be present in many patients at diagnosis. However, the cognitive impairment which is reversible upon drug cessation.
development of a frank dementia tends to occur later on in
the disease course and is especially related to the age of the

545

32 THERAPEUTICS

Box 32.1 Clinical criteria for diagnosis of Parkinson’s disease Table 32.1 Examples of non-neuroleptic drugs associated with
drug-induced Parkinsonism
Step 1: Diagnosis of Parkinsonian syndrome
The patient has bradykinesia, plus one or more of the following: Medication Comment

a. classic rest tremor, 4–6 Hz Cinnarizine, metoclo- Antiemetics
b. muscular rigidity
c. postural instability, without other explanation  pramide, prochlorperazine

Step 2: Exclusion criteria for PD suggesting an alternate diagnosis Antipsychotics Dose-dependent effects; clozapine
a. history of repeated strokes least associated with abnormal
b. history of repeated head injury movements
c. history of definite encephalitis
d. oculogyric crises Tetrabenazine Used to treat chorea through a
e. dopamine receptor blocking agent exposure at onset of catecholamine-depleting action
symptoms
f. more than one affected relative (often not applied) Sodium valproate, Unclear how they cause
g. sustained remission Non-steriodal anti- Parkinsonism
h. strictly unilateral features after 3 years inflammatory drugs,
i. supranuclear gaze palsy amiodarone, phenytoin,
j. cerebellar signs oral contraceptives
k. early severe autonomic involvement
l. early severe dementia Lithium Lithium causes postural tremor;
m. extensor plantar reports of Parkinsonism occurring
n. cerebral tumour or hydrocephalus on CT scan or MRI with lithium have usually been in
o. negative response to large doses of levodopa the context of prior exposure to
p. MPTP exposure  neuroleptics

Step 3 Supportive prospective positive criteria for PD (three or Phenelzine Only single case reports of drug-
more required for diagnosis of definite PD) 5-Fluorouracil induced Parkinsonism with these
Pethidine drugs
a. unilateral onset Vincristine-Adriamycin
b. rest tremor present
c. progressive disorder Amphotericin One case report of drug-induced
d. progressive persistent asymmetry Parkinsonism in a child after bone
e. an excellent (>70%) response to levodopa marrow transplantation and a
f. a sustained (>5 years) response to levodopa second in association with cytosine
g. severe levodopa-induced dyskinesias arabinoside therapy
h. clinical course >10 years
For a diagnosis, step one should be fulfilled with no exclusion Huntington’s or mitochondrial disease, respectively. Brain imag-
criteria and three supportive criteria should also be present. ing by computed tomography (CT) or magnetic resonance imaging
(MRI) may be necessary to exclude hydrocephalus, cerebrovascu-
CT, Computed tomography; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydro- lar disease or basal ganglia abnormalities suggestive of an under-
pyridine; MRI, magnetic resonance imaging; PD, Parkinson’s disease. lying metabolic cause. When there is dificulty in distinguishing
PD from ET, a form of functional imaging called [123I]β-CIT
Drug-induced Parkinsonism is more common in the elderly and (2ß-carbomethoxy-3β-(4-iodophenyl) tropane) single-photon emis-
in women. The clinical features can be indistinguishable from PD, sion computerised tomography (FP-CIT SPECT; also known as
although the signs in drug-induced Parkinsonism are more likely DaTSCAN) may be useful, because this technique can sensitively
to be bilateral at onset. Withdrawal of the offending agent will lead identify loss of nigrostriatal dopaminergic terminals in the striatum
to improvement and resolution of symptoms and signs in approxi- (Fig. 32.2). Thus, in ET, the SPECT scan is normal, whereas in PD,
mately 80% of patients within 8 weeks of discontinuation. Drug- reduced tracer uptake is seen (Jennings et al., 2004).
induced Parkinsonism may, however, take up to 18 months to fully
resolve in some cases. Further, in other patients, the Parkinsonism Differentiating PD from MSA and progressive supranuclear
may improve after stopping the drug, only to then deteriorate. In palsy is not an uncommon clinical problem and may be very dif-
this situation, the drug may have unmasked previously latent PD.  icult, particularly in the early disease stages and especially in the
case of MSA-Parkinsonism. FP-CIT SPECT cannot differentiate
Investigations PD from these other forms of degenerative Parkinsonism. MRI
brain scanning, anal sphincter electromyography, tilt table testing
The diagnosis of PD is a clinical one and should be based, prefer- for orthostatic hypotension and eye movement recordings may
ably, upon validated criteria. In young-onset or clinically atypical all be of some help, although they are rarely diagnostic in their
PD, a number of investigations may be appropriate. These include own right. Typically the diagnosis in these cases becomes appar-
copper studies and DNA testing to exclude Wilson’s disease and ent over time, and should always be considered when patients
546

PARKINSON’S DISEASE 32

Fig. 32.2 A normal FP-CIT SPECT scan image, showing symmet- development of involuntary movements known as dyskine-
ric tracer uptake in both striata (mirror image commas). In Parkin- sias. These typically occur after a number of years of treatment
son’s disease, the tail of the comma is lost at an early stage, with and relate as much to the duration of disease as to the drug
the most severe loss being contralateral to the side most affected itself.
clinically.
The irst problem that patients typically describe with
respond poorly to dopaminergic therapies with early involvement levodopa is a wearing-off effect, in which the patient inds
of other systems outside the nigrostriatal system such as auto- that the effect of the medicine does not last until their next
nomic dysfunction.  dose is due. This manifests itself as the patient starting to ‘go
off’ as they approach their next dosing time. With time this
Treatment evolves into more complex on–off problems, where patients
can ‘go off’ for no obvious reason. This stage of the illness
General approach is also often accompanied by levodopa-induced dyskinesias.
Dyskinesias are classed depending on their relationship to
The treatment of PD at the current time is wholly symptomatic. levodopa dosing occurring at the peak of levodopa response,
No drug has proven to have signiicant disease-modifying or neu- so-called peak dose dyskinesia (the commonest type), ‘dipha-
roprotective capabilities, although monoamine oxidase type B sic dyskinesia’ at the start and end of levodopa therapy, and
(MAO-B) inhibitors have been explored for such activity. At the the end of dose ‘wearing off’ dyskinesia. These problems
present time there are several ongoing clinical trials looking at emerge at a rate of approximately 10% per year, so that by 10
possible disease-modifying therapies which include the neuro- years into their illness all PD patients can expect to experi-
trophic factor GDNF, as well as the GLP-1 agonists exenatide ence some motor luctuations of this type. Notably, however,
and liraglutide. levodopa-induced dyskinesias and luctuations develop earlier
in younger patients with PD and relate to the dose of medi-
There is no accepted algorithm for the treatment of PD, cation they are given (Rascol et al., 2000). On–off episodes
although guidance has been produced by the National Institute may be extremely disabling and remain a major therapeutic
for Health and Care Excellence (NICE, 2017). A number of fac- challenge in the management of PD, although the develop-
tors may inluence the irst choice therapy for management of ment of deep brain stimulation and enteral delivery systems
motor symptoms, including patient preference, quality of life, for dopaminergic agents have proven beneicial in managing
severity and type of disease (tremor-dominant vs akinetic rigid), this aspect of PD.
comorbidities and potential beneits and harms of the medicines
(Table 32.2). There are limited pharmacotherapeutic options for the manage-
ment of dyskinesia, so management trends have shifted towards
The principles of treatment with levodopa have changed keeping the levodopa dose to a minimum or a ‘levodopa-sparing
little in practice since its initial introduction in 1967, when approach’. This takes the form of either later administration of
the drug was started in low doses and gradually increased levodopa, provided alternative treatments can give adequate
thereafter (Cotzias et al., 1967). The benefits that levodopa symptomatic control, or the use of combination therapies, in an
treatment confers make it the gold standard to this day, nearly effort to reduce the cumulative dose of levodopa given. However,
50 years on from its first introduction. Until quite recently the beneit of this approach beyond 5 years into the illness remains
it was not often the first-line approach in newly diagnosed a matter of debate. 
patients, but this has changed of late with the recognition of
the behavioural problems that dopamine agonists can induce. Drug treatment
Thus, many clinicians will now start patients on low-dose
levodopa in preference to dopamine agonists, even though Levodopa preparations
this is likely to precipitate the well-recognised motor com-
plications of long-term levodopa therapy earlier. These Immediate-release levodopa. Irrespective of the debate
include a premature wearing off of the anti-Parkinsonian regarding when to start levodopa therapy, there is no doubt that
effects of levodopa and fluctuations in the response with the levodopa remains the most effective oral symptomatic treatment
for PD. It is administered with the peripheral dopa-decarboxylase
inhibitors carbidopa or benserazide, where carbidopa plus
levodopa is known as co-careldopa (Sinemet) and benserazide
plus levodopa is co-beneldopa (Madopar). The decarboxylase
inhibitor blocks the peripheral conversion of levodopa to dopa-
mine and thereby allows a lower dose of levodopa to be admin-
istered. Levodopa readily crosses the blood–brain barrier and is
converted by endogenous aromatic amino acid decarboxylase
to dopamine and then stored in the surviving nigrostriatal nerve
terminals.

Immediate-release co-beneldopa is usually commenced in a
dosage of 50 mg, typically three times a day. The patient may be

547

32 THERAPEUTICS

Table 32.2 Potential benefits and harms of dopamine agonists, levodopa and monoamine oxidase type B inhibitors

Motor symptoms Levodopa Dopamine agonists Monoamine oxidase B inhibitors

More improvement in motor Less improvement in motor Less improvement in motor
symptoms symptoms symptoms

Activities of daily living More improvement in activities of Less improvement in activities of Less improvement in activities of
daily living
daily living daily living

Motor complications More motor complications Fewer motor complications Fewer motor complications

Adverse events Fewer specified adverse events* More specified adverse events* Fewer specified adverse events*

*Excessive sleepiness, hallucinations and impulse control disorders (see the summary of product characteristics for full information on individual medicines).
With kind permission from NICE (2017).

instructed in the early stage of the illness to take the drug with simplifying drug regimens, in relieving nocturnal akinesia, and in
food to minimise nausea. Paradoxically, in more advanced PD, co-prescribing with immediate-release levodopa during the day
it may be beneicial to take levodopa 30 minutes or so before to relieve end-of-dose deterioration.
food, as dietary protein can critically interfere with the absorp-
tion of the drug. If there is little or no response to 50 mg three Two commonly encountered problems with CR preparations
times daily, the unit dose may be doubled to 100 mg. Should are, irst, changing the patient from all immediate-release to all
the patient’s levodopa dose escalate to 600 mg/day with no CR levodopa. This is poorly tolerated, because CR levodopa has
signiicant response, the diagnosis of PD should be reviewed. a longer latency than immediate-release levodopa to turn the
Levodopa, commenced in the above way, is usually well toler- patient ‘on’ (typically 60–90 vs 30–50 minutes), and the patient’s
ated. Nausea, vomiting and orthostatic hypotension are the most perception is that the quality of their ‘on’ period is poorer. Second,
commonly encountered side effects. These adverse events may CR preparations should not be prescribed more than four times
be circumvented by increasing the levodopa dose more slowly, a day, because the levodopa may accumulate, causing unpredict-
or co-prescribing domperidone 10 or 20 mg three times daily; able motor luctuations and especially leading to dyskinesias later
however, recently there have been some concerns with the car- in the day. 
diac safety of this agent. Later in the illness, and in common
with all anti-Parkinsonian drugs, levodopa may cause vivid Co-careldopa intestinal gel. An intestinal gel preparation of
dreams, nightmares or even precipitate a confusional state, levodopa and carbidopa (Duodopa) is currently available that
which tends to indicate that the patient is starting to develop a is administered directly into the small bowel (speciically, the
PD dementia. jejunum) via a percutaneous route, using a portable electronic
pump. Through continuous delivery in this way, motor luctua-
Clinically relevant drug interactions with levodopa include tions may be signiicantly reduced. Although effective, this treat-
hypertensive crises with MAO-A inhibitors. Levodopa should, ment modality requires careful patient selection, and because
therefore, be avoided for at least 2 weeks after stopping the inhib- of its cost, it is constantly being reviewed by central agencies
itor, although the non-selective forms of these drugs are rarely authorising drug choice in PD. The endoscopic insertion of a per-
prescribed nowadays. Levodopa can also enhance the hypoten- cutaneous jejunostomy carries a deinite morbidity and mortality.
sive effects of antihypertensive agents and may antagonise the The treatment is also very expensive while mechanical problems
action of antipsychotics. The absorption of levodopa may be with tube detachment and blockage have been reported. Thus, it
reduced by concomitant administration of oral iron preparations.  is currently used only in advanced luctuating patients who are
deemed not to be suitable for deep brain stimulation or apomor-
Controlled-release levodopa. Both Sinemet and Madopar are phine infusions.
available as controlled-release (CR) preparations. The nomen-
clature for Sinemet CR is confusing, as the drug is marketed Other prolonged-release levodopa preparations that are in clin-
as Sinemet CR (carbidopa/levodopa 50/200) and also as Half ical trials include Rytary (IPX066) which is currently available in
Sinemet CR (carbidopa/levodopa 25/100). Trying to prescribe the USA. It utilises a mixed population of coated microspheres to
Half Sinemet CR unambiguously can be dificult. If the instruc- vary the rate of release in a controlled fashion to provide the ben-
tion is misinterpreted and a tablet of Sinemet CR is halved, the eit of immediate relief as well as prolonging that beneit through
slow-release mechanism is actually disrupted. slower release of the active agent. Two gastric retentive formu-
lations are also in development, which slow down the passage
Levodopa in CR preparations has a bioavailability of 60–70%, of the drug through the pylorus aperture to improve levodopa
which is less than the 90–100% obtained from immediate-release uptake. 
formulations. CR preparations have a response duration of 2–4
hours, compared with 1–3 hours for immediate release. Limited Dopamine agonists
beneit has been shown for CR use over immediate-release
levodopa in terms of dyskinesia development and response luc- In theory, dopamine agonists, which stimulate dopamine recep-
548 tuation frequency. However, CR preparations may be of help in tors both post- and pre-synaptically, would seem to be a very

PARKINSON’S DISEASE 32

attractive therapeutic option in PD, because they may bypass the Dopamine agonists have also been associated with impulse
degenerating nigrostriatal dopaminergic neurones. Unfortunately, control disorders. These disorders include pathological gam-
experience to date with the current oral agents reveals them to be bling, hypersexuality, punding and excessive shopping. The
less potent than levodopa and less well tolerated, with signiicant onset may relate to dopamine D2/3 receptor stimulation in
risks of side effects, for example, impulse control disorders, that predisposed individuals. Patients and their carers should be
have been more recognised since the beginning of this century. warned about these potential problems before the drug is pre-
scribed, and patients should be regularly screened for abnor-
Of the two main structural classes, the ergot- and non-ergot- mal behaviours while taking the agonist. However, in some
derived dopamine agonists differ in their afinity for different cases, patients hide this information from their treating clini-
members of the dopamine receptor families. Predominant activ- cian, as well as family, and the problems are identiied only
ity is through the D2-like receptor class, whereas some express when a major crisis emerges as a consequence of this behav-
a preferential binding for D3 subtypes over D2. It is not known iour, for example, house repossession, among others. This lat-
whether these differences are clinically signiicant, but experi- ter problem with impulse control disorders, although rare, has
ence to date would suggest not. Plasma half-lives vary consid- meant that these dopamine agonist therapies are now used less
erably; cabergoline is an ergot dopamine agonist with a plasma as irst-line treatments, and this has been relected in the NICE
half-life of 63–68 hours, meaning that once-daily dosing is pos- guidelines (NICE, 2017). 
sible, although it is now rarely used because of its ibrotic side
effects. Ropinirole and pramipexole are non-ergot derivatives Apomorphine
that originally had to be administered three times daily and have
become the dopamine agonists of choice nowadays. Slow-release Apomorphine is a specialised drug in the treatment of
preparations of ropinirole (XL) and pramipexole (PR) are avail- advanced PD, but almost certainly continues to be under-
able for once-daily dosing. A transdermally administered non- used. It is the most potent non-selective dopamine agonist
ergot dopamine agonist, rotigotine, is also available as a 24-hour available but has a short half-life, a single bolus administra-
adhesive patch. tion lasting for 45–60 minutes. It is therefore administered as
either a bolus or subcutaneous infusion depending on the pur-
There have been very few comparative studies performed pose. A bolus subcutaneous injection of apomorphine is suit-
between the dopamine agonists, so it is not possible to be able for patients who are optimised on their oral medications
deinitive as to which drug should be recommended. However, but who still suffer from troublesome, typically unpredict-
currently, ergot-derived dopamine agonists are avoided able ‘off’ periods or would benefit from rapid early-morning
because of the side effects and the need, therefore, for annual relief until their oral medication takes effect. Alternatively,
screening of patients receiving these drugs. Thus, ropinirole, continuous infusion is a useful therapeutic option in patients
pramipexole and rotigotine are the most widely prescribed who are no longer well controlled by standard oral therapies
dopamine agonists, and if a patient does not get on with one and in whom apomorphine injections have proven effec-
of these, it may be worthwhile changing from one agonist to tive. Frequent use of the injection (four to six times per
another, because there is variability in a given patient’s toler- day) is associated with increasing dyskinesia, so control is
ance to the different drugs. improved by the continuous infusional delivery of the drug
(Trenkwalder et al., 2015).
Dopamine agonist side effects. The principal side effects
of the dopamine agonists are nausea and vomiting, postural Initiation of apomorphine therapy can be as an in-patient
hypotension, hallucinations, confusion and, in some cases, or as an outpatient by a nurse specialist, geriatrician or neu-
major behavioural problems linked to impulse control disor- rologist. Nausea and vomiting at the start of therapy can be
ders. These latter problems can be very signiicant and lead to treated with domperidone, usually 20 mg three times a day
major inancial and social problems. Thus, there is a greater for 2–3 days before initiation. Other antiemetics such as pro-
emphasis now on informing patients about these side effects chlorperazine or metoclopramide cannot be used because they
when they are prescribed these drugs, with a recommenda- block dopamine receptors and make PD worse. Orthostatic
tion that this advice is clearly documented in the hospital hypotension can be managed with medication or with non-
notes (NICE, 2017). Ergot derivatives run the risk of causing pharmacological interventions. Neuropsychiatric disturbance,
pleuropulmonary ibrosis and therefore are not routinely used probably at a lower frequency than with oral agonists, and
anymore. skin reactions, including nodule formation, are other poten-
tial side effects. Apomorphine, in conjunction with levodopa,
Ropinirole and pramipexole were previously implicated in may, in rare cases, cause a Coomb’s positive haemolytic anae-
causing ‘sleep attacks’, with sudden onset of drowsiness, lead- mia, which is reversible. It is recommended that patients are
ing to driving accidents in some cases. The term sleep attack is screened before beginning treatment and at 6-monthly inter-
almost certainly a misnomer, however, as patients do have warn- vals thereafter. 
ing of impending sleepiness, although they may subsequently be
amnesic for up to several minutes while in this state. Excessive Catechol-O-methyl transferase inhibitors
sleepiness attributable to anti-Parkinsonian drugs is actually not
a new phenomenon and is almost certainly a ‘class effect’ of all Inhibitors of the enzyme catechol-O-methyl transferase (COMT)
dopaminergic therapies. It is essential to advise patients who are represent a useful addition to the range of therapies available for 549
taking all anti-Parkinsonian agents that they may be prone to
excessive drowsiness. This may be compounded by the use of
other sedative drugs and alcohol.

32 THERAPEUTICS

PD (Schrag, 2005). Use of the irst agent in this class, tolcapone, actually found, with a higher incidence of dyskinesias in patients
was originally suspended in Europe because of fears over hep- randomised to levodopa and entacapone compared with levodopa
atotoxicity, although the drug became available again in 2005, alone. Other than exacerbation of dyskinesias, COMT inhibitors
accompanied by strict prescribing and liver function monitoring may also cause diarrhoea, abdominal pain and dryness of the
guidelines. Entacapone is also available, and studies have not mouth. Urine discolouration is reported in approximately 8% of
shown derangement of liver function with this drug; thus, it is patients who are taking entacapone.
used much more.
It is best to avoid non-selective MAO inhibitors or a daily dose
COMT itself is a ubiquitous enzyme, found in the gut, liver, of selegiline in excess of 10 mg (which in reality never happens
kidney and brain, among other sites. In theory COMT inhibition in PD) when using entacapone. In addition, the co-prescribing
may occur both centrally, where the degradation of dopamine of venlafaxine and other noradrenaline (norepinephrine) reuptake
to homovanillic acid is inhibited, and peripherally, where con- inhibitors is best avoided. Entacapone may potentiate the action
version of levodopa to the inert 3-O-methyldopa is inhibited. In of apomorphine. Patients who are taking iron preparations should
practice, both tolcapone and entacapone act primarily as periph- be advised to separate this medication and entacapone by at least
eral COMT inhibitors and by so doing increase the amount of 2 hours. 
levodopa that enters the CNS.
Monoamine oxidase type B inhibitors
Placebo-controlled studies in patients with luctuating PD
have conirmed the eficacy of entacapone in decreasing ‘off’ The propargylamines selegiline and rasagiline are inhibitors
time and permitting a concomitant reduction in levodopa dose. of MAO-B. Inhibition of this enzyme slows the breakdown
A 20% reduction in ‘off’ time is reported, translating into nearly of dopamine, effectively having a ‘levodopa-sparing’ effect
1.5 hours less immobility per day. This reduction tends to occur in the striatum. The result of this is both a mild therapeutic
towards the end of the day, a time when many patients with PD effect and a possible delay in the onset of or reduction in
are at their worst in terms of motor function. A comparison of existing motor complications. Both drugs may also have an
entacapone and tolcapone suggested that tolcapone may be the antiapoptotic effect. Apoptosis is a form of programmed cell
more potent COMT inhibitor, achieving up to an extra 1.5 hours death thought to be important in several neurodegenerative
of ‘on’ time per day (Entacapone to Tolcapone Switch Study conditions, including PD. Whether the drugs have a neuro-
Investigators, 2007). protective effect by this or some other means remains contro-
versial, but the current consensus is that this is not the case.
When entacapone is prescribed, a 200 mg dose is usually given Different protocols and starting doses have made comparing
with each dose of levodopa administered, up to a frequency of outcomes from different trials impossible (Mínguez-Mínguez
10 doses/day. The increased dyskinesias means an overall reduc- et al., 2013). However, their mild symptomatic effect, ease of
tion of 10–30% in the daily dose of levodopa may be anticipated. use, relative absence of side effects and putative neuropro-
Entacapone can be employed with any other anti-Parkinsonian tection, in the absence of any other neuroprotective agents
drug, although caution may be needed with apomorphine. available, makes them still a common choice as first-line
Entacapone is also marketed as a compound tablet containing therapy for many doctors. A recent meta-analysis found a sig-
levodopa and carbidopa (Stalevo). Although each tablet contains nificant and comparable effect of the two drugs on Unified
200 mg of the COMT inhibitor, seven different doses of levodopa Parkinson’s Disease Rating Scale scores in early PD (Jost
are available (50, 75, 100, 125, 150, 175 and 200 mg) to provide et al., 2014).
lexibility. The compound tablet may help adherence by signii-
cantly reducing the total daily number of tablets a patient needs A single daily dose of 5 or 10 mg of selegiline is prescribed.
to take. Higher doses are associated with only minimal additional inhi-
bition of MAO. Selegiline may also be administered as a lyophi-
Tolcapone is prescribed as a ixed 100 mg three times a day lised freeze-dried buccal preparation. The dosage of rasagiline
regimen, increasing if necessary to 200 mg three times a day. It is 1 mg daily. Both selegiline and rasagiline may be used as
may only be used after the patient has tried and not responded de novo or adjunctive treatments in PD, although trial data
positively to entacapone and where provision for 2-weekly for the latter indication is strongest for rasagiline and buccal
monitoring of liver function tests for the irst 12 months, reduc- selegiline.
ing in frequency thereafter, is available. Again, a concomitant
reduction in levodopa may be necessary to offset an increase in Selegiline can rarely cause hallucinations and confusion, par-
dyskinesias. ticularly in moderate-to-advanced disease, typically through
enhancing the actions of levodopa centrally. The withdrawal of
The optimal way to use COMT inhibition is unknown. A selegiline may then be associated with signiicant deterioration in
patient experiencing end-of-dose deterioration, or generally motor function. Unlike selegiline, rasagiline is not metabolised to
underdosed, would seem to be the ideal candidate. However, amphetamine-like products, so neuropsychiatric side effects are
few comparative studies of COMT inhibitors versus dopamine less frequent. A critical interaction occurs with opioid analgesics;
agonists are available to provide guidance as to which class of selegiline in particular is associated with hyperpyrexia and CNS
drug is best to use and when. The STRIDE-PD study (Stocchi toxicity if administered concomitantly with pethidine. Selective
et al., 2010) assessed the potential beneit of combined treat- serotonin reuptake inhibitors should be used with caution in com-
ment with levodopa and entacapone in de novo PD patients to bination with MAOB inhibitors because there remains a small
address whether this combined treatment was associated with a
lower incidence of dyskinesias. Unfortunately, the opposite was
550

PARKINSON’S DISEASE 32

theoretical risk of serotonin syndrome, although there has been synthesis). Clinical trials have demonstrated proof of principle
only a single case report.  for cell transplantation studies using fetal dopamine cells, and
the future looks promising for stem cells as a more viable, qual-
Amantadine ity-controlled source of transplantable cells (Barker et al., 2015).
Hybridising these novel approaches with the more established
Amantadine was introduced as an anti-Parkinsonian treatment deep brain stimulation is also being postulated in a multifaceted
in the late 1960s. It has a number of possible modes of action, approach to managing this condition long-term. 
including facilitation of presynaptic dopamine release, blocking
dopamine reuptake, an anticholinergic effect (nicotinic antago- Patient care
nist), and also may act as a weak N-methyl-d-aspartate (NMDA)
receptor antagonist. Initially employed in the early stages of Common therapeutic solutions to problems encountered in the man-
treatment, where its effects are mild and relatively short-lived, it agement of people with PD are presented in Table 32.3. After diag-
is more commonly used as an antidyskinetic agent in advanced nosis, the provision of an explanation of the condition, education
disease, the only drug licensed for such use. and support are essential. PD charities produce an excellent range of
literature to help the newly diagnosed patient come to terms with the
Daily doses of 100–400 mg amantadine may be used. Some condition. Patients who drive are advised to inform their insurance
recommend even higher doses for improved antidyskinetic company and also the UK Driver and Vehicle Licensing Agency.
effect, although side effects become much more frequent at
higher doses. These side effects include a toxic confusional state A doctor will record impairments in the clinic, while the patient is
and peripheral and corneal oedema. Monitoring is not needed, more concerned with their disability and handicap. Thus, a patient
but attention needs to be paid to patients reporting sudden visual can be noted to have seemingly marked impairment and yet may
changes. Livedo reticularis, a persistent patchy reddish-blue mot- not complain about signiicant disability. The converse may also
tling of the legs, and occasionally the arms, is also a side effect.  be true. Not all patients, therefore, require immediate treatment.
Further, concomitant depression may distort the patient’s percep-
Antimuscarinic drugs tion of his or her disability, leading to inappropriate prescribing of
anti-Parkinsonian therapy. In this situation, the use of an antide-
The availability of antimuscarinic drugs such as trihexypheni- pressant may be more helpful. There is no good evidence base for
dyl and orphenadrine predated the introduction of levodopa by which antidepressant should be used, and both the tricyclic agents
nearly 90 years. Antimuscarinic drugs can have a moderate effect and selective serotonin reuptake inhibitors have their advocates.
in reducing tremor but do not have any signiicant beneit upon
bradykinesia. The use of antimuscarinic agents has declined Accurate adherence with the timing of therapy may be particu-
because of troublesome side effects, including constipation, uri- larly important in patients who are beginning to experience long-
nary retention, cognitive impairment and toxic confusional states. term treatment complications. It can be helpful for patients to
In selected younger patients, an antimuscarinic drug may still be keep diaries when they begin to experience problems with either
helpful, but close monitoring is advised.  bradykinesia or dyskinesia, so that these symptoms can be related
to drug and food intake. Careful changes in timing of drug therapy
Surgical treatment or meals may initially be suficient to reduce variation in perfor-
mance. Some patients experience troublesome early-morning bra-
Surgical approaches for the management of PD include both dykinesia. It may then be beneicial to prescribe an initial dose
lesioning (-otomies) and deep brain stimulation (a high-frequency of a rapidly acting agent, such as dispersible oral co-beneldopa,
signal that functionally turns off the nucleus being stimulated). to take on irst wakening so that the patient can then get up and
The functional effects are similar, but deep brain stimulation is dress. A combination of levodopa with dopamine agonists, which
preferred clinically and has the advantage of being reversible and are more slow acting, may be useful in the patient with motor luc-
controllable to a degree. Various targets in the basal ganglia have tuations. A combination of levodopa and a COMT inhibitor may
been considered, but overwhelmingly deep brain stimulation of be more appropriate in a patient with end-of-dose deterioration.
either the internal part of the globus pallidus or the subthalamic
nucleus is the therapy of choice in most patients. The interven- Other factors that need to be considered in patients with PD
tion is costly, but signiicant beneits can be gained, especially for are the beneits of adequate sleep and rest at night, which may be
patients who have previously had a good response to levodopa made more dificult if they have urinary frequency or problems
but are experiencing major motor luctuations or dyskinesia. with nocturnal bradykinesia. Judicious use of hypnotic therapy
Careful case selection is essential for all forms of surgical inter- may be appropriate, whereas a tricyclic antidepressant may offer
vention for PD: older and less biologically it patients, those with the dual beneit of sedation with anti-muscarinic effects. Low
active cognitive and/or neuropsychiatric problems, and patients friction sheets to assist turning in bed and encouragement of
with a suboptimal levodopa response are generally regarded as mobility through physiotherapy may also be helpful.
poor surgical candidates (Worth, 2013).
The treatment of the patient with severe disease remains one of
New potential surgical approaches also include the delivery the greatest challenges in the management of PD. On–off luctua-
of growth factors, dopamine cells and viral vectors (for the tions may be refractory to oral dopaminergic therapies. Sudden
delivery of growth factors or enzymes required for dopamine freezing episodes compound failing postural stability, leading to

551

32 THERAPEUTICS

Table 32.3 Common therapeutic solutions in the management of Parkinson’s disease

Problem Cause Possible solution
Exposure to levodopa
Early-onset dyskinesias in Delay introduction of levodopa, use lowest possible dose, use
young patient with Parkinson’s alternative agent (e.g. dopamine agonist, MAOB inhibitor), or start
disease amantadine

One dose of levodopa does not Advanced disease (pre- and post- More frequent, smaller doses of levodopa, COMT inhibitor, dopa-
last until the next (wearing off) synaptic changes) mine agonist or MAOB-inhibitor
Start slow-release levodopa in addition to immediate-release agents

Pain and immobility during the Evening dose of levodopa not Use slow-release levodopa preparation or slow-release dopamine
agonist last thing at night
night lasting long enough

Freezing episodes and/or un- Advanced disease (pre- and post- Dopaminergic therapies, apomorphine, Duodopa or surgery
predictable motor fluctuations synaptic changes) Physiotherapy helpful for freezing; sensory cues can help (stripes on
the floor, etc.).
Some recent evidence to suggest rivastigmine may help some
patients with freezing of gait

Mismatch between patient’s Consider underlying depression Consider antidepressant (e.g. citalopram)
symptoms and signs

Confusion and hallucinations Toxic (drug-related) psychosis Exclude intercurrent infection or other medical problem
with preserved cognition Review and reduce anti-Parkinsonian therapy
Consider atypical antipsychotic agent such as quetiapine

Fatigue and tiredness Underlying brain pathology or Reduce or stop dopamine agonists; modafinil may help and should
dopamine agonists be tried

Poor sleep or RBD Check no other cause for sleep For RBD, use clonazepam 0.25–0.5 mg at night or melatonin
problem such as going off at night, If insomnia is the major issue, try low-dose amitriptyline or a Z-drug
nocturia, sleep apnoea, etc.

Confusion and hallucinations Underlying brain pathology and Reduce anti-Parkinsonian therapy
with impaired cognition cholinergic deficit Cholinesterase inhibitor may be tried

COMT, Catechol-O-methyl transferase; MAOB, monoamine oxidase type B; RBD, REM sleep behavioural disorder.

increasing falls and injuries. In select patients, the use of apo- Parkinsonism. Behavioural disturbances require discussion
morphine, either as bolus injection (via a penject device) or as a with carers and, if possible, with the patient themselves. A
continuous subcutaneous infusion, may be helpful, as might the graded withdrawal of anti-Parkinsonian drugs is often indi-
use of cholinesterase inhibitors (Worth, 2013). cated, aiming to simplify the regimen to levodopa mono-
therapy and especially removing drugs that are well known
The presence of reduced dexterity in virtually all people with to cause neuropsychiatric problems such as amantadine and
PD means that thought needs to be given to the way in which dopamine agonists. In rare cases, it may be necessary to reduce
medication is dispensed and stored. If the patient is taking a com- the dose or even completely withdraw levodopa therapy to
plex regimen of drugs or has early cognitive problems, the use of control aggressive, sexually demanding or psychotic features.
pre-packaged therapies may improve adherence. When reduction in dopaminergic therapy is ineffective or not
tolerated because of unacceptable immobility, an atypical
Patients’ relatives also need emotional and social support antipsychotic drug may be considered. In practice, the choice
through what can be a very demanding period. It can be very is restricted to quetiapine or clozapine, because risperidone
dificult for relatives to cope with the patient’s loss of physical and olanzapine are associated with worsening Parkinsonism,
mobility, together with a personality change. The involvement of even in low doses (NICE, 2017). Further, both risperidone and
occupational therapists, social workers and specialists in pallia- olanzapine should not be used in cognitively impaired elderly
tive care in this situation is important. people because of an increased risk of stroke. Clozapine is
dificult to use for PD-associated psychosis because of the
Psychosis and dementia need to register the patient with a blood-monitoring pro-
gramme. When quetiapine is used, it should be commenced at
When cognitive impairment is problematic, the use of con- a low dose of 25 or 50 mg at night and increased slowly. The
ventional antipsychotic medication is inappropriate because sedative effects may be helpful in promoting sleep.
the pharmacological actions of such drugs, dopamine recep-
552 tor antagonism, can precipitate a catastrophic worsening of

PARKINSON’S DISEASE 32

Table 32.4 Management of autonomic/enteric problems in Parkinson’s disease

Symptom response to dopamine

replacement therapy Treatment options Cautionary notes

Faecal incontinence Unresponsive None available Check that this is not overflow
diarrhoea from faecal impaction.

Urinary incontinence Responsive Antimuscarinic drugs; Antimuscarinics agents could
incontinence pads worsen cognitive impairments,
constipation and produce a dry
mouth.

Erectile dysfunction Responsive Consider sildenafil or similar Consider if erectile dysfunction
agent is part of a more general major
autonomic problem.

Dysphagia (impaired Responsive Refer to speech and language Check no non-Parkinson’s
swallowing) and speech therapists disease cause for problems with
speech (e.g. dentures) or swal-
lowing.

Nocturia Consider antimuscarinic Make sure there are no primary
urological problems such as
prostatism.

Sialorrhea (excessive drooling) Responsive Glycopyrronium bromide inhaler/
oral medication;
Botox injections into salivary
glands
If neither of the above work
consider:
• antimuscarinic such as a

hyoscine patch
• low-dose clonidine
• sublingual atropine eye drops

Excessive sweating Unresponsive β-Blockers can occasionally help

Postural hypotension May be induced by dopamine Midodrine or fludrocortisone May worsen with dopamine ago-
replacement therapy nists and lead to falls; falls are a
leading cause of hospitalisation
in Parkinson’s disease

Constipation Responsive Bulking agents, osmotic laxative, May improve with a switch from

macrogol oral therapy to rotigotine patch

Weight loss Refer for nutritional advice Make sure no other cause for
Many ongoing trials, see Schrag et al. (2015) for further information. this such as underlying malig-
nancy

Cholinesterase inhibitors have shown promise in treating the Autonomic problems 553
neuropsychiatric features of PD and may also have modest cog-
nitive-enhancing beneits. Visual hallucinations, delusions, apa- Treating the autonomic problems where possible is critical to
thy and depression seem to be particularly responsive to these improving a patient’s quality of life. Understanding the root
agents. These effects have been demonstrated for rivastigmine, cause of the non-motor events is important because many
the only cholinesterase inhibitor licensed for use in PD demen- are either unresponsive to dopamine replacement therapy or
tia in a large, multicentre, double-blind, placebo-controlled study may actually be induced by them. Table 32.4 lists the main
(Emre et al., 2004). Although not licensed, memantine has also treatment options available for the major autonomic effects
been shown to be effective in smaller-scale clinical trials and can which commonly occur in patients. These include disorders
be used in combination with rivastigmine in some patients.  of gut motility, constipation or dificulty with swallowing,

32 THERAPEUTICS

disturbances of micturition, sometimes presenting as noctu- a research programme if possible, as he would be an ideal patient
ria, and postural hypotension. Constipation can be managed for emerging experimental therapies such as cell transplants or
in the usual way with osmotic laxatives and, if necessary, gene therapies. 
stimulant laxatives and stool-softening agents. The man-
agement of postural hypotension includes assessment of Case 32.2
the patient’s autonomic function to establish whether this
is primarily drug-related or associated with an autonomic Mr HM, a 47-year-old man, with PD is well controlled with ropinirole
neuropathy. If the patient is dizzy on standing, simple mea- XL 16 mg/day and rasagiline 1 mg once daily. He denies any prob-
sures such as advice on rising slowly may be adequate. The lems when you review him in clinic, but his wife e-mails you to say
use of elastic stockings, to reduce pooling of the blood in the that he spends a lot of time at night on eBay buying engine parts
lower limbs, is sometimes helpful, although poorly tolerated. for a particular type of car that he has always been interested in.
Pharmacological approaches include the use of midodrine (a
selective α1-adrenergic agonist) or ludrocortisone. It is also Questions
important to consider other therapies the patient is receiving
that might contribute to such symptoms, for example, diuret- 1. What is being described here?
ics, and to stop these if possible.  2. What is the cause of this behaviour?
3. How would you manage it? 
Case studies
Answers
Case 32.1
1. Impulse control disorder.
Mr ST, a 35-year-old man, develops a worsening tremor of his right 2. This is likely to be driven by his premorbid personality and the use
hand and has difficulty running on a treadmill at his local gym as
his right leg will not keep up. His father developed PD in his early of the dopamine agonist.
70s. 3. Mr HM needs to be seen in the PD clinic, although this does not

On examination he has a bilateral tremor more on the right than need to be done urgently (unless the level of expenditure on this
the left and does not swing his right arm when walking. He has no activity is excessive). In clinic the patient should be given the
other major deficits and no significant medical history. opportunity to bring this issue up, and if not then it should be
raised because often patients deny or do not recognise that this is
Questions an issue/problem. Once raised, it should be explained that this is
a well-known side effect of the ropinirole, and that this drug should
1. What is the most likely diagnosis? be stopped and replaced with levodopa. The rationale for this and
2. What other points do you need to consider? the consequences of doing this need explaining, and the patient
3. What treatment, if any, would you recommend?  may require specialist input, such as cognitive behavioural therapy
to help them wean off the dopamine agonist successfully. 
Answers
Case 32.3
1. PD. The asymmetric onset of tremor, bradykinesia of the right leg
and the loss of arm swing would all make one suspect this is the Mrs AB, a 63-year-old woman, has had PD for 5–6 years. She now
most likely diagnosis despite his young age. finds her medication is not working as well as it used to, and that she
takes a long time to get going in the morning and is rather fidgety
2. In all patients with young-onset PD, it is important to exclude last thing in the day. She is currently taking Madopar CR five times
other causes. It is thus essential to take a medication history a day and selegiline 10 mg once daily, as well as 8 mg ropinirole XL
to ensure that this could not be drug induced, although the once daily.
asymmetry of presentation would be against this. It is important
to exclude a metabolic cause given his age, such as Wilson’s Questions
disease, so relevant blood tests should be done, as well as an
MRI scan of the brain to exclude signal change within the basal 1. What is Mrs AB describing?
ganglia suggestive of a metabolic problem. Finally a genetic 2. What is causing these symptoms?
cause should be considered (e.g. Parkin mutation). However, 3. How would you treat them? 
even at this age most cases are sporadic and having a single
family member with the condition who developed it late in life Answers
is not significant. Given the condition is quite common, one
is allowed by chance to have another member of the family 1. Mrs AB has a combination of being ‘off’ in the morning and ‘on’
with PD. with dyskinesia in the evening.

3. Treatment options depend upon whether the motor symptoms 2. She is on a regimen of drugs that is suboptimal for someone with
impact on his quality of life. NICE (2017) suggests that if they do, PD for this length of time. Her dose of ropinirole is low; most
levodopa should be offered, whereas if they do not impact on his patients experience an optimal response when receiving 16–20
quality of life, either a dopamine agonist, levodopa or an MAO-B mg daily of the drug. In addition, she has no immediate-release
inhibitor could be considered. He should also be told about the Madopar in the morning, so it takes her a while to get going and
support networks that exist for PD and be encouraged to link up to then during the day the use of only Madopar CR at this frequency
means she is slightly overdosed in the evening.

554

PARKINSON’S DISEASE 32

3. She should reduce the Madopar CR to twice a day, increase twice a day and amantadine 100 mg twice a day. However, over
the ropinirole to 16 mg/day and start an immediate release of the last few months she has been seeing animals in her bedroom
Madopar (e.g. Madopar 62.5 or 125) three times a day.  at night and on occasions thinks there is someone else in the
house. She lives on her own, but her friend who comes with her
Case 32.4 to the clinic says she is becoming more withdrawn and suspicious
of others.
Mr CD, a 59-year-old man, has had PD for 12 years. He has
responded well to levodopa in the past but now finds that he has Questions
unpredictable ‘off’ periods during the day and peak dose dyskine-
sias that are present for several hours every day. He has a medi- 1. What is being described here?
cal history of hypertension and is known to have benign prostatic 2. What investigations would you suggest?
hypertrophy. His current regimen is Sinemet 110 six times a day; 3. What therapeutic management could be considered for Mrs EF?
Half Sinemet CR twice a day, amantadine 100 mg three times a 4. What is likely to happen to Mrs EF in the next few years? 
day and a rotigotine patch 12 mg once a day.
Answers
Question
1. Mrs EF has developed neuropsychiatric problems with her PD
What treatment would you recommend and why?  that involves visual hallucinations with delusions and a degree of
paranoia.
Answer
2. It is important to make sure that nothing else is causing this, such
Mr CD has now entered the advanced stages of PD with marked as a low-grade infection or some other comorbid condition or
motor fluctuations and as such is heading towards a more invasive metabolic problem. Thus, an infective screen and a series of rou-
therapeutic intervention. tine blood tests should be undertaken. It is unlikely to relate to a
In the first instance one could try fractionating his levodopa load, so, new intracranial problem such as encephalitis or a chronic sub-
for example, one could put him on Sinemet CR twice a day and then dural haematoma, but if there are focal neurological signs, then
Sinemet 62.5 eight times a day, while also increasing the amantadine imaging of the brain is recommended with or without cerebrospi-
up to the maximum dosage of 400 mg/day. nal fluid examination.
However, even if this is effective, the problems are likely to re-occur However, the most likely cause is her underlying PD with cortical
because his nigrostriatal pathway has now degenerated to the point Lewy body pathology which with her medication is driving her cur-
that the uptake, release and post-synaptic effects of the levodopa are rent neuropsychiatric syndrome.
erratic. He will therefore need to be considered for:
• a subcutaneous apomorphine pump 3. If no other cause is found, then the drugs should be reduced.
• deep brain stimulation The most likely agent is the amantadine, so this should be with-
• Duodopa infusion therapy (into the small bowel) drawn over the next few weeks. If she does not improve with
Given his age, response to therapy to date and the absence of major this change, then levodopa dose could be reduced, although
non-motor complications or comorbidities, he would be a good can- this may make her unacceptably immobile and ‘off’. If this
didate for any one of these treatments. However, in the UK it is very occurs, the Madopar needs to be re-introduced and rivastig-
difficult for him to have Duodopa treatment because of its expense, mine 1.5 mg twice a day needs to be started (after appropriate
unless there are exceptionally good reasons for him not to have electrocardiogram screening) or alternatively quetiapine (25 mg
already been treated or offered treatment with apomorphine or deep at night).
brain stimulation treatment.  Mrs EF also needs to be closely followed up ideally by a specialist
community nurse who can visit her at home.
Case 32.5
4. Mrs EF is likely to progress to a PD dementia because these symp-
Mrs EF, a 76-year-old woman, has had PD for about 10 years. She toms are typically an indication of this complication of PD.
is well controlled on Madopar 125 four times a day, Madopar CR

References Edwards, Y.J.K., Beecham, G.W., Scott, W.K., et al., 2011. Identifying 555
consensus disease pathways in Parkinson’s disease using an integrative
Barker, R.A., Drouin-Ouellet, J., Marmar, M., 2015. Cell-based therapies for systems biology approach. PLoS One. 6 (2), e16917. https://doi.org/10.13
Parkinson’s disease – past insights and future potential. Nat. Rev. Neurol. 71/journal.pone.0016917.
11 (9), 492–503.
Emre, M., Aarsland, D., Albanese, A., et al., 2004. Rivastigmine for demen-
Bellou, V., Belbasis, L., Tzoulaki, I., et al., 2016. Environmental risk factors tia associated with Parkinson’s disease. N. Engl. J. Med. 351, 2509–2518.
and Parkinson’s disease: an umbrella review of meta-analyses. Parkinson-
ism Relat. Disord. 23, 1–9. Entacapone to Tolcapone Switch Study Investigators, 2007. Entacapone to
Tolcapone switch: multicenter double-blind, randomized, active-con-
Braak, H., Del Tredici, K., Rüb, U., et al., 2003. Staging of brain pathology trolled trial in advanced Parkinson’s disease. Mov. Disord. 22 (1), 14–19.
related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211.
Hely, M.A., Reid, W.G., Adena, M.A., et al., 2008. The Sydney multicenter
Bras, J., Guerreiro, R., Hardy, J., 2015. SnapShot: genetics of Parkinson’s study of Parkinson’s disease: the inevitability of dementia at 20 years.
disease. Cell 160 (3), 570–572. Mov. Disord. 23, 837–844.

Cotzias, G.C., Van Woert, M.H., Schiffer, L.M., 1967. Aromatic amino acids
and modiication of parkinsonism. N. Engl. J. Med. 276, 374–379.

32 THERAPEUTICS

Jennings, D.L., Seibyl, J.P., Oakes, D., et al., 2004. (123I)beta-CIT and single- Schrag, A., 2005. Entacapone in the treatment of Parkinson’s disease. Lancet
photon emission computed tomographic imaging vs. clinical evaluation in Neurol. 4, 366–370.
Parkinsonian syndrome: unmasking an early diagnosis. Arch. Neurol. 61,
1224–1229. Schrag, A., Saubier, A., Chaudhuri, K.R., 2015. New clinical trials for nonmo-
tor manifestations of Parkinson’s disease. Mov. Disord. 30 (11), 1490–1503.
Jost, W.H., Friede, M., Schnitker, J., 2014. Comparative eficacy of sele-
giline versus rasagiline in the treatment of early Parkinson’s disease. Eur. Spillantini, M.G., Schmidt, M.L., Lee, V.M., et al., 1997. Alpha-synuclein in
Rev. Med. Pharmacol. Sci. 18 (22), 3349. Lewy bodies. Nature 388 (6645), 839–840.

Mínguez-Mínguez, S., Solís-García Del Pozo, J., Jordán, J., 2013. Rasagil- Stocchi, F., Rascol, O., Kieburtz, K., et al., 2010. Initiating levodopa/carbi-
ine in Parkinson’s disease: a review based on meta-analysis of clinical dopa therapy with and without entacapone in early Parkinson disease: the
data. Pharmacol. Res. 74, 78–86. STRIDE-PD study. Ann. Neurol. 68, 18–27.

National Institute for Health and Care Excellence (NICE), 2017. Parkinson’s Trenkwalder, C., Chaudhuri, K.R., García Ruiz, P.J., et al., 2015. Expert
disease in adults. NICE guideline [NG71]. NICE, London. Available at Consensus Group report on the use of apomorphine in the treatment of
https://www.nice.org.uk/guidance/ng71. Parkinson’s disease – clinical practice recommendations. Parkinsonism
Relat. Disord. 21 (9), 1023–1030.
Polymeropoulos, M.H., Lavedan, C., Leroy, E., et al., 1997. Mutation in
the alphasynculein gene identiied in families with Parkinson’s disease. Worth, P.F., 2013. When the going gets tough: how to select patients with
Science 276, 2045–2047. Parkinson’s disease for advanced therapies. Pract. Neurol. 13 (3), 140–152.

Rascol, O., Brooks, D.J., Korczyn, A.D., et al., 2000. A 5 year study of the
incidence of dyskinesia in patients with early Parkinson’s disease who were
treated with ropinirole or levodopa. N. Engl. J. Med. 342 (20), 1484–1491.

Further reading Walter, B.L., Vitek, J.L., 2004. Surgical treatment for Parkinson’s disease.
Lancet Neurol. 3, 719–728.
Ali, K., Morris, H.R., 2015. Parkinson’s disease: chameleons and mimics.
Pract. Neurol. 15, 14–15.

van der Brug, M.P., Singleton, A., Gasser, T., et al., 2015. Parkinson’s dis-
ease: from human genetics to clinical trials. Sci. Trans. Med. 7, 305–320.

556

THERAPEUTICS

33 Dementia

Denise Taylor

Key points Epidemiology

• Globally, 47.5 million people live with dementia; 850,000 Incidence and prevalence
people in the UK have dementia, and this number is projected
to rise to more than 1 million by 2025. Dementia is a global issue, with an estimated 47.5 million people
living with dementia worldwide; this estimate is predicted to
• In the UK, 62% of people with dementia are female, probably rise to more than 150 million by 2050 (Public Health England,
because life expectancy is higher in females and age is the big- 2016). In 2015, there were an estimated 856,700 people in the
gest known risk factor for dementia. UK with dementia, with 720,251 living in England, 45,321
in Wales, 70,162 in Scotland and 20,966 in Northern Ireland
• There is no cure for any form of dementia, except for the (Alzheimer’s Society, 2014). Established prevalence rates link
pseudo-dementias, which may respond to treatment. the risk of dementia with increasing age, rising from 1 in 688
people younger than 65 years, to 1 in 14 people older than 65
• Risk reduction for dementia includes reducing modifiable car- years, to 1 in 6 older than 80 years and 1 in 3 of older than 90
dio- and cerebrovascular risk factors. years. However, in February 2016, the actual number of people in
England with a recorded diagnosis in the record of their primary
• Early interventions include planning for the future in terms of care doctor was 426,000, indicating a prevalence of 0.756% or 1
advocacy and end-of-life care options. person in 132 (Health and Social Care Information Centre, 2016).
Thus, about 41% of people with signs and symptoms of dementia
• Pharmacological treatment is multifactorial and includes in England are not yet diagnosed.
pharmacological support of cognitive function and non-
pharmacological support of patients and their carer/family. Furthermore, recent research suggests the proportion of people
living with dementia has decreased by 20% over the last two
• Acetylcholinesterase inhibitors and memantine improve cogni- decades, linked mainly to a reduction in male smoking, leading
tive function, including improvements in social relationships, healthier lives and reduction of cardiovascular risks (Matthews
behaviour, engagement with the individual’s environment, et al., 2016). In the 1990s it was predicted there would be 250,000
language and delay entry to nursing home care. new cases of dementia each year, whereas study indings put this
at 210,000 per year (Winblad et al., 2016). 
• Acetylcholinesterase inhibitors delay the neurodegenerative
process. Prognosis

• Future treatments include monoclonal antibodies and small There is no cure for any of the dementias, with an average life
molecule treatment. expectancy post-diagnosis of 5–10 years; however, some people
have survived for 20 years.
• Maintaining physical and mental health by inclusion in
socially and mentally stimulating activities is an important Annual UK societal costs of dementia are estimated at £26.3
part of care. billion: £4.5 billion on state social care, £11.6 billion on unpaid
care, £4.3 billion on health care, £5.8 billion on individual social
• Healthcare professionals and carers need to adapt their com- care and £100 million on other costs. These are higher than the
munication style to best support the individual. cost of cancer, heart disease or stroke.

Definition In the UK, up to one-third of Alzheimer’s disease (AD) cases
may be attributable to potentially modiiable risk factors, and
The word dementia is an umbrella term for a host of neurodegen- 21.8% of AD cases could be attributed to physical inactivity.
erative diseases which cause progressive cognitive impairment, A 20% reduction in risk factors per decade could reduce UK
suficient to interfere with work, social function and relation- prevalence rates by 16.2% (300,000 cases) by 2050 (Winblad
ships. It is important to recognise that cognitive function is not et al., 2016). Table 33.1 describes the risk factors for dementia.
just about memory but includes language, visuospatial and per-
ceptual ability, thinking and problem solving, and personality.
This progressive impairment is the root cause of distress for car-
ers and family of people with dementia, as the person they love
seems to change and disappear. 

557

33 THERAPEUTICS

Table 33.1 Risk factors for dementia Table 33.2 Protective factors for dementia

Risk factors Association Protective factor Associated with…
Age
Higher blood pressure in midlife Higher levels of educa- Use it, don’t lose it (brain function)
Increased incidence of some diseases (en- tion
cephalitis, delirium)
Changes to nerve cells, DNA and cell struc- More mentally demand- Examples include teaching, research,
ture
Weakening of body’s natural repair systems ing occupations mathematics, writers, accountants,
Changes in the immune system
lawyers, medicine

Cognitive stimulation Doing puzzles, crosswords, learning a
second language, dancing, singing
Lifestyle factors Smoking – doubles risk of dementia by
increasing cardiovascular disease (stroke and
diabetes), narrowing cerebro- and cardiovas- Social engagement Being socially active improves mood,
cular blood vessels, causing oxidative stress relieves stress, reduces risk of depres-
to the brain sion and reduces loneliness
Lack of regular physical activity along with
sedentary lifestyle Alzheimer’s disease
Excessive alcohol consumption
Diet high in saturated fat, sugar and salt and AD is the most common form of dementia, accounting for
obesity in midlife 62% of people diagnosed with a dementia in the UK. AD was
irst described by Dr Lois Alzheimer in 1917 and includes
Concomitant Parkinson’s disease early- and late-onset variants. It has been proposed that the
disease Stroke prodromal period of AD is typically a 9-year decline in cogni-
Type 2 diabetes tive function, and part of that decline may possibly include a
High blood pressure diagnosis of amnestic MCI. It is increasingly understood that
taking active steps to reduce personal risk factors for dementia
Genetic Early onset/younger people with dementia could affect this progression. There is no licensed treatment
(small propor- (40,000 people in UK with dementia <65 for MCI.
tion of cases) years)
People with Down’s syndrome are more likely Causes of Alzheimer’s disease
to develop Alzheimer’s disease in early 30s
due to chromosome 21 missense The majority of AD is of idiopathic or sporadic origin. Identiied
Frontotemporal dementia (Pick’s disease); risk factors for developing AD are both modiiable and nonmodi-
Huntingdon’s chorea iable and are described in Table 33.3.

Subsequent public health strategies are aimed at people in Genetic research in families indicates that almost 50% of
individuals with AD have at least one irst-degree relative with
their middle years reducing cardiovascular and cerebrovascu- a dementia. This statement has resulted in controversy, but
lar risks and maintaining brain function to decrease individual researchers suggest that if the patient has late-onset AD, similarly
risks for dementia. Table 33.2 outlines these protective fac- affected relatives may have died of other causes before develop-
tors. A review of combined data for brain reserve and cogni- ing AD (Bateman et al., 2012). This has led other researchers to
postulate that perhaps the formation of plaque and neuroibrillary
tive decline from 22 studies of more than 29,000 participants tangles is not a process of normal aging at all but in fact the early
demonstrated a 46% lower risk of dementia in people with stages of AD. 
high levels of mental activity than in those with low levels

(Valenzuela and Sachdev, 2006). 

Clinical manifestations Pathophysiology of Alzheimer’s disease

It is now well established that a prodromal period exists in the The pathophysiology of AD is associated with an excess of
development of dementia, whereas in people with a genetic intracellular neuroibrillary tangles and extracellular amyloid-β.
missense mutation, the process may be established from Amyloid precursor protein is a chain of 771 amino acids found
birth. In those with sporadic disease, the process may be trig- widely throughout the body, including high concentrations in
gered some 20–30 years before the signs and symptoms are platelets, where it plays an as yet unknown function.
displayed. Symptoms, which may be termed mild cognitive
impairment (MCI), may or may not progress to a dementia. The cholinergic system is critical to normal memory and
However, indings suggest that individuals with predomi- other cognitive functions. In AD there is a selective loss of cells
nantly memory problems (amnestic MCI) on presentation will in the basal forebrain, and the depletion of neurons in this area
558 progress to dementia. correlates with memory and cognitive decline in AD. When the
irst mild symptoms of AD occur, there is already a signiicant
deicit in acetylcholine. Levels eventually reduce by 40–90% in

DEMENTIA 33

Table 33.3 Nonmodifiable and modifiable risk factors for Alzheimer’s disease

Non-modifiable Modifiable

Gender – females have greater incidence than men, but this is Physical and cardiovascular health in middle years
related to the longevity of females as compared with men Head injury – amyloid is deposited in the brain within 24 h of injury
Increasing age Education – a high level of education is a protective factor in familial
Genetic risk Alzheimer’s disease
• Early onset (40–55 years) linked to mutation of the amyloid pre- High intraneuronal calcium levels lead to cell damage and ultimately
cell death, which triggers amyloid deposition and formation of
cursor protein gene located on chromosome 21 (also referred to neurofibrillary tangles
as AD1 genetic indicator) Ongoing intellectual activity – the ‘use it or lose it’ hypothesis sug-
• Early onset (30–55 years) linked to mutation of the Presenilin 1 gests that continued learning is a protective factor in reducing the
(PS1) gene located on chromosome 14; follows autosomal-domi- risk of developing Alzheimer’s disease
nant inheritance (also referred to as AD3 genetic indicator) Environmental toxin as a neurotoxin rather than a causative factor
• Onset (40–90 years) linked to mutation of the Presenilin 2 (PS2) (e.g. excessive alcohol intake, pesticides, aluminum levels in water
gene located on chromosome 1; follows autosomal-dominant or diet)
inheritance (also referred to as AD4 genetic indicator)
• Familial Alzheimer’s disease (onset 40–90 years or older) linked
to the apolipoprotein E4 allele encoded on chromosome 19 (also
referred to as AD2 genetic indicator)

Adapted from Bateman et al., (2012).

moderate to severe AD. Other affected neurotransmitter systems presence is now used to improve the accuracy of AD diagnosis for 559
are noradrenaline, dopamine, serotonin, glutamate and gamma- clinical research studies (Albert et al., 2011).
aminobutyric acid (GABA).
The three dominantly inherited forms of early-onset AD
There are a number of hypotheses on the potential cause of (deined as occurring before 60 years of age) are associated with
the neuropathological processes that result in AD, and the most amyloid-β, presenilin 1 (PS1) and presenilin 2 (PS2) genetic mis-
accepted are outlined in the following sections. sense mutations, which alter the role of gamma-secretase, leading
to an increased production of AB42. In affected people this pro-
The neuroibrillary tangles hypothesis. It has been sug- cess remains unchecked throughout life, leading to early-onset
gested that neuroibrillary tangles (NFTs) form due to the dementia. For those with sporadic AD, there is a trigger which
hyperphosphorylation of tau protein within the cell to form starts this process at a later stage in the individual’s life, which
oligomers and then tangles. The tangles then impair the axo- ultimately leads to dementia (Bateman et al., 2012). 
nal low of nutrients in and waste products out of the cell,
resulting in cell death and dramatic loss in cholinergic neu- Genetic risk factors. The apolipoprotein E (APoE) gene
rons (Ballard et al., 2011). These cells produce acetylcholine enables the production of a protein, apolipoprotein E, which is
and project diffusely into the hippocampus, basal nucleus of responsible for linking lipids and proteins together to enable
Meynert and entorhinal cortex. the removal of cholesterol and other fats from the bloodstream.
If this process is blocked, then the risk of dementia increases.
NFTs have been found in brains of people with dementia pugi- There are three well-known alleles of the APoE gene: e2, e3 and
listica, in those with parkinsonism, in older people with Down’s e4. Greater than 50% of the population carry e3, which has a
syndrome and in older people without dementia. It has been pos- neutral role in AD development. e2, however, is rare and thought
tulated that NFTs may be a pathological substrate for memory to be protective, whereas e4 increases the risk of AD, and this
loss in AD, normal aging and MCI. Current research is focussed risk increases with the number of alleles carried. These alleles
on the development and testing of a vaccine against NFTs which are autosomal dominant and are inherited from both maternal
would, if successful, be aimed at preventing the AD process and paternal parents, meaning people may carry any combination
(Davtyan et al., 2016).  of e2 with e3 or e4 or both of each allele (Ballard et al., 2011;
Bateman et al., 2012).
The amyloid hypothesis. The amyloid hypothesis suggests
that the aberrant cleavage of amyloid precursor protein by β- and/ The presence of the e4 allele increases the risk of deposition
or gamma-secretase enzymes results in amyloid-β, a peptide of of β-amyloid in the brain from birth and subsequent develop-
36–43 amino acids, toxic to nerve cells. AB40 is a soluble form of ment of AD, although it must be stressed that this is not a 100%
amyloid-β and associated with cerebrovascular plaques. A combi- risk factor – environmental, dietary and physical properties
nation of the AB40 and the insoluble AB42, if not cleared, builds may decrease this risk. In people without the e4 allele, there is
up to form early plaques via oligomerisation in the limbic and a 10–15% risk of developing AD; this rises to greater than 75%
associated cortices. This blocks cell-to-cell transmission at syn- if both alleles are e4. The genetic forms of AD are described in
apses (Ballard et al., 2011). This affects synaptic eficacy, resulting Table 33.3. Evidence suggests that AD is the sum of inherent
in greater deposition of AB42, microglial and astrocyte activation host factors (a genetic predisposition) and external (environmen-
and inlammatory response. This in turn leads to altered neuronal tal) factor(s) which act as a neurotoxin or catalyst for the neuro-
homeostasis, oxidative injury and tangle formation and ultimately pathological processes. Genetic testing is not recommended at
in AD. Amyloid-β circulates in plasma, cerebrospinal luid and this time, although it is often included as part of clinical trials.
brain interstitial luid, mainly as soluble AB40. The extent of its

33 THERAPEUTICS

Table 33.4 Progression and staging of Alzheimer’s disease

Progression Clinical presentation Associated physical problems
Visuospatial problems (e.g. walking into things)
Early stages Recent memory impairment, forgetting names,
(1–3 years) losing direction when out, depression, impaired
activities of daily living, language difficulties

Middle stages Amnesia, aphasia, inability to calculate solutions, Falls, accidents involving cooking or other activities, impaired
(2–10 years) inability to problem solve, personality change, motor skills, may forget to eat and therefore have nutritional
behavioural changes (e.g. wandering); psychiatric problems, may be unable to use the toilet correctly and de-
changes such as delusions; inability to bathe, eat, velop chafing due to poor hygiene and soiling.
toilet or dress without assistance

Late stages Short- and long-term memory loss, mutism or Inability to communicate needs (hunger, toileting); difficulty
(8–12 years) nonsensical speech, posture becomes rigid and in in swallowing or chewing food; decreased immune response,
flexion, complete dependence on others, seizures susceptibility to infections increased; double incontinence;
bedridden patients are at risk of pressure sores and pneumonia

The progression and staging of AD are shown in Table 33.4. People with DLB demonstrate an extreme sensitivity to the extra-
It is important to note that as cognitive impairment increases pyramidal side effects of antipsychotic medication, with a two- to
over time, there is matching physical deterioration, resulting in
increasing frailty and vulnerability. Ultimately individuals move threefold increase in mortality even with atypical antipsychotics.
from relatively independent states of mobility to being bed- This may be explained by deicits in nigrostriatal dopaminergic
bound, mute and withdrawn.  neurones and may be mediated via acute blockade of postsynaptic
dopamine D2 receptors in the striatum (McKeith et al., 2005). 

Vascular dementia The rarer dementias

Vascular dementia (VaD) is the result of ischaemic changes within There are more than 100 diseases that can cause dementia; how-
the brain, associated with smoking, transient ischaemic attacks, ever, many are rare, and the most common of these are presented
strokes, long-term or poorly managed hypertension, atrial ibril- in the following sections.
lation and/or type II diabetes. Improved management of cardio-
vascular risks reduces the risk of vascular dementia.  Parkinson’s disease dementia

Dementia with Lewy bodies Long-term follow-up of people with Parkinson’s disease (PD) sug-
gests that up to 78% will eventually develop a dementia, with symp-
The cause of dementia with Lewy bodies (DLB) is not well under- toms such as luctuating cognition and visual hallucinations similar
stood, although there are proposed genetic links to the PARK11 to DLB. Consensus guidelines suggest that DLB and Parkinson’s
gene, also associated with Parkinson’s disease. Cases are spo- disease dementia are overlapping clinical syndromes and lie on dif-
radic, with no strong hereditary link, but the risk is heightened ferent points on the spectrum of Lewy body disease, sharing com-
with the inheritance of the e4 allele of apolipoprotein E (APoE) mon underlying neuropathological processes (McKeith, 2006).
as in AD. Furthermore, distinguishing DLB and Parkinson’s disease dementia
as separate entities may be useful in clinical practice but is of limited
Neuropathology value in terms of investigating and treating the underlying pathology. 

Neuropathology demonstrates the presence of abnormal collec- Frontotemporal dementia
tions of α-synuclein protein within the cytoplasm of Lewy bodies,
which are similar in structure to those seen in Parkinson’s disease. Frontotemporal dementia (FTD), previously known as Pick’s
Lewy bodies are also found in Pick’s disease and Huntington’s disease, is the largest cause of dementia for younger people in
chorea. Similarly, there are losses of dopamine-producing neu- the UK, usually affecting people between the ages of 45 and 64.
rones in the substantia nigra and a loss of acetylcholine-produc- However, 3 out of 10 people with FTD develop the condition at
ing neurones in the basal nucleus of Meynert as in AD. an older age. Autopsy studies show that neurodegeneration in the
frontal and temporal lobes is linked to deposition of abnormal
There is increasing evidence to suggest that there may be a tau proteins inside neurons, which clump together in spherical
range of Lewy body disorders, with older patients more likely to arrangements known as ‘Pick bodies’.
develop cortical disease. Historically DLB had been viewed as
a variant of AD, but it is a disorder in its own right and includes The frontal lobes regulate personality, emotions and behaviour,
Lewy body dementia, Lewy body variant of AD, diffuse Lewy as well as reasoning, planning and decision-making. The tem-
body disease, cortical Lewy body disease and senile dementia of poral lobes are involved in the understanding and production of
560 Lewy body type. language.

DEMENTIA 33

Progression rates of FTD range from less than 2 years to chance of inheriting it; however, in 1–3% of cases there is no
greater than 10 years, with people living 8 years on average after history of the disease in family members. Genetic testing is
symptom onset. About 10–15% of people with FTD have a strong available, but the family members need appropriate support.
family history, with several close relatives in different genera- Huntington’s disease is caused by mutations in the gene encoding
tions affected. Typically, in these cases, FTD is inherited from the protein called huntingtin, resulting in misshaped huntingtin
a parent as a genetic missense mutation in one of three genes: proteins which form aggregates with inclusion in neurons, result-
MAPT, GRN or C9ORF72. The children or siblings of a parent ing in cell death. 
with genetic missense mutation have a 50% chance of inheriting
it. These families should be offered referral to specialist genetics Multiple sclerosis
service for counselling with appropriate support. In comparison,
inherited early-onset AD affects less than 1 in 1000 people with If multiple sclerosis occurs in the brain, those affected may
AD (Warren et al., 2013).  experience varying degrees of cognitive impairment. However,
the decline is not usually suficiently severe or progressive to be
Corticobasal degeneration termed ‘dementia’ but is referred to as ‘cognitive dificulties’. 

Corticobasal degeneration is a rare disease, with neurodegenera- Niemann–Pick disease type C
tion affecting the cortex and basal ganglia, and has some overlap
with FTD. The cause is unknown, but neuropathology indicates Niemann–Pick disease type C is a rare inherited genetic disorder.
high levels of tau protein. Onset is usually between the ages of 60 Importantly, it is not related to FTD, which is also referred to as
and 80, with a life expectancy of 8 years post-diagnosis.  Pick’s disease. It is caused by an inability to deal with cholesterol
and other lipids. Lipid accumulates in all cells, including those
Progressive supranuclear palsy in the brain. 

Progressive supranuclear palsy is a rare progressive movement Normal pressure hydrocephalus
disorder, also known as Steele–Richardson–Olszewski syn-
drome. It affects many brain areas, resulting in symptoms similar Normal pressure hydrocephalus occurs when excess luid accu-
to those of Parkinson’s disease. Onset is usually in the 60s, but it mulates in the brain. This does not cause pressure to build up
can affect younger people. within brain tissue. 

The cause of progressive supranuclear palsy is unknown but Posterior cortical atrophy
is associated with high levels of tau deposition in affected brain
areas.  Posterior cortical atrophy, also known as Benson’s syndrome, is
a rare neurodegenerative condition where damage occurs in the
Creutzfeldt–Jakob disease posterior brain region. 

Creutzfeldt–Jakob disease (CJD) is a rare prion disease, with the Alcohol-related brain damage 561
most common sporadic variant normally affecting people older
than 40 years. Estimates suggest the disease affects about 1 in Binge drinking, or drinking excessive amounts of alcohol to
every 1 million people each year. The trigger for sporadic CJD become drunk, over a prolonged period of time can lead to a
is unknown and could be inherited or transmitted from person range of conditions known as alcohol-related brain damage
to person. (ARBD), the most common of which is alcoholic dementia, pre-
viously referred to as alcohol-related dementia. This includes
More recently, the new variant CJD, typically affecting Korsakoff’s syndrome, also known as Korsakoff’s psychosis
younger adults, was caused by eating meat from cattle infected (Zahr et al., 2011). Recent research suggests that APoE-e4 may
with bovine spongiform encephalopathy. In new variant CJD, be associated with a higher risk of Wernicke–Korsakoff in indi-
there may be many years between a person being infected and the viduals who drink heavily (Harwood et al., 2010).
development of symptoms. 
The exact number of people with ARBD is not known. It is
HIV-associated neurocognitive disorder likely to be under-diagnosed due to the stigma associated with
alcohol misuse and people not seeking help, together with health-
HIV has adverse effects on the immune system. These include care professionals’ lack of awareness of the process of ARBD.
the development of neurocognitive disorders in up to half of UK postmortem studies suggest ARBD affects about 1 in 200 of
people with HIV, called HIV-associated neurocognitive disorder the general adult population. Among those with alcoholic addic-
(HAND). This may be a direct result of the virus’s effects on a tion, this igure rises to one in three. It is not clear why some
weakened immune system, enabling infections and cancers.  people develop ARBD whereas others do not.

Huntington’s disease People with ARBD tend to be middle-aged, typically in their
40s or 50s, although they can be younger or older. ARBD is
Huntington’s disease is an inherited fatal genetic brain disease. thought to cause more than 10% of dementia in younger peo-
Children of a parent with Huntington’s disease have a 50% ple, deined as those aged under 65. ARBD is more prevalent in

33 THERAPEUTICS

Table 33.5 Differential diagnostic features of the main dementias

Feature Onset and progression Early symptoms Late symptoms
Alzheimer’s disease Predominantly memory loss Emergence of aphasia and agnosia
Insidious onset with progressive decline
of cognitive and physical function

Vascular dementia Sudden onset with stepwise progression Person has insight Shuffling gait with a wide base,
Periods of stability followed by an Emotional lability and depression differentiated from Parkinson’s
episode of sharp decline Focal neurological signs disease as has preserved arm swing,
presence of seizures and continued
cerebral ischaemia

Dementia with Lewy Fluctuating periods of alertness and Less severely impaired recent Hallucinations, periods of confusion
memory and psychotic symptoms
bodies confusion Early gait disturbance and par-
kinsonism with falls
Fluctuating cognitive function

Fronto-temporal Gradual but progressive changes in Apathy, poor judgement and Apathy, disinhibition – including
dementia behaviour, mood and personality insight, speech/language sexual, depression, euphoria
problems

people with poor socioeconomic backgrounds and affects men with dementia may express an emotion such as sadness or hap-
more frequently than women. However, affected women develop piness but not be able to remember the reason. This is because
ARBD at a younger age than men and after fewer years of alcohol factual memory for events and learning is stored in the hippo-
misuse.  campus which is one of the irst structures affected. However,
emotional memory is stored in the amygdala which generally is
Consequences of the dementia process only affected in the late stages.

Behavioural changes in dementia Agitation. Agitation has been deined as behaviour which is
seen as disruptive but nonaggressive (e.g. moaning, pacing, cry-
As the disease progresses, the resultant neuropathological dam- ing, arguing). It ranges to aggression in its severe forms, where the
age is associated with changes in behaviour, mood, personality person may be aggressive or endanger others or him- or herself
and the ability to communicate effectively. As a result of this, (e.g. kicking, screaming, throwing objects, self-injury, scratch-
95% of people with a dementia develop behavioural changes, ing). These behaviours can be very distressing to the caregiver
and these can be found challenging to those that care for them and are the behaviours most likely to lead to institutionalisation.
(informal and formal carers). These challenging behaviours are Therefore, support of the carer is key. Educational programmes
also referred to as behavioural and psychological symptoms of for carers using behavioural techniques are more effective than
dementia (BPSD). Symptoms include delusions, hallucinations, most pharmacological treatments (Marriott et al., 2000). 
agitation or aggression, depression, anxiety, elation or eupho-
ria, apathy or indifference, disinhibition, irritation or lability, a Diagnosis of the dementias
change in eating patterns and aberrant motor behaviour (wander-
ing). As dementia progresses, people lose the sense of whether There is considerable overlap of disease states, with dementias
it is day or night and subsequently disrupt carers’ sleep as they of mixed aetiology in combination of AD and VaD, or DLB and
get up and dressed in the middle of the night. This is called sun- PDD being relatively common. Currently, computed tomogra-
downing. Formal and informal carers worry about people walk- phy (CT) and/or magnetic resonance imaging (MRI) is used to
ing away from their chair/bed and ‘wandering’ around, going for exclude treatable forms of the symptoms (e.g. space-occupying
walks on their own (because they can get lost). However, it is lesions, hydrocephalus or ischaemic changes). These can
important to note that all people like to move around and enjoy a also be used to give a ‘probable’ diagnosis of dementia with
walk outside. Exercise should be built into the daily routine, and reference to consensus guidelines, clinical examination and
dementia care environments should include areas where people test results. Information for differential clinical and disease
can walk safely on their own. A wide variety of behaviours can features which may aid a probable diagnosis is described in
be displayed which in general are not harmful. However, they can Table 33.5.
be dificult to control and are a major reason for caregiver stress
and admission to long-term care. At present, a deinitive diagnosis can only be made at autopsy
or if the individual takes part in a clinical trial where lumbar
These symptoms may be caused by the disease affecting a par- punctures (to check levels of tau), genetic testing and positron
ticular area of the brain – for example, the sexual disinhibition emission test (PET) scanning or high-volumetric MRI scanning
observed in FTD, or the inability to convey a need for luid, food, is available.
562 pain relief or other symptom. It is important to note that people

DEMENTIA 33

Table 33.6 Possible signs of dementia

Sign Change displayed
Day-to-day memory
Difficulty recalling events that happened recently
Although long-term memory may remain relatively unaffected, short-term memory may become badly
impaired and may be identified as repeating the same questions, forgetting names and routes, and losing/
misplacing items.
People with dementia forget not only the specifics of an item or event but also the context.

Concentrating, planning or Difficulties making decisions, solving problems or carrying out a sequence of tasks – e.g. cooking a
organising meal, not knowing how to make a cup of tea or forgetting what order to put clothes on when getting
dressed
May begin to lose interest in people, objects and hobbies (e.g. sitting passively in front of the TV for hours,
sleeping for long periods and neglect of personal care)
Problems with tasks (e.g. working out change when paying in a shop, remembering appointments or paying
bills)

Judgement Inability to judge situations or people (e.g. putting on too many clothes on a hot day or too few on a
cold day)

Language Difficulties following a conversation or finding the right word for something. Conversations tend to be badly
affected, with frequent pauses, forgetting very commonplace words, losing the thread of what is being said
midsentence, and substituting unusual words (e.g. hand clock for watch).

Visuospatial skills Problems judging distances (e.g. on stairs) and seeing objects in three dimensions. If distinct visual im-
pairments such as inability to read or recognise signs, consider referral for occipital lobe scanning variant
Alzheimer’s disease.

Orientation Losing track of the day or date, becoming confused about where they are or forgetting the way home from
shopping or work

Changes in mood Becoming frustrated or irritable, withdrawn, apathetic or anxious, easily upset or unusually sad, suspicious,
depressed, or agitated. Dramatic mood swings which show noticeably more or less emotion than previously
can indicate possible cause for concern. Patients may become angry if friends/family comment on such
behaviour changes.

Visual hallucinations, delu- Seeing things that are not really there and/or believing things that are not true and/or paranoid beliefs that
sions or paranoiaa people are stealing from them or trying to harm them in some way

aHallucinations and paranoia are specific to certain forms of dementia, where it is the parts of the brain responsible for behaviour and emotional responses that
are most affected.

General signs and symptoms of dementia • language problems, including inability to ind the right word
or dificulty following conversations;
Dementia is neurodegenerative, so there is gradual onset, often
noticed at times of stress or change (e.g. when admitted to hos- • behavioural changes, including being more irritable, passive,
pital with an infection or when there is a change in environment withdrawn or suspicious.
such as going on holiday). The presentation of symptoms is All healthcare professionals are in a position to recognise early
inluenced by pre-morbid personality, and those with good social
skills can hide decline from relatives and carers. signs and symptoms of neurodegeneration and signpost or refer
people appropriately (Table 33.6). It is also important to remem-
Early symptoms include: ber that at each stage of dementia, there is an associated decline
• memory loss, especially for recent events; in physical functioning, which may affect caring and require sup-
• dificulties with learning and/or retaining new information; port from social services. 
• being more repetitive;
• misplacing objects (e.g. car keys or spectacles); Classification of dementias
• dificulty with complex tasks such as cooking, driving or deal-
There is no deinitive test for any dementia which is routinely
ing with inances; available in primary care. It is a process of careful history tak-
• reduced ability to reason and problem-solve; ing; observation of the person’s behaviour, cognition, mood, and 563
• impairment of spatial and visuospatial awareness (e.g. bump-

ing into objects, driving accidents, getting lost in a familiar
place);

33 THERAPEUTICS

Table 33.7 Proportion of different forms of dementia in UK Box 33.1 Differential diagnosis of dementia mnemonic
(Alzheimer’s Society, 2014)
D Drugs
Different forms of dementia % E Emotional problems, eyes, ears
M Metabolic
Alzheimer’s disease – includes posterior cortical 62 E Endocrine
atrophy N Nutritional deficiency
T Tumour
Vascular dementia 17 I Infection
A Anaemia or alcohol
Mixed dementia – Alzheimer’s disease and 10 S Systemic disease
vascular dementia together
effects on the individual from invasive procedures. Consensus
Dementia with Lewy bodies 4 guidelines outline deinitive ranges for such measurements and
are used to establish diagnosis in people entered into clinical tri-
Other rarer causes of dementia – includes cor- 3 als and deine outcome measures of eficacy and appropriateness
ticobasal degeneration, Down’s syndrome, HIV (Albert et al., 2011; Sperling et al., 2011).
dementia, prion disease, Huntington’s disease,
alcohol-related brain disease The most important part of the diagnostic procedure is tak-
ing an accurate and detailed history, paying particular attention
Parkinson’s disease dementia 2 to intellectual functioning and neurological symptoms. Details
of social and occupational history are important to discover.
Frontotemporal dementia – common in people 2 Athletes with a history of head injury or concussion (e.g. boxers)
<65 years, associated with Pick’s disease have a high risk of developing pugilistic dementia. Heavy alco-
hol drinkers may have ARBD. Interviewing carers or relatives is
intellectual functioning; and then the systematic exclusion of all especially important because individuals may be unaware they
other possible causes (i.e. a diagnosis of exclusion). It is impor- have a memory or cognitive problem, and the process may also
tant to note that in each country there may be a different propor- highlight a family history of dementia.
tion of the dementias. AD is most prevalent in the UK, whereas
in Japan it is vascular dementia. This is thought to be a product A useful mnemonic to remember the differential diagnosis of
of cultural, genetic and environmental confounders. Table 33.7 dementia is shown in Box 33.1. 
provides details of the proportion of dementia types in the UK.

The screening process Assessing cognitive function

Routine laboratory tests such as urea and electrolytes, full blood Psychological tests, including a mini-mental state examination
counts, thyroid function, folate, vitamin D, blood glucose or (MMSE), usually the Folstein (Folstein et al., 1975), assessment
HbA1c are all undertaken to exclude possible treatable causes of of perception (visuospatial deicits, mood, executive function,
cognitive decline (sometimes termed ‘pseudo-dementias’), such memory) and assessments for depression are also part of the dif-
as anaemia, thyroid disease, hyponatraemia, hypercalcaemia, ferential diagnostic process. They are also used to monitor sever-
hypo- or hyperglycaemia, renal impairment, serology (for vene- ity, progression of the disease and response to pharmacological
real disease, including syphilis) and substance or alcohol misuse. and non-pharmacological treatments interventions. Examples are
Other exclusions include investigating confusion associated with shown in Table 33.8 and also in the joint guidance on assess-
the start or withdrawal of a medication or substance (legal or ing cognition from the Alzheimer’s Society and Royal College of
illegal). A midstream urine (MSU) test excludes delirium associ- General Practitioners (2015). 
ated with urinary tract infections, and a chest and skull X-ray can
exclude a chest infection or a space-occupying lesion (SOL). If Diagnostic features of Alzheimer’s disease
available, head MRI for quantiication of brain changes and the
presence of space-occupying lesions, ischaemic lesions or other Key features include an insidious onset of symptoms, predomi-
trauma should be undertaken. An MRI can also be used to iden- nantly memory loss in the early stages. Progressive cognitive and
tify the extent of neurodegeneration in a particular region of the physical decline is observed, with the emergence of aphasia and
brain, which can aid determination of the inal diagnosis. agnosia (failure of recognition) in later stages, where good prin-
ciples of palliative care are needed. The 10 warning signs of AD
There is increasing sophistication in the use of positron emis- are described in Table 33.9.
sion tomography (PET) scanning, which allows greater accuracy
of diagnosis by the distribution of neurodegeneration in brain Ascertaining severity of Alzheimer’s disease
regions and the deposition of β-amyloid and intracellular neuro-
ibrillary tangles (NFTs) throughout the brain. Lumbar puncture The previously noted investigations can be supplemented by clin-
samples are also often used to measure levels of various proteins, ically based assessments such as biographical review, examples
564 including tau and β-amyloid. However, these are not routinely of which include the Clinician Interview Based Impression of
used in practice due to cost, lack of expertise and possible adverse

DEMENTIA 33

Table 33.8 Validated scales to test cognition

Scale Overview of scale Time to complete Cutoff point for dementia
<5 min 6–8/10
Abbreviated Mental Test A 10-item scale, validated in hospital but used in UK
Score (AMTS) primary care

6-Item Cognitive Impair- Three orientation items: count backwards from 20, <5 min 8/24
ment Test (6CIT) months of the year in reverse, learn an address
Validated in primary care

Mini-Cog Three-item word memory and clock drawing 2–4 min 5/8
Validated in primary care
Low sensitivity

General Practitioner As- Developed for primary care and includes a carers’ 5 min Part 1: 5–8/9 complete part 2,
sessment of Cognition interview 10 min 0–/9 cognitive impairment
(GPCOG) Part 2: 0–3/6 cognitive impair-
ment
Montreal Cognitive As- Tasks are executive function and attention, with some
sessment Scale (MoCA) language, memory and visuospatial skills 26/30
Validated in many conditions, including mild cogni-
tive impairment, Alzheimer’s disease and Parkinson’s
disease dementia

Addenbrookes Cognitive Validated in 5 domains: attention, memory, fluency, 10–20 min 82–88/100
10 min
Examination–III (ACE) language, visuospatial ≤24/30
Cut-point not valid in different
Folstein Mini-Mental State Eleven-item measure of cognitive functioning and its cultures and in particularly
Examination (MMSE) change that has been extensively studied and has highly educated or unedu-
good validity cated participants
Less effective for dementia with Lewy bodies and fron-
totemporal dementia due to its focus on memory

Table 33.9 Ten warning signs for Alzheimer’s disease

Warning sign Signs of normal aging

Memory loss that disrupts daily life Sometimes forgetting names or appointments but

Forgetting recently learned or inability to learn new information; repeatedly asking remembering them later

for the same information

Challenges in planning or problem solving Changes in managing finances or Making occasional errors when balancing a cheque-
following a plan, taking longer to do things book or household accounts

Difficulty completing familiar tasks at home, work or leisure Occasionally needing help with settings on microwave
Getting lost driving to familiar places; difficulty with project management at work; or television
difficulty remembering rules of a favourite game

Confusion with time or place Getting confused about the day of the week but work-
Losing track of dates, seasons or passage of time; may forget where they are or ing it out later
how they got there

Trouble understanding visual images and spatial relationships Vision changes related to cataracts
An early sign and includes trouble reading, judging distance and determining
colour or contrast; may also present as hallucinations; distorted perceptions (e.g.
passing a mirror and thinking someone else is in the room)

New problems with communication Sometimes having trouble finding the right word
Difficulty following or maintaining conversation; problems finding or using the
correct word 565

Continued

33 THERAPEUTICS

Table 33.9 Ten warning signs for Alzheimer’s disease—cont’d

Warning sign Signs of normal aging

Misplacing items Misplacing things like spectacles or TV remote oc-
May put items in unusual places (spectacles in the fridge); may accuse people of casionally
stealing; cannot retrace steps to find the item

Impaired or reduced judgement Making a bad decision occasionally
Make poor decisions, often involving money or large donations to telemarketers;
less attention to personal grooming

Withdrawal from work or social activities Sometimes feeling weary of work, family and social
May have trouble keeping up with favourite activities or remembering how to do obligations
them; may withdraw socially because of these changes

Changes in mood or personality Developing a specific way of doing things and being

May become confused, suspicious, depressed, fearful, anxious or even delusional; irritable when a routine is disrupted

may be easily upset doing routine tasks when out of their comfort zone

Adapted from Alzheimer’s Association (2009).

Severity (CIBIS) and the Clinician Interview Based Impression The types of symptoms exhibited after damage to a particular
of Change (CIBC). The latter can be adapted to include input area of the brain in VaD or any other dementia, which also inlu-
from the carer (CIBIC-plus). ences behaviour, can be seen in Table 33.10.

Severity in AD has historically been deined by the Folstein Generally, insight is more preserved than in AD, but this often
Mini-Mental State Examination (MMSE) score: leads to increasing distress for patients because they are more
• normal cognitive function: MMSE 27–30; aware of the prognosis of the disease. In late-stage VaD, there
• mild AD: MMSE 21–26; is a shufling gait, which can be distinguished from Parkinson’s
• moderate AD: MMSE 10–20; disease by its broad base and preserved arm swing. Fitting and
• moderately severe AD: MMSE 10–14; continued episodes of cerebral ischaemia are also late features of
• severe AD: MMSE <10 (National Institute for Health and this disorder. 

Care Excellence [NICE], 2016). Diagnostic features of dementia with Lewy
There is continued controversy about the use of the Folstein bodies
MMSE because it was originally designed to measure cogni-
tive function in people with mental illness, including schizo- People with DLB exhibit typically delirium-like cognitive states with
phrenia, but not dementia (Folstein et al., 1975). In March periods of luctuating confusion, which vary in duration and severity
2009 a judicial review highlighted the potential discrimina- from person to person and from time to time within an individual.
tory effects of the MMSE as a rating scale for the start and
withdrawal of treatment because of its limitations in people Visuospatial, visuo-perceptive and frontal deicits are com-
with previously poor intellect, non-white Caucasian ethnicity mon. Memory impairment is often less than in the other demen-
and low socioeconomic groups. This is due to the tendency for tias in the early stages.
the MMSE to suggest false negatives in these groups. It has
also been found to not be sensitive in people with previously Compared with people with AD, people with DLB are more
high intellect because it gives false negatives. However, the likely to have clouding of consciousness, signiicant Parkinsonism
Folstein MMSE is still used, but it is now copyrighted and features, less severely impaired recent memory and a large num-
incurs a charge for use (Folstein et al., 1975).  ber of different psychotic features. DLB is diagnosed on the pres-
ence of central features and core features; two of the latter are
Diagnostic features of vascular dementia needed for a diagnosis of probable DLB and one for possible
DLB (McKeith et al., 2005).
VaD generally presents with sudden onset, and the dementia
follows a stepwise progression. This means that there are peri- The central feature is progressive cognitive decline of sufi-
ods of cognitive stability followed by periods of rapid decline. cient magnitude to interfere with normal social and occupational
The neuropathology of VaD is distinctive, with either localised function and including one or more of the following core features:
or generalised areas of brain atrophy and ventricular dilatation • luctuating cognition,
and associated areas of cerebral ischaemia and evidence of arte- • recurrent visual hallucinations (usually people or animals),
riosclerosis in major vessels. This cerebral damage results in • spontaneous features of parkinsonism.
focal neurological signs (absent in AD), and commonly associ-
ated clinical features include emotional lability, depression, early Other features which may support a diagnosis of DLB include
566 memory problems, apraxia, agnosia, dysarthria and dizziness. repeated falls, syncope, transient loss of consciousness, syste-
mised delusions, hallucinations in other modalities, rapid eye
movement (REM) sleep behaviour disorder and depression.
However, less likely to be present are a history of stroke or any

DEMENTIA 33

Table 33.10 Area of brain degeneration and associated behaviour change in the dementias

Site of brain degeneration/lesion Change in behaviour exhibited

Frontal lobe Behaviour – disinhibited, over-familiar, tactless, over-talkative, jokes, pranks, errors of judge-
Involving motor cortex ment, sexual indiscretions, disregard for the feelings of others
Bilateral Mood – fatuous and euphoric
Concentration and attention – reduced
Insight – impaired
Contralateral spastic paresis or dysphasia, optic atrophy same side, anosmia, grasp reflex
reduced
Urinary incontinence

Parietal lobe Psychiatric changes less likely, neuropsychological disturbances often resembling hysteria
Nondominant lobe affected Visuospatial difficulties
Dominant lobe affected Dysphasia, motor and dressing apraxias, right–left side disorientation, finger agnosia,
agraphia, body image disorder

Temporal lobe Sometimes asymptomatic
Unilateral lesion/degeneration Personality change resembling frontal lobe symptoms but often accompanied by intellectual
Bilateral deficits and neurological signs
If dominant lobe affected Emotional instability and aggressive behaviour
Associated with epilepsy and increasing schizophrenic-like disorder
Specific learning impairment – in right-handed people, verbal skills affected; in left-handed
people, nonverbal skills affected
Amnesic syndrome and visual field defects
Language and intellectual impairment

Occipital lobe Disturbance in visual recognition, often misdiagnosed as hysteria
Complex visual hallucinations, often mistaken for non-organic mental illness

Corpus callosum Severe and rapid intellectual deterioration

Diencephalon and brainstem Amnesic, hypersomnia, akinetic mutism
Progressive intellectual deterioration, emotional lability with euphoria
Abrupt outburst of temper, excessive eating, endocrine pituitary disorder

other physical illness or brain disorder suficient enough to inter- Diagnostic features of frontotemporal dementia
fere with cognitive performance.
Age is a diagnostic factor, with 7 out of 10 people with FTD aged
The luctuation in cognition pattern is associated with: between 45 and 64 years, as well as the presence of four main
• hallucinations, usually visual but also auditory; variants:
• periods of confusion and attention deicit; • behavioural variant;
• other psychotic symptoms; • semantic dementia deicits in verbal and nonverbal under-
• early gait disturbances;
• extrapyramidal features, such as rigidity, bradykinesia, tremor standing of memory;
• progressive non-luent aphasia, a language disorder in which
and ixed posture (i.e. signs of parkinsonism and Parkinson’s
disease) (McKeith et al., 2005).  people have problems speaking;
• FTD associated with motor disorder, including motor neurone
Diagnostic features of the rarer dementias
disease, corticobasal degeneration and progressive supranu-
Diagnostic features of Parkinson’s disease dementia clear palsy. 

A differential diagnosis is made on the following criteria: Diagnostic features of corticobasal degeneration
• Those people with Parkinson’s disease who develop a demen-
Early presenting symptoms affect movement and include stiff- 567
tia more than 12 months after the initial motor symptoms ness, jerky movements and a unilateral inability to control hand
should be diagnosed with Parkinson’s disease dementia. movement. Eventually this affects other limbs, leading to loss of
• If the dementia precedes the motor symptoms or the duration
of the motor symptoms is less than 12 months, then the diag- balance and coordination, and is also associated with cognitive
nosis is DLB (McKeith, 2006).  deicits, including memory loss, perceptual dificulties and dif-
iculties in swallowing and speaking. 

33 THERAPEUTICS

Diagnostic features of progressive supranuclear Diagnostic features of Niemann–Pick disease type C
palsy
Niemann–Pick disease type C mainly affects school-age children
The tau pathology results in paralysis of eye movements (causing but can occur at any time, from early infancy to adulthood, and
double vision), affecting balance control and resulting in frequent symptoms start with progressive loss of movement and dificul-
falls. Other symptoms include stiff or slow movements, dificul- ties with walking and swallowing.
ties walking and speaking, swallowing problems and personal-
ity changes. A parkinsonian-like tremor may be present, but it is Dementia occurs most commonly in those people who develop
much less prominent than in Parkinson’s disease. symptoms in late adolescence or early adulthood, with the main
symptoms including confusion, memory problems and dificul-
A small proportion of people with progressive supranuclear ties in concentrating and learning. 
palsy develop an overlapping condition with FTD, but the
majority experience cognitive dificulties rather than a demen- Diagnostic features of normal pressure
tia syndrome. This cognitive impairment may affect the speed hydrocephalus
of thought processes and memory, but affected individuals will
remain aware of what is going on around them.  Symptoms include dificulties with walking, dementia syndrome
and urinary incontinence. Generally, there is no cause, but it may
Diagnostic features of Creutzfeldt–Jakob disease develop after recovery from a head injury, brain haemorrhage or
severe meningitis. 
In sporadic CJD, the disease progression is rapid over a
few months, with early symptoms including minor lapses of Diagnostic features of posterior cortical atrophy
memory, mood changes and loss of interest. Within weeks,
the person may experience clumsiness, feel muddled, become Initially, people with posterior cortical atrophy tend to have a rel-
unsteady when walking, and have slow or slurred speech. atively well-preserved memory but experience visual problems,
Symptoms progress to jerky movements, shakiness, stiffness such as dificulty recognising faces and objects in pictures, which
of limbs, incontinence and loss of the ability to move or speak. then affect literacy and numeracy. Symptoms of posterior cortical
By this stage, the person is unlikely to be aware of his or her atrophy occur in the mid-50s or early 60s, but diagnosis may take
surroundings or disabilities. The majority of people affected longer because of the subtle onset. 
by CJD usually die within 6 months of their early symptom
development.  Diagnostic features of alcohol-related brain damage

Diagnostic features of HIV-associated neurocognitive ARBD is deined as long-term decline in memory or thinking
disorder caused by excessive alcohol use resulting in thiamine deiciency
and neurodegeneration associated with the toxicity of alcohol
Cognitive dificulties include mild deicits in short-term memory, itself on neurons. Associated alcohol misuse factors include
learning, thinking, concentration and reasoning.  repeated head injuries sustained from falls or ights and associ-
ated damage to the cardiovascular system, including raised blood
Diagnostic features of Huntington’s disease pressure and cholesterol. However, these are all also risk factors
for other dementias. 
This neurodegeneration starts in the striatum, which is why irst
symptoms depict abnormal movements, including twitches Treatment of dementia
and muscle spasms and problems with balance and coordina-
tion. Other symptoms include depression, mood swings, irri- Alzheimer’s disease
tability and cognitive impairment, including dificulties with
concentration, planning and organisational skills. The age of Currently there are two pharmacological groups licensed for
onset and disease course vary for each person, and dementia the treatment of the symptoms of AD: the acetylcholinesterase
can occur at any stage of the illness. Some may experience inhibitors (AChEIs) donepezil, rivastigmine and galantamine,
short-term memory loss or develop obsessive behaviours. and the N-methyl-d-aspartate (NMDA) receptor antagonist
Unlike in AD, people with Huntington’s disease dementia con- memantine. The NICE (2016) technology appraisal guid-
tinue to recognise people and places until the very late stages ance for prescribing donepezil, galantamine, rivastigmine
of the disease.  and memantine states that treatment aims are to promote
independence, maintain function and treat symptoms, includ-
Diagnostic features of multiple sclerosis cognitive ing cognitive, non-cognitive (hallucinations, delusions, anxi-
difficulties ety, marked agitation and associated aggressive behaviour),
behavioural and psychological symptoms. Donepezil, galan-
Symptoms include memory, concentration and problem solv- tamine and rivastigmine are all recommended as treatment
ing. Emotional problems include mood swings and personality options for managing mild and moderate AD. Memantine is
changes.  recommended as an option for managing moderate AD for
568

DEMENTIA 33

people who cannot take AChEIs and as an option for manag- Galantamine also enhances the action of acetylcholine on nico-
ing severe AD. Information to guide the prescribing of medi- tinic receptors. Although these agents belong to the same group,
cines for dementia is shown in Table 33.11. they all produce their pharmacological effect in a slightly dif-
ferent way. Therefore, if a response to one agent is not seen, it
Acetylcholinesterase inhibitors is justiiable to try another. This also applies to the individual
experience of adverse effects.
Acetylcholinesterase inhibitors exert their pharmacological activ-
ity by inhibiting the enzyme acetylcholinesterase to increase the AD is progressive, which means that there will be less ace-
concentration of acetylcholine at sites of neurotransmission. tylcholine produced throughout the course of the disease. At the
start of treatment with an AChEI, patients usually improve from

Table 33.11 Prescribing and monitoring medicines for dementia

Donepezil Rivastigmine Galantamine Memantine

Activity Reversible acetylcholin- Pseudo-irreversible with greater Reversible competitive Uncompetitive NMDA-
esterase inhibitor activity, selectivity acetylcholinesterase AChEI with enhanced receptor antagonist
dose-dependent activity Dose-dependent activity action of acetylcholine on which modulates
Greater selectivity muscarinic receptors pathological levels of
acetylcholinesterase Dose-dependent activity glutamate

Dosing Start at 5 mg once daily Start 1.5 mg twice daily with morn- Initially 4 mg twice daily 5 mg once daily, increas-
and increase to 10 mg ing and evening meals for 4 weeks increasing ing by 5 mg/week to a
once daily after 4 weeks If well tolerated at 2 weeks, increase to 8 mg twice daily for maximum of 20 mg once
Evening dosing, just before to 3 mg twice daily 4 weeks to maintenance daily
retiring; if insomnia and Subsequent increases to 4.5 mg dose of 12 mg twice daily If sedation occurs,
vivid dreaming, change to and then 6 mg twice daily based change to an evening
morning. on good tolerability and minimum dose to aid sleep
2 weeks of treatment before dose
increase

Forms avail- 5 mg and 10 mg tablets Capsules 1.5 mg, 3 mg, 4.5 mg, Immediate-release tablets Tablets 5 mg, 10 mg,
able (UK) Oral solution 1 mg/1 mL 6 mg 8 mg or 12 mg twice-daily 15 mg, 20 mg film
Orodispersible tablets 5 Oral solution 2 mg/1 mL dosing Oral solution 10 mg/1 mL
mg, 10 mg Patches 4.6 mg/24 h, 9.5 mg/ Oral solution 4 mg/1 mL sugar-free
24 h, 13 .3 mg/24 h Modified release cap-
sules; 8 mg, 16 mg,
24 mg once daily

General Low side-effect profile Low side-effect profile but may Low side-effect profile Low side-effect profile:
(nausea 14%, vomiting 8% cause severe anorexia in some and (nausea 24%, vomiting constipation, dizziness,
and diarrhoea 12%) weight loss (nausea 47%, vomiting 13% and diarrhoea 9%) diarrhoea. Uncommon
31% and diarrhoea 19%) side effects include
Licensed for use in Parkinson’s abnormal gait, confusion,
disease dementia fatigue, hallucinations

Pharmacoki- Peak concentration t1/2 approximately 2 h Serum max 0.5 to 1 h tmax between 3 and 8 h
netics 3–4 h post-dose Inhibition lasts 10 h t1/2 7–8 h Linear pharmacokinetics
t1/2 = 70 h (steady state in Renal excretion of rivastigmine Reduce dose in moder- No CYP450 catalysed-
3 weeks) and inactive metabolites involving ate hepatic impairment metabolism
Linear pharmacokinetics cytochrome isoenzymes: CYP1A2, and avoid in severe 90% renally excreted
Metabolised in liver CYP2D6, CYP3A4/5, CYP2E1, impairment If moderate renal impair-
CYP450 system, modify CYP2C9, CYP2C8, CYP2C19 or Avoid if eGFR <9 mL/ ment, titrate to 10 mg,
dose in mild to severe CYP2B6 min/1,73 m2 and if tolerated, increase
hepatic impairment CYP450 minimally involved in me- Food affects absorption with monitoring to 20 mg
Renally excreted tabolism but does not affect extent In severe renal impair-
Food does not affect Dose adjustment in moderate of absorption ment, maximum dose
absorption hepatic and renal impairment may Protein binding 18% 10 mg daily
95% protein bound be necessary Linear pharmacokinetics Food does not affect
Food delays absorption and affects in dose range of 4–16 mg absorption
AUC twice daily 45% protein bound
Protein binding 40%

Continued

569

33 THERAPEUTICS

Table 33.11 Prescribing and monitoring medicines for dementia—cont’d

Donepezil Rivastigmine Galantamine Memantine

Cautions Asthma, COPD, sick sinus Asthma, COPD, sick sinus syndrome, Asthma, COPD, sick sinus Avoid in severe hepatic
syndrome, supraventricular supraventricular conduction disor- syndrome, supraventricu- impairment
conduction disorders, sus- ders, susceptibility to peptic ulcers lar conduction disorders, Avoid concomitant
ceptibility to peptic ulcers Common adverse effects mainly susceptibility to peptic NMDA antagonists (e.g.
Common adverse effects cholinergic, especially GI, also ulcers amantadine, ketamine,
mainly cholinergic, espe- excessive mucous production and Common adverse effects dextromethorphan)
cially GI, also excessive leg cramps mainly cholinergic, espe- Caution if history or
mucous production and If treatment is interrupted >3 days, cially GI, also excessive diagnosis of epilepsy or
leg cramps re-initiate at 1.5 mg twice daily to mucous production and seizures
reduce adverse effects (vomiting) leg cramps
Skin application-site reactions may Stevens–Johnson
occur with patch, mild or moderate syndrome and acute
in intensity generalised exanthema-
Not an indication of sensitisation tous pustulosis have been
but may lead to allergic contact reported – informed
dermatitis patients to discontinue at
the first sign of a rash

Pharmaco- Cholinesterase inhibitors (cholinomimetics) should not be given concomitantly with other cho-
dynamic linomimetics, and they have the potential to antagonise the effect of anticholinergic medica-
cautions tion. If anticholinergic medications such as atropine are abruptly stopped, there is a potential
risk of exacerbation of cholinesterase inhibitors effects. Pharmacodynamic interactions with
medicinal products that significantly reduce the heart rate, such as digoxin, β-blockers, certain
calcium-channel blocking agents and amiodarone are possible, and caution should be taken
with medicinal products that have potential to cause torsades de pointes. In such cases, an
ECG should be considered.
An exaggerated response to succinylcholine-type muscle relaxation during anaesthesia could
occur.

Always check in the latest Summary of Product Characteristics because this is more explicit than in the BNF for interactions with other medication.
AChEI, Acetylcholinesterase inhibitor; AUC, area under the curve; BNF, British National Formulary; COPD, chronic obstructive pulmonary disease; ECG, electrocar-
diogram; eGFR, estimate of glomerular filtration rate; GI, gastro-intestinal; NMDA, N-methyl-D-aspartate; tmax, time to maximal response; t1/2, half-life of a drug.

pretreatment function and assessment scores. As the disease pro- dizziness. These are generally mild and transient, and they often
gresses, the amount of acetylcholine produced will be less than disappear within a few days of continued treatment. However,
at pretreatment, so individual patient performance will decline, in some patients, these effects may be severe and result in sig-
eventually to a stage where the agent will seem to have little clini- niicant weight loss. To reduce these effects, the medication can
cal effect. One of the dificulties with measuring improvement or be taken after food, and/or an anti-emetic may be co-prescribed.
response to a treatment is that because the disease is progressing, Another approach is extending the time period required to reach
signs and symptoms may seem to worsen rather than improve. the maximum therapeutic dose for such patients. If there is no
However, AChEIs ensure that any acetylcholine that is produced history of Parkinson’s disease or DLB, then long-acting meto-
(at any stage of the disease) will be available for neuronal trans- clopramide may be given during the dose titration period. The
mission for longer. This means that the symptoms of AD, such alternative for those patients with Parkinson’s disease or DLB is
as functions in activities of daily living, cognitive function and domperidone at 10–20 mg three or four times daily.
behaviour, will be alleviated to some extent for the time that the
patient remains on treatment. Each of these agents has different Selection of any concomitant medication for a person with
formulations which may help people with swallowing dificulties dementia should include an analysis of its propensity to cause
or problems with dose titration. antimuscarinic effects because this interferes with memory and
may exacerbate or cause confusion. Examples include hyo-
Cautions for use. AChEIs should be prescribed with caution scine, oxybutynin, procyclidine, antipsychotics (including some
in patients with ‘sick sinus syndrome’ or other supraventricular atypicals), tricyclic antidepressants, furosemide, digoxin and
cardiac conduction conditions, patients with concomitant asthma cimetidine. 
or obstructive pulmonary disease and those with, or at risk of,
peptic ulcer disease. Rivastigmine should be prescribed with cau- Controversies associated with treatment. Numbers needed
tion in patients with renal impairment or mild to moderate hepatic to treat for AChEIs range from 3 to 7 at low dose and delay dis-
impairment. ease progression by at least 6 months, with increasing evidence
from clinical practice that some patients beneit for periods of
All AChEIs cause gastro-intestinal effects such as diar- greater than 7 years (Livingston and Katona, 2000). There is
570 rhoea, muscle cramps, fatigue, nausea, vomiting, insomnia and robust evidence demonstrating that these agents delay the need

DEMENTIA 33

for institutionalisation of the person with dementia by making are currently ive fully human monoclonal antibodies in clinical
it easier for the carer to provide care in the home environment trials (olanezumab, ducanumab, gentenerumab, crenezumab and
(Geldmacher et al., 2003).
Biogen/Eisai’s BAN2401), all with slightly different modes of
The heterogeneous nature of AD itself and the fact that many action. Some of the dificulties of treatment with monoclonal
people have a mixed dementia syndrome imply that each patient antibodies are that they possess limited brain bioavailability and
may have a unique set of symptoms which one medication is not
able to address.  can cause immunogenicity and serious adverse effects such as

Stopping and changing treatment. If a patient seems to have cerebral oedema. 
no improvement in objective scores but also no deterioration, Small molecules. Small molecules aid in prevention and
it could be argued that the neurodegenerative process is being
held at steady state. Therefore, the agent should be continued. If treatment by reducing amyloid-β production, tau aggregation
a patient has failed to tolerate the maximum effective dose of a or neuroinlammation. Examples include gamma-secretase and
particular agent over a 3-month assessment period, an alternative β-secretase modulators to reduce aberrant cleavage of amy-
should be considered.
loid precursor protein (APP); inhibitors of tau aggregation;
If withdrawing an AChEI, evidence suggests that patients
should be carefully reviewed for the next 48–72 hours and for 2 and tau vaccines and azeliragon, an antagonist of the receptor
weeks after discontinuation. This is because when an AChEI is of advanced glycation end products (RAGE), which leads to
withdrawn, the person with dementia can rapidly decline, and it inlammation and oxidative damage when occupied. RAGE also
then becomes apparent that the medication was producing effects mediates transport of amyloid-β from the blood into the brain
in areas that had not been previously acknowledged. Dementia
is a syndrome affecting many parts of a person’s cognitive func- (Connelly, 2015). 
tion, including personality, communication and behaviours, Other targets. Other targets include the repositioning of
as well as memory. Just because a poor response in memory is
seen, this does not mean the medicines are not being effective agents currently used to treat hypertension (calcium channel
in other aspects. If the medicines are restarted within 2 weeks, blockers) and diabetes (pioglitazone), as well as exploring the
patients often return to their level of function before withdrawal. effect of insulin resistance on brain function (Kim, 2015). 
If the period before restarting is longer than this, the deterioration
appears to remain, although further progression may be halted for Treatment of rarer dementias
a further period of time if medication is restarted. 
For all rarer dementias, there is currently no cure and generally
N-Methyl-D-aspartate receptor antagonist – no licensed treatment; consequently, management is symptom-
memantine atic, combining medication, physiotherapy, occupational therapy
and speech and language support. The exceptions are as follows:
Memantine is a voltage-dependent, moderate-afinity uncom- • Rivastigmine is licensed for use in Parkinson’s disease
petitive NMDA-receptor antagonist. It blocks excessive calcium
ion inlux into the neuron to prevent associated neuronal death dementia.
but allows normal physiological functioning. It is licensed for • The current triad of antiretroviral medication regimen has
the treatment of people with moderate through to severe AD.
Studies demonstrate signiicant improvement in cognition and resulted in a reduction in HIV-related dementia to approxi-
functioning (activities of daily living) global outcomes and also mately 2%, from 20% to 30% (Alzheimer’s Society, 2015a).
that fewer people taking memantine develop agitation (Hermann • If normal pressure hydrocephalus is diagnosed and treated
et al., 2011). early with cranial surgery to drain excess luid, symptoms
generally improve after surgery, with some people making an
Memantine is licensed for use in patients with moderate and almost complete recovery. In the majority of these cases, AD
severe AD and may be co-prescribed with AChEIs dependent on is the cause of posterior cortical atrophy; therefore, AChEIs
specialist advice. It should also be considered at mild stages of and/or memantine may be of beneit.
AD if AChEIs cannot be tolerated or are contraindicated (NICE, • In ARBD, treatment is based on the person staying alcohol-
2016).  free and rehabilitation from either dementia services, acquired
brain injury services or the community mental health team.
Emerging treatments for Alzheimer’s disease Any improvement in the person’s abilities is usually greatest
in the irst 3 months of abstinence but can continue for 2–3
Since a Global Summit on Dementia in 2013, in response to the years. About 25% of people affected by ARBD make a very
World Health Organization report (WHO, 2012), there has been good recovery, with about 50% achieving partial recovery and
wider international collaboration on potential treatments and needing support to manage their lives but possibly still being
sharing of information. Currently, there are several compounds able to live in their own homes or in sheltered housing. The
in 3- to 4-year phase III clinical trials looking at the prevention of inal 25% make no recovery and generally require long-term
amyloid and tau deposition using monoclonal antibodies. residential care (Alzheimer’s Society, 2015b). 

Monoclonal antibodies. Monoclonal antibodies clear toxic Treatment strategy for behavioural and
amyloid-β directly or by microglia and astrocyte activation. There psychological symptoms of dementia

First-line treatment for any challenging behaviour is either a psy- 571
chological or alternative therapy intervention (NICE and Social
Care Institute for Excellence [SCIE], 2011). These interventions
should be given suficient chance to exert an effect before trying

33 THERAPEUTICS

Box 33.2 Potential causes of behavioural change Short-term pharmacological management of behavioural
and psychological symptoms of dementia. If the behaviours
• Depression are anxiety or mood related, then second-line treatment is low
• Pain (remember that patients walk into objects) doses of selective serotonin reuptake inhibitors (SSRIs). These
• A superimposed acute confusional state (delirium) caused by have reduced antimuscarinic effects compared with tricyclic anti-
depressants, and sertraline is the safest in terms of cardiovascular
infection (chest and urinary tract infections are most common) risks.
• New medication being started or one stopped (including
Occasionally an antipsychotic may be appropriate if all other
purchased and recreational, e.g. alcohol) avenues have been tried and the individual is a danger to him-
• Side effect or withdrawal effect of a medicine or herself or others and/or is extremely distressed. Risperidone
• Communication problems (check glasses for correct prescrip- is the only licensed antipsychotic in the UK for the treatment
of severe aggression in AD which has not responded to other
tion/clean; hearing aids [battery/turned on], denture use) treatments, but it can only be prescribed for a maximum period
• Aggression might indicate the person wants to communicate of 6 weeks. The Royal College of Psychiatrists (2016) recom-
mend that the treatment decision is made by a specialist in
but cannot and becomes frustrated dementia after discussion with the person’s carer and/or fam-
• Recent change in environment/staff/routine ily and the multidisciplinary team, and the reason recorded in
• Review to determine if this is a common trigger (antecedent); the patient’s medical record. The lowest dose producing the
desired effect should be used, and the continued need should
linked to a behaviour be reviewed regularly and the treatment discontinued when
• Identify what changes this behaviour (e.g. distraction) appropriate. 

an alternative. If they are effective, then the person should just be Longer-term prescribing of antipsychotics. If a chal-
monitored. It is important to remember that the disease is always lenging behaviour continues and requires longer-term man-
progressing, and therefore challenging behaviours will stop agement, then an alternative to an antipsychotic must be
or change. Box 33.2 details the possible causes of behavioural considered because rates of mortality are increased over those
change. who do not take long-term antipsychotics. The long-term
negative outcomes of being prescribed an antipsychotic in
Psychological and alternative therapies. Psychological and dementia were shown in the DAART-AD trial (Ballard et al.,
alternative therapies are irst-line non-pharmacological treatment 2009). This study identiied that at 24 months, the survival
options and include adapting the environment (e.g. lighting, rate for those receiving an antipsychotic was 46% compared
space to walk, colour schemes, access to outdoors). Behavioural with 71% in the placebo arm; 36 months’ survival was 30%
interventions include distraction, reality orientation, occupational compared with 50%; and at 42 months, it was 26% compared
activities, reminiscence, cognitive stimulation and singing. Any with 53%.
possible underlying causes should be explored (e.g. pain, anxi-
ety, depression, a recent change or upsetting event). Lavender Potential alternatives include acetylcholinesterase inhibi-
oil (aromatherapy and massage) and melissa oil (aromatherapy) tors, memantine, citalopram, gabapentin and pregabalin.
have both demonstrated signiicant improvement in agitation ver- If highly antimuscarinic agents are initiated, monitoring is
sus placebo (Fu et al., 2013). required because they reduce cognitive functioning by reduc-
ing cholinergic load and are linked with increased mortality
Improving the staff knowledge of behavioural and psycho- and morbidity (Fox et al., 2011). People with dementia tend
logical symptoms of dementia (BPSD) and how to manage to be very sensitive to any centrally acting medication, and
them using non-pharmacological methods has been shown to the prolonged action of sedatives increases the risk of falls.
result in a sustained 50% reduction in the use of antipsychot- Therefore, if necessary, the smallest possible dose should be
ics over a year. In addition, improving social interaction also prescribed for the shortest time. 
resulted in reduced rates of prescribing for patients with severe
dementia (Fossey et al., 2006). Patient care

More importantly, treating unrecognised pain was found to Safer medicines use
reduce agitation signiicantly, as well as other neuropsychiatric
symptoms (Husebo et al., 2011). Two-thirds of prescribing of antipsychotics in people with
dementia is inappropriate and associated with increased mor-
Behavioural treatment and carer support are priorities in man- bidity and mortality for as long as it is prescribed. Both typical
aging sundowning. These are in addition to minimising napping and atypical antipsychotics are associated with large side-effect
during the day, regular exercise and establishing a day and night proiles, with numbers needed to harm ranging from 4 to 13.
routine. Use of bright light (Lux) in the morning can reduce the Deaths related to antipsychotic prescribing are associated with
incidence of agitation in the evening. Small studies have shown cerebrovascular and cardiovascular events, as well as pneumo-
that people with dementia who receive light therapy in winter nia (Wang et al., 2005).
months display reduced behavioural problems such as agitation
(NICE and SCIE, 2011). If highly antimuscarinic agents are initiated, monitoring their
effect is important because they reduce cognitive functioning by
Increasingly, forms of psychotherapy and modiied cognitive-
based therapy are being used with some success in people with
dementia in the mild to moderate stages (Junaid and Hegde,
2006). Other psychosocial interventions include reminiscence
and/or validation therapy; interactions with animals, music and
572 children; and cognitive stimulation therapy (Toh et al., 2016). 

DEMENTIA 33

reducing cholinergic load and are linked with increased mortality Preventing dementia
and morbidity (Fox et al., 2011).
Reducing cardiovascular risk
Medication should be reviewed regularly to reduce the presence
of iatrogenic disease and to gain maximum beneit from medi- If 1000 people with hypertension were treated with adequate
cines for dementia and cognitive functioning by lessening the use treatment for 5 years, then 19 cases of dementia would be pre-
of highly antimuscarinic medication. It is important to ensure that vented (Kelly et al., 2009).
the carer (with the permission of the person with dementia) is
also involved in all aspects of medicines use because the carer Aspirin does not improve cognitive functioning, but it will
is the person ensuring adherence with any medication regimen. prevent further ischaemic events and should be prescribed if
For advice on medicines optimisation, please see Table 33.12. indicated.
When the disease becomes end stage, then there should be a judi-
cial review of all medication, and the principles of good palliative Before and at all stages of dementia, people need advice on
care should be put into place.  lifestyle changes to keep healthy and improve cerebrovascu-
lar and cardiovascular perfusion. There is robust evidence to

Table 33.12 Suggestions to enhance medicines optimisation and prescribing

Problem Suggestions
Labelling issues
Carers appreciate complete directions such as ‘at night’ or ‘after breakfast’ so that they can plan dosing
schedules according to mealtimes. If a medication is being taken for sleep, e.g. then directions such as ‘take
1 h before bedtime’ can help so that the medication is starting to take effect before the recipient actually
goes to bed.

Disease progression Disease progression effects physical functions as well and includes swallowing and chewing difficulties.
Always ask if there is a problem because many carers just try to get the medication into the person any way
they can, often mixing it with yoghurt, jam or mashed potato. Where possible, ensure liquid formulations are
used if this is a problem. Carers value any support in this area because they have been told how important it
is for the medicines to be taken but do not realise the potential effects of opening a long-acting capsule into
yoghurt.
Poor memory, a reduced sense of smell and the effects of medication may result in a reduced food and fluid
intake, resulting in weight loss, dehydration and electrolyte disturbance. The provision of sip feeds may be
useful in people at this stage of the disease.
Control of bowels and bladder may reduce over time; in moderate to moderately severe stages, people
may forget where the toilet is or not recognise the physical signs associated with bowel and bladder control.
Regular toileting (on waking and after meals and before bed) may help, but also the provision of incon-
tinence aids may be needed. Also think about the need for skin care to ensure that skin breakdown and
possible pressure sores do not occur.

Simplifying medication Consider the use of long-acting preparations (e.g. galantamine XL) as an alternative to twice-daily dosing or
regimens patches if a long-acting form is needed. Long-acting preparations will take longer to reach steady state, but
this often reduces the incidence of side effects and improves adherence to complex medication regimens.

Repeat dispensing issues Concomitant medicines that run out at different times and may have different prescribers – try to rationalise
prescribing and ordering to ensure a common quantity of medication is available.
Prescriptions for the cognitive enhancer are often collected from a different place, increasing strain on the
carer, especially if it means ringing a consultant’s secretary to ensure a prescription is sent and sufficient
quantities are ordered to last until the next appointment. You may be able to help ensure that the prescriber
understands exactly what is needed and by when.
Changing brands of concomitant medication can be confusing for any person, let alone someone with a
memory problem who may just remember shape and/or colour. Great care is needed when making these
changes to ensure that it is fully understood that it is the same medication and not another new one. Parallel
imports may also be confusing.

Remembering medication Memory and/or compliance aids may be a welcome addition to help make sense of the medication, as
would a medication reminder card which also includes brief details of what to take and when. If you are
helping individuals with a memory problem who live on their own, it is recommended to find out how they 573
currently try to remember to take their tablets (many write notes for themselves and then tick things off the
calendar or have a note on the fridge or a telephone call from a family member) and see if you can help
improve the system. Try not to introduce anything too complex because they may not remember new infor-
mation or routines. Suggestions that fit with their current daily activities may be most successful. It may also
help to telephone them for a few days to see how they are getting on.

Continued

33 THERAPEUTICS

Table 33.12 Suggestions to enhance medicines optimisation and prescribing—cont’d

Problem Suggestions

Medicines review Discuss with the carer and person with dementia what they feel is most important; they will generally have
one pressing issue which they would like to resolve.
There is often at least one medication that people are not using either at all or as prescribed. Try to establish
why. It may be that the behaviour has changed and the item is no longer needed or that an adverse event
occurred which has put them off using the medication. If the latter, then a smaller dose or alternative medi-
cation may be more appropriate. Asking key questions can help identify what actually happened. Always
communicate this with the prescriber (with the individual’s permission) because this reduces waste and un-
necessary prescribing and helps keep accurate records of medication regimens.
Check that the time of day a dose is to be taken is appropriate if a side effect occurs (e.g. if insomania and/or
nightmares occur in people on donepezil, ensure the dose is taken in the morning because this will improve
sleep patterns).

Managing side effects Diarrhoea, nausea, vomiting, anorexia and headache are common side effects on initiation and on dose titra-
tion of AChEIs. Carers need support to understand this is normal and that tolerance will generally develop.
These may be transient (5–7 days), but if continuous, then a shared decision should be made on the balance of
benefits and adverse reactions. Due to the different modes of action, another agent may be tried.
Antiemetics
For nausea/vomiting on initiation or dose titration of AChEIs, domperidone is preferred because it does not
cross the blood–brain barrier or have anticholinergic side effects. Domperidone should be taken regularly
three or four times daily for 3 or 4 days and then reduced to zero as symptoms subside. Long-acting meto-
clopramide is an option for those without movement disorders.
Diarrhoea
If diarrhoea is a problem, loperamide may be co-prescribed. The dose and frequency are generally titrated
to the side effect and then taken regularly. Ensure that the dose is not so high or continued too long as to
cause constipation.
Donepezil is prescribed at night; however, it may cause vivid dreams interfering with sleep, in which case,
this may be best administered in the morning.
Memantine
Side effects include dizziness, headache, confusion, hallucinations (which can also be part of the dementia
process) and tiredness. Keeping a diary of tiredness is recommended because a short nap in the mid-after-
noon may reduce the problem, as would administering the dose at night to aid sleep.

Referral of side effects If side effects of AChEIs are severe and/or debilitating, then refer back to the prescriber. Referral should
also be made if there are signs of urinary flow difficulties or worsening of asthma, COPD or cardiovascular
symptoms, especially blackouts.
With memantine, if hallucinations are distressing the individual, refer to specialist. NICE guidelines set out
strict conditions to be met before the use of an antipsychotic.

Starting new medicines If new medicines are started (including purchase of OTC products for coughs and colds), check whether they
cause anticholinergic side effects because this will increase confusion, impair memory function and possibly
antagonise the effect of the cholinesterase inhibitor. Dextromethorphan and memantine are contraindicated.

Concomitant prescribed Ensure understanding of what each medication is for and common side effects associated with each, high-
medicines (for other medical lighting those that need to be reported immediately. It is often helpful to provide a medicine reminder chart
conditions) which indicates what each is for, including common side effects and when to take them. Always check for
interactions.
Remember that any agent which has anticholinergic side effects will increase confusion and reduce cognitive
functioning (as well as the other adverse effects, such as constipation, dry mouth, cardiovascular effects).
Therefore, where possible, check for anticholinergic load (e.g. oxybutynin, antidepressants or antipsychotics)
and recommend alternatives if possible.
Remember that any medication with CNS effects (e.g. benzodiazepines, opiates or dopaminergic agents)
may negatively affect cognitive functioning. Benzodiazepines are also amnestic.
Any agent which has the potential to cause confusion, e.g. long-acting hypoglycaemic agents, non-steroidal
anti-inflammatory agents and H2 antagonists such as cimetidine, should be carefully monitored and/or with-
drawn if possible.
Side effects of aspirin are well known. Ask about gastro-intestinal problems, and check for excessive bruising
after falls or knocks.

Stopping cognitive Stopping cholinesterase inhibitors can produce a dramatic decline in cognitive and physical functioning
enhancers which may require the agent to be restarted.

574 AChEIs, Acetylcholinesterase inhibitors; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; NICE, National Institute of Health and Care
Excellence; OTC, over-the-counter.

DEMENTIA 33

demonstrate that an active lifestyle and using the brain to learn Supporting people with concerns about
a new language, dance or take part in gym activities along- possible dementia
side a healthy diet reduce the risk of dementia (Public Health
England, 2016).  People often worry about the possibility of dementia if their
memory seems to be less effective as they get older. With aging,
Herbal supplements, aromatherapy and social our mental speed tends to decline, with thinking, problem solv-
and behavioural interventions ing and recall all becoming slower. Being very busy, depressed
or anxious can impair the way in which short-term memories
People with dementia and family members may use various are laid down. If short-term memories are not laid down, then
herbal supplements to try to prevent and/or delay the onset of long-term memories will not be formed. For example, if you
dementia. are not paying complete attention to a person when he or she
is speaking, the information will not be retained completely,
Claims of cognitive enhancement have been made for which results in reduced recall of the conversation, disruption
a number of supplements; the key ones are listed here. of the short-term memory process and consequent inability to
Cochrane Reviews on Dementia and Cognitive Improvement recall the conversation or interaction. Forgetting the occasional
(http://dementia.cochrane.org/) hosts a number of systematic word or making a poor decision once in a while is nothing to
reviews on herbal supplements, aromatherapy and social and be worried about. The time to seek help or refer to memory ser-
behavioural interventions for people with dementia. Another use- vices is when changes in cognitive functioning impair an indi-
ful resource is the NICE-SCIE guideline on supporting people vidual’s ability to care for him- or herself or participate in work
with dementia (NICE and SCIE, 2011). or social interactions. Healthcare professionals are often reluc-
tant to discuss cognitive changes with people, but further infor-
Ginkgo biloba mation and signposting is welcomed so that they can address
their own concerns. 
The proposed mechanism of action of ginkgo biloba is to
increase blood supply by dilating cerebral blood vessels and Communicating with people with dementia and
decreasing blood viscosity. There are some isolated reports of their carers
bleeding with ginkgo biloba with a theoretical interaction with
aspirin or warfarin, possibly resulting in increased bleeding The most important thing to remember when talking to people
(Bent et al., 2005). The prescriber should be consulted before with dementia is that they are still able to communicate and will
use in these circumstances. It is also proposed that the com- probably enjoy the opportunity. The following points will aid
pound modiies neurotransmitter systems and decreases the effective communication, but supporting information may be
density of oxygen free radicals. The evidence for improve- necessary from relatives or caregiver(s) when accurate and reli-
ment in cognitive functioning is inconsistent with three studies able information is needed (e.g. an accurate medication history).
showing equivalence to placebo and one showing a substantial People with dementia may make up answers if they think they
positive effect. However, it is known that ginkgo appears to be should know but are unable to remember an answer. 
safe to use and is well tolerated; it is unknown whether long-
term use has any effect on the onset of dementia (Birks and Adapting communication skills
Grimley Evans, 2009). 
The fundamental principle of communication with people with
Vitamin E dementia is to try to capitalise on the preserved memory systems.
Therefore, the following strategies are advisable:
Vitamin E has an antioxidant effect, and it was thought this might • Simplify sentences.
reduce the onset of the neurodegenerative process. However, a • Simplify vocabulary.
review in 2012 stated there was no evidence of the eficacy of • Use yes-or-no, not multiple choice, questions.
vitamin E in the prevention or treatment of people with AD or • Talk about the here and now, not the abstract.
mild cognitive impairment and that the risks to individuals out- • Use direct language wherever possible.
weighed any beneits (Farina et al., 2012).  • Avoid teasing and sarcasm.
• Check that what you say is understood.
Folic acid, vitamin B12 and iron • Summarise information.
• Provide written information.
The dietary supplement folic acid, vitamin B12 and iron are linked • Use a slow speech rate.
with cognitive dysfunction, confusion and/or memory problems, • Speak clearly and audibly.
when there is a deicit. Older people may not eat suficient fresh • Use a pleasant, accepting tone.
green vegetables or dietary protein to sustain normal levels. In • Vary the pitch and tone of the voice.
addition, active transport mechanisms for vitamin B12 absorption • Limit the number of participants in the conversation.
are often impaired. However, if a deiciency has not been identi-
ied, supplementation with folic acid, vitamin B12 or iron will Skilled communicators can establish a conversation with the
generally not have any clinical effect.  person in a time and place that they remember and thus allow

575

33 THERAPEUTICS

them to participate. It is also increasingly important to read the Questions
person’s body language as the disease progresses. This is because
often the person cannot communicate effectively with words, and 1. What do you think could have potentially caused these behaviours?
physical exhibitions of agitation, depression, pain or frustration Three months later, Mr TB and Mrs LB arrive at the pharmacy
may be conveyed via pacing, withdrawal or shouting/hitting, for
example.  looking shocked and a little upset. You take them to the counsel-
ling room. Mr TB gives you a prescription for donepezil 5 mg each
Information provision for carers evening and says that they have just been told that he probably
has AD. Mr TB says he has had ‘every test possible and that’s what
The physical and psychological support of carers is very impor- they’ve come up with’. It is a shock to both of them because no
tant; it is well evidenced that if they are not given the support one in Mr TB’s family has ever had a dementia. They both want to
they need, then the caring process breaks down, and early insti- know more about this medicine.
tutionalisation occurs (Eska et al., 2013). People need and want 2. What information should you provide Mr TB and Mrs LB about
different advice at different stages of the illness, so always offer the benefits of treatment while also ensuring they understand this
information even if it is not always accepted. Wide-ranging guid- medicine is not a cure?
ance for carers and healthcare professionals can be found in the
NICE-SCIE (2011) guideline. As the disease progresses, carers The next weekend, Mr TB’s daughter, their only child, visits the
may seek advice on how to manage behavioural changes and the pharmacy and asks to speak to you. She is 32 years old, recently
reasons for their development. Useful information is provided by married and planning to start a family. She wants to know what her
the Alzheimer’s Society (2015c). chances are of developing AD and whether she should consider
not having a baby.
People with dementia and/or their carers may seek informa- 3. How do your respond to Mr TB’s daughter? 
tion on a number of issues to address before insight into care
is lost. Awareness of any local dementia services and signpost- Answers
ing people for information is therefore important. Topics may
include: 1. Mr TB is neither delusional nor obsessive; these incidents are signs of
• access to inancial, social and healthcare advice and services; short-term forgetfulness and changes in visuospatial co-ordination.
• legal issues, such as continuing to drive or end-of-life care; Although simvastatin can cause depression and amnesia in some
• occupational therapy for living aids, such as stair lift, people, this is generally seen early in the treatment.
Early recognition allows early diagnosis and the ability to rule out
stair gates, shower and bathing aids, walking and dressing treatable pseudo-dementias. Depending on your local organisa-
aids; tions and memory clinics available, you could suggest that Mrs
• memory aids, including tools and prompts, as well as activi- LB makes an appointment for her husband to see his primary care
ties for improving cognitive and memory function; doctor (with Mrs LB co-attending) to discuss possible referral for
• carer support and education on caring for a person with a memory clinic assessment. In some areas/countries, you may be
dementia.  able to refer Mr TB, or they could self-refer.

Case studies 2. Mr TB and Mrs LB should be informed that acetylcholinesterase
inhibitors (AChEIs), like donepezil, are not a cure for AD, or any
Case 33.1 dementia, but they can improve the symptoms associated with
dementia. Importantly, these medicines work very well for one-
576 Mrs LB is well known at your pharmacy because she organises third of people and somewhat well for another third; for the
the repeat prescriptions for her husband and collects these every remaining third, they seem not to have an effect. AChEIs have
2 months. Mr TB, her husband, has hypertension and is pre- linear kinetics; subsequently, effects are dose dependent, and it
scribed losartan and simvastatin. Mr TB has recently retired; he may take up to 3 weeks or longer to attain steady state. Therefore,
was a banker, and you have only met him occasionally. Mrs LB has if response appears to be negative, a dose increase should be
asked if she can speak with you. She seems quite upset and emo- tried and/or a change to another AChEI because they each have
tional. She says that over the last few months, her husband has a slightly different mode of action. It should be explained to Mr
been acting increasingly out of character. She has found him tak- TB and Mrs LB that the medicine needs to be taken at the same
ing his tablets again because he was adamant he had not taken time of day. However, because donepezil can cause nightmares
them earlier, although Mrs LB had watched him take them. In and affect sleeping, this would require a change to morning dos-
addition, he has been getting dressed as if he was going to work, ing. All AChEIs can cause nausea, vomiting and diarrhoea, so Mr
in his suit with a packed briefcase. Mrs LB has had to remind TB and Mrs LB should be informed that because of this, doses
him that he has retired and no longer needs to go to work. Of are started low and titrated up over 2-week intervals to ensure
more concern is that Mr TB has started to have small accidents that tolerance occurs. This titration will also affect the time taken
in the car – minor incidents such as hitting the garage door when for maximum efficacy to be reached. These effects can be man-
reversing or the curb when driving. Mrs LB would like to know if aged with antispasmodics that do not act on the central nervous
these could be side effects of one his medicines. This is because system, such as long-acting metoclopramide, domperidone or
on a few occasions recently he has taken double the dose of his loperamide, as appropriate. It is always important to remember
medications. that any sedative medication, such as phenothiazines and sedative
antihistamines, will impair cognitive functioning, especially if it is
also highly antimuscarinic.

3. Because Mr TB’s AD is not familial, you should explain to his
daughter that there is unlikely to be a genetic risk (although this
could be confirmed if needed). You could say that evidence
shows that good public health interventions can reduce the risk of
dementia. This includes reducing cardiovascular risks, appropri-
ate treatment of ischaemic heart and vascular disease, keeping

DEMENTIA 33

fit and exercising three to four times weekly for 30–40 minutes to the key reason for people with dementia being admitted to care
maintain an ideal body weight and engaging in social and mental facilities.
activities to maintain good brain function. These can all reduce Rivastigmine may cause bradycardia, which may contribute to
the risk of experiencing dementia. Environmental changes, such the occurrence of torsade de pointes in patients with uncompen-
as avoiding centrally acting toxins and brain injury (sports such sated heart failure, recent myocardial infarction, bradyarrhythmias,
as boxing, rugby and football with repeated head trauma), can hypokalaemia or hypomagnesaemia or concomitant medicines
also reduce this risk. Although there are compounds being inves- which induce QT prolongation and/or torsade de pointes (e.g.
tigated in phase III studies for prevention of dementia, these are antipsychotics, citalopram, antiarrhythmics). Rivastigmine therapy
with populations with genetic risk factors. Currently, there are no has been associated with hypertension. Atenolol is well known to
pharmacological or herbal remedies which reduce the risk of idio- cause bradycardia leading to syncope, which leads to falls.
syncratic dementia.  Therefore, it would be appropriate to suggest withdrawing the
atenolol used for blood pressure control, as it has led to brady-
Case 33.2 cardia. An alternative would be to suggest increasing the dose of
enalapril to control the rise in blood pressure, rather than adding a
Mr SJ is a slim 65-year-old gentleman who has atrial fibrillation new medication. If the bradycardia still continued and the rivastig-
and is prescribed digoxin, enalapril, warfarin and simvastatin. He mine was still considered beneficial, then a pacemaker could be
had been going to his primary care doctor for his warfarin tests – used to control heart rate and reduce falls. 
sometimes twice in the same day – and then forgetting about
them a week later. His wife said he was also quite withdrawn and Case 33.3
had lost interest in his garden and radio shows. It was the nurse in
his local surgery who referred him to his primary care doctor for a Mrs AS is a 76-year-old woman, and before her AD was diag-
dementia screen because she was concerned about his behaviour. nosed 5 years ago, she was fiercely independent and an active
Mr SJ was subsequently prescribed rivastigmine 1.5 mg capsules member of the community. Mrs AS now attends the local church
twice daily, and 2 weeks ago this was increased to 3 mg capsules service once a week and a coffee morning with her friends.
twice daily. Today, he and his wife are at the pharmacy. They would However, she has resigned her previous secretarial position on
like to know what Mr SJ can take for his nausea because it is put- a local women’s group. She was started on galantamine XL 8 mg
ting him off his food, and he has already lost 2 kg in weight over and subsequently increased to galantamine XL 24 mg once daily
the last 2 weeks. about 9 months ago. Her husband has been pleased with the
effect because she is more sociable and plays with the grand-
Questions children again. However, Mrs AS has started to get very agi-
tated in the evening and refusing to sit down. She has been
1. What advice do you give Mr and Mrs SJ on managing the nausea insisting that she wants to walk to post a letter and then gets
and weight loss? very angry when her husband locks the door to prevent her
Nine months later, Mr SJ is admitted to hospital for investiga- from leaving the house. Last night, Mrs AS was so angry that
tion into two recent falls at home, both of which resulted in exten- she slapped her husband. He has asked your advice on what
sive bruising because of the warfarin. Mr SJ did not fall or trip; Mrs course of action he should take. He wants to know if he should
SJ described the fall as though his legs just gave way. Mr SJ said encourage her to take an over-the-counter sleeping aid or if
he felt a little dizzy, and the next thing he could recall was that he he should just persevere in trying to explain that she does not
was on the floor. The primary care doctor recently started atenolol need to go out.
25 mg once daily because Mr SJ’s blood pressure had increased
to 150/95 mmHg. The rivastigmine he was prescribed has been Questions
successful because he is now socially engaged, able to complete
activities of daily living and is very happy within himself. The con- 1. How do you respond to Mrs AS’s husband’s concerns?
sultant asks your opinion on whether the rivastigmine should be Eight months later, the primary care doctor for the local care
stopped because they consider it likely that Mr SJ’s fall was due to
bradycardia caused by rivastigmine. home contacts you about Mrs AS. Mrs AS was admitted 2 months
ago when her husband was unable to look after her following a
2. What information could you provide to the consultant, and what small stroke. The staff have explained that Mrs AS has settled
treatment options would you recommend?  in well and enjoys her daily walk in the garden and her sing-
ing group sessions. She has always been friendly and polite and
Answers never gets angry. However, over the last 2 days, Mrs AS has
lashed out at the same member of staff while he was helping her
1. Nausea and vomiting are associated with dose increases of AChEIs wash and dress. This morning, this staff member received a black
and can be managed either by slowing down the rate of titration eye, and the staff member wants Mrs AS’s behaviour addressed.
and/or co-prescription of an antiemetic such as metoclopramide. The primary care doctor asks if you think risperidone 500 micro-
Because weight loss can impair physical strength, and resultant grams at night would be an appropriate choice for Mrs AS.
electrolyte imbalances may affect cognitive function in older 2. How do you respond to the primary care doctor’s question? 
people, it is important to address this issue. An alternative would
be to consider rivastigmine patches to see if a more controlled Answers
dose release over 24 hours would have a reduced incidence of
nausea. Mr SJ should be encouraged to eat small amounts more 1. This behaviour sounds like ‘sundowning’, where people experi- 577
frequently until his body has time to develop tolerance to the dose ence night–day reversal and associated agitation. This might be
increase, which usually takes about 2 weeks. caused by too much napping during the day or inadequate expo-
sure to bright light (dimmed lights, closed curtains or blinds or not
2. Rivastigmine is positively enhancing Mr SJ’s life and therefore being out of the house during the daytime) to suggest daytime,
that of his wife and family. This is important because carer stress is

33 THERAPEUTICS

leading to a loss of time orientation. As night approaches, there respect to nudity, would not undress in front of him and had always
should be clear signals of closing curtains, turning down lights, insisted on washing and bathing herself. He said it was under-
calming the environment and establishing a routine which is sug- standable that Mrs AS had become upset and angry when a male
gestive of night time. Lavender and Melissa officinalis oils can be assistant was helping her, as this had never happened before, and
used as a massage (even only to the hands or feet) or used via she would have felt threatened. The recommendation is to ensure
a diffuser for inhalational effects to help decrease incidences of a female staff member helps Mrs AS when washing and dressing.
agitated behaviour. It is best if these are used before the expected Therefore, it is important to always question the reason behind a
behaviour, as part of a routine before bedtime and sleeping. behavioural change and ensure that the family members are also
Short courses of small doses of z-hypnotics may also help if the oils informed. They may highlight possible reasons for the change. An
are ineffective. However, tolerance quickly develops, and so does antipsychotic should only be prescribed when the individual is a risk
the potential for adverse effects such as postural hypotension, falls to him- or herself or others and after trialling non-pharmacological
and decline in cognitive function, including memory impairment, interventions. An antipsychotic should not be prescribed for seda-
as well as additional medication and possible interactions. tion and in this situation would be unlikely to reduce Mrs AS’s fear
2. When behaviour changes occur, there should always be an ABC and distress. Good practice indicates that an antipsychotic should
assessment. A = antecedent (what causes the behaviour), B = only be prescribed after a team discussion and further discussion
behaviour, and C = change (what changes the behaviour). This with the patient and family outlining the associated increased risks
assessment needs to be undertaken to review Mrs AS’s recent for morbidity and mortality. The decision to prescribe should be
change in behaviour. documented in the patient’s medical record and reviewed fre-
On further inquiry, the care home revealed that there has been quently to ensure it is still appropriate. The lowest possible dose
a new male member of staff involved in helping Mrs AS to wash to achieve the required effect should be prescribed. However, in
and dress. When Mrs AS’s husband was contacted, he was very this case, the cause of Mrs AS’s changed behaviour was identified,
upset. He explained that his wife was a very private person with and therefore no new medication was prescribed.

References

578 Albert, M.S., DeKosky, S.T., Dickson, D., et al., 2011. The diagnosis of mild Eska, K., Graessel, E., Donath, C., et al., 2013. Predictors of institutionaliza-
cognitive impairment due to Alzheimer’s disease: recommendations from tion of dementia patients in mild and moderate stages: a 4-year prospec-

the National Institute on Aging-Alzheimer’s Association workgroups tive analysis. Dement Geriatr. Cogn. Dis. Extra. 3 (1), 426–445.
on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. Farina, N., Isaac, M.G.E.K.N., Clark, A.R., et al., 2012. The use of vitamin E for

7270–7279. https://doi.org/10.1016/j.alz.2011.03.008. Alzheimer’s dementia and mild cognitive impairment. Cochrane Database
Syst. Rev. 2012 (11) Art No., CD002854. https://doi:10.1002/14651858.CD
Alzheimer’s Association, 2009. 10 early signs and symptoms of Alzhei- 002854.pub3.
Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. ‘Mini-mental state’.
mer’s. Available at: http://www.alz.org/alzheimers_disease_10_signs_of_ A practical method for grading the cognitive state of patients for the clini-
cian. J. Psychiatr. Res. 12 (3), 189–198.
alzheimers.asp. Fossey, J., Ballard, C., Juszczak, E., et al., 2006. Effect of enhanced psy-
chosocial care on people with severe dementia: cluster randomised trial
Alzheimer’s Society, 2014. Dementia UK, Update 2014, second ed. Avail-
antipsychotic use in nursing home residents. Br. Med. J. 332, 756–761.
able at: https://www.alzheimers.org.uk/info/20025/policy_and_inluencing/ Fox, C., Livingston, G., Maidment, I.D., et al., 2011. The impact of an-
251/dementia_uk.
Alzheimer’s Society, 2015a. Rarer causes of dementia. Available at: https:// ticholinergic burden in Alzheimer’s dementia – the Laser-AD study. Age
www.alzheimers.org.uk/download/downloads/id/1767/factsheet_rarer_ Ageing. 40 (6), 730–735.
causes_of_dementia.pdf. Fu, C.-Y., Moyle, W., Cooke, M., 2013. A randomised controlled trial of the
use of aromatherapy and hand massage to reduce disruptive behaviour in
Alzheimer’s Society, 2015b. What is alcohol-related brain damage? Avail-
people with dementia. BMC Complement Altern. Med. 13, 165. https://
able at: https://www.alzheimers.org.uk/download/downloads/id/1765/
factsheet_what_is_alchol-related_brain_damage.pdf. doi.org/10.1186/1472-6882-13-165.
Geldmacher, D.S., Provenzano, G., McRae, T., et al., 2003. Donepezil is
Alzheimer’s Society, 2015c. Changes in behaviour. Available at: https://www.
associated with delayed nursing home placement in patients with Alzhei-
alzheimers.org.uk/site/scripts/documents_info.php?documentID=159.
Alzheimer’s Society and Royal College of General Practitioners, 2015. mer’s disease. J. Am. Geriatr. Soc. 51 (7), 937–944.
Harwood, D.G., Kalechstein, A., Barker, W.W., et al., 2010. The effect of
Helping you to assess cognition: a practical toolkit for clinicians. Avail-
able at: https://www.alzheimers.org.uk/downloads/download/1045/ alcohol and tobacco consumption, and apolipoprotein E genotype, on
helping_you_to_assess_cognition_a_practical_toolkit_for_clinicians.
Ballard, C., Hanney, M.L., Theodoulou, M., et al., 2009. The dementia the age of onset in Alzheimer’s disease. Int. J. Geriatr. Psych. 25 (5),
antipsychotic withdrawal trial (DART-AD): long-term follow up
of a randomised placebo-controlled trial. Lancet Neurol. 8 (2), 511–518.
151–157.
Health and Social Care Information Centre, 2016. Patients in England with
Ballard, C., Gauthier, S., Corbett, A., et al., 2011. Alzheimer’s disease.
a record of dementia diagnosis on their clinical record: February 2016.
Lancet 377 (9770), 1019–1031. Quality and Outcomes Framework dementia subset. Available at: http://
Bateman, R.J., Xiong, C., Benzinger, T.L.S., et al., 2012. Clinical and bio- content.digital.nhs.uk/media/20384/Dementia-Diagnosis-Summary-
February-2016/pdf/qual-outc-fram-rec-dem-diag-feb-2016-sum.pdf.
marker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Hermann, N., Li, A., Lanctôt, K., 2011. Memantine in dementia: a review
Med. 367 (9), 795–804. of the current evidence. Expert Opin. Pharmacother. 12 (5), 787–800.

Bent, S., Goldberg, H., Padula, A., et al., 2005. Spontaneous bleeding as- https://doi.org/10.1517/14656566.2011.558006.
Husebo, B.S., Ballard, C., Sandvik, R., et al., 2011. Eficacy of treating pain
sociated with ginkgo biloba: a case report and systematic review of the
literature. J. Gen. Intern. Med. 20 (7), 657–666. to reduce behavioural disturbances in residents of nursing homes with

Birks, J., Grimley Evans, J., 2009. Ginkgo biloba for cognitive impair- dementia: cluster randomised clinical trial. Br. Med. J. 343, d4065.
ment and dementia. Cochrane Database Syst. Rev. 2009 (1), Art. No.
CD003120. https://doi:10.1002/14651858.CD003120.pub3. Junaid, O., Hegde, S., 2006. Supportive psychotherapy in dementia. Adv.

Connelly, D., 2015. Closing in on Alzheimer’s disease. Pharm J. 295 Psych. Treat. 13 (1), 17–23.
Kelly, S.P., Lawlor, B.A., Kenny, R.A., 2009. Blood pressure and
(7876/7). https://doi.org/10.1211/PJ.2015.20069081.
dementia – a comprehensive review. Ther. Adv. Neurol. Disord. 2 (4),
Davtyan, H., Zagorski, K., Rajapaksha, H., et al., 2016. Alzheimer’s disease
Advax(CpG)-adjuvanted MultiTEP-based dual and single vaccines in- 241–260.

duce high-titer antibodies against various forms of tau and Aβ pathologi- Kim, T.W., 2015. Drug repositioning approaches for the discovery of new

cal molecules. Sci. Rep. 6 (28912). https://doi.org/10.1038/srep28912. therapeutics for Alzheimer’s disease. Neurother. 12 (1), 132–142.

DEMENTIA 33

Livingston, G., Katona, C., 2000. How useful are cholinesterase inhibitors in Royal College of Psychiatrists, 2016. FR/ID/09: psychotropic drug prescrib-
the treatment of Alzheimer’s disease? A number needed to treat analysis. ing for people with intellectual disability, mental health problems and/or

Int. J. Geriatr. Psych. 15 (3), 203–207. behaviours that challenge: practice guidelines. Available at: http://www.
rcpsych.ac.uk/pdf/FR_ID_09_for_website.pdf.
Marriott, A., Donaldson, C., Tarrier, N., Burns, A., 2000. Effectiveness of cogni- Sperling, R.A., Aisen, P.S., Beckett, L.A., et al., 2011. Toward deining the
preclinical stages of Alzheimer’s disease: recommendations from the
tive – behavioural family intervention in reducing the burden of care in carers National Institute on Aging–Alzheimer’s Association work groups on
diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7 (3),
of patients with Alzheimer’s disease. B. J. Psych. 176 (6), 557–562.
Matthews, F.E., Stephan, B.C.M., Robinson, L., et al., 2016. A two decade 280–292.

dementia incidence comparison from the cognitive function and aging Toh, H.M., Ghazali, S.E., Subramaniam, P., 2016. The acceptability and use-

studies I and II. Nat. Commun. 7, 11398. fulness of cognitive stimulation therapy for older adults with dementia: a

McKeith, I.G., 2006. Consensus guidelines for the clinical and pathologic narrative review. Int. J. Alzheimers Dis. Article ID 5131570.
diagnosis of dementia with Lewy bodies (DLB): report of the Consortium
on DLB International Workshop. J. Alzheimers Dis. 9 (Suppl. 3), 417. Valenzuela, M.J., Sachdev, P., 2006. Brain reserve and dementia: a system-

McKeith, I.G., Dickson, D.W., Lowe, J., et al., 2005. Diagnosis and manage- atic review. Psychol. Med. 36, 441–454.
ment of dementia with Lewy bodies: third report of the DLB Consortium. Wang, P.S., Schneeweiss, S., Avorn, J., et al., 2005. Risk of death in elderly
Neurol. 65, 1863–1872.
users of conventional vs. atypical antipsychotic medications. N. Engl. J.
National Institute for Health and Care Excellence (NICE), 2016. Donepezil,
Med. 353, 2335–2341.
galantamine, rivastigmine and memantine for the treatment of Alzhei- Warren, J.D., Rohrer, J.D., Rossor, M.N., 2013. Frontotemporal dementia.

mer’s disease. Technology appraisal guidance [TA217]. Available at: Br. Med. J. 347, 4827.
https://www.nice.org.uk/guidance/ta217.
National Institute for Health and Care Excellence, Social Care Institute for Winblad, B., Amouyel, P., Andrieu, S., et al., 2016. Defeating Alzheimer’s

Excellence (NICE-SCIE), 2011. The NICE-SCIE guideline on supporting disease and other dementias: a priority for European science and society.
Lancet Neurol. 15 (5), 455–532.
people with dementia and their carers in health and social care. Available World Health Organization (WHO), 2012. Dementia a public health priority.
at: https://www.nice.org.uk/guidance/cg42/.
Public Health England, 2016. Health matters: midlife approaches to reduce Available at: http://www.who.int/mental_health/publications/dementia_
dementia risk. Available at: https://www.gov.uk/government/publications/
health-matters-midlife-approaches-to-reduce-dementia-risk/health- report_2012/en/.
matters-midlife-approaches-to-reduce-dementia-riskhttps://publichealth Zahr, N.M., Kaufman, K.L., Harper, C.G., 2011. Clinical and pathological
matters.blog.gov.uk/2016/03/22/health-matters-midlife-approaches-to-
reduce-dementia-risk/. features of alcohol-related brain damage. Nat. Rev. Neurol. 7, 284–294.

Further Reading National Institute for Health and Care Excellence, 2013. NICE quality

Taylor, D., 2013. Dementia. In: Dodds, L.J. (Ed.), Drugs in Use, ifth ed. standard: dementia: independence and wellbeing. Available at: https://
Pharmaceutical Press, London.
www.nice.org.uk/guidance/qs30.
National Institute for Health and Care Excellence, 2015. NICE advice: National Institute for Health and Care Excellence, 2015. NICE pathways for
low-dose antipsychotics in people with dementia. Available at: https://
www.nice.org.uk/advice/ktt7. dementia. Available at: https://pathways.nice.org.uk/pathways/dementia.
National Institute for Health and Care Excellence, 2015. NICE guideline:
National Institute for Health and Care Excellence, 2015. NICE advice:
management of aggression, agitation and behavioural disturbances in dementia, disability and frailty in later life – mid-life approaches to delay
dementia: valproate preparations. Available at: https://www.nice.org.uk/
advice/esuom41/chapter/Key-points-from-the-evidence. or prevent onset. Available at: https://www.nice.org.uk/guidance/ng16.
Seeley, W.W., Miller, B.L., 2013. Alzheimer’s disease and other dementias.
National Institute for Health and Care Excellence, 2010. NICE advice:
management of aggression, agitation and behavioural disturbances in In: Hauser, S.L. (Ed.), Harrison’s Neurology in Clinical Medicine, third
dementia: carbamazepine. Available at: https://www.nice.org.uk/advice/ ed. McGraw-Hill Medical, New York.
esuom40/chapter/Key-points-from-the-evidence. Taylor, D.A., Rajei-Dehkordi, Z., 2010. Practice guidance: pharmaceutical
care in dementia. Available at: http://www.rpharms.com/public-health-

resources/mental-health.asp.

Useful websites CPPE Dementia Resources: https://www.cppe.ac.uk/programmes/l/
dementia-e-01/
Alzheimer’s Association: http://www.alz.org/
Alzheimer’s Society: http://alzheimers.org.uk/ Alzheimer’s Society Factsheet: driving and dementia: https://www.alzheimers.
Alzheimer’s Society and Royal College of General Practitioners, Helping org.uk/site/scripts/download_info.php?downloadID=1118

you to assess cognition: a practical toolkit for clinicians: https:// World Health Organization (WHO) dementia resources: http://www.who.int
www.alzheimers.org.uk/site/scripts/download_info.php?ileID=2532
Cochrane Reviews on Dementia – a number of systematic reviews of herbal /topics/dementia/en/
supplements, aromatherapy and social and behavioural interventions for
people with dementia: http://dementia.cochrane.org/our-reviews

579