Dementia Symptoms Diagnosis Management

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Pharmacology

dementia include hypertension, atrial brillation,hypercholesterolaemia, smoking and diabetes(Husband and Worsley, 2006). Te course andmanagement o vascular dementia is diferent romAlzheimers disease, where the average survival is

45 years as patients die rom cardiovascularor cerebrovascular events.

Dementia with Lewy bodies

Tis type o dementia accounts or 1520% o alldementia cases. Lewy bodies are eatures o manyneurodegenerative diseases, o which dementia is aprimary example. Dementia with Lewy bodies hascommon eatures o both Alzheimers disease andParkinsons disease. Similar to Alzheimers disease, thistype o dementia has a slow progression. Dementiawith Lewy bodies can be diferentiated clinically romAlzheimers disease based on specic clinical eaturesthat will not be covered in this article. Lewy bodies areintracytoplasmic, eosinophilic, round-to-elongatedinclusions ound in vacuoles o injured or ragmentedneurons, present in the subcortical and corticalregions o the brain. Te presence o Lewy bodiesis accompanied with decits o both dopaminergicand cholinergic neuronal transmission. Tere are nodrugs available to treat or slow down the progress odementia with Lewy bodies; treatments are used toimprove the quality o lie.

Other types of dementia

Other types o dementia include rontotemporaldementia, Huntingtons disease, HIV dementia(associated with patients inected with HIV) and manyothers. Generally the pathophysiology o dementia isunclear, and the number o drugs available to managedementia is very limited. Te drugs currently availablein the UK market or managing dementia targetthe cholinergic decit theory o dementia but ullunderstanding o this condition and its managementis not yet known.

DiagnosisDiagnosis o dementia must be carried out by a

specialist, and is based on taking a medical history,observations, and testing intellectual unction andmemory. Symptoms o dementia may be conused withother conditions because many conditions can presentwith cognitive impairment. In addition, symptomsdifer between the diferent types o dementia.Dementia is under-diagnosed and it is estimatedthat only a third o people with dementia receiveormal diagnosis at any time during their illness. Latediagnosis oen happens, at which stage those suferingorm the condition are incapable o making inormedchoices. One o the main tests used to assess patientsto aid diagnosis o dementia is the mini mental stateexamination (MMSE) (see Box 1). Tis is a series o

tests on orientation, memory, attentionand calculation, language, writing and drawing,is commonly used. Accurate diagnosis o the typeo dementia is important to guide themanagement approaches.

Knowing about dementiaDementia is generally not well understood andproessional approaches to its management are not

very clear. Tereore in November 2006, the NationalInstitute or Health and Clinical Excellence (NICE)in collaboration with the Social Care Institute orExcellence (SCIE) issued clinical guidelines to aid

Box 1. Summary of Mini Mental State

Examination (MMSE)

MMSE consists of a series of tests that look at five areasof mental assessment. These are:

nOrientation

nMemory test 1 (looking at remembering three objects)

nAttention and calculation

nMemory test 2 (remembering questions from memory test 1)

nLanguage, writing and drawing

MMSE has a maximum score of 30 points. Classification of

dementia is as follows:

n2126: mild dementia

n1020: moderate dementia

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health and social care services to support thesepatients (NICE-SCIE guidelines, 2006).

Dementia is a progressive condition, andinterventions aim to relieve some o the symptomsand improve the quality o lie o patients and theircarers. Other behavioural and psychological symptomso dementia such as agitation, hallucinations andaggression, may also be present. Tese symptoms

require urther drug management as they can causeproblems to both patients and carers.

Prevention of dementiaTe evidence or preventing dementia is inconclusive.Vascular dementia may be prevented by maintaininga healthy liestyle and to reduce cardiovascular risks(NHS Direct, 2007). Among the drugs researchedto prevent dementia are the statins, hormonereplacement therapy, vitamin E, and non-steroidalanti-inammatory drugs. Te NICE-SCIE guidelines(2006) have indicated that none o above mentionedtherapies should be used specically or primaryprevention o dementia because o a lack o good

clinical trial evidence. Gingko biloba was alsoconsidered to prevent and treat the symptoms odementia, but there is no conclusive evidence itsbenets, (Mantle et al, 2000; McCarney et al, 2008).

Non-drug treatmentsPsychological interventions have been researched inthe management o dementia. Tese interventions

target symptoms o cognitive impairment andpsychotic symptoms and behavioural disturbances,e.g. agitation, anxiety, depression, and aggression.Research is inconclusive in this area because o a lacko established, randomized controlled trials (RCs).Although this is based on the little evidence present,NICE-SCIE highlighted that cognitive stimulationwas one o the main interventions with conclusiveevidence. Patients enrol onto cognitive stimulationprogrammes. For the non-cognitive symptoms, e.g.psychotic disturbances, NICE-SCIE recommends thatindividual patients are assessed early and individualcare plans are prepared. A systematic review odiferent psychological approaches to managing

Pharmacology

Drug Indication Dosing schedule

Donepezil (Aricept) Mild to moderate 5 mg once daily; increase

dementia in Alzheimers disease after one month to10 mg once daily

Galantamine (Reminyl) Mild to moderate 4 mg twice daily, increased to

dementia in Alzheimers 8 mg twice daily for 4 weeks,

disease maintenance 8-12 mg twice daily

Galantamine XL Mild to moderate 8 mg once daily for 4 weeks, 24 hours

(once-daily preparation) dementia in Alzheimers disease increased to 10 mg once for 4 weeks,

maintenance 16-24 mg daily

Rivastigmine (Exelon) Mild to moderate dementia 1.5 mg twice daily, increased in steps

in Alzheimers disease or of 1.5 mg twice daily at intervals of at

in Parkinsons disease least 2 weeks, maximum 6 mg twice d

Memantine (Ebixa) Moderate to severe 5 mg in the morning, increased

dementia in Alzheimers disease in steps of 5 mg weekly intervals,

up to a maximun of 10 mg twice daily

*One month at usual dose

Table 1. Summary of the four available drugs

for managing dementia


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Pharmacology

moderate dementia in Alzheimers disease, whereasthe cholinesterase inhibitor rivastigmine is licensed ormildmoderate dementia in both Alzheimers diseaseand Parkinsons disease (see Table 1).

Te benets o these drugs in managing dementiais not yet clear; they will help the symptoms byenhancing cognitive ability and improve the qualityo lie or some patients, but it is not clear who will

benet rom their use. Cholinesterase inhibitors actby inhibiting the enzyme cholinesterase. Tis enzymeis responsible or the hydrolysis o acetylcholine, andreducing its efect. Cholinesterase inhibitors increasethe amount o acetylcholine, thereby enhancingcholinergic transmission in the synaptic cle(Tomson et al, 2001). Te three available agents diferslightly in their mode o action. A recent CochraneReview (Birks, 2006) looked at 13 randomized,placebo controlled trials and concluded that althoughthe three cholinesterase inhibitors diferered in theirmode o action, there were no diferences betweenthem with regards to e cacy. Te clinical evidenceor using these agents is limited to their use in the

Duration of action Adverse effects Costs*

24 hours Nausea, vomiting, insomnia, diarrhoea 95.42

8 hours Nausea, vomiting, insomnia, diarrhoea 90

24 hours Nausea, vomiting, insomnia, diarrhoea 90

8 hours Nausea vomiting, insomnia, diarrhoea 83.94

Hallucinations, dizziness, confusion 73.94

dementia was published in 2005(Livingston etal, 2005). Among the highlighted interventionsare behavioural management therapies, educatingcarers on how to deal with dementia patients, andcognitive stimulation. Non-drug approaches are beingresearched and is beyond the scope o this article.Other highlighted approaches are aromatherapy,multisensory stimulation, use o music, and dancing.

Drug treatmentsTe cholinesterase inhibitors (donepezil, galantamine,rivastigmine) are the main pharmacologicalapproaches or managing dementia. Another availableagent is memantine, which is am N-methyl-D-aspartate (NMDA)-receptor antagonist, which afectsglutamate transmission. Antipsychotic medications arealso documented or managing the behavioural andpsychological symptoms o dementia.

Cholinesterase inhibitors

Donepezil and galantamine are cholinesteraseinhibitors licensed or the treatment o mild-to-


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treatment o Alzheimers disease dementia.Dosing o the drugs difer; donepezil is the easiest

to use, as it is a once-daily preparation initiated at5 mg and increased i necessary to 10 mg once aday. Rivastigmine is taken twice a day, increased atintervals o 2 weeks, to the usual dose o 6 mg twicea day. Galantamine is also titrated slowly at intervalso 4 weeks, to the usual dose o 12 mg twice a day; aonce-daily preparation is now available. Rivastigmineand galantamine have a more complicated titrationschedule, which afects the choice o these medicinesor prescribers and carers. Generally, titration o

these drugs should be carried out slowly to improvetolerance, and slower titration schedules arerecommended in clinical practice.

Memantine

Memantine is the most recently introduced agent.Memantine is slightly diferent rom the cholinesterasinhibitors. It is licensed or treating moderate tosevere dementia resulting rom Alzheimers disease,rather than mild-to-moderate symptoms. It actsby modulating glutamate, which is involved inprogression o neurodegenerative dementia.

Adverse effectsDrugs used or managing dementia have a rangeo adverse efects, and this might afect prescribingchoices. Cholinesterase inhibitors result in cholinergicefects and thereore should always be startedat a low dose and titrated according to responseand tolerability. Tere are reports o less adverseevents with donepezil compared with galantamine.Cholinergic efects include nausea, vomiting,diarrhoea, anorexia, headache and dizziness, whichare a result o the increased acetylcholine activity.Tere are adverse efects asscociated with memantineuse, such as constipation, headache, hypertension,dizziness and drowsiness.

InteractionsDonepezil and galantamine are metabolized by

cytochromes 2D6 and 3A4, and levels o the drugscan be altered by other drugs afecting the unctiono these enzymes. Tis can include enzyme-inducing(e.g. riampicin and phenytoin) and enzyme-inhibitindrugs (e.g. erythromycin and itraconazole). Te exteno the interaction i not clear and drug combinationsshould be used with care. Rivastigmine is least likelyto interact with other medicines, which might be auseul actor in the elderly population which is usuallysubject to polypharmacy.

PrescriptionOnce initiated by a specialist, cognitive assessment

is repeated at around 3 months, to give an indicationo the degree o response to these treatments.Cholinesterase inhibitors should be discontinuedin those who do not respond to them. I treatmentis stopped, specialists usually perorm a cognitiveassessment 4-6 weeks aer discontinuation. Isignicant deterioration occurs during this shortperiod, they may be re-introduced (BNF, 2008).

Antipsychotics in dementiaBehavioural and psychological symptoms odementia can respond to the action o antipsychotics.ypical antipsychotics were used or decades in themanagement o behavioural disturbances associated

Box 2. Summary of NICE guidance

on Alzheimers disease

n Alzheimers disease must be diagnosed in a specialist clinic.Assessment should involve cognitive, global and behaviouralfunctioning, activities of daily living and the likelihood ofcompliance with treatment

n To consider the usage of one of the three cholinesteraseinhibitors (donepezil, galantamine and rivastigmine) inmanaging of patients with Alzheimers disease of moderateseverity (MMSE score 1020)

n A carers view of the condition should be sought before,and during drug treatment

n Patients who continue drug therapy should be reviewed

every 6 months. The review should continue to involveMMSE score, global, functional and behavioural assessment.Drug treatment should continue if MMSE score remains ator above 10 points and if treatment is considered to havea worthwhile effect on the condition. (Note: In patients,who score below 10, abrupt withdrawal of therapy is notrecommended and gradual discontinuation is preferredwith continuous assessment)

n Therapy with any of the cholinesterase inhibitors shouldbe initiated with drugs of lowest cost. Change of therapy

may be based on intolerance to therapy and adverseeffects, concordance, medical morbidity and possibledrug interaction

n Patients with mild Alzheimers disease currently receivingcholinesterase inhibitors may be continued on therapyuntil they, their carers, and/or their specialist consider it isappropriate to stop

n NICE does not recommend memantine for moderatelysevere to severe Alzheimers disease, except as part of awell-designed clinical study. Patients who are receivingmemantine for moderately severe to severe Alzheimersdisease can continue treatment until they, their carers orspecialist consider it is appropriate to stop.

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Key Pointsn Dementia is a generic term that is used

to describe a progressive and irreversible

syndrome, the characteristics of which are a

deterioration of intellectual capacity and aninability to carry out day-to-day activities.

n Drugs used for managing dementia have

a range of adverse effects, and this might

affect prescribing choices.

n The cholinesterase inhibitors (donepezil,

galantamine, rivastigmine) are the main

pharmacological approaches for managing

dementia.

n Cholinesterase inhibitors result in cholinergic

effects and therefore should always be

started at a low dose and titrated according

to response and tolerability.

n Complicated treatment regimens should be

simplified to aid patients in compliance.

with dementia. Tey are efective in controllingthose symptoms which probably arise because othe extrapyramidal side-efects that occur. Atypicalantipsychotics, e.g. risperidone, olanzapine, quetiapineand aripiprazole, replaced the older agents, as they didnot afect the cognitive decline. Te role and saety oantipsychotics has now changed due to the warnings

issued regarding the increased mortality rom theincidence o stroke associated with olanzapine,risperidone, quetiapine and aripiprazole when usedin dementia. Tis ollowed an advisory note romCommittee on Saety o Medicine (CSM) in March2004, advising that olanzapine and risperidone areassociated with an increased risk o stroke in patientswith dementia (MHRA, 2004). Tis has led to thereduced prescribing o antipsyhotics or managingbehavioural and psychological symptoms o dementia.Donepezil, rivastigmine and galantamine can beefective in reducing behavioural disturbances indementia, but the efects appear some weeks aer

treatment (aylor et al, 2007).

ConclusionFurther research into dementia is required to ullyunderstand the pathogenesis and the managementapproaches or the condition. As non-medicalprescribers, it is important to be amiliar with drugs tobe avoided in patients with dementia or pre-existingcognitive impairment, even i you do not prescribe inthis area. Drugs that can cause conusion should beclosely monitored when prescribed or this group opatients. In addition, complicated treatment regimensshould be simplied to aid these patientsin compliance.

ReferencesAlzheimers Society (2007) Dementia UK.: A report into the

prevalence and cost o dementia prepared by Personal SocialServices Research Unit at the London School o Economics andthe Institute o Psychiatry. http://www.alzheimers.org.uk/downloads/Dementia_UK_Summary.pd

(accessed 30 July 2008)

Birks J (2006) Cholinesterase inhibitors or Alzheimers disease.Cochrane Database of Systematic Reviews 2006, Issue 1. Art.No.: CD005593.

British National Formulary (BNF) 55. September 2008. BMJPublishing Group Ltd and RPS Publishing, London

Husband A, Worsley A (2006). Diferent types o dementia. PharmJ277: 57982

McCarney R, Fisher P, Ilife S et al (2008) Ginkgo biloba or mildto moderate dementia in a community setting: a pragmatic,randomised, parallel-group, double-blind, placebo-controlledtrial. Int J Ger Psych 2008; Jun 9 [Epub ahead o print]

Mantle D, Pickering A, Perry EK (2000) Medicinal plant extracts

or the treatment o dementia: a review o their pharmacology,e cacy and tolerability. CNS Drugs13: 20113

MeReC Bulletin (2007) Te treatment o dementia. NationalPrescribing Centre. Volume 18 Number 1. http://tinyurl.com/6k7pjd (accessed 30 July 2008)

Medicines and Healthcare Products Regulatory Agency (MHRA)(2004) Atypical antipsychotic drugs and stroke. March 2004.http://tinyurl.com/65jgt (accessed 31 July 2008)

National Institute or Health and Clinical Excellence and Social CareInstitute or Excellence (NICE) (2006). NICE clinical guideline.Dementia. Supporting people with dementia and their carersin health and social care. http://guidance.nice.org.uk/cg42(accessed 30 July 2008)

NHS Direct (2007) Dementia prevention. http://www.nhsdirect.nhs.uk/articles/article.aspx?articleId=124&sectionId=9 (accessed 31July 2008)

aylor D, Paton C, Kerwin R (2007) Te Maudsley (Te SouthLondon And Maudsley NHS Foundation rust Oxleas NHSFoundation rust) Prescribing Guidelines, 9th edn. InormaHealthcare, London

Tomas H (2001) Te aetiology and pathology o dementia. HospPharm 8: 33-40

Tomson FC, Fraser K, Kelly J, Martin M, Lyons D (2001) Drugtreatment o dementia. Hosp Pharm8: 419s

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Dementia Symptoms Diagnosis Management

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