Assessment and treatment of cognitive deficits in dementia Julia Gifford MB BCh and Roy Jones BSc, FRCP, DipPharmMed

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1 Assessment and treatment of cognitive deficits in dementia Julia Gifford MB BCh and Roy Jones BSc, FRCP, DipPharmMed SPL Our series Prescribing in older people gives practical advice for successful management of the special problems faced by this age group. Here, the authors discuss how cognitive deficits in dementia are assessed and describe current recommended treatment. Figure 1. Several assessment tools are available for cognitive impairment Dementia is a syndrome that results in progressive deterioration of cognitive function caused by a number of different disorders. It occurs predominantly in older people and is of great international importance, affecting an estimated 24.3 million people worldwide. 1 In the UK there are about people (1.1 per cent of the entire UK population) with dementia, a number forecast to reach 1 million by Research into the causes of dementia, particularly Alzheimer s disease (AD), has resulted in the availability of dementia-specific drugs and some understanding of the risk factors. Accurate assessment and diagnosis are therefore important to be able to target these treatments appropriately. Cognitive deficits in dementia The cognitive deficits in dementia are not confined to memory and may include impairment in language, praxis, organisational skills, attention and judgement. Significant cognitive impairment results in loss of social functioning. Behavioural changes also occur that can be particularly troublesome to Prescriber 19 March

2 Alzheimer s disease Vascular dementia Frontotemporal dementia Dementia with Lewy bodies Dementia in Parkinson s disease prominent and progressive memory impairment, especially for recent events language deficits spatial and visuoperceptual difficulties difficulty in handling complex tasks impairment of reasoning ability practical inability, dyspraxia global cognitive impairment abrupt onset, stepwise deterioration vascular risk factors patchy cognitive impairment focal neurological signs and symptoms nocturnal confusion either prominent personality changes or problems with language memory and visuospatial changes less prominent, especially initially onset more common under age 65 progressive cognitive decline simultaneous or later development of parkinsonian features well-formed visual hallucinations fluctuating attention and alertness REM sleep behaviour disorder (acting out dreams) falls parkinsonian features before onset of dementia cognitive slowing executive dysfunction poor memory retrieval Table 1. Characteristic presentations and patterns of cognitive change the family/carer. Several different forms of dementia have been described that have characteristic presentations and patterns of cognitive change (see Table 1). AD is the most prevalent dementia, especially in the older age group. It is estimated that 62 per cent of people with dementia in the UK have AD, while vascular dementia and mixed dementias account for nearly one-third (27 per cent). 2 Assessment of cognitive deficits It is important to talk not only to the patient but also to someone who knows them well. The subject may have little insight into changes in their cognition or behaviour, although these may impact on others. Both the presence and severity of the symptoms should be determined by asking about the effect they have on the subject s ability to function independently. More formal assessment of cognitive deficits is made using psychometric tests. A basic dementia blood screen should be performed at the time of presentation, usually within primary care. It should include routine haematology, biochemistry tests (including electrolytes, calcium, glucose and renal and liver function), thyroid function tests, serum vitamin B 12 and folate levels. 4 The NICE guideline also recommends that structural imaging (MRI or CT scanning) should be used in the assessment of people with suspected dementia to exclude other cerebral pathologies and to help establish the subtype diagnosis. 4 Assessment tools (see Table 2) The Mini-Mental State Examination (MMSE) is the most widely used tool world-wide and is a useful screening tool, but an MMSE score on its own must be interpreted with caution. The score is affected by age, education and language skills. Despite its limitations, the MMSE is used widely in secondary and research settings. It is sensitive to changes in cognition resulting from treatment and its use has been recommended by NICE to assess response to drug treatment. 3,4 The Clock test is a useful adjunct to the MMSE, adding an assessment of organisational skills (executive function). The simplest version gives a score out of 3 (1 mark for drawing a circle, 1 for the correct numbers 1-12 and 1 for putting hands at the right time, eg 11.10). The Abbreviated Mental Test Score (AMTS), 6-Item Cognitive Impairment Test (6-CIT), 7-Minute Screen and General Practitioner Assessment of Cognition (GPCOG) are other short screening tools suitable for primary care and these are referenced in the NICE guideline. 4 There are several lengthier assessment tools used in secondary care and research settings to help differentiate between subtypes of dementia and to identify response to treatment. Treatment Treatment of the cognitive deficits in dementia should begin with a 46 Prescriber 19 March

3 review of relevant co-morbidities and the patient s current medications (including all over-thecounter products). There are a number of treatable conditions that can cause a dementia syndrome (see Table 3), and these should be screened for. Many drugs can cause confusion, particularly the wide range of drugs with anticholinergic properties (eg drugs for incontinence or depression), and antipsychotic drugs should be avoided as far as possible because they are not that effective and may worsen cognition. Hearing and visual impairments must also be addressed. Depression is often associated with dementia and, where appropriate, should be treated; uncommonly, depression may be the main cause of an apparent dementia ( pseudodementia ). Medical conditions such as hypertension, hypercholesterolaemia and atrial fibrillation should be managed as optimally as possible. Mini-Mental State Examination (MMSE) Clock drawing Abbreviated Mental Test Score (AMTS) 6-Item Cognitive Impairment Test (6-CIT) 7-Minute Screen General Practitioner Assessment of Cognition (GPCOG) tests short-term memory, orientation, naming, comprehension, attention and constructional praxis takes minutes to perform scores from 0-30 (mild 21-26, moderate 10-20, severe <10) tests visuospatial skills and executive function several scoring methods, 3-point score is the simplest tests short-term memory, orientation, long-term memory and attention 3-5 minutes to perform scores 0-10 (less than 6 suggests dementia) tests short-term memory, orientation (temporal) and attention 3-4 minutes to perform negative scoring 0-28 (scores more than 8 are significant) tests orientation (temporal), cued recall, visuospatial skills and verbal fluency 7-10 minutes to perform cognitive test informant questions 6 minutes to perform Drugs for dementia Current recommendations suggest that treatment with drugs for dementia should be initiated and supervised only by a specialist experienced in the management of dementia, but treatment can be continued by general practitioners under a shared-care protocol. 5 There are four specific drugs licensed for the treatment of AD donepezil (Aricept), galantamine (Reminyl), memantine (Ebixa) and rivastigmine (Exelon) 6-9 while one, rivastigmine (but not the transdermal patch), is also licensed for the treatment of dementia associated with Parkinson s disease (see Table 4). The most recent guidance issued by NICE, 3 which was amended following an appeal and a judicial review (September 2007), recommends the use of the Table 2. Assessment tools (references for all these tests will be found in the NICE dementia guideline 4 ) cholinesterase inhibitors (CIs) in the management of patients with AD of moderate severity only (MMSE score 10-20). Memantine is not recommended for use in patients with moderate to severe dementia except as part of clinical studies. This review has taken three years and has been very controversial. 10 That the antidementia drugs provide consistent albeit usually modest positive clinical effects in a number of patients is not denied by NICE. However the area of argument concerns the cost of the drugs and the pharmacoeconomic issues, which centre on the use of NICE s preferred methodology using the QALY (quality of life adjusted year). Most professionals and others involved in the care and Endocrine disorders Infections Toxins Table 3. Treatable causes of dementia hyper/hypothyroidism hyper/hypoparathyroidism Cushing s syndrome Addison s disease HIV/AIDS syphilis encephalitis alcohol drugs (especially those with anticholinergic effects) heavy metals Deficiency states B vitamins, especially B 12, thiamine, folic acid Other normal-pressure hydrocephalus subdural haematoma tumour depressive pseudodementia Prescriber 19 March

4 Drug Main mechanism Mild Moderate Severe Dosing of action (MMSE >20) (MMSE 20-10) (MMSE <10) donepezil AChEI mg od rivastigmine* AChEI mg bd/ mg patch galantamine AChEI mg od/bd memantine NMDA mg bd antagonist *also licensed for treating mild to moderately severe dementia in Parkinson s disease (not transdermal patch) not recommended by NICE only recommended by NICE as part of clinical studies AChEI = acetylcholinesterase inhibitor NMDA = N-methyl-D-aspartate (glutamate) MMSE = Mini Mental State Examination (maximum score 30) Table 4. Current treatments in Alzheimer s disease licensed indications, NICE recommendations and dosage regimens Cholinesterase inhibitors Memantine nausea vomiting diarrhoea headache anorexia dizziness dizziness constipation hypertension headache somnolence Table 5. Common side-effects of cholinesterase inhibitors and memantine management of people with AD do not believe that this is an appropriate methodology, nor does it give an accurate picture of the true costs and benefits. The fact that NICE refused to make its methodology available for appropriate scrutiny has also been criticised. 11 The CIs are relatively easy to use and head-to-head studies have failed to show any significant differences between them in terms of efficacy, but donepezil is probably the best tolerated. Patients should be warned about possible sideeffects (see Table 5), which occur in about a third of patients, and in some medical conditions they should be used with caution (see Table 6). There is also a variable response but up to half the patients given these drugs will show a slower rate of cognitive decline. 5 The choice of drug may come down to practical considerations, eg dosing formulations or regimens. If there is a poor response it is worth trying a second CI. The patient is usually assessed after three to six months of treatment. NICE recommends that the drugs should only be continued while the MMSE remains above 10 and the patient s global, functional and behavioural condition remains at a level where the drug is considered to be having a worthwhile effect. Many specialists repeat the cognitive assessments four to six weeks after discontinuation to assess deterioration; 5 if this does occur then consideration should be given to restarting therapy. There is some evidence that the CIs are also useful in dementia with Lewy bodies; however, they are probably more effective in improving hallucinations than cognition. 4 Where there is thought to be a mixed dementia, a CI can be used to treat the AD component. In vascular dementia it is particularly important to treat any risk factors for stroke including hypertension, diabetes, atrial fibrillation and hypercholesterolaemia. There is a lot of interest by the public in nonprescription drugs such as ginkgo biloba and vitamin E. The evidence for benefit in improving cognition is not very strong but patients will often try them. Nonpharmacological interventions for cognitive symptoms of dementia may sometimes be helpful. People with mild to moderate dementia of all types should, if possible, be given the opportunity to participate in a structured group cognitive stimulation programme. 4 Summary Significant memory and cognitive impairment is a major feature of dementias such as AD. Apart from general assessment of the patient, it 48 Prescriber 19 March

5 Cholinesterase inhibitors cardiovascular gastrointestinal pulmonary urinary outflow obstruction Memantine Table 6. Medical conditions requiring cautious use of antidementia drugs is important to speak to someone who knows them well and make a formal assessment of any cognitive deficit using one of several available tests. Other causes of cognitive impairment should be considered including medical problems and concurrent drug therapy, particularly those with anticholinergic properties. Hearing and vision should be maximised. CIs are effective in people with mild and moderate AD, although for economic reasons NICE only currently recommends their use in patients with moderately severe AD as defined by an MMSE score of There are circumstances, however, where an MMSE score on its own is misleading (for example, in someone where English is not their first language); alternative methods of assessment should be used in such cases. CIs are easy to use and provide significant benefit to a number of patients. Some patients cannot tolerate or are not suitable for CI sick sinus syndrome conduction defects active peptic ulcer or predisposition to ulcers asthma, obstructive airways disease epilepsy or predisposition to epilepsy therapy, and in such cases consideration should be given to using memantine, which can be helpful despite not being currently recommended by NICE. References 1. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366: Knapp M, Prince M. Dementia UK. A report into the prevalence and cost of dementia prepared by the Personal Social Services Research Unit (PSSRU) at the London School of Economics and the Institute of Psychiatry at King s College London for the Alzheimer s Society. Alzheimer s Society, Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer s disease. NICE Technology appraisal guidance 111. November 2006 (amended September 2007) Dementia: Supporting people with dementia and their carers in health and social care. NICE Guideline CG42. November index.jsp?action=byid&o= British national formulary , Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer s disease. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD DOI: / CD pub2. ab html. 7. Birks J, Grimley Evans J, Iakovidou V, et al. Rivastigmine for Alzheimer s disease. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD DOI: / CD reviews/en/ab html. 8. Loy C, Schneider L. Galantamine for Alzheimer s disease and mild cognitive impairment. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD DOI: / CD pub3. www. cochrane.org/reviews/en/ab html. 9. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD DOI: / CD pub5. reviews/en/ab html. 10. Raw deal for dementia patients in the UK. Editorial. Lancet Neurology 2007;6(10): Bird SM, Matthews F, Muniz G. NICE judgement: good law risks bad science. Lancet Neurology 2007;6(10): Dr Gifford is a clinical research fellow and Professor Jones is director and honorary consultant geriatrician at RICE The Research Institute for the Care of Older People, Royal United Hospital, Bath Forum If you have any issues you would like to air with your colleagues or comments on articles published in Prescriber, the Editor would be pleased to receive them and, if appropriate, publish them on our Forum page. Please send your comments to: The Editor, Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, or to prescriber@wiley.com Prescriber 19 March