Dementia Symptoms Diagnosis Management

Pharmacology

Dementia: symptoms, diagnosis and management Rasha Salama

Abstract This article provides an overview of dementia. It looks at the incidence of dementia, the three main types of this condition and the suggested clinical management guidelines for Alzheimer’s disease dementia, with specific focus on the main pharmacological approach to this condition. The management is discussed with specific reference to the National Institute of Health and Clinical Excellence (NICE) guidelines released in 2006 with regards to Alzheimer’s disease dementia.

D

ementia is a generic term that is used to describe a progressive and irreversible syndrome. Its main characteristics include a gradual progressive deterioration of intellectual capacity, and inability to carry out day-to-day activities, which are accompanied in later stages by changes in social behaviour. The progressive nature of this condition can result in complexity of issues for carers and social care staff with problems such as aggressive behaviour, restlessness, wandering, eating problems, incontinence, delusions, hallucinations and mobility problems, which can lead to falls and fractures (MeReC bulletin 2007).

How common is it? Globally, dementia affects 24.3 million people, with the numbers of cases increasing every year (Husband and Worsley, 2006). In the UK there are currently around 700 000 cases of dementia (Alzheimer’s Society, 2006) Dementia affects around 5% of the those aged over 65 years, rising to 20% of the over 80s, but to a much lesser extent in those under 65 years. There is a greater prevalence in females than males (NICE-SCIG guidelines, 2006). This is thought to be due mainly to Rasha Salama is a Senior Lecturer in School of health and Life Sciences, De Montfort University, Leicester. Email: [email protected]

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longevity, but may also be due to education and, to some extent, hormonal influences.

Types of dementia There are many types of dementia, but the commonest types seen in clinical practice include: Alzheimer’s disease;, vascular dementia; and dementia with Lewy bodies. Alzheimer’s disease Alzheimer’s disease is the most common type of dementia, accounting for 60% of all cases (NICESCIG guidelines, 2006). Alzheimer’s disease presents insidiously with a very gradual progression, where a sufferer would initially experience short-term memory loss and language deficits and little dysphasia. With progression of the disease, complex psychomotor symptoms appear, and at end stages the sufferer may not be able to recognize their family. On a physiological basis, the brain is thought to develop abnormal structures known as neurofibrillary tangles and amyloid plaques, with chronic inflammation in nervous tissues (neurons and synapses) leading to a neurovascular dysfunction (Thomas, 2001). Cholinergic deficits, i.e. a deficit in the transmission of the cholinergic pathways and the neurotransmitter acetylcholine, are thought to be involved the pathogenesis of this condition. Acetylcholine is a neurotransmitter that is involved in learning, memory and attention. This theory is based on autopsy data, which showed high levels of destruction in the cholinergic neurons in brains of patient with Alzheimer’s disease. Vascular dementia Vascular dementia accounts for 20% of dementia cases. As the name suggests, it is associated with infarcts or small vessel disease. Vascular dementia covers dementia caused by ischaemic or haemorrhagic cerebrovascular lesions, where multi-infarct dementia resulting from a series of small strokes is the most common type. Vascular dementia is more common in males than females, and it has a sudden onset compared to dementia associated with Alzheimer’s disease. The risk factors for vascular

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dementia include hypertension, atrial fibrillation, hypercholesterolaemia, smoking and diabetes (Husband and Worsley, 2006). The course and management of vascular dementia is different from Alzheimer’s disease, where the average survival is 4–5 years as patients die from cardiovascular or cerebrovascular events. Dementia with Lewy bodies This type of dementia accounts for 15–20% of all dementia cases. Lewy bodies are features of many neurodegenerative diseases, of which dementia is a primary example. Dementia with Lewy bodies has common features of both Alzheimer’s disease and Parkinson’s disease. Similar to Alzheimer’s disease, this type of dementia has a slow progression. Dementia with Lewy bodies can be differentiated clinically from Alzheimer’s disease based on specific clinical features that will not be covered in this article. Lewy bodies are intracytoplasmic, eosinophilic, round-to-elongated inclusions found in vacuoles of injured or fragmented neurons, present in the subcortical and cortical regions of the brain. The presence of Lewy bodies is accompanied with deficits of both dopaminergic and cholinergic neuronal transmission. There are no drugs available to treat or slow down the progress of dementia with Lewy bodies; treatments are used to improve the quality of life. Other types of dementia Other types of dementia include frontotemporal dementia, Huntington’s disease, HIV dementia (associated with patients infected with HIV) and many others. Generally the pathophysiology of dementia is unclear, and the number of drugs available to manage dementia is very limited. The drugs currently available in the UK market for managing dementia target the cholinergic deficit theory of dementia but full understanding of this condition and its management is not yet known.

Box 1. Summary of Mini Mental State Examination (MMSE) MMSE consists of a series of tests that look at five areas of mental assessment. These are: n Orientation n Memory test 1 (looking at remembering three objects) n Attention and calculation n Memory test 2 (remembering questions from memory test 1) n Language, writing and drawing MMSE has a maximum score of 30 points. Classification of dementia is as follows: n 21–26: mild dementia n 10–20: moderate dementia n <10: severe dementia

tests on orientation, memory, attention and calculation, language, writing and drawing, is commonly used. Accurate diagnosis of the type of dementia is important to guide the management approaches.

Knowing about dementia Dementia is generally not well understood and professional approaches to its management are not very clear. Therefore in November 2006, the National Institute for Health and Clinical Excellence (NICE) in collaboration with the Social Care Institute for Excellence (SCIE) issued clinical guidelines to aid

Diagnosis Diagnosis of dementia must be carried out by a specialist, and is based on taking a medical history, observations, and testing intellectual function and memory. Symptoms of dementia may be confused with other conditions because many conditions can present with cognitive impairment. In addition, symptoms differ between the different types of dementia. Dementia is under-diagnosed and it is estimated that only a third of people with dementia receive formal diagnosis at any time during their illness. Late diagnosis often happens, at which stage those suffering form the condition are incapable of making informed choices. One of the main tests used to assess patients to aid diagnosis of dementia is the mini mental state examination (MMSE) (see Box 1). This is a series of

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Dementia affects over 24 million people worldwide.

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Pharmacology

Table 1. Summary of the four available drugs for managing dementia Drug

Indication

Dosing schedule

Donepezil (Aricept)

Mild to moderate dementia in Alzheimer’s disease

5 mg once daily; increase after one month to10 mg once daily

Galantamine (Reminyl)

Mild to moderate dementia in Alzheimer’s disease

4 mg twice daily, increased to 8 mg twice daily for 4 weeks, maintenance 8-12 mg twice daily

Galantamine XL (once-daily preparation)

Mild to moderate dementia in Alzheimer’s disease

8 mg once daily for 4 weeks, 24 hours increased to 10 mg once for 4 weeks, maintenance 16-24 mg daily

Rivastigmine (Exelon)

Mild to moderate dementia in Alzheimer’s disease or in Parkinson’s disease

1.5 mg twice daily, increased in steps of 1.5 mg twice daily at intervals of at least 2 weeks, maximum 6 mg twice daily

Memantine (Ebixa)

Moderate to severe dementia in Alzheimer’s disease

5 mg in the morning, increased in steps of 5 mg weekly intervals, up to a maximun of 10 mg twice daily

*One month at usual dose

health and social care services to support these patients (NICE-SCIE guidelines, 2006). Dementia is a progressive condition, and interventions aim to relieve some of the symptoms and improve the quality of life of patients and their carers. Other behavioural and psychological symptoms of dementia such as agitation, hallucinations and aggression, may also be present. These symptoms require further drug management as they can cause problems to both patients and carers.

Prevention of dementia The evidence for preventing dementia is inconclusive. Vascular dementia may be prevented by maintaining a healthy lifestyle and to reduce cardiovascular risks (NHS Direct, 2007). Among the drugs researched to prevent dementia are the statins, hormone replacement therapy, vitamin E, and non-steroidal anti-inflammatory drugs. The NICE-SCIE guidelines (2006) have indicated that none of above mentioned therapies should be used specifically for primary prevention of dementia because of a lack of good

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clinical trial evidence. Gingko biloba was also considered to prevent and treat the symptoms of dementia, but there is no conclusive evidence its benefits, (Mantle et al, 2000; McCarney et al, 2008).

Non-drug treatments Psychological interventions have been researched in the management of dementia. These interventions target symptoms of cognitive impairment and psychotic symptoms and behavioural disturbances, e.g. agitation, anxiety, depression, and aggression. Research is inconclusive in this area because of a lack of established, randomized controlled trials (RCTs). Although this is based on the little evidence present, NICE-SCIE highlighted that cognitive stimulation was one of the main interventions with conclusive evidence. Patients enrol onto cognitive stimulation programmes. For the non-cognitive symptoms, e.g. psychotic disturbances, NICE-SCIE recommends that individual patients are assessed early and individual care plans are prepared. A systematic review of different psychological approaches to managing

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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 et al, 2005). Among the highlighted interventions are behavioural management therapies, educating carers on how to deal with dementia patients, and cognitive stimulation. Non-drug approaches are being researched and is beyond the scope of this article. Other highlighted approaches are aromatherapy, multisensory stimulation, use of music, and dancing.

Drug treatments The cholinesterase inhibitors (donepezil, galantamine, rivastigmine) are the main pharmacological approaches for managing dementia. Another available agent is memantine, which is am N-methyl-Daspartate (NMDA)-receptor antagonist, which affects glutamate transmission. Antipsychotic medications are also documented for managing the behavioural and psychological symptoms of dementia. Cholinesterase inhibitors Donepezil and galantamine are cholinesterase inhibitors licensed for the treatment of mild-to-

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moderate dementia in Alzheimer’s disease, whereas the cholinesterase inhibitor rivastigmine is licensed for mild–moderate dementia in both Alzheimer’s disease and Parkinson’s disease (see Table 1). The benefits of these drugs in managing dementia is not yet clear; they will help the symptoms by enhancing cognitive ability and improve the quality of life for some patients, but it is not clear who will benefit from their use. Cholinesterase inhibitors act by inhibiting the enzyme cholinesterase. This enzyme is responsible for the hydrolysis of acetylcholine, and reducing its effect. Cholinesterase inhibitors increase the amount of acetylcholine, thereby enhancing cholinergic transmission in the synaptic cleft (Thomson et al, 2001). The three available agents differ slightly in their mode of action. A recent Cochrane Review (Birks, 2006) looked at 13 randomized, placebo controlled trials and concluded that although the three cholinesterase inhibitors differered in their mode of action, there were no differences between them with regards to efficacy. The clinical evidence for using these agents is limited to their use in the

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Box 2. Summary of NICE guidance on Alzheimer’s disease n Alzheimer’s disease must be diagnosed in a specialist clinic. Assessment should involve cognitive, global and behavioural functioning, activities of daily living and the likelihood of compliance with treatment n To consider the usage of one of the three cholinesterase inhibitors (donepezil, galantamine and rivastigmine) in managing of patients with Alzheimer’s disease of moderate severity (MMSE score 10–20) n A carer’s 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 involve MMSE score, global, functional and behavioural assessment. Drug treatment should continue if MMSE score remains at or above 10 points and if treatment is considered to have a worthwhile effect on the condition. (Note: In patients, who score below 10, abrupt withdrawal of therapy is not recommended and gradual discontinuation is preferred with continuous assessment) n Therapy with any of the cholinesterase inhibitors should be initiated with drugs of lowest cost. Change of therapy may be based on intolerance to therapy and adverse effects, concordance, medical morbidity and possible drug interaction n Patients with mild Alzheimer’s’ disease currently receiving cholinesterase inhibitors may be continued on therapy until they, their carers, and/or their specialist consider it is appropriate to stop n NICE does not recommend memantine for moderately severe to severe Alzheimer’s disease, except as part of a well-designed clinical study. Patients who are receiving memantine for moderately severe to severe Alzheimer’s disease can continue treatment until they, their carers or specialist consider it is appropriate to stop.

treatment of Alzheimer’s disease dementia. Dosing of the drugs differ; donepezil is the easiest to use, as it is a once-daily preparation initiated at 5 mg and increased if necessary to 10 mg once a day. Rivastigmine is taken twice a day, increased at intervals of 2 weeks, to the usual dose of 6 mg twice a day. Galantamine is also titrated slowly at intervals of 4 weeks, to the usual dose of 12 mg twice a day; a once-daily preparation is now available. Rivastigmine and galantamine have a more complicated titration schedule, which affects the choice of these medicines for prescribers and carers. Generally, titration of

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these drugs should be carried out slowly to improve tolerance, and slower titration schedules are recommended in clinical practice. Memantine Memantine is the most recently introduced agent. Memantine is slightly different from the cholinesterase inhibitors. It is licensed for treating moderate to severe dementia resulting from Alzheimer’s disease, rather than mild-to-moderate symptoms. It acts by modulating glutamate, which is involved in progression of neurodegenerative dementia.

Adverse effects Drugs used for managing dementia have a range of adverse effects, and this might affect prescribing choices. Cholinesterase inhibitors result in cholinergic effects and therefore should always be started at a low dose and titrated according to response and tolerability. There are reports of less adverse events with donepezil compared with galantamine. Cholinergic effects include nausea, vomiting, diarrhoea, anorexia, headache and dizziness, which are a result of the increased acetylcholine activity. There are adverse effects asscociated with memantine use, such as constipation, headache, hypertension, dizziness and drowsiness.

Interactions Donepezil and galantamine are metabolized by cytochromes 2D6 and 3A4, and levels of the drugs can be altered by other drugs affecting the function of these enzymes. This can include enzyme-inducing (e.g. rifampicin and phenytoin) and enzyme-inhibiting drugs (e.g. erythromycin and itraconazole). The extent of the interaction if not clear and drug combinations should be used with care. Rivastigmine is least likely to interact with other medicines, which might be a useful factor in the elderly population which is usually subject to polypharmacy.

Prescription Once initiated by a specialist, cognitive assessment is repeated at around 3 months, to give an indication of the degree of response to these treatments. Cholinesterase inhibitors should be discontinued in those who do not respond to them. If treatment is stopped, specialists usually perform a cognitive assessment 4-6 weeks after discontinuation. If significant deterioration occurs during this short period, they may be re-introduced (BNF, 2008).

Antipsychotics in dementia Behavioural and psychological symptoms of dementia can respond to the action of antipsychotics. Typical antipsychotics were used for decades in the management of behavioural disturbances associated

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Key Points n 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 an inability 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.

References Alzheimer’s Society (2007) Dementia UK.: A report into the prevalence and cost of dementia prepared by Personal Social Services Research Unit at the London School of Economics and the Institute of Psychiatry. http://www.alzheimers.org.uk/ downloads/Dementia_UK_Summary.pdf (accessed 30 July 2008) Birks J (2006) Cholinesterase inhibitors or Alzheimer’s disease. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005593. British National Formulary (BNF) 55. September 2008. BMJ Publishing Group Ltd and RPS Publishing, London Husband A, Worsley A (2006). Different types of dementia. Pharm J 277: 579–82 McCarney R, Fisher P, Iliffe S et al (2008) Ginkgo biloba for mild to moderate dementia in a community setting: a pragmatic, randomised, parallel-group, double-blind, placebo-controlled trial. Int J Ger Psych 2008; Jun 9 [Epub ahead of print] Mantle D, Pickering AT, Perry EK (2000) Medicinal plant extracts for the treatment of dementia: a review of their pharmacology, efficacy and tolerability. CNS Drugs 13: 201–13 MeReC Bulletin (2007) The treatment of dementia. National Prescribing Centre. Volume 18 Number 1. http://tinyurl. com/6k7pjd (accessed 30 July 2008)

with dementia. They are effective in controlling those symptoms which probably arise because of the extrapyramidal side-effects that occur. Atypical antipsychotics, e.g. risperidone, olanzapine, quetiapine and aripiprazole, replaced the older agents, as they did not affect the cognitive decline. The role and safety of antipsychotics has now changed due to the warnings issued regarding the increased mortality from the incidence of stroke associated with olanzapine, risperidone, quetiapine and aripiprazole when used in dementia. This followed an advisory note from Committee on Safety of Medicine (CSM) in March 2004, advising that olanzapine and risperidone are associated with an increased risk of stroke in patients with dementia (MHRA, 2004). This has led to the reduced prescribing of antipsyhotics for managing behavioural and psychological symptoms of dementia. Donepezil, rivastigmine and galantamine can be effective in reducing behavioural disturbances in dementia, but the effects appear some weeks after treatment (Taylor et al, 2007).

Conclusion Further research into dementia is required to fully understand the pathogenesis and the management approaches for the condition. As non-medical prescribers, it is important to be familiar with drugs to be avoided in patients with dementia or pre-existing cognitive impairment, even if you do not prescribe in this area. Drugs that can cause confusion should be closely monitored when prescribed for this group of patients. In addition, complicated treatment regimens should be simplified to aid these patients in compliance.

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Medicines and Healthcare Products Regulatory Agency (MHRA) (2004) Atypical antipsychotic drugs and stroke. March 2004. http://tinyurl.com/65jgtf (accessed 31 July 2008) National Institute for Health and Clinical Excellence and Social Care Institute for Excellence (NICE) (2006). NICE clinical guideline. Dementia. Supporting people with dementia and their carers in 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§ionId=9 (accessed 31 July 2008) Taylor D, Paton C, Kerwin R (2007) The Maudsley (The South London And Maudsley NHS Foundation Trust Oxleas NHS Foundation Trust) Prescribing Guidelines, 9th edn. Informa Healthcare, London Thomas H (2001) The aetiology and pathology of dementia. Hosp Pharm 8: 33-40 Thomson FC, Fraser K, Kelly J, Martin M, Lyons D (2001) Drug treatment of dementia. Hosp Pharm 8: 41–9s

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