Update on dementia - Part 2: Prevention, pharmacotherapy and supportive care

Chun-Chung Chan 陳鎮中, Po-Tin Lam 林鈿

HK Pract 2005;27:268-274

Summary

Management of dementia patients is complex. Pharmacotherapy has a prominent role in alleviating cognitive symptoms although the effects of currently available drugs are of modest efficacy. Other aspects of the management become more important as the disorder progresses to later stages. Supportive and holistic approach are the mainstay of treatment. On the other hand, since the disorder is non-curative, efforts are devoted to the identification and modification of various potential risk factors in order to reduce this growing epidemic.

摘要

治理痴呆病人是複雜的。雖然現有葯物的療效仍有其局限性，葯物治療在改善識別能力方面有顯著成效。 當病情漸趨嚴重時，其他治理方法變得更為重要。支持性的和全人性的取向便成為治療時的主要考慮。 另一方面，由於痴呆症是不能根治的，我們應努力尋找致病因素及其改善方法以控制它的不斷增長。

Introduction

Management of dementia starts with a timely identification of relevant warning symptoms,¹ and correct diagnosis in terms of the subtypes^2,3 and associated disabilities. Pharmacological therapy of cognitive symptoms is just one of the various aspects of management strategies including non-pharmacological interventions, behavioural and psychological symptoms of dementia (BPSD) management, caregiver training and support. Since curative therapy is currently not available, focus is on the two ends of the spectrum, namely primary prevention, and supportive and end-of-life issues should not be ignored.

Risk factors for and prevention of dementia

Since curative therapy is not available and the impact of the disease on the patients, relatives, health system and the society is massive, attempts to identify the various risk factors and preventive modalities become significant. Many potential candidates for Alzheimer's disease are recognized (Table 1) and some of the most studied modifiable ones will be discussed below.

Hypertension

Hypertension is a risk factor for both Alzheimer's disease and vascular dementia, mediated through atherosclerosis. It is well shown in the Nun Study that the presence of infarcts in the basal ganglia, deep white matter and thalamus are associated with an increased risk of dementia and fewer Alzheimer's disease specific lesions are needed when associated with hypertension to result in clinically evident disease.⁴ Most longitudinal studies have found a relationship between high blood pressure and the risk of cognitive decline.^5,6 In addition, more recent studies have shown a possible U-shaped relationship between baseline blood pressure and subsequent performance on cognitive tests or risk of developing dementia.^7-9

However, randomised controlled studies have yielded conflicting results on the effect of anti-hypertensive treatment on dementia prevention. A recent review of four major trials using dementia as secondary end-point in older hypertensive patients yielded an insignificant outcome with respect to the pooled odds ratio (0.89, 95% confidence interval 0.75-1.04). Exclusion of the use of drugs affecting the renin-angiotensin system led to a more promising pooled odds ratio (0.75, confidence interval 0.60-0.94).¹⁰

Diabetes mellitus

It is customary to attribute the mechanism of diabetes mellitus (DM) to its vascular complication, i.e. atherosclerosis or angiopathy. Upcoming evidence suggested additional mechanisms which may be related to insulin resistance and signaling failure,^11,12 leading to the hypothesis of Alzheimer's disease as a brain-type DM.

Cumulating evidence from large cross-sectional and longitudinal studies supported that the diagnosis and duration of DM, insulin treatment and coexisting hypertension are all associated with a stronger risk for dementia, including Alzheimer's disease.^13-15 However, a recent Cochrane review on the effect of treatment of DM on the development of cognitive impairment and dementia found that there were no studies which were appropriate for inclusion in a meta-analysis due to the unsatisfactory trial quality.¹⁶ Thus, it is not clear whether treatment of diabetes will reduce the risk or not.

Smoking

In the early 1990s, there was supporting evidence from case control studies that smoking has a protective effect.^17,18 This was widely reported and tobacco companies began to sponsor conferences on dementia. In fact, the protective effect has biological plausibility in that nicotine is a cholinergic agonist. However, more recent cohort studies and reviews have confirmed the opposite conclusion; and the limitations in case control studies have been criticized.^19,20

Alcohol drinking

Flavonoids in wine are natural anti-oxidants and thus are implicated as a potential protective candidate for Alzheimer's disease, as one of the pathogeneses is oxidative stress. Early cohort studies failed to document a significant association between alcohol drinking and risk of dementia. Later larger studies however supported a J-shaped relationship between the amount of alcohol and risk of cognitive dysfunction and incident dementia.^21,22 Light to moderate drinking might be protective compared with total abstinence and heavy drinking.

Cognitive pharmacotherapy

Currently available and approved medications for the management of the cognitive symptoms of Alzheimer's disease are cholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) receptor antagonist. Less evidence is given to the use of selegiline and vitamin E.

Cholinesterase inhibitors

In Alzheimer's brains, cholinergic deficit is evidenced by reductions in cholinergic cells in the nucleus basalis and septal nuclei, decline of basocortical projections and reduced activity of cerebral cortical choline acetyltransferase. This leads to the famous "cholingeric hypothesis"^23,24 postulating the cognitive deficits of Alzheimer's disease as related to a decrease in the central acetylcholinergic activity and increasing intrasynaptic acetylcholine can enhance cognitive function and clinical well being.

Cholinesterase inhibitors were thus developed along such thoughts and were shown to be modestly effective. In general, this class of drugs was shown to be consistently better than placebo in various trials on cognition, activities of daily livings (ADL) and clinicians' global impression in patients with mild to moderate Alzheimer's disease. The effect on cognition is modest, translating into only 2 to 5 points difference on ADAS-Cog, a scale sampling 11 areas of cognition with range of scores from 0 (best) to 70 (worst).²⁵ The treatment-placebo differences are largely secondary to continuing decline on the part of the placebo patients and temporary stabilization of the treated cohort during 3 to 6 month studies. A recent meta-analysis revealed that they were also associated with a beneficial effect on neuropsychiatric and functional outcomes.²⁶ One study indicated that tacrine, one cholinesterase inhibitor, may have a survival benefit of about 6 months for up to 3 years' use.²⁷

There are four cholinesterase inhibitors currently available, namely tacrine, donepezil, rivastigmine and galantamine. Tacrine is seldom used nowadays because of hepatotoxicity and inconvenience of frequent dosing. The effects of the other three are generally comparable. Titration of dose is required (Table 2). The choice is based mainly on clinicians' preference, patients' tolerance and cost. However, there is some evidence that shifting from one to another after failure of one to achieve improvement may still be beneficial in some patients, partly due to their difference in pharmacodynamics and receptor properties.²⁸ Studies suggested that donepezil and galantamine may also be effective in patients with vascular dementia.^29,30

The side effect profile is mostly cholinergically mediated, mild and short lived (Table 3). Significant effects can occur in about 15% or fewer, of patients receiving higher doses and are often related to an early upward titration of medications. Caution should be paid to patients with asthma, chronic obstructive airways disease, cardiac conduction defects, and clinically significant bradycardia. Patients who are going to receive general anesthesia with succinylcholine type drugs may have the latter effect being prolonged.

NMDA receptor antagonist

Memantine is the only drug of this class currently available and is approved for symptomatic treatment of moderate to severe Alzheimer's disease. It works by antagonizing glutamate activation of the NMDA receptor, which is involved in memory and learning. It was effective in reducing deterioration on multiple scales of clinical efficacy in patients with mini-mental state examination (MMSE) score of 3-14.³¹ For vascular dementia, beneficial effects are also seen, especially in patients with a low MMSE score or small vessel disease.³² Dizziness is the most common side effect. Confusion and hallucination may occur at lower frequency (6 and 3% respectively).

Selegiline/Vitamin E (Alpha-tocopherol)

Selegiline, a monoamine oxidase inhibitor, and vitamin E both have antioxidant properties. In one controlled trial the progression to a composite outcome of death, institutionalization, loss of ability in ADL and progression to severe dementia was delayed but no effect on cognitive measure was demonstrated.³³ However, this study was criticized for the need of statistical adjustment as the placebo group had higher mini-mental state examination score at baseline.

There was no additive effect of selegiline plus vitamin E. It was concluded in the practice parameter from the American Academy of Neurology that selegiline has a less favourable risk-benefit ratio and vitamin E should be considered in an attempt to slow the progression of Alzheimer's disease.³⁴

Supportive care

The course of dementia, especially of Alzheimer's disease, can conventionally be divided into three stages (Figure 1) During the early stage, patients are usually symptom free or have only subtle abnormalities. As the disease progresses, the gradual decline in cognition and functional abilities becomes noticeable to the patient and caregivers and it marks the mild to moderate stage. The rate of decline varies among patients and behavioural symptoms are common at this stage. During the later severe stage, functional ability is lost completely and institutionalization is usually inevitable. .

The approach in managing late stage dementia differs from that of earlier stages, mainly in the form of enhancing the quality of life and management of associated issues (Table 4).

Managing patients is often viewed as a risk-benefit analysis. For severely demented patients, the balance for many interventions almost always shifts toward the side of inconclusive effectiveness yet causing considerable harm and discomfort. Important examples here include tube feeding, use of respirator, physical restraint³⁵ and antibiotic use.

Provision of meaningful activities

In Hong Kong, it is not uncommon to find demented patients being refrained from going out of their homes and be accompanied by a foreign-language speaking domestic maid. More sadly, they may be restrained onto the bed or chair for most of the time at institutions. The need for social and recreational activities is often overlooked. However, studies have shown that activity programmes can provide structure to the patients' day, preserve remaining capabilities, minimize the consequences of cognitive and functional deficits, and create an environment for social interaction.³⁶

Mobility maintenance

The need for demented patients to retain some sense of purposeful activity may be evidenced in the frequently described persistent wandering of some patients. Ambulation is important as it itself is a meaningful activity and an important outlet for physical energy that may otherwise precipitate problem behaviours. Ambulation allows them to join more activities, and helps prevent medical complications. Complications are less if adequate assistance and supervision are provided. One uncommon condition is related to pacers who ambulate most of the day. They may need extra caution on food intake as more calories may be required to maintain adequate nutritional status.

Treatment of medical conditions

Aspiration pneumonia and other inter-current infections are relatively common because of various predisposing factors including compromised immunity, inability to ambulate, incontinence and swallowing difficulties. Antibiotics may not extend survival³⁷ and other aggressive treatments lead to discomfort of demented patients as they are unable to understand the need for medical procedures. Infections often recur as soon as antibiotic treatment is terminated as the underlying causes of infection are irreversible. A palliative approach which assures maximal comfort without striving for maximal survival may be more appropriate. Patients were found to be equally comfortable either treated with antibiotics or with analgesics and antipyretics.³⁸ In clinical practice, the challenge remains when to make the determination to forgo antibiotics treatment.

Treatment of chronic medical conditions need to take into consideration three aspects: inability to report symptoms, reduced life expectancy, and induction of discomfort by therapeutic interventions. Even in mild dementia, patients may already have difficulty in reporting symptoms. This poses a difficulty on not only diagnosis making, assessing the response to interventions, but also monitoring of side effects and adverse events related to treatments. Reduced life expectancy implies that preventive interventions that do not have an immediate impact may not be appropriate. For the same reason, treatment of chronic conditions, such as hypertension and diabetes, should be less aggressive and should keep prevention of side effects as the main emphasis. Discomfort caused by interventions may lead to significant abnormal behaviours such as agitation, which often ends in physical restraints.

Nutritional problems

Food refusal can be related to a number of conditions besides simply the patients' own food preference. In fact, they may have a change in food choice because of the dementia. It is important to exclude concomitant depression which is prevalent and difficult to recognize yet treatable. Trial of antidepressant may not only improve the mood but also the food intake. Caution should be paid to anorexigenic side effects of medications including selective serotonin reuptake inhibitors, analgesics, etc.

Swallowing difficulty may occur as patients forget how to chew and swallow as dementia progresses. It could be tackled by changing the consistency of the diet and the addition of fluid thickener to liquids. Initiation of long-term tube feeding is often a difficult clinical dilemma when the above measures are bound to fail at the very late stage. It has been well documented in various trials that tube feeding in patients with progressive degenerative dementia cannot prevent aspiration, reduce the risk of pressure ulcers or infections, improve function or prolong survival.³⁹ It also deprives patients of the enjoyment generated by tasting the food and of the contact with caregivers during the feeding process. However, this is still widely practiced in most parts of the world including Hong Kong. The underlying explanations are complex, including discretion of medical professions, inadequate nursing staff power and societal and cultural misconception. Both professionals and families need to be prepared for a time when patients will be unable to eat or drink by mouth. To decide whether tube feeding is appropriate, ethical and medical issues are involved in this choice as well as personal beliefs and cultural background.

Management of behavioural symptoms

Behavioural and psychological symptoms of dementia (BPSD) are an integral part of the disease process and present severe impact to patients, caregivers, clinicians and society at large. However, they are treatable and more amenable to therapy than other symptoms of dementia. Treatment offers the best chance to alleviate suffering, reduce family burden and lower societal costs in patients with dementia. They are grouped into two categories, namely behavioural and psychological symptoms and details of individual symptoms including treatment are well documented elsewhere (Table 5).⁴⁰ Physical restraints are often used to control behavioural problems such as pacing and wandering. However, their use has been shown to be of limited, if any, value in preventing injuries and falls, but on the other hand, are liable to increase agitated behaviour, distress and even falls.⁴¹

For difficult behavioural symptoms, referral to psychogeriatricians or geriatricians with special interest in dementia should be considered.

End-of-life issues

Patients with dementia should be respected both physically and emotionally. Despite the lack of mental competence and physical independence, they should not be deprived of receiving appropriate therapies and at the same time be given ineffective and potentially harmful treatments. The last stage of life should be well prepared if possible at the early stage of dementia when the patients are still capable of indicating their personal preferences before they enter a stage of mental incapacity. However, it is often not possible and the decision will be left to proxy surrogates and/or responding clinicians. The decision-making strategies should be based on the last competent indication of patients' wishes and their best interest, i.e. analysis of benefits versus burden.⁴² Recently, there have been discussions among the profession and the public on substituted decision-making and advance directive in relation to medical treatment in response to a consultation paper by the Law Reform Commission locally.

Caregiver support

Support by caring relatives is the key to continuing community care of people with dementia. The emotional relationship between the responsible relative and the demented person significantly determines whether family care can be maintained. Troublesome BPSD and the burden that they create for the family caregiver are key factors in precipitating a move from family care to a nursing home or other residential care.

Caregivers are vulnerable to develop psychological distress and have their own physical problems being aggravated. There are many ways to intervene to prevent and reduce caregivers' stress, including individual support, counselling, cognitive therapy, stress management, education, support network development, and various training programmes. Respite care is another important tool to alleviate the burden and stress of caregivers. It can be defined in simple terms as a service which provides a break from the responsibility and confinement of caring for a dependent. Various modes of operations provided by different sectors of the health and social welfare system are available to suit different needs, e.g. adult day-care centres, short period institutional care, and respite camp. For best benefits, it should be initiated in a prophylactic manner to prevent caregiver breakdown.

Conclusion

Dementia, like most other prevalent and chronic diseases, is non-curative at the present moment. Symptomatic treatment focusing on the cognitive dysfunction is one of the mainstays of current management approach. However, the efficacy is modest and the effect is mediated through stabilization instead of genuine improvement. Identification of possible risk factors and understanding of their biological plausibility becomes an important way to tackle the disorder from its root. Recently there have been quite a number of potential candidates being discovered and interventional trials are underway to evaluate their effectiveness in prevention. Finally, management of late stage disease needs a holistic and supportive care approach such that patients are treated with dignity and their caregivers' stress is relieved.

Key messages

1. Hypertension, diabetes mellitus and smoking are risk factors for both Alzheimer's disease and vascular dementia.
2. Light to moderate alcohol drinking may be protective compared with total abstinence and heavy drinking.
3. Cholinesterase inhibitors have a modest effect on improving the cognitive, neuropsychiatric symptoms and functional outcome of patients with Alzheimer's disease.
4. Memantine helps to reduce deterioration in moderate to severe stage of Alzheimer's disease.
5. Supportive care of demented patients requires a holistic approach and is aimed at comfort care, enhancing the quality of life and management of associated medical problems.