Dementia

Dementia is a syndrome in which impairment of cortical or subcortical function leads to deterioration of cognitive processes or intellectual abilities including memory, judgement, language, communication, and abstract thinking. Unlike delirium mere is no gross clouding of consciousness. There may be changes in personality and behaviour disturbances. Dementia is usually progressive, though not always irreversible, and loss of social and other skills often leads to complete dependence on others. Although dementia is more prevalent in the elderly it is not an inevitable consequence of ageing. Dementia can result from many conditions including:

• neurodegenerative diseases: Alzheimer’s disease, Pick’s disease, Huntington’s chorea, Parkinson’s disease, Lewy-body disease, multiple sclerosis, progressive supranuclear palsy
• vascular diseases: multiple cerebral infarcts, occlusion of carotid artery, cranial arteritis
• trauma: subduralhaematoma
• neoplasms
• CNS infections: encephalitis, syphilis, toxoplasmosis, AIDS, Creutzfeldt-Jakob disease
• endocrine/metabolic disorders: hypothyroidism, uraemia, hepatic failure, cardiac failure, respiratory failure, hypoxia, hyponatraemia
• toxic insults: alcohol, solvents, heavy metals, drug therapy
• hydrocephalus
• nutritional deficiency: vitamin B₁₂, folic acid, thiamine
• depression
• sleep disorders: obstructive sleep apnoea, narcolepsy Alzheimer’s disease is the most common cause of dementia and accounts for over half of all patients; about one-third of dementia cases are due to vascular disease. Treatment of dementia can be broadly divided into control of disturbed behaviour and attempts to improve or preserve cognitive function (see below). Although many drugs have been tried in the management of cognitive impairment most have produced little or no benefit.

Alzheimer’s disease

Alzheimer’s disease is a progressive degenerative condition affecting mainly patients over 60 years of age. The rare early-onset form of Alzheimer’s disease (familial Alzheimer’s disease) is sometimes referred to as pre-senile dementia. Death usually occurs within 10 years of onset. Apart from age other risk factors include Down’s syndrome and a family history of Alzheimer’s disease. Presence of the s4 allele of apolipoprotein E is another risk factor; it correlates with prevalence and age of onset in some forms of Alzheimer’s disease but use for routine clinical or predictive testing is not recommended.

Elevated levels of plasma homocysteine have been linked with the development of dementia and Alzheimer’s disease. Cardiovascular risk factors such as diabetes, hypercholesterolaemia, hypertension, and obesity have also been associated with an increased risk Dialysis dementia, an irreversible condition which has occurred in dialysis patients, has been associated with excess aluminium in the dialysing fluid but the role of aluminium in Alzheimer’s disease, if any, is unclear.

Deficiencies in numerous neurotransmitters have been found in patients with Alzheimer’s disease but reduced choline acetyltransferase activity leading to reduced synthesis of acetylcholine remains the most consistent defect correlating with the severity of the condition. Attempts to increase acetylcholine concentrations in the brain have included use of acetylcholine precursors, cholinesterase inhibitors, enhancers of acetylcholine release, and cholinergic agonists. However, none replace lost cholinergic neurones and therefore none affect overall progression of the disease.

Treatments using precursors of acetylcholine such as lecithin or choline alone are not generally considered to produce useful improvements, although it has been suggested that choline alfoscerate may be of some benefit.

Donepezil, galantamine, rivastigmine, and tacrine are the main cholinesterase inhibitors. All have produced modest improvement in cognition and global clinical impression in patients with mild to moderately severe disease. However, mere is a lack of long-term studies and little evidence of their effectiveness in advanced disease although donepezil is licensed for the treatment of severe dementia in many countries.

Tacrine is often poorly tolerated and may cause serious hepatotoxicity; for these reasons it is rarely used now. Donepezil, galantamine, and rivastigmine may be more acceptable to patients. A systematic review found no evidence of any difference between these 3 drugs with regard to efficacy although mere appeared to be fewer adverse effects associated with donepezil compared with rivastigmine. In the UK, NICE recommends that the use of donepezil, galantamine, and rivastigmine is limited to patients with moderate dementia and given under the following conditions:

• treatment should only be started under specialist supervision
• patients who continue on the drug should be reviewed every 6 months
• treatment should only be continued if there was evidence of benefit

In a somewhat controversial decision, NICE considered that these 3 tings could no longer be recommended in the treatment of mild dementia because their cost-effectiveness was questionable; however, it was recommended mat those currently taking one of these tings for mild dementia should continue on therapy until it was considered appropriate to stop. Other cholinesterase inhibitors that have been tried in Alzheimer’s disease include metrifonate and physostigmine.

Fampridine, which enhances acetylcholine release from nerve terminals has also been tried in Alzheimer’s disease but mere is little evidence of clinical benefit.

Limited improvement has been reported with some cholinergic agonists but pilocarpine may exacerbate the dementia. Muscarinic M1 agonists such as cevimeline and xanomeline have been investigated on the basis mat muscarinic M1 receptors appear to be preserved throughout the course of Alzheimer’s disease. However, these drugs have not been successful in improving symptoms of the disease. An alternative line of investigation is the stimulation ofnicotinic receptors using nicotine. A hypothesis mat free radicals may initiate and maintain mechanisms responsible for neurodegeneration in Alzheimer’s disease has prompted the investigation of drugs such as vitamin E (e.g. α-tocopherol), ginkgo biloba, idebenone, and selegiline for antoxidant therapy but their value remains to be confirmed.

Although some US guidelines suggested consideration of vitamin E supplementation in an attempt to slow progression of the disease, more recent ones no longer recommend it for the treatment of cognitive symptoms because of limited evidence of efficacy as well as safety concerns. Selegiline has produced mixed results in a large number of controlled studies and US guidelines note that few clinicians actually use the drug in clinical practice. A systematic review has found no convincing evidence that ginkgo biloba is effective in the treatment of dementia or cognitive impairment. Neurotropic or nootropic drugs such as piracetam are considered to enhance memory and cognition.

They have been tried in preventing cognitive deficits associated with Alzheimer’s disease and other dementias but there is little convincing evidence of clinical usefulness. The N-methyl-D-ospartate (NMDA) receptor antagonist memantine has shown some benefit in various dementias and is used in the treatment of moderately severe to severe Alzheimer’s disease; it is thought to act through modulation of the effects of the neurotrans-mitter glutamate. However, in the UK, NICE has not recommended memantine in the treatment of patients with moderately severe to severe disease because of insufficient evidence of clinical effectiveness.

Many drugs with vasodilator activity were originally tried in dementia when it was believed that the condition was due to ‘cerebrovascular insufficiency’, but overall there is little convincing evidence of benefit. Ergot derivatives such as codergocrine mesilate and nicergoline have been the most commonly used; however, any effectiveness is now attributed to their action as metabolic enhancers or nootropic tings and their place in therapy has still to be established.

The calcium-channel blacker nimodipine has been of benefit in dementia of various aetiologies but its role in therapy remains unclear.

Observations have suggested mat oestrogens may reduce the risk and delay the onset of Alzheimer’s disease in post-menopausal women receiving HRT. However, a large controlled study found that combined HRT increased the risk of substantial decline in global cognitive function, did not prevent the development of mild cognitive impairment, and doubled the risk of dementia. A beneficial effect of oestrogens on cognitive function in postmenopausal women who already have mild or moderate Alzheimer’s disease has not been demonstrated in controlled studies.

Some retrospective studies also indicate an inverse association between the use of anti-inflammatory drugs such as NSAIDs and the risk of developing Alzheimer’s disease. However, mere is currently insufficient evidence to support the use of NSAIDs in the treatment of Alzheimer’s disease.

The possibility of an association between statin therapy and a reduced risk of developing dementia has also been mooted. Evidence has been conflicting and further study is ongoing.

A vaccine for Alzheimer’s disease is being investigated. Memylmioninium chloride, which is thought to dissolve and prevent the aggregation of tau protein filaments in the brain, is also under investigation.

A less marked degree of impaired memory, without dementia, is seen in some patients. Many, but not all, patients with such mild cognitive impairment (MCI) go on to develop Alzheimer’s disease, and mere has been considerable interest in treating them, in the hope of retarding progression to the more severe condition. However, appropriate strategies for management are unclear: although treatment with cholinesterase inhibitors, antoxidants, and other drugs used for Alzheimer’s disease has been investigated, there has been some concern about a possibly increased risk of death in patients with MCI treated with galantamine (see Effects on the Cardiovascular and Cerebrovascular Systems). In the UK, NICE does not recommend the use of cholinesterase inhibitors in patients with MCI.

Vascular dementia

Vascular dementia is a syndrome produced by ischaemic, hypoxic, or haemorrhagic brain lesions. Vessel occlusion is the most common cause of vascular dementia and produces a variety of cognitive deficits depending on the site of ischaemia. Among the major forms of dementia recognised are those due to multiple infarcts, single strategic infarcts, and subcortical white matter ischaemia (Binswanger’s disease). Vascular dementia has a more acute onset than dementia due to Alzheimer’s disease and in contrast to the continuous progression of Alzheimer’s disease often has a stepwise progression.

Risk factors for vascular dementia parallel those for stroke and similar methods for prevention and treatment may be of use but there is a lack of evidence from adequately controlled trials. Cholinergic deficits are well documented in patients with vascular dementia; cholinesterase inhibitors such as donepezil and galantamine have been found to be well tolerated and effective in these patients. Positive results have also been seen with the NMDA receptor antagonist memantine. However, in me UK, NICE does not recommend me use of cholinesterase inhibitors or memantine for cognitive decline in vascular dementia.

Lewy-body dementia

Lewy-body dementia is distinguished from other types of dementia by a state of fluctuating cognitive impairment and confusion; hallucinations, paranoid delusions, a tendency to fall for no apparent reason, and transient clouding or loss of consciousness are also characteristic symptoms. In addition, mild extrapyramidal symptoms may be present and mere is increased susceptibility to the extrapyramidal adverse effects of antipsychotics (see the Elderly, under Precautions of Chlorpromazine on site). Severe cholinergic deficits in patients with Lewy-body dementia have prompted treatment with cholinesterase inhibitors. Donepezil and rivastigmine have been shown to be well tolerated and effective, but further studies are needed to establish their role.