132 CHAPTER 5 Organic illness Dementia: general overview Essence Dementia is a syndrome characterized by progressive, usually irreversible, global cognitive deficits. Often memory impairment is the first symptom with progression to other defi cits including dysphasia, agnosia, apraxia, impaired executive function, and personality disintegration. For a diagnosis to be made there must be significant impairment of normal functioning and other possible diagnoses (see Differential diagnosis b p. 133), particularly delirium or depression, should be excluded. Common causes Alzheimer s disease (62%), vascular dementia (15%), mixed (10%), Lewy body dementia (4%), fronto-temporal dementia (2%), other (3%). Reversible causes (15%): subdural haematoma, NPH, vitamin B 12 deficiency, metabolic causes, hypothyroidism. Aetiology Parenchymal/degenerative Alzheimer s disease; vascular dementia; fronto-temporal dementia (including Pick s disease); Parkinson s disease; Huntington s disease; Wilson s disease; MS; motor neurone disease (MND); Lewy body disease; progressive supranuclear palsy; corticobasal degeneration. Intracranial Tumour; head trauma; subdural haematoma; CVA; normal pressure hydrocephalus (NPH). Infection Creutzfeldt Jakob disease (prion disease); neurosyphilis; HIV-associated dementia; tuberculosis (TB); subacute sclerosing panencephalitis (SSPE); other. Endocrine Hypothyroidism; hyperparathyroidism; Cushing s and Addison s disease. Metabolic Uraemia; hepatic encephalopathy; hypoglycaemia; calcium imbalance; magnesium imbalance; electrolyte imbalance. Vitamin deficiency B 12 ; folate; pellagra (niacin); thiamine. Toxins Prolonged alcohol misuse; heavy metal poisoning. Clinical features (see Box 5.1) Memory impairment: starts with short-term and progresses to longterm. History of personality change, forgetfulness, social withdrawal, lability of affect, disinhibition, silliness, diminished self-care, apathy, fatigue, deteriorating executive functioning. Other specific cognitive deficits are seen in cortical dementias (see b p. 133). Hallucinations and delusions often paranoid (20 40%) and poorly systematized. Anxiety and/or depression in 50%. Neurological features (e.g. seizures, focal defi cits, primitive reflexes, pseudobulbar palsy, long-tract signs). Catastrophic reaction, ( b p. 88). Pathological emotion spontaneous lability. Sundowner syndrome as evening approaches confusion increases and falls become common.
DEMENTIA: GENERAL OVERVIEW 133 Differential diagnosis Delirium; depression (pseudodementia b p. 520); amnestic disorders (b p. 148); learning disability (LD); psychotic disorders; normal ageing (b p. 514). Investigations Include: FBC; LFT; U&E; glucose; erythrocyte sedimentation rate (ESR); thyroid-stimulating hormone (TSH); calcium; magnesium; phosphate; Venereal Disease Research Laboratory (VDRL) test for syphilis; HIV; vitamin B 12 and folate; C-reactive protein; blood culture; LP; EEG; chest X-ray (CXR); ECG; CT (optima and axial protocol); MRI; SPECT. Principles of management Assessment: diagnostic, functional, and social. Cognitive enhancement: acetylcholinesterase inhibitors (tacrine; donepezil; rivastigmine); antioxidants (selegiline, vitamin E);? hormonal (oestrogen; HRT). Treat psychosis/agitation: consider antipsychotics. Treat depression/insomnia: SSRIs; hypnotics. Treat medical illness. Psychological support: to both patient and care-givers. Functional management: maximize mobility; encourage independence with self-care, toilet, and feeding; assist with communication. Social management: accommodation; activities; financial matters; legal matters (power of attorney, wills, and curatorship). Box 5.1 Clinical syndromes of dementia Dementias may be classified in terms of primary site of pathology. Since site of pathology in the brain correlates with neuropsychiatric symptomatology, this is a useful system of classification. 1. Cortical dementias involve primarily the cortex and are divided into: Fronto-temporal e.g. Pick s disease (p. 142). Characterized by prominent personality change which may manifest as a frontal lobe syndrome. A common cause of early-onset dementia, it is often undiagnosed. Language impairments tend to involve reduction in content (semantic anomia). CT shows fronto-temporal atrophy and SPECT shows fronto-temporal metabolism. Posterior parietal e.g. Alzheimer s disease (p. 134). Characterized by early memory loss and focal cognitive deficits. Personality changes are later manifestations. Language impairments involve problems with word-finding (lexical anomia). CT (optima protocol) shows thinning (<12 mm) of the cortex of the medial temporal lobe. 2. Subcortical dementias Parkinson s disease (p. 168); Huntington s disease (p. 170); Wilson s disease (p. 171); Binswanger encephalopathy (p. 144); progressive supranuclear palsy (PSNP) (p. 167); HIV-associated dementia (p. 163); NPH (p. 150). Clinical features: gross psychomotor slowing; depressed mood; movement disorders; mild amnesia; and personality changes. 3. Cortical subcortical dementias e.g. Lewy body dementia (p. 140). Clinical features: cortical and subcortical symptoms. 4. Multifocal dementias e.g. CJD (p. 146). Clinical features: rapid onset and course; involves cerebellum and subcortical structures.
134 CHAPTER 5 Organic illness Alzheimer s disease 1 Also termed dementia of the Alzheimer type (DAT), this is the most common cause (70%) of dementia in older people. It is a degenerative disease of the brain with prominent cognitive and behavioural impairment that is suffi ciently severe to interfere signifi cantly with social and occupational function. It affects approximately 500 000 people in the UK and more than 30 million worldwide. A larger number of people have less severe impairments that usually evolve into the full disorder with time. The percentage of the total population aged over 65 is increasing in the developed world, meaning that the burden of DAT-related health care is likely to increase. Epidemiology Risk of DAT increases with age: 1% at age 60yrs; doubles every 5yrs; 40% of those aged 85yrs. Age-specific incidence is the same for men and women approximately 50% excess prevalence in women (explained by the greater number of at-risk women given their longer lifespan). Risk factors include: Down s syndrome, previous head injury, or hypothyroidism; family history of Down s syndrome, Parkinson s disease, or DAT. Possible protective factors Smoking; oestrogen (e.g. hormone replacement therapy [HRT]); non-steroidal anti-inflammatory drugs (NSAIDs); vitamin E; higher level of pre-morbid education. Pathophysiology Amyloid plaques insoluble β-amyloid peptide deposits as senile plaques or β-pleated sheets in the hippocampus, amygdala, and cerebral cortex. Increased density with advanced disease. Neurofibrillary tangles (NFTs) consist of phosphorylated tau protein and are found in the cortex, hippocampus, and substantia nigra. (NFTs also found in normal ageing, Down s syndrome, dementia pugilistica, and progressive supranuclear palsy.) However, even low densities of NFTs in the cortices of the medial temporal lobes should be considered abnormal. The co-occurrence of amyloid plaques and NFTs was described by Alois Alzheimer in his original description of the disorder and is now accepted universally as a hallmark of the disease. Up to 50% loss of neurons and synapses in the cortex and hippocampus. Genetics: 40% have a positive family history of DAT (esp. early onset: <55yrs). Autosomal dominant inheritance affects <1% of those with dementia. Chromosome 21 the gene for amyloid precursor protein (APP) is found on the long arm. Also implicated in Down s syndrome. Chromosome 19 codes for apolipoprotein E4. Presence of E4 alleles increases risk of DAT; some 15% of Europeans carry the allele.
ALZHEIMER S DISEASE 1 135 Chromosome 14 codes for presenilin 1 (implicated in B-amyloid peptide). Chromosome 1 codes for presenilin 11 (implicated in B-amyloid peptide). Cholinergic hypothesis: the pathological changes lead to degeneration of cholinergic nuclei in the basal forebrain (nucleus basalis of Meynert). This results in dcortical acetylcholine (ACh). Pray, do not mock me: I am a very foolish fond old man, Fourscore and upward, not an hour more or less; And, to deal plainly, I fear I am not in my perfect mind. Methinks I should know you and know this man; Yet I am doubtful: for I am mainly ignorant what place this is, and all the skill I have remembers not these garments; nor I know not where I did lodge last night. Do not laugh at me; For as I am a man, I think this lady to be my child Cordelia. Shakespeare: King Lear, Act II Scene 7
136 CHAPTER 5 Organic illness Alzheimer s disease 2 Clinical features Symptoms usually start insidiously but fi rst presentation may be related to an identifiable life event. Early symptoms Failing memory (with disorientation being common, especially for time), muddled effi ciency with activities of daily living (ADLs), spatial dysfunction, and changes in behaviour such as wandering and irritability. By the time the patient presents to clinicians, cognitive deficits are usually apparent. Middle symptoms Intellectual and personality deterioration aphasia, apraxia (evidenced by awkwardness with the sequence of dressing), and agnosia (inability to recognize parts of the body). Occasionally, a patient may present with Gerstmann syndrome (b p. 73), indicating right parietal disease, characterized by finger agnosia, R/L disorientation, acalculia, and dysgraphia), BPSD (behavioural and psychological symptoms in dementia). Impaired visuospatial skills and executive function are common. Late symptoms Fully dependent. Physical deterioration, incontinence, gait abnormalities, spasticity, seizures (3%), tremor, weight loss, primitive reflexes, extrapyramidal signs. Psychiatric symptoms Delusions (15%) usually of a paranoid nature. Auditory and/or visual hallucinations (10 15%) which may be simple misidentification, and indicate rapid cognitive decline. Depression is common, requiring treatment in up to 20% of patients. Behavioural disturbances include aggression, wandering, explosive temper, sexual disinhibition, incontinence, excessive eating, and searching behaviour. Personality change often reflects an exaggeration of premorbid traits with coarsening of affect and egocentricity. Clinical subtypes and course Mayeux (1985) described four groups: The most common presentation is a gradual and progressive decline without distinguishing features. A group with early onset (<65), more aphasia and apraxia, a rapid course with severe intellectual decline, and poor survival rate. A group with extra-pyramidal signs, severe functional impairment, and associated psychotic symptoms. A benign group with little or no progression over a 4-yr follow-up. Factors associated with poor prognosis Greater severity of disease at presentation Being male Onset <65yrs Parietal lobe damage Prominent behavioural problems Severe focal cognitive deficits such as apraxia Observed depression Absence of misidentification syndrome
ALZHEIMER S DISEASE 2 137 Assessment Detailed history An informant questionnaire such as the IQCODE can be helpful in this regard). Mental state examination Noting any clouding of consciousness (delirium), symptoms of depression, psychosis, etc. Cognitive testing is essential and may begin with a Mini Mental State Examination (MMSE), but later involve specific neuropsychological testing. Physical examination To detect presence or absence of focal signs, reflexes, and plantar responses, as well as gait disturbance and signs of Parkinson s disease. Blood tests (b p. 133). EEG useful to exclude delirium, Creutzfeldt Jakob disease (CJD), etc. to be considered in atypical cases only. Brain imaging: CT cortical atrophy, esp. over parietal and temporal lobes and ventricular enlargement. MRI (optima protocol) atrophy of grey matter (hippocampus, amygdala, and medial temporal lobe). Single photon emission tomography (SPET) reduced regional cerebral blood flow (rcbf) in temporal and posterior parietal lobes (also frontal lobes in advanced disease). PET 20 30% reduction in oxygen and glucose metabolism in temporal and posterior parietal lobes. Magnetic resonance spectroscopy (MRS) dn-acetylaspartatetypically reserved for use in combination with structural imaging where the diagnosis is in doubt.
138 CHAPTER 5 Organic illness Alzheimer s disease 3: pharmacological treatments 1 Acetylcholinesterase inhibitors (AChEIs) were the first drugs to be licensed for the treatment of DAT. They act by enhancing ACh at cholinergic synapses in the CNS, and in this way may slow progression of the disease, reducing time spent in full nursing care. They have beneficial effects on cognitive, functional, and behavioural symptoms of the disease and are recommended as first-line agents in the treatment of mild moderate DAT. (See Box 5.2.) First generation AChEIs Tacrine Developed in the 1980s; easily absorbed with a short ½ life; liver metabolism; non-linear kinetics; non-selective (also acts at parasympathetic receptors outside the CNS). Problems: Gastrointestinal tract (GIT) side-effects; iliver enzymes/hepatotoxicity; wide dose range, therefore unpredictable kinetics; 4x daily dosage. Second generation AChEIs Similar efficacy over 6mths; long-term efficacy unknown. Switching between agents is acceptable. Donepezil Piperidine derivative, developed in 1996; GIT absorbed with liver metabolism; long ½ life (70hrs); highly selective (acts centrally only); linear kinetics. Problems: GIT side-effects at high dose; bradycardia; GIT bleed (rare); contraindicated in asthma. Benefi ts: selective therefore dside-effects; no liver toxicity; predictable kinetics; narrow dose range; 1x daily dosage. Dose: 5 10mg/day. Rivastigmine Developed in 1998; short ½ life (12hrs); inhibits AChE and butyrylcholinesterase in CNS. Problems: GIT side-effects; 2 daily dosage. Benefi ts: Not metabolized by the liver and least likely to cause drug drug interactions. Dose: start with 1.5mg twice daily (BD); increase to 3 6mg BD now available in a modified release once daily (OD) form or 24hr patch (thought to be helpful in reducing GI side-effects). Galantamine Selectively inhibits AChE and acts as an allosteric ligand at nicotinic ACh receptors; metabolized in liver; short ½ life (5hrs); selective. Problems: 2 daily dosage. Dose: 4 12mg BD. NMDA-receptor partial antagonist The NMDA receptor binds excitatory glutamate in the CNS and has a role in LTP and learning/memory function. Memantine In Feb 2002, this new agent was approved in Europe for the treatment of moderately severe to severe DAT (MMSE 3 14). It is a non-competitive, PCP-site, N-methyl-D-aspartate (NMDA) antagonist that may protect neurons from glutamate-mediated excitotoxicity. Trials show benefits of memantine augmentation of donepezil. Cochrane review indicates use in DAT, vascular, and mixed dementia. Other (possible) treatment strategies Although only at experimental stages, there is some evidence for other approaches to DAT.
ALZHEIMER S DISEASE 3: PHARMACOLOGICAL TREATMENTS 139 These include: antioxidants (vitamin E; selegiline); anti-inflammatories; secretase inhibitors; metal chelators; amyloid-b-peptide vaccination; cholesterol-lowering drugs; red wine (!). There is ongoing work looking at possible neuroprotective effects of lithium. Box 5.2 NICE guidance on drug treatment for Alzheimer s disease donepezil, rivastigmine, and galantamine (No 19) The three drugs donepezil, rivastigmine, and galantamine should be made available in the NHS as one component of the management of those people with mild and moderate Alzheimer s disease (AD) whose MMSE score is above 12 points, under the following conditions: Diagnosis that the form of dementia is AD must be made in a specialist clinic according to standard diagnostic criteria. Assessment in a specialist clinic, including tests of cognitive, global, and behavioural functioning and of activities of daily living, should be made before the drug is prescribed. Clinicians should also exercise judgement about the likelihood of compliance; in general, a carer or care-worker who is in sufficient contact with the patient to ensure compliance should be a minimum requirement. Only specialists (including old age psychiatrists, neurologists, and care of the elderly physicians) should initiate treatment. Carers views of the patient s condition at baseline and follow-up should be sought. If GPs are to take over prescribing, it is recommended that they should do so under an agreed shared-care protocol with clear treatment end points. A further assessment should be made, usually 2 4 months after reaching maintenance dose of the drug. Following this assessment, the drug should be continued only where there has been an improvement or no deterioration in MMSE score, together with evidence of global improvement on the basis of behavioural and/or functional assessment. Patients who continue on the drug should be reviewed by MMSE score and global, functional, and behavioural assessment every 6 months. The drug should normally only be continued while their MMSE score remains above 12 points, and their global, functional, and behavioural condition remains at a level where the drug is considered to be having a worthwhile effect. When the MMSE score falls below 12 points, patients should not normally be prescribed any of these three drugs. Any review involving MMSE assessment should be undertaken by an appropriate specialist team, unless there are locally agreed protocols for shared care. 1 Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer s disease: current status and new perspectives. Lancet (Neurol) 2: 539 47.