Uraemia; hepatic encephalopathy; hypoglycaemia; calcium \200 Clinical features (see Box 5.1) \200 Memory impairment: starts with short-term and progresses to long- term. History of personal ity change, forgetfulness, social withdrawal, lability of affect, disinhibition, \200\230s illiness \200\231, diminished self-care, apathy, fatigue, deteriorating executive functioni ng. Other speci \201 c cognitive de \201 cits are seen in cortical dementias (see b p. 13 3). Hallucinations and delusions often paranoid (20 \200\22340%) and poorly systematized. A nxiety and/or depression in 50%. Neurological features (e.g. seizures, focal de \201 cits, primitive re \202 exes, pseudobulbar palsy, long-tract signs). Catastrophic reaction, ( P athological emotion \200\224spontaneous lability. Sundowner syndrome \200\224as evening app roaches confusion increases and falls become common. \200 \200 \200 b p. 88). 05_Semple_Chap05.indd 132 12/7/2012 3:28:32 PM DEMENTIA: GENERAL OVERVIEW 133 Differential diagnosis Delirium; depression (pseudodementia b p. 520); amnestic disorders ( b p. 148); learning disability (LD); psychotic disor- ders; normal ageing (b p. 514). Inves tigations Include: FBC; LFT; U&E; glucose; erythrocyte sedimenta- tion rate (ESR); thyroid- stimulating hormone (TSH); calcium; magnesium; phosphate; Venereal Disease Research Laborat ory (VDRL) test for syphi- lis; HIV; vitamin B12 and folate; C-reactive protein; blood cult ure; LP; EEG; chest X-ray (CXR); ECG; CT (optima and axial protocol); MRI; SPECT. Principles of management \200 \200 Assessment Cognitive enhancement donepezil; rivastigmine); antioxidants (selegiline, vitami n E); ? hormonal (estrogen; HRT). Treat psychosis/agitation Treat depression/insomnia Treat medical illness . Psychological support Functional management with self-care, toilet, and feeding; assist with communication. Social management matters (power of attorney, wills, an d curatorship). : diagnostic, functional, and social. : acetylcholinesterase inhibitors (tacrine; \200 \200 \200 \200 : consider antipsychotics. : SSRIs; hypnotics. : to both patient and care-givers. : maximize mobility; encourage independence : accommodation; activities; \201 nancial matters; legal Box 5.1 Clinical syndromes of dementia Dementias may be classi \201 ed in terms of primary site of pathology. Since site of patho logy in the brain correlates with neuropsychiatric symp- tomatology, this is a useful syste m of classi \201 cation. 1. Cortical dementias involve primarily the cortex and are divide d into: Fronto-temporal 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 SP ECT shows fronto-temporal metabolism. Posterior \200\223parietal by early memory loss and f ocal cognitive de \201 cits. Personality changes are later manifestations. Language impair ments involve problems with word- \201 nding (lexical anomia). CT (optima protocol) shows thinning (<12 mm) of the cortex of the medial temporal lobe. 2. Subcortical dementias Parki nson \200\231s disease (p. 168); Huntington \200\231s dis- ease (p. 170); Wilson \200\231s disease (p. 171); Binswanger encephalopathy (p. 144); progressive supranuclear palsy (PSNP) (p. 167); HIV-associated dementia (p. 163); NPH (p. 150). Clinical features: gross psychom otor slowing; depressed mood; movement disorders; mild amnesia; and personality changes. 3. Cortical \200\223subcortical dementias e.g. Lewy body dementia (p. 140). Clinical features : cortical and subcortical symptoms. 4. Multifocal dementias e.g. CJD (p. 146). Clinical fe atures: rapid onset and course; involves cerebellum and subcortical structures. e.g. Pick \200\231s disease (p. 142). Characterized by e.g. Alzheimer \200\231s disease (p. 134). Characterized 05_Semple_Chap05.indd 133 12/7/2012 3:28:33 PM CHAPTER 5 Organic illness 134 Alzheimer \200\231s disease 1 Also termed \200\230dementia of the Alzheimer type \200\231 (DAT), this is the most common cause (70%) of dementia in older people. It is a degenerativ e disease of the brain with prominent cognitive and behavioral impairment that is suf \201 ciently severe to interfere signi \201 cantly with social and occu- pational function. It affects approximately 500 000 people in the UK and more than 30 million worldwide. A large r 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 develop ed 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 th ose aged 85yrs. Age-speci \201 c incidence is the same for men and women \200\224approxima tely 50% excess prevalence in women (explained by the greater number of at-risk women given their longer lifespan). Risk factors include: Down \200\231s syndrome, previous head injur y, or hypothyroidism; family history of Down \200\231s syndrome, Parkinson \200\231s diseas e, or DAT. Possible protective factors Smoking; estrogen (e.g. hormone replace- ment therapy [HRT]); n on-steroidal anti-in \202 ammatory drugs (NSAIDs); vitamin E; higher level of pre-morbid e ducation. Pathophysiology \200 -amyloid peptide deposits as senile Amyloid plaques \200\224insoluble plaques or -pleated sheets in the hippocampus, amygdala , and cerebral cortex. Increased density with advanced disease. Neuro \201 brillary tangle s (NFTs) \200\224consist of phosphorylated tau protein and are found in the cortex, hippoca mpus, and substantia nigra. (NFTs also found in normal ageing, Down \200\231s syndrome, dem entia 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-occurre nce of amyloid plaques and NFTs was described by Alois Alzheimer in his original descriptio n of the disorder and is now accepted universally as a hallmark of the disease. Up to 50% l oss of neurons and synapses in the cortex and hippocampus. Genetics : 40% have a positive f amily history of DAT (esp. early onset: <55yrs). Autosomal dominant inheritance \200\224aff ects <1% of those with dementia. \200 Chromosome 21 \200\224the gene for amyloid precursor protein (APP) is found on the long arm . Also implicated in Down \200\231s syndrome. Chromosome 19 \200\224codes for apolipoprotei n E4. Presence of E4 alleles increases risk of DAT; some 15% of Europeans carry the allele. 05_Semple_Chap05.indd 134 12/7/2012 3:28:33 PM ALZHEIMER \200\231S DISEASE 1 135 B-amyloid Chromosome 14 \200\224codes for presenilin 1 (implicated in peptide). Chromosome 1 \200\224 codes for presenilin 11 (implicated in peptide). B-amyloid Cholinergic hypothesis : the pathological changes lead to degeneration of cholinergic nucle i in the basal forebrain (nucleus basalis of Meynert). This results in dcortical acetylchol ine (ACh). Pray, do not mock me: I am a very foolish fond old man, Fourscore and upward, not an hour m ore or less; And, to deal plainly, I fear I am not in my perfect mind. Methinks I should kn ow you and know this man; Yet I am doubtful: for I am mainly ignorant what place this is, a nd 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 05_Semple_Chap05.indd 135 12/7/2012 3:28:33 PM CHAPTER 5 Organic illness 136 Alzheimer \200\231s disease 2 Clinical features Symptoms usually start insidiously but \201 rst presenta- tion may be related to an identi \201 able life event. \200 Early symptoms especially for time), muddled ef \201 ciency with activities of daily livin g (ADLs), spatial dysfunction, and changes in behavior such as wandering and irritability. By the time the patient presents to clinicians, cognitive de \201 cits are usually apparen t. Middle symptoms apraxia (evidenced by awkwardness with the sequence of dressing), and ag nosia (inability to recognize parts of the body). Occasionally, a patient may present with Gerstmann syndrome (b p. 73), indicating right parietal disease, characterized by \201 ng er agnosia, R/L disorientation, acalculia, and dysgraphia), BPSD (behavioral and psychologi cal symptoms in dementia). Impaired visuospatial skills and executive function are common. Late symptoms gait abnormalities, spasticity, seizures (3%), tremor, weight loss, primitive re \202 exes, extrapyramidal signs. Psychiatric symptoms Delusions (15%) \200\224usually of a paranoid nature. Auditory and/or visual hallucinations (10 \200\22315%) \200\224which may be simple misidenti \201 cation, and indicate rapid cognitive decline. Depression is c ommon, requiring treatment in up to 20% of patients. Behavioral disturbances temper, sexual disinhibition, incontinence, excessive eating, and searching behavior. Personality change with coarsening of affect and egocentricity. Failing memory (with disorientation being common, Intellectual and personality deterioration \200\224aphasia, Fully dependent. Physical deterioration, incontinence, include aggression, wandering, explosive often re \202 ects an exaggeration of premorbid traits Clinical subtypes and course Mayeux (1985) described four groups: \200 The most common pr esentation is a gradual and progressive decline without distinguishing features. A group wi th early onset (<65), more aphasia and apraxia, a rapid course with severe intellectual dec line, and poor survival rate. A group with extra-pyramidal signs, severe functional impairm ent, and associated psychotic symptoms. A benign group with little or no progression over a 4-yr follow-up. Factors associated with poor prognosis \200 Greater severity of disease at presentation \200 Being male \200 Onset <65yrs \200 Parietal lobe damage \200 Prominent behaviora l problems \200 Severe focal cognitive de \201 cits such as apraxia \200 Observed depr ession \200 Absence of misidenti \201 cation syndrome 05_Semple_Chap05.indd 136 12/7/2012 3:28:33 PM ALZHEIMER \200\231S DISEASE 2 137 Assessment \200 Detailed history be helpful in this regard). Mental state examination (delirium), symptoms of depression, psychosis, etc. Cognitive testing Examination (MMSE), but later involve spec i \201 c neuropsychological testing. Physical examination re \202 exes, and plantar respo nses, as well as gait disturbance and signs of Parkinson \200\231s disease. Blood tests EEG etc. \200\224to be considered in atypical cases only. Brain imaging \200 An informant questionnaire such as the IQCODE can Noting any clouding of consciousness is essential and may begin with a Mini Mental State To detect presence or absence of focal signs, \200 (b p. 133). useful to exclude delirium, Creutzfeldt \200\223Jakob disease (CJD), : CT \200\224cortical atrophy, esp. over parietal and temporal lobes and ventricular enlargem ent. MRI \200\224(optima protocol) atrophy of gray matter (hippocampus, amygdala, and media l temporal lobe). Single photon emission tomography (SPET) \200\224reduced regional cerebra l blood \202 ow (rCBF) in temporal and posterior parietal lobes (also frontal lobes in ad vanced disease). PET \200\22420 \200\22330% reduction in oxygen and glucose metabolism in t emporal and posterior parietal lobes. dN-acetylaspartate- Magnetic resonance spectroscopy ( MRS) \200\224 typically reserved for use in combination with structural imaging where the d iagnosis is in doubt. 05_Semple_Chap05.indd 137 12/7/2012 3:28:33 PM CHAPTER 5 Organic illness 138 Alzheimer \200\231s disease 3: pharmacological treatments1 Acetylcholinesterase inhibitors (AChEIs) were the \201 rst drugs to be licensed for the treatment of DAT. They act by enh ancing ACh at cholin- ergic synapses in the CNS, and in this way may slow progression of th e dis- ease, reducing time spent in full nursing care. They have bene \201 cial effects on cognitive, functional, and behavioral symptoms of the disease and are recommended as \201 rst-line agents in the treatment of mild \200\223moderate DAT. (See Box 5.2.) First generation AChEIs \200 Tacrine Developed in the 1980s; easily absorbed with a short life; liver metabolism; non -linear kinetics; non-selective (also acts at parasympathetic receptors outside the CNS). P roblems: Gastrointestinal tract (GIT) side-effects; iliver enzymes/hepatotoxicity; wide dos e range, therefore unpredictable kinetics; 4x daily dosage. Second generation AChEIs Similar ef \201 cacy over 6mths; long-term ef \201 cacy unknown. Switching between agents is acceptable. \200 Donepezil with liver metabolism; long life (70hrs); highly selective (acts centrally onl y); linear kinetics. Problems: GIT side-effects at high dose; bradycardia; GIT bleed (rare) ; contraindicated in asthma. Bene \201 ts: selective therefore dside-effects; no liver tox icity; predictable kinetics; narrow dose range; 1x daily dosage. Dose: 5 \200\22310mg/day. Rivastigmine and butyrylcholinesterase in CNS. Problems: GIT side-effects; 2 \227 daily dos age. Bene \201 ts: Not metabolized by the liver and least likely to cause drug \200\223dru g interactions. Dose: start with 1.5mg twice daily (BD); increase to 3 \200\2236mg BD \200 \224now available in a modi \201 ed release once daily (OD) form or 24hr patch (thought to be helpful in reducing GI side-effects). Galantamine at nicotinic ACh receptors; metaboliz ed in liver; short life (5hrs); selective. Problems: 2 \227 daily dosage. Dose: 4 \200 \22312mg BD. Piperidine derivative, developed in 1996; GIT absorbed Developed in 1998; short life (12hrs); inhibits AChE Selectively inhibits AChE and acts as an allosteric ligand NMDA-receptor partial antagonist The NMDA receptor binds excitatory glutamate in the CNS an d has a role in LTP and learning/mem- ory function. \200 Memantine the treatment of moderately severe to severe DAT (MMSE 3 \200\22314). It is a non -competitive, PCP-site, N-methyl-D-aspartate (NMDA) antagonist that may protect neurons fro m glutamate-mediated excitotoxicity. Trials show bene \201 ts of memantine augmentation of donepezil. Cochrane review indicates use in DAT, vascular, and mixed dementia. Other (poss ible) treatment strategies Although only at experi- mental stages, there is some evidence f or other approaches to DAT. In Feb 2002, this new agent was approved in Europe for 05_Semple_Chap05.indd 138 12/7/2012 3:28:33 PM ALZHEIMER \200\231S DISEASE 3: PHARMACOLOGICAL TREATMENTS 139 These include: antioxidants (vitamin E; selegiline); anti-in \202 ammatories; secretase in hibitors; metal chelators; amyloid-B-peptide vaccination; cho- lesterol-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 \200\231s disease \200\224donepezil, rivastigmine, and galantamine (No 19) The three drugs \200\224donepezil, rivastigmine, and galantamine \200\224should be made ava ilable in the NHS as one component of the management of those people with mild and moderate Alzheimer \200\231s disease (AD) whose MMSE score is above 12 points, under the following conditions: \200 Diagnosis that the form of dementia is AD must be made in a specialist c linic according to standard diagnostic criteria. Assessment in a specialist clinic, includi ng tests of cognitive, global, and behavioral functioning and of activities of daily living , should be made before the drug is prescribed. Clinicians should also exercise judgment ab out the likelihood of compliance; in general, a carer or care-worker who is in suf \201 ci ent contact with the patient to ensure compliance should be a minimum requirement. Only spe cialists (including old age psychiatrists, neurologists, and care of the elderly physicians ) should initiate treatment. Carers \200\231 views of the patient \200\231s condition at ba seline and follow-up should be sought. If GPs are to take over prescribing, it is recommend ed that they should do so under an agreed shared-care protocol with clear treatment end poi nts. A further assessment should be made, usually 2 \200\2234 months after reaching mainten ance dose of the drug. Following this assessment, the drug should be continued only where t here has been an improvement or no deterioration in MMSE score, together with evidence of g lobal improvement on the basis of behavioral and/or functional assessment. Patients who con tinue on the drug should be reviewed by MMSE score and global, functional, and behavioral a ssessment every 6 months. \200 The drug should normally only be continued while their MMSE score remains above 12 points, and their global, functional, and behavioral condition remains at a level where the drug is considered to be having a worthwhile effect. When the MMSE score falls below 12 points, pa tients should not normally be prescribed any of these three drugs. Any review involving MMS E assessment should be undertaken by an appropriate specialist team, unless there are local ly agreed protocols for shared care. 1 Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer \200\231s disease: curre nt status and new perspectives. Lancet (Neurol) 2: 539 \200\22347. 05_Semple_Chap05.indd 139 12/7/2012 3:28:33 PM CHAPTER 5 Organic illness 140 Dementia with Lewy bodies (DLB) Common form of senile dementia (715 \200\22320% of cases in hospital1 and community-based samples2) that shares clinical and pathological features of both DAT and Parkinson \200\231s disease. Epidemiology Age of onset: 50 \200\22383yrs. Age at death: 68 \200\22392yrs. 4>5. Clinical features Dementia (relative sparing of STM); Park insonism (770%: bradykinesia, limb rigidity, gait disorder); \202 uctuating cognitive per formance and level of consciousness; complex hallucinations \200\224visual (760%): often pe ople and animals, auditory (720%) \200\224with associated emo- tional responses; signi \201 cant depressive episode (740%); recurrent falls/ syncope (730%: due to autonomic dysfu nction), transient disturbances of consciousness (mute and unresponsive for several minutes ); antipsy- chotic sensitivity (760%). The mean survival time/rate of cognitive decline is similar to Alzheimer \200\231s disease (but rapid deterioration over 1 \200\2232yrs does oc cur). Worsening of Parkinsonism is similar in rate to Parkinson \200\231s disease (10% decl ine per year). See Box 5.3 for a summary of diagnostic criteria. Pathological \200\230mixe d \200\231 picture. Lewy bod- ies Eosinophilic intracytoplasmic neuronal inclusions of abno rmally phosphory-lated neuro \201 lament proteins aggregated with ubiquitin and A-synuclei n, found in brainstem nuclei (esp. basal ganglia), paralimbic, and neocortical structures. Associated neuronal loss (esp. brain-stem and basal forebrain cholinergic projection neuron es \200\224with associated dACh trans- mission in neocortex). Lewy neurites Distinctive pat tern of ubiquitin and A-synuclein immunoreactive neuritic degeneration \200\224in substanti a nigra, hippocampal region (CA2/3), dorsal vagal nucleus, basal nucleus basilis of Meynert , and transtentorial cortex (may be more relevant to neuropsy- chiatric symptom formation t han cortical Lewy bodies). Alzheimer-type changes Senile plaques present in a similar densi ty and distribution, fewer neuro \201 brillary tangles, less tau pathology. Vascular disea se occurs in 730% with unknown clinical signi \201 cance. Differential diagnosis Other dem entia syndromes (esp. DAT), delir- ium, neurological causes (e.g. Parkinson \200\231s disea se, progressive supranuclear palsy, multiple system atrophy, CJD), psychiatric disorders (e .g. late-onset delusional disorder, depressive psychosis, mania). features Typically Investigations \200 CT/MRI Moderate increases in deep white-matter lesions, frequent periventricular lucencies on MRI. SPECT HMPAO scan temporal lobes relatively preserved. SPECT FP-CIT putamen (like Pa rkinson \200\231s disease). ApoE genotype : relative sparing of medial temporal lobes in most cases. (blood \202 ow): global (esp. occipital), medial (presynaptic dopamine transporter): reduced in : ifrequency of (cid:1)4 allele. Management \200 Antipsychotics reactions (40 \200\22350%) \200\224e.g. irreversible Parkinsonism, impairmen t of Avoid/use with great caution: severe sensitivity 05_Semple_Chap05.indd 140 12/7/2012 3:28:33 PM DEMENTIA WITH LEWY BODIES 141 consciousness, neuroleptic malignant syndrome (NMS)-like autonomic disturbances \200\224wit h 2 \200\2233-fold increase in mortality. AChEIs Not yet recommended by National Guidelines , substantial provisional evidence suggests AChEIs effective in some DLB cases (icognitive function, dapathy/psychosis/agitation). Other or BDZs for psychiatric and behavioral sympto ms. Clonazepam may be useful for sleep disturbance (vivid dreams, muscle atonia, excessive jerking, and other complex movements). Anti-Parkinsonian medication \200\224use cautiously for clinically signi \201 cant motor symptoms (risk of exacerbating psychotic symptoms). No clear evidence for antidepressants, anticonvulsants, Box 5.3 Consensus criteria for the clinical diagnosis of probable and possible dementia wit h Lewy bodies3 \200 The central feature required for a diagnosis of DLB is progressive cognitive decline of suf \201 cient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usuall y evident with progression. De \201 cits on tests of attention and of fronto-subcortical s kills and visuospatial ability may be especially prominent. Two of the following core featu res are essential for a diagnosis of probable DLB; one is essential for possible DLB. \200 Fluctuating cognition with pronounced variations in attention and alertness. Recurrent visu al hallucinations, which are typically well-formed and detailed. Spontaneous motor features of Parkinsonism. Features supportive of the diagnosis are: \200 Repeated falls; syncope; transient loss of consciousness; neuroleptic sensitivity; systemat ized delusions; hallucinations in other modalities. A diagnosis of DLB is less likely in the presence of: \200 \200 Stroke, evident as focal neurological signs or on brain imaging. Evidence on physical exami nation and investigation of any physical illness, or other brain disorder, suf \201 cient to account for the clinical picture. 1 Weiner M (1999) Dementia associated with Lewy bodies: dilemmas and directions. Arch Neuro l 56: 1441. 2 Holmes C, Cairns N, Lantos P, et al. (1999) Validity of current clinical criteria for Alz heimer \200\231s disease, vascular dementia and dementia with Lewy bodies. Br J Psych 174: 45 \200\22350. 3 McKeith I, Del Ser T, Spano P, et al. (2000) Ef \201 cacy of rivastigmine in dementia with Lewy bodies: a randomized, double-blind, placebo-controlled international study. Lancet 356: 2031 \200\2236. 05_Semple_Chap05.indd 141 12/7/2012 3:28:33 PM CHAPTER 5 Organic illness 142 Fronto-temporal dementia (FTD) (Pick \200\231s disease)1,2 A form of dementia, characterize d by preferential atrophy of fronto- temporal regions, with usually early onset (accounts f or 20% of presenile cases). Early symptoms include personality change and social disinhibi tion, preceding memory or other cognitive impairment (Box 5.4). Clinical features Profound alteration in character/social conduct, rela- tive preservation of perception, spatial skil ls, praxis, memory. Decline/ impaired regulation of social conduct: (e.g. breaches of etiqu ette, tact- lessness, disinhibition, changes in usual behavior, passivity, inertia, overac- tivity, pacing, and wandering). Emotional blunting: e.g. primary emotions (happiness, sadn ess, fear) and social emotions (embarrassment, sympa- thy, empathy). Impaired insight: of s ymptoms and expression of distress. Dietary changes: overeating, preference for sweet foods . Perseverative behaviors (e.g. drinking from an empty cup). Speech: echolalia, perse- vera tion, verbal stereotypies, mutism. Cognitive: frontal lobe dysfunction: impaired attention, ineffective retrieval strategies, poor organization, lack of self-monitoring and concern f or accuracy. Neurological: no early signs; primitive re \202 exes and Parkinsonism (with p rogression); MND signs (in a minority). Onset usually 45 \200\22365yrs, can occur before ag e 30 and in the over 65s. 4=5. Mean time to death 8yrs (range 2 \200\22320yrs). Family hist ory (FHx) in 50%. Clinical subtypes Disinhibited form: orbito-medial frontal and ante- rior temporal regional pathology. Apathetic form: extensive frontal (esp. dorsolateral) lobe pa thology. Stereotypic form: marked striatal/variable cortical involvement (often temporal>fr ontal). Note: changes in social behavior often related to right-hemispheric pathology. Repe titive/com- pulsive behaviors may be associated with striatal pathology and the dis- inhibi ted form, suggesting temporal lobe pathology (unlike OCD, anxiety is not experienced). Path ological features Macroscopic: bilateral atrophy of frontal and anterior temporal lobes, de generation of the striatum. Microscopic: 3 subtypes (similar distribution of changes within frontal/temporal lobes): Common (microvacuolar) type (60%) \200\224loss of large cortical nerve cells, spongiform degeneration (microvacuolation) of the super \201 cial neurophil, minimal gliosis, and no swellings or inclusions in remaining nerve cells; Pick type (25%) \200\224loss of large cortical nerve cells, widespread gliosis, minimal or no spongiform (m icrovacuolar) change, swollen neurons and inclusions positive for tau and ubiquitin (in mos t cases); limbic system and striatum more seriously damaged; Associated with MND (15%) demo nstrating microvacuolar (rarely Pick-type) histological features like MND. Differential dia gnosis DAT, cerebrovascular dementia, rare forms of fronto-temporal lobar degeneration (e.g . \200\230semantic \200\231 dementia, progressive non- \202 uent aphasia, progressive apr axia). Investigations Neuropsychology: Impaired frontal lobe function, relatively spared me mory, speech, and perceptuospatial functions. EEG: 05_Semple_Chap05.indd 142 12/7/2012 3:28:34 PM FRONTO-TEMPORAL DEMENTIA 143 usually normal. CT/MRI: bilateral (asymmetrical) abnormalities of fron- tal/temporal lobes. SPECT: frontal and/or temporal lobe abnormalities. A signi \201 cant proportion of patien ts will have normal structural imaging. Genetics: associations with: 17q21 \200\22322 (fami lial inheritance) and mutations in the tau gene; 3; 9q21 \200\22322 (familial amyotrophic l ateral sclerosis). Management Currently, no speci \201 c treatments. AChEIs: unlikely to b e bene \201 cial (no speci \201 c abnormality of the cholinergic system). SSRIs: of limit ed bene \201 t for behavioral symptoms (disinhibition, overeating, and compulsions). Box 5.4 Behavioral features of FTD speci \201 ed in diagnostic criteria Core features \200 \200 \200 \200 \200 Insidious onset and gradual progression. Early decline in social interpersonal conduct. Ear ly impairment in regulation of personal conduct. Early emotional blunting. Early loss of in sight. Supportive features \200 Behavioral disorder: \200 \200 \200 \200 \200 \200 Speech and language: \200 Decline in personal hygiene and grooming. Mental rigidity and in \202 exibility. Distracti bility and impersistence. Hyperorality and dietary changes. Perseverative and stereotyped b ehavior. Utilization behavior. Altered speech output (aspontaneity and economy of speech/ pressured speech). \200 Stereo typy of speech. \200 Echolalia. \200 Perseveration. Mutism. \200 Physical signs: \200 \200 \200 \200 Investigations: \200 Primitive re \202 exes. Incontinence. Akinesia, rigidity, and tremor. Low and labile blood pressure. Neuropsychological : signi \201 cant impairment on frontal lobe tests; absence of severe a mnesia, aphasia, or perceptuospatial disorder. EEG : normal on conventional EEG, despite cl inically evident dementia. Brain imaging and/or temporal abnormality. (structural and/or functional): predominant frontal 1 Neary D, Snowden JS, Gustafson L, et al. (1998) Frontotemporal lobar degeneration: a cons ensus on clinical diagnostic criteria. Neurology 51: 1546 \200\22354. 2 Snowden JS, Neary D , Mann DM (2002) Frontotemporal dementia. Br J Psychiat 180: 140 \200\2233. 05_Semple_Chap05.indd 143 12/7/2012 3:28:34 PM CHAPTER 5 Organic illness 144 Vascular dementia Vascular dementia is the second most common cause of dementia after DAT, accounting for 20% of cases. It can coexist with DAT and results from thromboembolic or hyp ertensive infarction of small and medium-size vessels. Features that suggest vascular demen tia include: sudden onset; stepwise deterioration; and risk factors for cardiovascular dise ase. Its pres- entation is variable and three syndromes are commonly recognized.1 1. Cognitive de \201 cits following a single stroke Not all strokes result in cogni- tive impairment, but when they do the de \201 cits depend upon the site of the infarct. Cogniti ve de \201 cits tend to be particularly severe with certain mid- brain and thalamic stroke s. Cognitive de \201 cits may remain \201 xed or recover, either partially or completely . 2. Multi-infarct dementia (MID) Multiple strokes lead to stepwise deteriora- tion in cognit ive function. Between strokes there are periods of relative stability. There are often risk factors for cardiovascular disease. 3. Progressive small-vessel disease (Binswanger disease) Multiple microvas- cular infarcts of perforating vessels lead to progressive lacunae formation and white matter leukoariosis on MRI. This is a subcortical dementia with a clinical course characterized by gradual inte llectual decline, general- ized slowing, and motor problems (e.g. gait disturbance and dysa rthria). Depression and pseudobulbar palsy are not uncommon. Epidemiology Most common in th e 60 \200\22370yrs age group. 4>5. Other risk factors include: family or personal history o f cardiovascular disease, smoking, diabetes mellitus, hypertension, hyperlipidaemia, polycy thae- mia, coagulopathies, sickle cell anemia, valvular disease, atrial myxoma, and carotid artery disease. There are rare familial cases with onset in the 40s \200\224cerebral autos omal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Cli nical features2 Onset may follow a CVA and is more acute than DAT. Emotional and personalit y changes are typically early, followed by cognitive de \201 cits (including memory de \201 cits) that are often \202 uctuating in severity. Depression with episodes of affecti ve lability and confusion are common, especially at night. Behavioral slowing, anxiety, and occasional episodes of cerebral ischaemia occur frequently. Physical signs include fea- tu res of arteriovascular disease together with neurological impairments (e.g. rigidity, akine sia, brisk re \202 exes, pseudobulbar palsy). 10% have sei- zures at some point. Course is stepwise, with periods of intervening stabil- ity. Prognosis is poorer than in DAT with av erage lifespan of 5yrs from onset. Cause of death is usually ischaemic heart disease (50%), CVA, or renal failure. Investigations \200 \200 b p. 133). Routine \200\230dementia screen \200\231 ( Serum cholesterol, clotting screen, vasculitis screen (ESR; C-reactive protein [CRP]; complement; anti-nuclear factor [ANF]; rh eumatoid factor; anti-DNA antibodies; antiphospholipid antibodies; etc.), and 05_Semple_Chap05.indd 144 12/7/2012 3:28:34 PM VASCULAR DEMENTIA 145 syphilis serology are additional tests in unusual cases (e.g. \200\230young strokes \200 \231). ECG, CXR, CT, and MRI are essential. Other investigations may include: echocardiogra phy (for cardiac/ valvular defects or disease); carotid artery Doppler ultrasound. \200 Management \200 \200 Establish causative factors. Medical or surgical diseases that are contributory need to be treated early. Daily aspirin may delay course of disease. General health interventions incl ude changing diet, stopping smoking, managing hypertension, optimizing diabetic control, an d increasing exercise. \200 1 Rossor M, Brown J (1998) Vascular and other dementias. In: R Butler and B Pitt, eds, Semi nars in old age psychiatry. London, Gaskell. 2 Gelder M, Gath D, Mayou R, et al. (1996) Oxf ord textbook of psychiatry, 3rd edn. Oxford: Oxford University Press. 05_Semple_Chap05.indd 145 12/7/2012 3:28:34 PM CHAPTER 5 Organic illness 146 Prion diseases Prion diseases are rapid, aggressive, dementing illnesses caused by depos- i ts of prion proteins throughout the brain. They are rare and are best considered as slow vi rus infections. Prions spread throughout the brain by causing irreversible change in neighb oring tissue. The typical pathological \201 nding is a spongy encephalopathy, and in term s of the nosology of the dementias, prion disease is considered a multifocal dementia. Whil e prion diseases tend to respect the species barrier (e.g. \200\230scrapie \200\231 is a p rion disease limited to sheep), there is emerging evidence that this is not always the case (e.g. vCJD). Three diseases are recognized in humans. Creutzfeldt \200\223Jakob disease (CJD) A rare disease (approximately 50 cases/year in UK) of 50 \200\22370yrs-olds with equal sex distribution. 85% cases are spontaneous or sporadic ; 10% result from genetic mutation; 5% result from iatrogenic transmission during transplan t surgery of dura, corneal grafts, and pituitary growth hormone. The clinical picture is on e of rapidly deteriorating dementia, cerebellar and extra-pyramidal signs, myoclonus, and d eath within a year. EEG shows periodic complexes. CT atrophy of cortex and cerebellum. New variant CJD (vCJD): BSE The rise of vCJD followed an epidemic of bovine spongiform ence phalopa- thy (BSE) in cattle. BSE is a prion disease of cows that is thought to have been s pread by cattle feeds that contained CNS material from infected cows. The disease in humans affects mainly young people in their 20s and is characterized by early anxiety and depress ive symptoms, followed by personality changes, and \201 nally a progressive dementia. Ata xia and myo- clonus are prominent and the typical course is 1 \200\2232yrs until death. EEG and CT changes are similar to CJD. Kuru This was a rare disease of New Guinea cannibals who ate the brains of their deceased r elatives. The incubation period was prolonged \200\224 up to 40yrs before disease onset, th en progression was rapid and fatal (Box 5.5). 05_Semple_Chap05.indd 146 12/7/2012 3:28:34 PM PRION DISEASES 147 Box 5.5 Recent research reveals \200\230cannibalism genotype \200\231 Researchers at University College London have recently suggested that cannibalism was commo n and widespread in human ancestors. They analyzed DNA from 30 elderly Fore women from Papu a New Guinea who had participated in many cannibalistic feasts before they were banned by t he Australian government in the 1950s. It was the practice of the Fore for women and childr en to consume the brains of dead kin in the belief that this act would \200\230recycle \200\231 the spirit of the dead within the living. At the peak of the epidemic (1920 \200 \2231950) kuru killed 1% of the population annually. Most of the women survivors tested by researchers had a particular genotype that was much less common in the younger population, indicating that it conferred substantial protection against the disease. Interestingly, non e of the patients who have to date contracted new variant CJD in Britain carry the protecti ve genotype. This suggests that this genotype is protective against prion diseases in human s. The researchers then examined DNA from various ethnic groups around the world and found that all, except the Japanese, carried the protective genotype to a similar degree. Genetic tests showed that this gene could not be there by chance, but was a result of natural sele ction. This implies that ancestral human populations were exposed to some form of prion dis ease. Researchers conclude that frequent epidemics of prion disease caused by cannibalism i n human ancestors would explain the worldwide existence of the protective genotype in moder n humans. From Mead S, Stumpf MP, Whit \201 eld J, et al. (2003) Balancing selection at the prion pr otein gene consistent with prehistoric kurulike epidemics. Science 300: 640 \200\2233. 05_Semple_Chap05.indd 147 12/7/2012 3:28:34 PM CHAPTER 5 Organic illness 148 Amnestic disorders The amnestic disorders are syndromes characterized by memory impair- men t (anterograde and/or retrograde amnesia), which are caused by a gen- eral medical conditio n or substance use, and where delirium and dementia have been excluded as causative of the amnesia. Amnestic disorders may be transient or chronic (< or >1mth). Amnestic conditions u sually involve some or all of the following neuroanatomical structures: frontal cortex; hip pocampus and amygdala; dorsomedial thalamus; mamillary bodies; and the periaqueductal gray matter (PAG). In terms of neurochemistry, gluta- mate transmission at the NMDA receptor is often implicated in amnesia, mainly due to its role in memory storage in the limbic system: long-term potentiation (LTP). A number of amnestic disorders are recognized: Wernicke \200 \231s encephalopathy (b p. 572) An acute syndrome, with a classic tetrad of symptoms (ataxi a, ophthalmo- plegia, nystagmus, and acute confusional state), caused by thiamine deple- ti on, usually related to alcohol abuse, and associated with pathological lesions in the mamil lary bodies, PAG, thalamic nuclei, and the walls of the third ventricle. Korsakoff psychosi s (b p. 572) Amnesia and confabulation associated with atrophy of the mamillary bod- ies, u sually following Wernicke \200\231s encephalopathy (rarer causes include: head injury; hypo xia brain injury; basal/temporal lobe encephalitis; and vascular insult). Vascular disease Insults to the hippocampus (especially involving the posterior cerebral ar tery or basilar artery) may result in an amnestic disorder. Other regions implicated includ e: parietal \200\223occipital junction; bilateral medio-dorsal thala- mus; basal forebrain nuclei (e.g. aneurysm of the anterior communicating artery). Head injury An open or closed head injury involving acceleration or deceleration forces may result in injury to the anterior temporal poles (as this structure collides with the tempo ral bone). Anterograde or post-traumatic amnesia (PTA) is prominent with retrograde amnesia relatively absent. Prognosis is related to length of PTA \200\224better prognosis associat ed with PTA of less than 1wk. HSV encephalitis Affects medial temporal lobes and results in de \201 cits in short-term m emory (STM) storage. Temporal lobe surgery Bilateral damage or surgery to the medial temporal lobes results in a n ina- bility to store new short-term memories (e.g. \200\230patient HM \200\231) (see Box 5.6). 05_Semple_Chap05.indd 148 12/7/2012 3:28:34 PM AMNESTIC DISORDERS 149 Hypoxic brain damage Hypoxia following asphyxia from CO poisoning, near drowning, etc., may damage sensitive CA1 and CA3 neurons in the hippocampus. This results in problems with STM storage.