THE CLINICAL ASSESSMENT OF THE PATIENT WITH EARLY DEMENTIA

Transcription

1 THE CLINICAL ASSESSMENT OF THE PATIENT WITH EARLY DEMENTIA See end of artile for authors affiliations Correspondene to: Dr John D W Greene, Southern General Hospital, Institute of Neurologial Sienes, 1345 Govan Road, Glasgow G51 4TF, UK; john. greene@sgh.sot.nhs.uk D S Cooper, J D W Greene J Neurol Neurosurg Psyhiatry 2005; 76(Suppl V):v15 v24. doi: /jnnp ementia is a linial state haraterised by a loss of funtion in at least two ognitive domains. When making a diagnosis of dementia, features to look for inlude memory impairment and at least one of the following: aphasia, apraxia, agnosia and/or disturbanes in exeutive funtioning. To be signifiant the impairments should be severe enough to ause problems with soial and oupational funtioning and the deline must have ourred from a previously higher level. It is important to exlude delirium when onsidering suh a diagnosis. When approahing the patient with a possible dementia, taking a areful history is paramount. Clues to the nature and aetiology of the disorder are often found following areful onsultation with the patient and arer. A foused ognitive and physial examination is useful and the presene of speifi features may aid in diagnosis. Certain investigations are mandatory and additional tests are reommended if the history and examination indiate partiular aetiologies. It is useful when assessing a patient with ognitive impairment in the lini to onsider the following straightforward questions: Is the patient demented? If so, does the loss of funtion onform to a harateristi pattern? Does the pattern of dementia onform to a partiular pattern? What is the likely disease proess responsible for the dementia? An understanding of ognitive funtion and its anatomial orrelates is neessary in order to asertain whih brain areas are affeted. This, in turn, aids diagnosis. A disussion of the loalisation of all ognitive proesses is beyond the sope of this review. It is, however, partiularly important to have an understanding of memory and its subdivisions, whih is neessary to aid in differential diagnosis. We shall then illustrate how the history and examination, inluding bedside ognitive testing, are used in diagnosis. TYPES OF MEMORY When onsidering any memory disorder it is important to have an understanding of the main types of memory; otherwise erroneous use of the term short term memory may ause onfusion. 1 Memory an be thought of in terms of working memory, episodi memory (anterograde and retrograde), semanti memory, remote memory, and impliit memory (table 1). Classially, early Alzheimer s disease (AD) auses defets in anterograde episodi memory (for example, the ability to remember an address after five minutes or longer). 2 The relevane of this is that aspets of memory are subserved by different strutures. Certain disease proesses have a tendeny to start foally and progress in a typial anatomial pattern. They have, therefore, a largely preditable neuropsyhologial signature. For example, initially AD pathology tends to be perihippoampal, then spreads to temporo-parietal assoiation ortex and latterly involves frontal lobes. This is mirrored by the initial ognitive defiit of anterograde episodi memory, progressing to attentional, semanti memory and visuo-pereptual impairment, with personality hange ourring as a later feature. TAKING A HISTORY AND THE EXAMINATION OF THE MEMORY IMPAIRED PATIENT It is vital to obtain a orroborating history from a relative or lose friend in addition to the patient s aount if they an provide one. The need to physially examine the patient, looking for signs pointing to a partiular ause, is disussed below. History taking It is useful to interview the patient and the aompanying person separately. The absene of a onerned relative or friend at the appointment may lessen the likelihood of dementia in a patient omplaining of memory problems. Interviewing the patient separately enables the ooperation and language skills to be assessed without them being masked by interruptions or assistane from a third party. It also allows an assessment into the degree of insight of the affeted individual. Conversation with the patient may be as important as any formal ognitive assessment. The presene of word finding diffiulties, paraphasi errors, and inappropriate behaviour is helpful in v15

2 v16 determining the likely ause of the dementia. Doumentation of speifi examples is a useful way of providing information that an be utilised by subsequent liniians. Diffiulties with speifi aspets of memory are suggested by ertain problems enountered in day to day ativities. Anterograde memory defiienies are suggested by the losing of objets, repetitive questioning, diffiulty taking messages, an inreasing reliane on lists, the failure to follow plots of films or television programmes, and getting lost (navigation). Semanti memory breakdown may manifest as a diminution of voabulary with words being substituted by thing. The meaning of unusual or infrequently used words may be lost. 3 The level of alertness and ooperation during the interview should be assessed. If alertness is dereased, auses of this should be sought for example, by a areful srutiny of the drug history. Delirium as opposed to dementia should be onsidered if the patient appears poorly responsive. Important features to note in the history inlude: symptoms at onset the tempo of evolution of symptoms the impat on work and family life issues of safety (for example, driving) a family history of dementia risk fators for example. vasular past medial history. The age of the patient is important as dementia in the young has a different aetiologial profile than that seen in the elderly. AD, however, remains the most ommon dementia even in younger people, followed by vasular dementia and frontotemporal lobar degenerations. Geneti and metaboli disorders are more ommon in this age group and other diagnoses to onsider inlude vasulitis, infetions (for example, AIDS, tuberulous meningoenephalitis, Lyme disease, subaute slerosing panenephalitis (SSPE)) and Creutzfeldt-Jakob disease (CJD). 4 Formal ognitive assessment A more detailed assessment of memory is neessary and performed by using several speifi bedside ognitive tests. The role and method of using suh tests has been overed in a previous supplement. 5 During a thorough ognitive assessment it is useful to examine the following: Orientation in time and plae Attention for example, serial sevens, months of the year or WORLD bakwards Memory for example, address reall, name of prime minister, et Language for example, naming of items, reading, writing, omprehension, repetition Table 1 Classifiation of memory Classifiation of memory Definition Working memory Episodi memory Anterograde Retrograde Semanti memory Impliit memory The immediate retention of new information for a few seonds Personally experiened events that rely on temporal and ontextual lues for retrieval Newly enountered information Past events Word meaning and general knowledge Learned responses not available for onsious refletion, e.g. driving, playing musi. Exeutive funtion for example, letter and ategory flueny Praxis for example, alternating hand movements, imitation of gestures NEUROLOGY IN PRACTICE Visuospatial funtion for example, drawing a lok fae, overlapping pentagons. Rating sales The widely used mini mental state examination (MMSE) provides useful information in grading established dementia but does have limitations, partiularly in deteting early disease. It ontains a rude test of delayed reall, with only three items being employed and not enough time allowed between registration and reall. It laks a timed test to detet problems with verbal flueny. The language items are also very easy, with all but signifiantly aphasi patients tending to perform at eiling on these items. 6 The Addenbrooke s ognitive assessment (ACE) has been developed to address the defiienies of the MMSE. 7 It also has the advantage of being brief enough to allow a liniian to use it within the time onstraints of a new patient appointment. 7 It should be noted that even the ACE is no math for formal neuropsyhology assessment. Suh servies, are, however, pathy, and in some servies are non-existent, so the liniian must remain ompetent at assessing ognition. THE FOCUSED EXAMINATION OF THE PATIENT WITH DEMENTIA Neurologial system Aside from the mental state examination and speifi tests of ognitive funtion it is important to examine the neurologial system in any patient with possible ognitive impairment. Neurologial examination is, however, often normal in the early stages of many neurodegenerative dementias and speifi abnormalities may point to rarer or potentially treatable auses of dementia (table 2). It is important to assess the patient at rest for any involuntary movements, inluding horea, tremor, dystonia, and myolonus (whih may be spontaneous or stimulus sensitive). The musles should be observed for fasiulations. The presene or absene of primitive reflexes (frontal release signs) should be determined. An oular examination should involve areful assessment of visual auity, pupillary responses, eye movements, opti diss, and visual fields. Assessment of speeh and swallowing may reveal the presene of bulbar features. Examination for pyramidal or extrapyramidal signs is important and gait should be assessed wherever possible. Ataxia is unusual in AD, dementia with Lewy bodies, and frontotemporal dementia; its presene should raise the possibility of a different ause. The presene or absene of apraxia should be assessed by asking the patient to perform alternating hand movements or opy gestures. A peripheral neuropathy may be present and when ooperation allows signs of this should be sought. The signifiane of these findings in relation to speifi potential diagnoses is outlined in table 2. Examination of other systems Examination of other systems is also useful in looking for evidene of multisystem disease. In addition to the neurologial examination, patients should be assessed for signs of immunoompromise (predisposing to opportunisti infetions suh as progressive multifoal leuoenephalopathy (PML), toxoplasmosis or primary erebral lymphoma possibly indiating HIV/AIDS). Features of systemi disease may indiate an underlying neoplasm, vasulitis, infetion, or a metaboli disorder. Uveitis may indiate saroidosis, Behçet s

3 NEUROLOGY IN PRACTICE Table 2 Physial sign Ataxia Involuntary movements Myolonus Extrapyramidal signs Pyramidal signs Abnormal neurologial signs and their signifiane in dementia Opti dis pallor Papilloedema Cortial blindness Anosmia Abnormal eye movements Other ranial nerve signs Alien hand Visual field defet Pupillary abnormalities (Argyll Robertson pupil) Peripheral neuropathy Early onset inontinene Bulbar features Fasiulations Seizures Grimaing faial expression Seen in Paraneoplasti disease, erebellar tumour, Whipple s disease, Creutzfeldt-Jakob disease (CJD), AIDS dementia omplex, spinoerebellar ataxia (SCA), Wernike-Korsakoff syndrome, Hallervorden-Spatz, ornithine transarbamylase defiieny, Niemann-Pik disease, mitohondrial disorders, adrenoleuodystrophy, neurodegeneration with brain iron aumulation (NBIA), lead poisoning Huntington s disease (HD), inherited metaboli disorders inluding Wilson s disease, CJD, ortiobasal degeneration (CBD), systemi lupus erythematosis, Whipple s disease, Hallervorden Spatz, Lesh-Nyhan Post-anoxia, CJD, Alzheimer s disease (AD), subaute slerosing panenephalitis (SSPE), myoloni epilepsies, Hashimoto s enephalopathy, dementia with Lewy bodies, CBD Dementia with Lewy bodies, Parkinson s disease, progressive supranulear palsy (PSP), vasular dementia, frontotemporal dementia (FTD), CJD, Wilson s disease, HD, dentato-rubro-pallido-luysian atrophy (DRPLA), neuroaanthoytosis, erebral autosomal dominant arteriopathy with subortial infarts and leuoenephalopathy (CADASIL), Niemann-Pik, mitohondrial disorders, NBIA Motor neuron disease, CJD, LCBD, B12 defiieny, multiple slerosis (MS), SCA, multi system atrophy, hydroephalus, AD, Hallervorden Spatz, CADASIL, mitohondrial disorders, adrenoleuodystrophy, FTD MS, B12 defiieny Tumour, subdural haematoma, hydroephalus Vasular disease, AD, CJD Subfrontal meningioma, head injury, AD, PD, HD Progressive supranulear palsy, Wernike-Korsakoff, Whipple s disease, CBD, mitohondrial ytopathies, erebellar tumours, auses of raised intraranial pressure, CJD, mitohondrial disorders, HD, Niemann Pik type C Saroidosis, tumours, neoplasia, tuberulous meningitis CBD Tumour, vasular disease, CJD Neurosyphilis Vitamin B12 defiieny, paraneoplasti disorders, neuroaanthoytosis, spinoerebellar ataxia, Hallervorden Spatz, adrenoleuodystrophy, NBIA, lead poisoning, systemi lupus erythematosus (SLE) Tumour, hydroephalus, PSP Frontal dementia (motor neuron disease) Frontal dementia (motor neuron disease), rarely CJD Vasulitis, neoplasia, primary angiitis of the nervous system, limbi enephalitis, AIDS dementia omplex, neurosyphilis, SSPE, Hashimoto s enephalopathy Wilson s disease disease, or multiple slerosis (MS). The presene of ardia disease, hypertension, or a previous transient ishaemi attak or stroke may suggest erebrovasular disease. Armed with the above theoretial knowledge regarding memory and its subdivisions along with how to eliit information from history taking and examination, we an now return to trying to ahieve a diagnosis in a patient with possible dementia. IS IT DEMENTIA? Conditions mimiking dementia The first and most important question to be asked when assessing the memory impaired patient is Is this dementia?. Conditions mimiking dementia are onsidered under the term pseudodementia and often relate to affetive disorders that represent treatable psyhiatri pathology, suh as anxiety or depression. Table 3 Clinial features of delirium versus dementia Feature Delirium Dementia Progression Flutuating with luid intervals, often worse at night Fairly onsistent over the ourse of a day Consiousness Altered Clear Attention Impaired with pronouned Relatively normal distratibility Memory Impaired Impaired Thinking Disorganised, delusional Pauity of thought Sleep wake yle Disrupted Often normal Pereption Halluinations and illusions Halluinations generally ommon, often visual absent in early stages Certain features may point to an early pseudodementia rather than a dementia, but often it is the linial assessment over time that enables a distintion between the two to be made. Biologial features of depression should be enquired about in all ases (anorexia, weight loss, sleep disturbane, and motor retardation) although none of these are exlusive to pseudodementia. Emotional blunting, loss of interest, pessimism, guilt, and negative ruminations may be present. An identifiable emotional preipitant may be present in pseudodementia, along with a relatively abrupt onset and lak of progression. Some organi dementias, however, present with anxiety and depression and may be mistaken initially for a pure psyhiatri illness. Delirium that is, an aute onfusional state may also be mistaken for dementia. Delirium is haraterised by an abrupt onset of pronouned attentional abnormalities with disordered pereption and memory. There is often signifiant variation in ognitive performane and behaviour. Table 3 illustrates some of the linial differenes observed between delirium and dementia. IF IT IS DEMENTIA, WHAT SORT OF DEMENTIA IS IT? The whole brain is not affeted equally in dementia. Psyhologial proesses are organised into speifi brain areas and therefore different diseases reflet the distribution of pathology within the anterior, medial, and posterior ortex by produing distint neuropsyhologial syndromes. Cortial and subortial dementias Defiits in ertain areas, espeially relatively early in the disease, may point to a speifi dementia. One of the more widely used ategorisations of dementia is into ortial (predominantly involving the erebral ortex) and subortial v17

4 v18 Table 4 A omparison of ortial and subortial dementia aording to neuropsyhologial profile Charateristi Cortial Subortial Speed of ognitive Normal Slowed proessing Planning, problem solving, initiative (frontal exeutive abilities) Preserved in early stages Impaired from onset Personality Intat until late, unless Apatheti, withdrawn frontal type Memory Severely amnesi Forgetful Language Aphasia Normal exept for dysarthria and redued output Visuospatial and Impaired Impaired pereptual diffiulties Mood Depression not Depression ommon unommon in early Alzheimer s disease Agnosia/prosopagnosia Often present Not usually seen forms (primarily affeting the basal ganglia, thalamus, and deep white matter) (table 4). Examples of ortial dementias inlude AD and CJD. The linial manifestations of ortial dementias inlude agnosia, spatial disorientation, language problems, apraxia, amnesia, and problems with visuospatial funtioning depending on the loation of the pathology. Examples of subortial dementias inlude Parkinson s disease, Huntington s disease, vasular dementia, progressive supranulear palsy, Wilson s disease, and AIDS dementia omplex. Patients with a subortial dementia show slowness and rigidity of thinking (bradyphrenia) often with perseveration. Although forgetful, they do not have a severe amnesia. There is diffiulty in planning and sequening of events and the pattern of ognitive impairment may be similar to that seen in frontal lobe dysfuntion. Some disorders display signs of both a ortial and subortial dysfuntion relatively early in the disease. Examples of ortio-subortial onditions inlude ortial dementia with Lewy Bodies (DLB) and ortiobasal degeneration (CBD). WHICH DEMENTIA IS IT? After detailed history taking and examination, the liniian may be onfident whih disease proess is responsible for the symptoms. Often, however, the linial piture will not be suffiiently distintive to allow the liniian to be ertain whih type of dementia is responsible. For this reason as Figure 1 Approximate relative frequenies of the dementias. AD, Alzheimer s disease; DLB, dementia with Lewy bodies. NEUROLOGY IN PRACTICE well as the importane of never missing a treatable ause of dementia it is usually appropriate to arrange investigations. INVESTIGATIONS Reommended investigations in all patients with dementia inlude full blood ount, erythroyte sedimentation rate, urea and eletrolytes, liver funtion tests, vitamin B12, red ell folate, thyroid funtion, hest x ray, and omputed tomographi (CT) brain san. In some irumstanes, it may be onsidered appropriate to perform immunologial tests for vasulitis, serum angiotensin onverting enzyme, HIV testing, paraneoplasti antibodies, and sreening for inborn errors of metabolism. Additional investigations are reommended in speifi irumstanes and inlude brain magneti resonane imaging (MRI), funtional imaging (SPECT), erebrospinal fluid analysis, and eletroenephalography. Further speialised investigations to be onsidered inlude a slit lamp examination (looking for the Kaiser-Fleisher rings of Wilson s disease), ardia sreening for emboli, and further speifi geneti sreening for individual disorders. Cerebral biopsy should be onsidered if a treatable ause is thought possible (for example, a erebral vasulitis) in the absene of an alternative diagnosis. The role of laboratory and imaging investigations is examined by Weisje von der Flier et al in this supplement (p v45). TYPES OF DEMENTIA Alzheimer s disease (AD) AD is the most ommon ause of dementia, aounting for approximately two thirds of all ases (fig 1). AD is assoiated with age and Down syndrome. There also exists familial AD, assoiated with mutations of APP (amyloid b protein preursor), PS (presenilin)-1, and PS-2. The disease results from the aumulation of abnormal b amyloid leading to seondary neuronal injury and aumulation of tau in neurofibrillary tangles. AD does not exhibit a global deline from onset but rather a relatively preditable pattern through various stages. By far the most ommon presentation is with amnesia, in partiular a failure of anterograde episodi memory. Delayed reall (for example, a name and address after five minutes) is the most sensitive measure of early AD. Typially patients with AD perform well on test of working memory, inluding digit span. 2 Although foal features have been reported at onset in AD these represent the very small minority. Depression is relatively ommon early in the disease and this may ause problems with diagnosis. A progressive disturbane of semanti memory is seen as the disease advanes and verbal flueny beomes impaired. Category flueny is more severely affeted than letter based verbal flueny. Remote memory for famous faes and events is impaired and shows a gentle temporal gradient (that is, more distant memories are relatively well preserved ompared with more reently aquired ones). In the middle stages of the disease it is ommon to find visual and pereptual diffiulties emerging. Ideomotor apraxia ours rendering tasks suh as dressing and eating diffiult. Language skills deline as the illness progresses and pauity of speeh is evident. Comprehension is impaired and reading, writing, and alulation all beome affeted. In notable ontrast to frontotemporal lobar degeneration (FTD), basi aspets of personality, demeanour, soial interation, and behaviour are strikingly preserved well into the disease. Most patients retain at least partial insight for some time.

5 NEUROLOGY IN PRACTICE Figure 2 Magneti resonane imaging (MRI) in Alzheimer s disease: bilateral hippoampal atrophy with generalised ortial atrophy. Clinial diagnosti riteria have been developed that may be about 80% sensitive (NINCDS-ADRDA) although these are not widely used in the lini in the authors experiene. In AD, as the disease progresses akinesia, rigidity, and myolonus may all develop, refleting the more widespread involvement of ortial and subortial strutures. Both extrapyramidal and pyramidal signs may be observed in later stages and myolonus seen in a minority. By this stage ognition is often severely impaired with a disintegration of personality and inontinene. Death often ours when immobility or poor nutrition predispose to bronhopneumonia. It is worth stressing that it is not unommon for a ombination of pathologies to exist that is, AD and erebrovasular disease. Figures 2 and 3 show the appearanes that may be seen on MRI and SPECT sanning in AD. Creutzfeldt-Jakob disease CJD is an invariably fatal prion disease of humans whih has been desribed in sporadi, geneti, variant, and iatrogeni forms. All forms of CJD are haraterised histologially by neuronal loss, gliosis, and spongiform hange along with the deposition of an abnormal proteinaeous partile (the prion). Sporadi CJD is the most ommon form of CJD and exists worldwide (or at least wherever surveillane systems are in plae) at an inidene of approximately one ase per one million of the population per year. Sporadi CJD is haraterised by an extremely rapidly progressive dementia with death ourring in the majority by six months after onset. Myolonus is a ommonly observed sign with other hard neurologial signs (suh as pyramidal features or ataxia) often observed. Variant CJD emerged in the UK in 1996 and is ommonly regarded as representing the transmission of bovine spongiform enephalopathy to humans probably after the onsumption of ontaminated beef produts. Affeted individuals are typially younger than those with sporadi CJD (the mean age at onset is 28 years). Early sensory symptoms and psyhiatri features are hallmarks of variant CJD. CJD may also be inherited in an autosomal dominant manner if there is an assoiated mutation in the gene enoding for normal prion protein. CJD has been reported iatrogenially as a result of human growth hormone injetions, neurosurgery, and orneal grafting. Cerebral MRI is useful in variant CJD where high signal bilaterally in the posterior thalamus (the pulvinar sign ) is frequently seen (fig 4), partiularly on FLAIR (fluid attenuated inversion reovery) sequenes. In sporadi CJD high signal in the basal ganglia strutures may be observed although this is less speifi than the pulvinar sign. Cerebrospinal fluid analysis for the protein shows a high sensitivity and speifiity in sporadi CJD if the patient group is arefully seleted. The eletroenephalogram (EEG) has been reported as showing periodi, sharp wave omplexes in up to two thirds of patients with sporadi CJD. SUBCORTICAL DEMENTIAS Progressive supranulear palsy (PSP) This disorder harateristially presents with a parkinsonian syndrome, with ognitive dysfuntion being an early and onsistent feature. There is bradykinesia, extrapyramidal rigidity, and a tendeny to falls experiened usually within a year of onset. Age at onset is typially over 40 years and progression is gradual. A vertial gaze supranulear palsy is harateristi, partiularly if downward saades are impaired. Cognitive defiits onsist of problems with exeutive funtion with ognitive slowing and diffiulty planning and sequening events. There is often a redution in verbal output refleted in a poor performane in tests of verbal flueny. Patients show defetive learning with impaired reall. Idiopathi Parkinson s disease (IPD) Reent studies suggest that up to three quarters of older patients with idiopathi Parkinson s disease go on to develop dementia. Risk fators for the development of dementia in IPD inlude older age, bradykinesia, akineti-rigid IPD, depression, early visual halluinations, and a bilateral onset of IPD. The major ognitive dysfuntions our in the areas of exeutive funtion and memory. In ommon with other subortial dementias language abilities are relatively spared in IPD. Huntington s disease Huntington s disease is a fully penetrant, autosomal dominant ondition aused by a CAG repeat expansion in exon 1 of IT15 gene enoding the Huntingtin protein. It is the most ommon geneti disorder to ause dementia. Onset of disease is most ommon in late middle age. There is often a prior history of a mood disorder and the disease is haraterised by a slow deterioration of intelletual funtion along with personality hange. Minor motor abnormalities are observed initially for example, fidgety movements of the hands and feet during times of stress and general restlessness. As the disease progresses extrapyramidal signs are observed, often as horea with dystonia, parkinsonism, and bradykinesia. Attentional and frontal exeutive dysfuntion is seen early in the disease. Memory impairment is seen and the defiit is primarily aused by impaired retrieval of new information. Depression is ommon. 4 Young patients may present atypially with an extrapyramidal syndrome, the so-alled Westphal variant. v19

6 v20 MIXED CORTICAL-SUBCORTICAL DEMENTIAS Frontotemporal dementia (FTD) Frontotemporal degeneration is assoiated with a foal degeneration of the frontal and temporal lobes. Several variants exist within this group inluding a dementia of frontal type, progressive aphasia, and semanti dementia. Figure 4 MRI showing the pulvinar sign (high signal in the posterior thalamus) seen in variant Creutzfeldt-Jakob disease (CJD). NEUROLOGY IN PRACTICE Figure 3 Typial posterior hypoperfusion seen on SPECT (single photon emission omputed tomography) in Alzheimer s disease. The aetiology of the ondition is unknown although it may be seen after the development of motor neuron disease when the neuronopathy is of the amyotrophi form displaying bulbar palsy, weakness, wasting, and fasiulations. The pathologial hanges seen in FTD are varied. Many ases are assoiated with tau inlusions but mild spongiform hange with neuronal loss and gliosis may our in the absene of inlusions. The linial phenotype reflets the anatomial distribution of the pathology, rather than the partiular pathologial proess. The frontal variant of FTD In ontrast to patients with AD, those with frontal dementia often remain utterly unaware of the hanges wrought to their personality. The initial presentation may be subtle but is haraterised by personality hange, emotional problems, and behavioural disturbane. Patients may appear apatheti, withdrawn, inappropriately joular, soially disinhibited, faetious, or unmotivated. There is a redued apaity to demonstrate appropriate emotional responses suh as happiness, fear, and surprise. Sympathy, empathy, and embarrassment are often laking and may be replaed by impulsivity and arelessness. The presentation is quite distint from that seen in AD. Memory is typially unaffeted early in the ourse of the disease with problems largely seondary to poor onentration and usually relating to diffiulties with working (immediate) memory. The severe amnesi presentation of AD is not the pattern seen here.

7 NEUROLOGY IN PRACTICE Figure 5 Bilateral anterior temporal lobe atrophy in frontotemporal dementia. Impairment in planning and organising of omplex ativities is almost invariably observed in FTD. This reflets defiits in sustained attention, goal setting, and flexibility. Suh diffiulties may manifest through problems funtioning at work or the inability to manage finanes. When onfronted with their failures patients appear disinterested and unperturbed. Mental rigidity and an inability to appreiate the more subtle aspets of language, suh as irony, are ommon. Verbal perseveration and eholalia frequently our. Speeh is fatually empty and redued in quantity and has been desribed as onrete. In advaned ases omprehension beomes impaired and muteness ensues. Stereotyped and perseverative behaviours may develop. Deterioration in self are with neglet of washing and grooming is often reported. Many patients develop a sweet tooth and exhibit hyperorality. Sparing of the posterior orties means that visuospatial problems are absent until the terminal stages. Neurologial signs are minimal and onsist of primitive reflexes, with akinesia and rigidity observed in the terminal stages. 8 Semanti dementia: progressive fluent aphasia This variant of FTD reflets seletive atrophy of the left anterior temporal lobe (fig 5). Patients display inreasingly empty, irumloutory speeh refleting the profound loss of semanti knowledge. Presenting omplaints may relate to forgetting of names of things with an unawareness of the parallel deline in word omprehension. The fluent dysphasia observed in suh patients is oupled with a severe anomia, redued voabulary, and a pronouned impairment of single word omprehension. Patients exhibit a surfae dyslexia that is, an inability to read words with irregular spelling suh as dough, pint, or island. Suh patients are often erroneously desribed as having a poor memory or being onfused, as the language disorder makes it impossible for them to proess verbal material. Assessment of memory in aphasi patients should be based on pratial day-to-day ativities and on tests of non-verbal memory. Figure 6 show bilateral frontotemporal hypoperfusion in a SPECT san seen in frontotemporal dementia. Progressive non-fluent aphasia This variant of FTD reflets foal left perisylvian atrophy. Here, a progressive deline in language output ours with a relative absene of other psyhologial defiits. Speeh is non-fluent, effortful, and laking in prosody. Artiulation is disturbed, word finding pauses our, and syntati errors are prominent. The ommuniation diffiulties are evident to both the patient and the observer. Repetition and reading aloud are impaired and there is pronouned anomia. Patients have diffiulties reiting the days of the week or similar well rehearsed series. With disease progression speeh beomes unintelligible. Comprehension is, by ontrast, relatively preserved. Vasular dementia The term vasular dementia is hampered by lak of agreement regarding definition. It omprises several different entities, suh as multi-infart disease, large ortial infarts, and diffuse small vessel ishaemia. The linial piture in vasular dementia depends on the site and number of the infarts. Diagnosis depends on: the linial piture brain imaging findings the presene of predisposing fators. There is ommonly an aumulation of neurologial and psyhologial defiits. There may be multiple ortial infarts ausing a step-wise deterioration in funtion. Dysarthria, dysphagia, rigidity, visuospatial defiits, ataxia, and pyramidal or extrapyramidal signs may our depending on the site of the pathology. Alternatively, subortial defiits may our exlusively, with infarts involving the thalamus, basal ganglia, or internal apsule. These may present without any sudden deteriorations, rather manifesting as impaired attention and poor exeutive funtion. It is important to differentiate this syndrome from other auses of subortial dementia and it may oexist with other dementias (for example, AD). Small vessel disease is assoiated with a syndrome of gait apraxia, urinary inontinene, and pseudobulbar palsy. Urinary and gait disturbanes typially our relatively early in the disease ourse and sometimes before there are overt signs of ognitive impairment. This pattern of disease is assoiated with brain imaging findings of launes in the deep grey matter nulei with assoiated ishaemi demyelination histopathologially (known as Binswanger s disease). A ombination of ortial and subortial pathology is not unommonly seen leading to a mixture of ognitive impairments. Dementia with Lewy bodies (DLB) Lewy bodies are neuronal inlusions omposed of abnormally phosphorylated neurofilament proteins aggregated with ubiquitin and a-synulein that are deposited in brainstem nulei, paralimbi, and neoortial areas. The linial phenotype often involves visual halluinations, parkinsonism, and flutuating attention and alertness with intervals of luidity. The visual halluinations are typially well formed and detailed. Halluinations our in other modalities not unommonly and delusions also are a feature. The ognitive profile reflets a ombination of ortial and subortial disease (table 5). There is ognitive slowing with impairment of frontal exeutive funtions and attention. In addition there are pronouned visuospatial and memory problems impliating parieto-oipital regions. The presene of aphasia, agnosia, and apraxia may lead to onfusion with AD. Along with the ognitive effets, DLB is assoiated with repeated falls and episodes of transient loss of onsiousness. v21

8 v22 These ognitive impairments may develop before or after parkinsonism symptoms and signs inluding akinesia, rigidity, and tremor. Cortiobasal degeneration Cortiobasal degeneration (CBD) usually presents with an asymmetri akineti-rigid syndrome, progressing to death within 4 6 years. Ideomotor limb apraxia is often observed and there are assoiated visuospatial and onstrutional diffiulties. The alien hand sign (spontaneous, oordinated hand movements outside of the patient s ontrol) may develop in one limb. This may be assoiated with ortial sensory loss, dysarthria, ataxia, horea, pyramidal signs, Table 5 Figure 6 Bilateral frontotemporal hypoperfusion on SPECT in frontotemporal dementia. dysarthria and/or buofaial apraxia. Dysalulia and a nonfluent aphasia may be observed and frontal dysfuntion may also our. Memory impairment is typially less pronouned than that observed in AD. REVERSIBLE DEMENTIAS AND HOW TO IDENTIFY THEM Reversible dementias represent a minority of dementias but the importane of identifying them is obvious. Cliniians should have an understanding of what may differentiate reversible dementias from the progressive, largely untreatable neurodegenerative onditions. Some treatable dementias may not be ured, but the disease ourse may be modified by Cognitive features of Alzheimer s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy Bodies (DLB) Cognitive domain AD FTD DLB NEUROLOGY IN PRACTICE Anterograde episodi memory (e.g. address reall) Typially impaired Preserved early in the disease Reognition better than reall. Forgetful Semanti memory Less affeted than anterograde memory Impaired in semanti dementia (progressive non-fluent aphasia) Verbal flueny (e.g. naming lists) Category flueny typial more impaired Dereased verbal flueny with Redued output than letter based verbal flueny perseveration Frontal exeutive funtion Preserved in early stages Impaired Impaired from onset Working memory (e.g. digit span) Preserved Impaired (poor onentration) Visuospatial funtion Often preserved in early stages Preserved in early stages Often impaired, halluinations are ommon Soial interation Strikingly preserved Affeted early, stereotyped, perseverative behaviours may exist Flutuations in funtion frequently desribed, assoiated with delusions. Depression ommon

9 NEUROLOGY IN PRACTICE Table 6 Illnesses assoiated with a potentially treatable dementia Depressive pseudodementia Spae oupying lesions Benign tumours, espeially subfrontal meningiomas Subdural haematoma Hydroephalus Defiieny states Vitamins B12, B1 (Wernike-Korsakoff), B6 Niain (Pellagra) Endorine disease and metaboli disorders Hypothyroidism Chroni hypoalaemia Reurrent hypoglyaemia Cushing s disease Addison s disease Uraemia Hepati enephalopathy Hashimoto s enephalopathy Infetions AIDS dementia omplex Lyme disease Tuberulosis (TB) Syphilis Inflammatory and vasulitides Systemi lupus erythematosis Giant ell arteritis Polyarteritis nodosa Behçet s disease Neurosaroidosis Aloholi dementia Chroni intoxiations Heavy metals Drugs Carbon monoxide poisoning Wilson s disease Whipple s disease Limbi enephalitis (paraneoplasti or assoiated with voltage gated potassium hannel antibodies) addressing the underlying ause (for example, vasular disease and modifiation of risk fators). Causes of dementia amenable to treatment are outlined in table 6. Examples of non-neurologial linial features assoiated with speifi, potentially treatable auses of dementia are shown in table 7. Imaging an ontribute to making a positive diagnosis of dementia, suh as MRI showing hippoampal atrophy in early AD. It is, however, also of use in exluding some reversible auses of dementia, suh as a benign tumour. Claims that linial predition rules an allow the liniian to differentiate between, say, early AD and spae oupying lesions have not been borne out by the evidene, and we feel that, at the least, a brain CT is mandatory for investigating the dementing patient. Benign tumours Change in personality may be the only manifestation of a slow growing frontal tumour suh as a meningioma. Deeper tumours, around the pituitary or third ventrile, may present solely with ognitive impairment. Chronisubduralhaematoma This an present with subaute dementia, often with flutuations. There may be no obvious history of head trauma, espeially in aloholis or in patients on antioagulants. It is eminently surgially treatable, and must not be missed. Normal pressure hydroephalus Traditionally, it was laimed that this disorder should be suspeted if the linial triad of gait apraxia, subortial dementia, and urinary dysfuntion are present. The feet are said to show the glued to the floor sign when the patient tries to walk. Imaging shows ventriular dilatation out of proportion to the degree of sulal enlargement. Subsequent pressure monitoring may show B waves, or a therapeuti trial of lumbar punture may signifiantly improve gait, in whih ase shunting is indiated. There is, however, urrent debate as to whether this entity exists. It is laimed that suh patients may in fat have AD, and the apparent improvement from lumbar punture may relate to hanges in amyloid in erebrospinal fluid (CSF) as a result of this proedure. Metaboli and endorine Metaboli disorders tend to produe delirium rather than dementia, but hypoalaemia and reurrent hypoglyaemia an present with dementia, usually with a movement disorder. Hypothyroidism must obviously be exluded in any patient with ognitive impairment. Addison s and hypopituitarism may oasionally present with ognitive impairment. In any young patient with dementia, espeially if showing a subortial pattern with a movement disorder, Wilson s disease must be exluded. This is a disorder of opper metabolism, and treatment beomes less effetive if the diagnosis is delayed. Infetions HIV may ause a diret infetion of the brain, resulting in a subortial dementia. White matter hanges are seen on MRI, and CSF shows a pleoytosis with oligolonal bands. A more rapidly progressive dementia an our in AIDS due to opportunisti infetions, suh as erebral toxoplasmosis, Table 7 Examples of non-neurologial linial features assoiated with potentially treatable auses of dementia Clinial sign Disease Lymphadenopathy HIV/AIDS, malignany, saroidosis, tuberulosis (TB) Signs of immunoompromise HIV/AIDS, malignany 0 Herpes simplex ( old sores ) 1 Herpes zoster 2 Oral andida 3 Hairy leuoplakia 4 Kaposi s saroma Hepatomegaly Malignany Cahexia Nutritional defiieny Aloholism Malignany AIDS Hypertension Vasular disease Kaiser-Fleisher rings Wilson s disease Uveitis Saroid, TB, multiple slerosis Rash 5 Erythema nodosum Saroid, TB 6 Vasuliti purpura Systemi vasulitides 7 Butterfly rash Systemi lupus erythematosus (SLE) 8 Erythema hronium migrans Lyme disease 9 Casel s neklae Niain defiieny Non-pulsatile, tender temporal Giant ell arteritis arteries Hyperpigmentation of skin Addison s disease Cushingoid appearane Cushing s syndrome Pretibial myxoedema Hypothyroidism Loss of eyebrows Hypothyroidism Oral/genital uleration Behçet s disease Blue gums (a lead line ) Lead poisoning Arthritis Whipple s disease, SLE, Lyme disease, Behçet s disease v23

10 v24 ryptooal meningitis, or progressive multifoal leuoenephalopathy. Syphilis, although rare, is beoming less unommon, and should be onsidered in the dementing patient, espeially if aompanied by supportive neurologial signs suh as Argyll Robertson pupils. Whipple s disease should be onsidered if there is oulomastiatory myorhythmia, oular palsies, or ataxia. Cerebral vasulitis When onsidering a diagnosis of vasulitis it is important to remember that vasulitis may our as a primary ondition (that is, Wegener s granulomatosis, temporal arteritis, polyarteritis nodosa, Churg-Strauss syndrome, primary angiitis of the nervous system) or as part of a multisystem disorder that may ause a vasulitis (for example, systemi lupus, saroid, Behçet s disease, lymphoma, and ryoglobulinaemia). Vasulitis affeting the entral nervous system in isolation is rare. Autoimmune enephalopathies Paraneoplasti limbi enephalitis may present with subaute onset ognitive impairment, often with seizures, and is assoiated with paraneoplasti antibodies. This disorder gives the liniian the opportunity to identify an oult primary aner at an early stage, with the possibility of early treatment. Certain other antibodies have been identified in the ontext of ognitive impairment for example, thyroid antibodies in Hashimoto s enephalopathy. Whether suh antibodies are impliated in the pathogenesis is, however, less lear. More reently, a voltage gated potassium antibody mediated limbi enephalitis has been desribed, whih appears to respond well to immunosuppression if diagnosed and treated early.... Authors affiliations S Cooper, J D W Greene, Southern General Hospital, Institute of Neurologial Sienes, Glasgow, UK REFERENCES NEUROLOGY IN PRACTICE 1 Hodges JR, Greene JDW. Disorders of memory. In: Kennard C, eds. Reent advanes in linial neurology 8. Churhill Livingstone, Greene JDW, Hodges JR. The dementias. In: Berriers GE, Hodges JR, eds. Memory disorders in neuropsyhiatri pratie. Cambridge: Cambridge University Press, 2000: Neary D, Snowdon JS. Sorting out the dementias. Prat Neurol 2002;2: Sampson EL, Warren JD, Rossor MN. Young onset dementia. Postgrad Med 2003;80: Kipps CM, Hodges JR. Cognitive assessment for liniians. J Neurol Neurosurg Psyhiatry 2005;76(suppl I):i Folstein MF, Folstein SE, MHugh PR. Mini mental state. A pratial method for grading the ognitive state of patients for the liniian. J Psyhiatr Res 1975;12: Mathuranath PS, Xuereb JH, Bak T, et al. Cortiobasal degeneration of frontotemporal dementia? A report of two ases and a review of the literature. J Neurol Neurosurg Psyhiatry 2000;68: Neary D, Snowden JS. Sorting out the dementias. Pratial Neurology 2002;2: