34.1 Introduction [link]
34.2 Clinical syndromes associated with specific areas of the cerebral cortex [link]
34.3 Subcortical syndromes [link]
34.4 Neuropsychological syndromes [link]
34.5 Wernicke–Korsakoff syndrome [link]
34.6 The Dementias [link]
34.6.1 Approaches to a differential diagnosis [link]
34.6.2 Alzheimer’s disease [link]
34.6.3 Dementia with Lewy bodies and Parkinson’s disease dementia [link]
34.6.4 Frontotemporal degenerations [link]
34.6.5 Prion diseases [link]
34.6.6 Vascular cognitive impairment [link]
34.6.7 Miscellaneous causes of dementia [link]
34.7 Acute confusional states and delirium [link]
34.8 Hallucinosis [link]
34.9 Psychiatric disorders in neurological practice [link]
34.10 Disorders of sexual behaviour [link]
34.11 Eating disorders [link]
34.1.1 General principles
The diseases which disrupt the cerebral cortex and its subcortical connections result in a wide variety of clinical features. These include the classical syndromes of higher cortical dysfunction such as the dysphasias, dyspraxias, amnesias, and agnosias together with a wide variety of behavioural and emotional disturbances. Such disorders frequently overlap with the clinical disciplines of clinical psychology and psychiatry. Historically there has been a broad split between those diseases which are seen by neurologists and those that are seen by psychiatrists. To some extent the distinction reflects the different clinical approaches employed; neurologists concentrate on the generality of disease caused by lesions in defined areas, whereas psychiatrists often deal with diseases that show a greater interaction with the individuals own personal history and place in society (Lishman 1987). In this chapter disturbances of higher cortical function, the dementias, and behavioural aspects of neurological lesions are discussed. Awareness of the occasional presentation of psychiatric disease to the neurologists is important and further details are available in textbooks of psychiatry. A review of clinical syndromes referable to identified areas of the cerebral cortex, is followed by a functional approach which discusses the main neuropsychological syndromes. The more generalized cognitive impairment seen with the dementias such as Alzheimer’s disease, dementia with Lewy bodies, and the frontotemporal lobar degenerations are then reviewed followed by areas of neuropsychiatric overlap.
34.1.2 Anatomy and physiology of the cerebral cortex
The human cerebral cortex consists of six laminae comprising in total some 28 × 109 neurones and approximately the same number of glial cells: from the external surface, these are the molecular layer, the external granular, the external pyramidal, the internal granular, the internal pyramidal, and the multiform or fusiform. The interconnection of the neurons comprises a staggering 1012 synapses. Despite this dramatic development, the basic structural organization of the cerebral cortex in modular terms is the same across species. The basis of the modular organization is the minicolumn representing some 80–100 neurons connected vertically and within each minicolumn are all of the major cortical neuronal types. Two broad categories of neuronal cell types can be distinguished, the large pyramidal cells which are the origin of the main outflow tracts and which utilize glutamate as the main neurotransmitter. The smaller non-pyramidal cells have predominantly local connections and primarily utilize the inhibitory amino acid gamma aminobutyric acid together with a variety of coexistent neuropeptides. There is an increasing sub-categorization of the small non-pyramidal cells and an increasing understanding of the intrinsic connectivity of these cells within the minicolumns. Cortical columns are minicolumns bound together by horizontal connections over a short range and which share physiological features based in part upon shared input and output characteristics. Layers 2 and 3 project to other cortical areas and layers 5 and 6 are primarily sub-cortical projections. Columns vary only from 300 to 600 microns in diameter across a very wide range of species. The expansion of the human brain is due to the increase of the total number of modular units rather than a difference in their size (Rakic 1995).
The organization of the cerebral cortex, in terms of the functional characteristics of the cortical columns, was established using single cell recording for the somatic sensory cortex by Mountcastle and the visual cortex by Hubel and Wiesel (Mountcastle 1997). The response characteristics of a somatic sensory column depend both upon modality and topography of the receptive fields. Similarly in the visual cortex, columns can be defined by various properties of increasing complexity from ocularity and place through to orientation. This modular organization in anatomical and functional terms accords with the general view from cognitive psychology of modular processing (Fodor 1983). As the modular processing becomes more complex, the defining characteristics of the cortical column become the inputs from other columns, the outputs of which represent a further level of cortical processing. This achieves greatest complexity in the association cortices or homotypical cortical areas.
There is regional specialization within the cerebral cortex which is reflected to some extent in architectonic differences, such as that originally identified by Brodmann (1909). However, particularly at the higher level of cortical processing, as represented by the association areas, cortical operations are also distributed. Evidence for distributed networks is provided both by functional brain imaging (Ramnani et al. 2004) and by anatomical evidence of enormous convergent and reciprocal connections, for example those between the parietal and frontal cortex (Goldman 1988).
34.2 Clinical syndromes associated with specific areas of the cerebral cortex
A number of clinical syndromes are recognized as characteristic of lesions in specific areas of the cerebral cortex. The syndromes largely, but not invariably, involve loss of function, although in some instances loss of inhibition may present as release phenomena. The descriptions of many of these clinical syndromes were derived from patients with discrete lesions due to ischaemic infarcts or tumours and formerly required follow-up to post mortem to determine the location. Modern neuroimaging has considerably improved the power of such studies.
It should be emphasized, however, that the observed associations are between clinical syndromes and brain areas and do not necessarily locate function to a specific brain region. Although a specific function may be lost following damage at a given site, the function itself is more likely to depend upon successful integration of a neural network. The particular area would be part of such a network and assumed to be of central importance.
In addition to the location of clinical syndromes to specific cortical areas, some syndromes may be better interpreted as representing disconnections of one area from another. The concept of disconnection syndromes was originally postulated by Dejerine and other early neurologists, and re-explored in considerable detail by Geschwind (1965). Some of the clinical syndromes arising from damage to the corpus callosum are most easily explained in terms of disconnection.
Functional imaging has contributed further to our knowledge of localization of function. Baseline measures of blood flow or cerebral glucose metabolism with positron emission tomography, PET scanning, can identify areas of reduced basal function when abnormalities on structural imaging may not be readily apparent. Activation studies can provide information on changes in cerebral blood flow, or deoxygenation of haemoglobin, and thus regions which are activated during a specific cognitive task relative to another. Such functional imaging studies have revealed that activation is often widely distributed, indicating that distributed networks are involved in such cognitive tasks. However, as with structure function relationships, caution has to be exercised in their interpretation. Whilst lesion studies show areas which may be necessary for a particular function, they can only localize deficits and it cannot be inferred that the specific function occurs in that area. They will show areas and structures that are necessary but not sufficient for that function. Similarly, activation may occur in areas that are not necessarily essential to a function. For example, activation studies of language may show areas of increased blood flow in the right hemisphere and yet lesion studies indicate that dysphasia rarely occurs with lesions in the same area.
The most widely used activation studies involve subtraction paradigms (Petersen et al. 1988). A baseline task is compared statistically with an activation task that engages the cognitive component of interest. When the baseline data are subtracted then areas that are activated are believed to relate directly to the particular cognitive component under study. More sophisticated models have been used to deal, for example, with language function where it may be difficult to identify an appropriate baseline task. In these paradigms, referred to as cognitive conjunctions, areas of common activation rather than areas of different activation are sought (Price and Friston 1997). Functional imaging has provided valuable insights into the distributive networks involved in many cognitive processes such as language (Gabrieli 1998; Price 1998). It does however remain a research tool and as yet has had limited impact on routine neurological management.
The frontal lobes lie rostral to the central sulcus and superior to the Sylvian fissure. It is in humans that the frontal lobes show the greatest development compared with other primates. Within the frontal lobes are the primary motor cortices located within the precentral area together with the supplementary motor areas and the frontal eye fields. The dominant frontal lobe encompasses Broca’s area and the adjacent area of the motor cortex is involved with the motor control of the oropharynx, lesions of which result in impairment of articulation and phonation. It is, however, the prefrontal cortex, Brodmann’s areas 9, 10, 11, 12 and 45, 46, and 47 which are particularly developed in humans and yet have a less clearly defined function.
The frontal cortex has widespread connections with other areas of the brain. The pyramidal cells of the motor cortex form the major fronto-striatal outflow tract. Similarly there are extensive projections from subcortical structures into the frontal cortex, notably the dopaminergic, noradrenergic, and cholinergic cortical projection systems.
Early studies with experimental frontal lobe lesions in non-human primates revealed impaired performance on a number of tasks which suggested perseverative responses and difficulty in switching between preferred modes of response. These difficulties with switching cognitive sets were explored further using the Wisconsin card-sorting test (Milner 1963). Patients tend to perseverate on these tasks and yet on other tasks such as cognitive estimates patients may be quite impulsive and unable to monitor their performance.
The combination of perseverative responses, lack of initiative, and impulsivity have been brought together in the hypothesis of a supervisory attentional system for the frontal lobes (Norman and Shallice 1980). In this model the frontal lobes have an important role in both selecting appropriate behavioural responses and inhibiting inappropriate ones. This can explain the paradoxical combination of both aspontaneity and lethargy together with impulsivity even within the same patient. Breakdown in such a system results in markedly impaired social behaviour and adaptability, and yet formal testing on intelligence may often be spared (Shallice 1982). One of the most distinctive features of the frontal lobe syndrome is a change in personality, most commonly towards disinhibition. The effect upon personality of massive bifrontal lesions was well demonstrated by the celebrated case of Phineas Gage who in 1848 had a crowbar driven through the front of his skull. He was described as ‘fitful, irreverent, indulging at times in the greatest profanity…. manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillatory’. The disinhibited behaviour may result in childish excitement, ‘moria’, or joking and pathological punning, ‘Witzelsucht’; there may in addition be sexual indiscretions and exhibitionism. Alternatively, the syndrome may present with lack of initiative and profound psychomotor slowing with inability to persist with a task, abulia. This may be accompanied, particularly with bifrontal lesions, by urinary incontinence which can occasionally be seen with unilateral lesions. This incontinence is commonly associated with lack of concern and social awareness which is a useful clinical clue since this type of incontinence is rarely found with generalized dementing conditions such as Alzheimer’s disease until late in the disease.
The behavioural disturbance can be striking and precede changes on formal tests of frontal lobe function by many years. A distinction has been drawn between dorsolateral frontal lesions which may be associated with cognitive decline and apathy and with orbitomedial with prominent behavioural change (Devinsky et al. 1995; Blair and Cipolotti 2000). Often the changes in behaviour are most apparent to the spouse who may feel that they are married to somebody entirely different. Some of the behavioural features in frontal lobe lesions resemble the impairment of social interactions found in autistic spectrum disorder (Section 9.6.4).
Clinical examination may be less revealing than the history and often patients perform relatively well on formal tests of intelligence. Specific tasks, however, such as the Wisconsin card-sorting test, the Weigl sorting test, cognitive estimates, verbal fluency, and bimanual motor tasks will show impairment but even this may be patchy and inconsistent. The patient’s appearance, however, may be clearly abnormal, appearing unkempt, unwashed, and lacking all spontaneity. Neurological examination may reveal primitive reflexes such as the rooting reflexes, both tactile and oral, and sucking reflexes if severe. Grasp reflexes are easily elicited by running the hand across the palm and may be elicited from the foot (Seyffarth and Denny-Brown 1948). The grasp reflex and instinctive grasp reaction can be seen as part of a more generalized magnetic behaviour, elicited as utilization behaviour (Lhermitte 1983; Shallice et al. 1989). This is a striking example of environmental dependency in which presentation of an object will elicit a behavioural response regardless of whether or not it is appropriate. Patients offered spectacles, for example, may place them on their nose followed by further pairs, until three or four are stacked upon one another, the inappropriateness of this completely eluding the patient.
As lesions extend more posteriorly in the dominant frontal lobe there may be an associated non-fluent anterior dysphasia and impairment of speech production. Lesions in relation to the orbital surface may result in unilateral visual failure and anosmia. The latter will rarely be found unless specifically sought and is a characteristic feature of olfactory groove meningiomata (Fig. 34.1). Prominent changes in tone may be found on examination which increases in response to the stimulus, so-called paratonia or Gegenhalten. More posteriorly placed lesions may result in mild pyramidal signs but most striking are bifrontal medial lesions causing prominent gait impairment with truncal instability, often referred to as gait apraxia (Meyer and Barron 1960). With the availability of CT and MR scanning, frontal lobe tumours are far more readily diagnosed. However, with the gradual onset of personality changes, many cases are still missed until late. In general, prominent frontal lobe syndromes are seen more commonly with tumours and degenerative disease than with vascular disease (Bogousslavsky 1994), with the exception of anterior cerebral artery infarcts which commonly result in abulia (Kumral et al. 2002).
34.2.2 The temporal lobes
The Sylvian fissure separates the temporal lobe from the frontal lobe and rostral part of the parietal lobe. There is, however, no clear boundary between the posterior temporal lobe and the parietal and occipital lobes. The temporal lobes have easily discernible gyri, the superior, middle, and inferior temporal gyri, and also the parahippocampal and hippocampal convolutions. The hippocampus demonstrates a three-layered cortical structure in contrast to the six-layered neocortex. Heschl’s gyrus in the Sylvian fissure represents the primary auditory receptive area and fibres terminating here do so in a tonotopic arrangement. Deep within the temporal lobe is the amygdala.
Discrete lesions of the anterior temporal poles may be clinically silent and in general, lesions of the non-dominant temporal lobe are less obvious clinically; sometimes the only clue on neurological examination being a superior quadrantic visual field defect or behavioural change. However, bitemporal lesions and those of the dominant temporal lobe may result in profound functional impairments. The predominant lesion of the dominant temporal lobe is that of a language impairment, classically a Wernicke’s aphasia (Section 34.4.4) or rarely a pure word deafness or auditory verbal agnosia.
Unilateral lesions of the dominant temporal lobe can be shown to result in impairment of memory for verbal material by contrast to impaired visual memory with non-dominant lesions (Milner 1971). Unilateral lesions of Heschl’s gyrus rarely result in deafness but careful testing with binaural testing reveals subtle abnormalities in the area contralateral to the lesions. The inability to recognize faces, prosopagnosia, is usually seen with bilateral lesions but well described with unilateral non-dominant temporoparietal lesions (Warrington and James 1967). Patients with prosopagnosia may have a variety of deficits ranging from an inability to recognize the face through to loss of familiarity and inability to match faces. This can sometimes be so severe that patients may be incapable of recognizing members of their own family but can immediately do so on hearing their voice.
Vary rarely lesions of the temporal lobe can result in a true auditory agnosia. Simple perception of sound and pure tone is intact but the interpretation of complex sounds is severely impaired. In pure auditory agnosia recognition of all noises, the sound of a bell, dogs barking, running water is lost (Hecaen 1962). More common is the loss of appreciation of music, or amusia seen with right temporal lobe lesions. The patient’s appreciation of melody, timbre, and rhythm all tend to be impaired and they may also have difficulty in musical recognition (Stewart et al. 2006).
Bilateral temporal lobe lesions are far more devastating. These cases are rare and occur after herpes encephalitis or in the later stages of frontotemporal degeneration (Section 34.6.4). They are normally associated with a dysphasia but in addition profound memory impairments (Section 34.4.7) (Milner 1958; Milner et al. 1968). Bilateral removal of the temporal lobes in the monkey produces a striking behavioural state referred to as the Kluver–Bucy syndrome. The monkeys show increased exploratory behaviour in which they will examine objects by oral and manual manipulation with apparent inability to recognize them visually. They are usually placid but with hypersexuality. Similar behaviours in humans have been described with herpes encephalitis and with frontotemporal degenerations (Cummings and Duchen 1981; Lilly et al. 1983). The frontotemporal degenerations encompass a variety of neuropathologies, including Pick’s disease. They are often associated with obsessional behaviour, change in eating habits, hypereligiosity, and both hypo and hypersexuality. Reduced empathy and diminished emotional responses are characteristic. Some of these features may reflect involvement of the amygdala (Section 34.6.4). The rare lipoid proteinosis Urbach–Wiethe disease can result in progressive bilateral degeneration of the amygdalae. Studies in such patients reveal that the appreciation of fear can be particularly impaired but patients do develop deficits in both negative and positive emotional processing (Siebert et al. 2003)
A variety of episodic symptoms may be found with temporal lobe lesions which are usually on an epileptic basis and range from auditory hallucinations to disruption of time perception and disturbances of sexual behaviour. In addition, however, chronic bilateral lesions, particularly those of the medial temporal lobes may cause profound disintegration of personality and behaviour. In its extreme form patients react to any stimulus by excessive rage with screaming, biting, and spitting. This distressing clinical picture is seen most commonly in survivors of herpes encephalitis.
34.2.3 The parietal lobes
The parietal lobes lie behind the central sulcus and above the Sylvian fissure but the posterior boundaries with the occipital and temporal lobes are not clearly defined. Immediately behind the central sulcus is the primary sensory cortex which is delineated posteriorly by the post central sulcus. The superior temporal sulcus curves upwards posteriorly into the inferior parietal lobule in relation to the angular gyrus. This is adjacent to the posterior extremity of the Sylvian fissure, which also curves up into the inferior parietal lobule in relation to the supramarginal gyrus. The parietal lobes are well developed in man and continue to develop until about the seventh year of life. There are extensive connections with other association areas.
Lesions within the parietal lobes can present with an enormous variety of disturbances of higher cortical function, some of which are quite dramatic in their presentation. Dominant parietal lobe lesions are often associated with dysphasia. This may be predominantly a motor or sensory dysphasia depending upon the anteroposterior location. Inferior parietal lesions are associated with deficits of verbal short-term memory as assessed by digit span. More posterior lesions are associated with dyslexia, dysgraphia, and dyscalculia, and ideational apraxia is a consistent feature of dominant parietal lobe lesions. Gerstmann’s syndrome refers to the association of finger agnosia, dyscalculia, right left disorientation, and agraphia. Although this is commonly seen with lesions of the dominant angular gyrus (Gerstmann 1940), this particular clustering of deficits is no more common than other patterns. Lesions of either parietal lobe may result in visuospatial disturbance. The integration of visual information with spatial information in the posterior parietal lobe can give rise to visuomotor or optic ataxia (Rondot et al. 1977), in which patients have difficulty touching an object under visual guidance. This forms a major component of Balint’s syndrome (Hecaen and Ajuriaguerra 1954), in which patients also have an inability to direct gaze into the peripheral field despite full eye movements. Both parietal lobes are involved with selective attention (Mesulam 1981). Patients with non-dominant parietal lesions have marked impairment of selective attention which will affect both right- and left-sided space but most commonly left-sided space. This may be so severe that they will ignore the left side of the body resulting in problems in dressing and in shaving only one-half of their face. If this is associated with a left hemiplegia they may be unaware of the deficit, anosognosia, and indeed deny that the paralysed limb has anything to do with them.
On examination, patients with parietal lobe lesions may show the obvious neglect of the left side with an arm hung loosely at the side or out of the sleeve of their jacket with the left face unshaven and associated pyramidal signs. Field defects are most commonly inferior quadrantanopias. Gaze impersistence, an inability to sustain lateral gaze on testing eye movements, is seen quite commonly and can be frustrating for the examiner. Cortical sensory loss may be found in the contralateral limbs and is most readily picked up by testing two-point discrimination, which is impaired together with astereognosis, that is inability to recognize objects by their shape, or alternatively inability to recognize figures written on the hand, agraphesthesia. Neglect can be unmasked by simultaneous tactile or visual stimuli, when the patient may only recognize one of the two simultaneously presented stimuli, ignoring that contralateral to the lesion. The sensory testing may be difficult with patients showing considerable variability and being easily fatigued (Critchley 1953). Simple bedside tests of visuospatial function which can be helpful include drawing a cube or clock face, when patients will often ignore features to the left hand side. So-called dressing apraxia can be assessed by watching the patient put on clothing and the task made more difficult by inverting one sleeve.
34.2.4 The occipital lobes
The occipital lobes are separated on the medial surface from the parietal lobes by the parieto-occipital fissure but there are no clearly defined margins between the parietal and temporal lobes on the lateral surface. The occipital lobes subsume the termination of the visual pathways, and the primary visual cortex, Brodmann area 17, lies on either side of the calcarine fissure which runs from the occipital pole to the splenium of the corpus callosum. It has the histological characteristic that its fourth layer is divided into two granular cell layers by a thickened band of heavily myelinated fibres, the external band of Baillarger. This band is visible to the naked eye, hence the name of striate cortex. The classical findings with lesions of the occipital cortex are homonymous visual field defects; a homonymous hemianopia when confined to one occipital lobe. Bilateral lesions may cause altitudinal defects, since the termination of the optic radiation is topographically arranged with lower retinal fibres terminating in the cortex below the calcarine fissure. Superior quadrantic defects are found with inferior lesions and vice versa.
With extensive bilateral lesions a variety of abnormalities are found ranging from complete cortical blindness, through to subtle visual disturbances. With complete cortical blindness the pupillary responses are preserved as is visual imagery in dreams, but cortical evoked responses and the alpha rhythm on the EEG are both lost. Strikingly, patients with complete cortical blindness may develop a visual anosognosia, Anton’s syndrome, with denial of their loss of sight. These patients may walk around as if they can see but will bump into objects and often explain their difficulties by complaining about the light or their loss of glasses. With partial recovery from cortical blindness or with lesions involving the visual association areas there may be a variety of disturbances of higher visual processing. These may fractionate into distinct syndromes such as visual disorientation in which the ability to locate objects within the visual field is considerably impaired and patients may be effectively blind. Other syndromes involve selective loss of colour, achromatopsia, and very rarely impairment of movement perception (Zihl et al. 1983; Shipp et al. 1994). Rarely patients may develop genuine visual object agnosia if the lesion involves the occipitotemporal areas. These patients are unable to recognize objects by sight but can do so on palpation or by sound. The lesions are usually bilateral but may be found with dominant lesions. These syndromes of visual disorientation and visual agnosia reflect the dorsal ‘where’ and ventral ‘what’ processing streams respectively. The dorsal stream links visual information with spatial information in the parietal lobe. The ventral stream links the visual information with semantic stores in the temporal lobe.
Patients may complain of a variety of visual hallucinations and illusions, more commonly with bilateral or non-dominant lesions. Many of these are associated with epileptic phenomena, such as elementary unformed hallucinations and flashes of light, colours or geometric forms. They may be seen within the setting of a hemianopic disturbance. Striking visual illusions may occur with metamorphopsias and marked changes in shape. In addition polyopia, or multiple images, may be seen or the striking disturbance of palinopsia in which perserveration of visual images occurs and colour may spread outside the geometric confines of the object.
34.3 Subcortical syndromes
Although the cerebral cortex is viewed as the main seat of cognitive behaviour, it is becoming increasingly recognized that damage to subcortical structures can give rise to profound behavioural and cognitive disturbance. In many instances, these may mimic deficits arising from lesions within the cerebral cortex, for example the dysphasia and dyspraxia which may be seen with dominant thalamic lesions (Graff et al. 1984). These may share characteristics with cortical lesions by virtue of the extensive neural interconnections; an interpretation supported by observed changes in metabolism within connected areas of the cerebral cortex demonstrated on single photon emission tomography scanning subsequent to subcortical infarcts (Perani et al. 1987). Many of the behavioural disturbances are discussed elsewhere, but some structures are particularly notable. The importance of the amygdalae in behaviour has already been referred to and rare instances of a Kluver–Bucy syndrome have been described (Cummings and Duchen 1981). In addition, bilateral damage to the amygdalae can result in disturbance of memory as well as disturbed social behaviour (Tranel and Hyman 1990) and impaired emotional facial recognition (Adolphs et al. 1999); the latter may contribute to some of the social behavioural disturbances in frontotemporal degeneration (Lavenu et al. 1999).
Disease of the basal ganglia can give rise to prominent cognitive and behavioural dysfunction, most commonly observed with massive destructions following haemorrhage, infarcts, or intoxications. Bilateral thalamic infarcts are dominated by disturbances of attention, but fluctuating aphasia is characteristic of left-sided lesions, whereas right thalamic infarcts can result in the ‘left neglect’ syndromes which mimic non-dominant parietal lesions (Castaigne et al. 1981; Graff et al. 1984). Thalamic haemorrhages tend to be more dramatic in their presentation and usually cause a relatively fluent aphasia with marked fluctuation and superimposed hypophonia (Luria 1977). Caudate lesions are more commonly associated with behavioural disturbances, usually abulia, than with motor syndromes (Bhatia and Marsden 1994). A syndrome of dysphasia with dysarthria and orofacial dyspraxia can occur with dominant head of caudate infarcts (Naeser et al. 1982), and dysphasic syndromes can also occur with lesions of the adjacent white matter or internal capsule (Damasio et al. 1982). Apraxia is very rare with lesions confined to basal ganglia but can be seen more commonly with lesions of the thalamus (Pramstaller and Marsden 1996). Bilateral lesions of the basal ganglia can result in profound behavioural disturbance. Marked apathy, similar to a frontal lobe syndrome, can occur with bilateral lesions of the globus pallidus, so-called pure psychic akinesia (Laplane et al. 1984). Bilateral infarction of the head of caudate has resulted in severely aggressive and criminal behaviour (Richfield et al. 1987). Occlusions of the basilar artery at the bifurcation, the so-called ‘top of the basilar’ syndrome, result in complex disorders of eye movement with convergent spasm, retraction nystagmus, and skew deviation. It is commonly accompanied by memory disturbance, an agitated confusional state with prominent visual hallucinations, so-called peduncular hallucinosis (Caplan 1980).
In addition, isolated brainstem lesions can result in cognitive impairment predominantly executive with sparing of posterior cortical function and memory, presumed to be due to involvement of ascending forebrain projections (Garrard et al. 2002). A dysexecutive syndrome can also be seen with cerebellar lesions and include visuospatial and memory deficits—the cerebellar cognitive affective syndrome. More posterior lobar and vermal lesions are reported to have more prominent behavioural changes with blunting of affect or disinhibition (Schmahmann and Sherman 1998)
34.4 Neuropsychological syndromes
In the preceding section clusters of neuropsychological deficits which are characteristic of damage to particular areas of cerebral cortex were described. Often relatively pure deficits may present to neurologists and more detailed understanding of the precise nature of the functional impairment, over and above the localizing significance, can be helpful in diagnosis and management.
34.4.1 Disorders of perception and the agnosias
Lissauer introduced the terms apperceptive and associative ‘mind blindness’ to distinguish between patients whose abilities to perceive and discriminate an object are impaired and those patients who are unable to recognize the object having correctly perceived it. Subsequently Freud introduced the term agnosia which subsequently replaced the term ‘mind blindness’.
Visual agnosias have been most widely studied and Lissauer’s original analysis has subsequently been proved useful in the analysis of neurological patients. In order to perceive an object a number of features must be analysed and processed such as shape, colour, location within space and movement; these may each be selectively damaged. Shape discrimination can be assessed by asking the patient to discriminate between rectangles and squares of increasing similarity (Efron 1968). Preservation of shape and location but with loss of colour, or achromatopsia, is rare (Zeki 1990) and is usually seen with bilateral damage to the fusiform and lingual gyri. There is commonly an associated superior altitudinal field defect (Meadows 1974a). Impairment of visual location, visual disorientation (Holmes 1918), can cause great impairment and render the patient functionally blind. Finally patients have very rarely been described with inability to detect movement indicating a further dimension of early visual processing (Zihl et al. 1983).
These abnormalities of early visual processing are most commonly seen with bilateral occipital and occipito-parietal lesions but can be seen with unilateral lesions in which case the deficit is found in the contralateral field of vision. In these instances the functional impairment may be less prominent and patients less likely to present with a specific history. These disorders of visual processing are usually due to ischaemic lesions, but visual disorientation can be found in degenerative lesions of the occipital and parietal cortex, sometimes referred to as posterior cortical atrophy, which can be a presenting feature of Alzheimer’s disease (Benson et al. 1988).
In apperceptive agnosia there is impairment of the generation of a structured percept of an object despite adequate initial processing of shape, colour, and location. This impairment can be demonstrated in patients who have difficulty coping with perceptually difficult visual stimuli, such as incomplete line drawings, overlapping line drawings (De et al. 1969), fragmented letters, and unusual views (Warrington and Taylor 1973). Unlike the retinotopic organization of early visual processing, the entire visual field is involved in patients with apperceptive agnosia, and the minimal lesion is usually found in the posterior non-dominant parietal lobe.
Associative visual agnosia is very rare (Hecaen and Angelergues 1963). Patients can describe an object well and copy drawings of it precisely but it has no meaning for them. They are, however, able to recognize the object immediately through other sensory channels. Patients with visual agnosia usually have bilateral lesions but these can occur with unilateral left posterior parietal lesions. Classically, visual agnosia has been interpreted as a disconnection of the percept from a central meaning system but an alternative interpretation is the existence of modality-specific meaning systems and visual agnosia would thus be seen as a loss of the specific meaning system associated with the visual domain i.e. a visual semantic memory impairment (McCarthy and Warrington 1990).
Within the overall category of visual agnosias some defects have been singled out for particular consideration because they present as striking clinical deficits, examples include the inability to recognize colour, colour agnosia, and inability to recognize faces, prosopagnosia. Colour agnosia (Hecaen and Albert 1978), implies intact colour perception and semantic knowledge of colour, but the majority of cases appear to have an associated impairment of colour naming. Faces present a perceptually difficult visual task and clearly problems in visual processing and perception will result in difficulty in face recognition. However, some patients present with a relatively selective impairment of facial recognition, prosopagnosia. Such cases can present a striking clinical picture in that patients may be unable to recognize those very close to them but can immediately do so when they hear them speak or by looking for other clues in their dress or mannerisms. Prosopagnosia is usually associated with right occipito-temporal lesions and commonly associated with a left homonymous superior quadrantanopia (Meadows 1974b). Prosopagnosia can be analysed in a similar way to object recognition, employing tests to assess perceptual analysis such as matching pictures of faces and matching facial expressions. Some patients may have normal performance on face matching tasks but be quite unable to recognize familiar faces (De 1986). Others may show intact face matching but be unable to match facial expression (Etcoff 1984). These theoretical aspects of prosopagnosia have generated a number of information processing models of face recognition (Bruce and Young 1986).
Agnosias in other sensory domains have been far less well studied and have a less secure theoretical basis. Following Lissauers original terminology these have also been divided into apperceptive and associative agnosias (Vignolo 1982). Cortical deafness can occur with bilateral temporal lesions which result in deficits of discrimination, temporal sequencing and spatial localization of sound. Pure word deafness as an isolated agnosia for speech sounds (Goldstein 1974) usually overlaps with Wernicke’s aphasia. Auditory agnosia is extremely rare and refers to patients with intact hearing and intact language comprehension but who are unable to recognize meaningful non-verbal sounds. Amusia, an inability to produce and/or appreciate music, is seen most commonly with non-dominant hemisphere lesions (Brust 1980), although the reading and writing of music notation may be seen with left hemisphere lesions.
Tactile agnosia is even less secure as a distinct syndrome. Patients with parietal lesions will often have difficulty with the appreciation of size, texture, and shape of objects held in the hand, and astereognosis, which is more strictly referred to as stereoanasthesia or stereohypoasthesia. These patients will have impairment of two-point discrimination and sometimes subtle proprioceptive changes. Strictly speaking astereognosis should exist when shape and discrimination is intact as evidenced by the patients’ description, but recognition impaired. Astereognosis, however, may occur as a disconnection syndrome in patients with callosal lesions (Geschwind and Kaplan 1962). In such patients objects can be recognized in the right hand but not in the left, they can, however, be correctly identified from a visual array. This is interpreted as disconnection of the sensory information from the right parietal cortex reaching the left hemisphere language area. Although rarely diagnosed, patients are also reported with olfactory and gustatory agnosias.
34.4.2 Disorders of spatial awareness and the body image
We are aware of the existence of our bodies, their position in space, and the relation of their parts to one another because we receive data through numerous sensory channels; these include vision, cutaneous sensibility, and proprioceptive information from the muscles, joints, and labyrinths. The somatic impulses pass via the ventral nucleus of the thalamus to the supramarginal gyrus which is thus concerned with awareness of the opposite side of the body. This concept of the body in consciousness is known as the body-image or body-schema.
Symptoms of disorders of the body-image may be positive or negative. The chief positive symptom is the phantom, an illusion of the persistence of a part of the body lost by amputation such as a phantom limb, or an illusory awareness of a part from which sensation has been lost through interruption of afferent pathways. Phantom limbs after amputation may be painless or painful (Riddoch 1941). The painless phantom soon becomes less obtrusive, and gradually shortens eventually to disappear. Painful phantoms may persist indefinitely and cause much distress.
Impairment of spatial sense together with neglect is most commonly seen following right parietal lesions and can present a dramatic clinical picture. Such patients frequently manifest spatial disorientation both for external space and for the body-image. These patients often have an associated left hemiparesis, again indicating a relationship with the non-dominant parietal lobe (Benson et al. 1976). Patients with right hemisphere lesions exhibit neglect that is most obvious to the left side of the body and left space and these patients may not shave the left side of their face, may eat food only on the right side of the dinner plate, and may demonstrate neglect dyslexia. Most striking is inattention to left-sided deficits, such as left hemiparesis, so called anosognosia (Babinski 1914). In a less severe degree, patients may recognize their left hemiparesis but are unconcerned, a complication which can make rehabilitation extremely difficult (Denes et al. 1982).
There are two main theories of spatial neglect in association with lesions of the non-dominant parietal lobe. In the one it is proposed that there is a central representation of space which is damaged; in the other it is proposed that there is a defect of selective attention, a function for which the right hemisphere is dominant. The widely quoted evidence for the former is the report of two patients who were asked to imagine and describe a plaza in Milan, first when facing the cathedral and then from the perspective of the cathedral itself. The patients’ descriptions ignored the left side on both occasions but resulted in a complete description when both imagined pictures were combined (Bisiach and Luzzati 1978).
Apraxia may be defined as the inability to carry out a purposive movement, the nature of which the patient understands, in the absence of severe motor weakness or paralysis, sensory loss or ataxia. For example, a patient who is asked to protrude his tongue is unable to do so on request, though he may carry out inappropriate movements such as opening his mouth; yet a moment later he spontaneously protrudes his tongue to lick his lips. Apraxia may involve any movement which is normally initiated voluntarily; movements of the eyes, face, muscles of articulation, chewing and swallowing, manipulation of objects, gestures with the upper limb, walking or sitting down. Apraxia is seen most commonly with left hemisphere lesions and is then found in association with dysphasia.
The terminology of apraxia is particularly confusing since it includes a number of conditions that are not genuinely apraxic and additionally employs terms which are derived from the theoretical framework developed by Liepmann at the turn of the century. He defined three types of apraxia, namely limb kinetic, ideomotor, and ideational. These were based upon a theoretical neuroanatomical model similar to those which have been developed for speech. Limb-kinetic apraxia represents a loss of dexterity particularly of hand movements and affecting all classes of movement. This can be the most difficult to identify in the presence of basal ganglia and pyramidal dysfunction (see Leiguarda and Marsden 2000; Zadikoff and Lang 2005). Ideomotor dyspraxia refers to the poor performance of a motor act in response to a verbal command; the patients know what to do but not how to achieve it. It has been interpreted in terms of disconnection although the most secure disconnection model for ideomotor dyspraxia is seen in patients with lesions of the anterior corpus callosum who have difficulty with performing tasks to command using the left hand, i.e. the ‘praxis centre’ in the left hemisphere is disconnected from the right motor cortex which controls the left hand (Geschwind 1965). This is sometimes referred to as callosal apraxia and is commonly seen with anterior cerebral artery infarcts.
Ideational apraxia was defined by Liepmann as an inability to perform a sequential motor act, even though each could be carried out separately. However, this is relatively non-specific and may be a feature of frontal lobe lesions reflecting a difficulty of programming rather than of dyspraxia. Ideational apraxia has been defined as an impairment in manipulation of actual objects (De Renzi et al. 1968). Subsequently, it was postulated that these patients have an agnosia for tool usage (De Renzi and Lucchelli 1988) and in this context is associated with lesions of the posterior dominant parietal lobe. Patients with clinically obvious apraxia are relatively rare but severely disabled. They have considerable difficulty with using a knife and fork and many other common tasks which require manual dexterity and they will often look at their hands in a bemused way. By contrast, patients who demonstrate ideomotor dyspraxia at the bedside may not be functionally disabled, representing merely a feature of a specific neurological examination. Assessment at the bedside includes dexterity, pantomime of transitive such as ‘show me how to use a screwdriver’, and intransitive such as ‘show me how to wave goodbye’ movements, use of real objects, sequence of movements, and copying hand postures; the latter exploring visuospatial motor encoding.
In addition to the syndromes described above, which relate to manual dexterity, other body part dyspraxias have been described. A dissociation between limb apraxia and an axial dyspraxia, demonstrated by difficulty with adopting truncal postures such as a boxer’s stance, has been described. Patients with gait apraxia show severe impairment of walking and often of standing with additional truncal instability (Meyer and Barron 1960). Orofacial dyspraxia is found with dominant frontal lesions and often associated with a cortical dysarthria (Nathan 1947); such patients show a characteristic inability to make oral movements to command but with sparing of eye movements. When asked to cough they will frequently repeat the word ‘cough’, they will be observed however to carry out such motor acts spontaneously. This may be seen on a degenerative basis (Tyrrell et al. 1991).
Dressing apraxia and constructional apraxia reflect the difficulties with spatial encoding rather than motor programming and illustrate some of the confusion of terminology. Dressing apraxia is associated with non-dominant parietal lobe lesions and is normally seen in a context of spatial impairment and left-sided neglect. Constructional apraxia (Kleist 1922) refers to a disorder of the spatial disposition of an action and is illustrated at the bedside by inability to copy a cube or to make a simple arrangement of matches. This was originally identified as a disconnection syndrome between spatial analysis and voluntary action. This remains to be proven and apparent constructional apraxia may be due to more than one defect. Patients with left hemisphere lesions may make dyspraxic errors and commonly they will retain the spatial organization but simplify a diagram, whereas those with right hemisphere lesions show impairment of the spatial organization and will often neglect the left side (Arrigoni and De Renzi 1964; Warrington et al. 1966).
Since so much of the complexity of human behaviour depends upon language, impairment in this domain often presents early and with striking features. Historically the language disorders were also the first to be associated with precise focal brain lesions. The terms dysphasia and aphasia are often used interchangeably. American usage favours dysphasia for developmental or congenital language disorders, reserving aphasia for the acquired disorders of language. In Europe dysphasia has been applied in the strict sense of a partial acquired language disorder with aphasia referring to complete absence of language. This, however, is rarely adhered to strictly.
Aphasias are disturbances of language and not simply motor speech dysfunctions, thus a patient with aphasia will also have impairment of other aspects of language such as writing. The term aphemia is often used for patients with impaired speech but with intact writing. Dysarthrias refer to impaired speech sound production and dysphonia to local disturbances of the larynx and pharynx. Different terms have been used to describe the clinical spectrum of language disturbance. Many of these arose out of the early descriptions of neurologists which were based on a variety of theoretical constructs, for example conduction, transcortical motor and transcortical sensory aphasias were terms introduced to describe syndromes based upon theoretical models of language developed by Wernicke and Lichtheim. These models implied precise localization of function with fibre tracts connecting them. These were assumed to have an anatomical basis. Subsequently considerable advances were made in analysing individual components of speech comprehension and production using information- processing models. The theoretical models and diagrams in these instances relate to individual components of the process without implying any anatomical correlates. However, in some instances the information processing models can be correlated with the earlier theoretical and neurological models (Shallice 1981a). With improved techniques of neuro-imaging and particularly the opportunities of functional neuroimaging with activation paradigms on positron emission tomography scanning, considerable advances in the anatomical correlates of the individual processes in language can be anticipated.
A broad distinction between fluent and non fluent aphasias is followed here as this can provide a useful starting point for the clinician (Goodglass et al. 1964; Benson 1967) and within this framework the broad distinction between disturbances of production and comprehension are considered. Disturbances of reading, the dyslexias; of writing, the dysgraphias; and of calculation, the dyscalculias, are often associated but are considered separately.
Many of the clinical language syndromes can be identified by simple bedside testing although detailed neuropsychological assessment is required both for quantitation and careful dissection of the individual components of language failure. Examination should include careful observation of the patient’s spontaneous speech which can be assisted by the use of picture description. The fluency should be noted and the occurrence of paraphasias documented. These may be phonemic paraphasias in which one or two of the syllables of the word are mistaken or substituted, for example ‘stable’ for ‘table’, a pattern more commonly found with anteriorlesions. By contrast semantic paraphasias, the substitution of semantically similar words, for example ‘chair’ for ‘table’, are found more commonly with posterior lesions. Comprehension can be tested at the single word and at the sentence level and there are a variety of neuropsychological tests available for this such as the Peabody test. For bedside testing, word comprehension can be assessed by giving the patient verbal instructions but care has to be exercised both in patients in whom intellect may be impaired and in patients with dyspraxia, if the task is motor dependent. Individual word comprehension can be tested by verbal definition and confrontational naming, which can also assess word retrieval. Repetition can provide evidence of dissociations between errors in spontaneous speech and repetition, and serves to distinguish the clinical syndromes of conduction aphasias and the transcortical aphasias. Finally both reading and writing should be assessed.
Aphasias are most commonly encountered in the setting of strokes and neoplasms producing focal lesions, and patients will often have associated neurological signs such as hemiparesis or visual field defects. More difficult to assess are patients with aphasia as part of a more generalized cognitive impairment, such as occurs with degenerative dementias. In addition patients with psychosis or with acute confusional states can create problems, although the language process itself is preserved if carefully observed. Thus paraphasic errors are rare in the psychosis although the rare schizophrenic ‘word salad’ can create diagnostic difficulty. However other evidence of disturbed behaviour is apparent, whereas the patient with jargon aphasia as part of a Wernicke’s dysphasia is seen to behave normally in the realm of non-language behaviour. The mute patient presents a particular diagnostic challenge. Patients may be mute because of a severe dysphasia, but more commonly are anarthric in which case writing will be preserved. Alternatively mutism may be associated with disturbances in attention such as occurs with frontal and subfrontal disease and may be seen in akinetic mutism.
Clearly any assessment of a patient requires knowledge of handedness. The vast majority of people have language represented in the left hemisphere. Very rarely, less than 1 per cent of right-handed individuals may develop aphasia with right hemisphere lesions, termed crossed aphasia in dextrals (Zangwill 1979). In approximately half of patients who are left-handed language also resides in the left hemisphere.
Non-fluent and Broca’s aphasia
In 1861 Broca described the case of Monsieur Leborgne who had sustained a stroke with damage to the left inferior frontal gyrus and underlying white matter. The patient was initially mute and was then left with a severe non-fluent aphasia. Broca’s original terminology for this, aphemia, has subsequently been confined to patients with impairment of speech but preservation of writing, usually with lesions of the dominant inferior motor cortex. The term aphasia, introduced by Trousseau, supplanted the term aphemia (Schiff et al. 1983). The striking feature of Broca’s aphasia is that the speech is non-fluent being both slow and reduced in output and patients are often mute initially. The content of the speech may be impaired with frequent phonemic errors and is usually agrammatic with the omission of prepositions, adjectives, and adverbs. Repetition and confrontation naming are normally impaired although the patients are often helped by cueing. Writing is faulty both in morphology and in terms of spelling and grammar.
One of the clinically distinguishing features of Broca’s aphasia is that the impairment is largely confined to language expression with relative preservation of comprehension. Indeed auditory comprehension of individual words is very well preserved, although performance on tests used to explore sentence comprehension is usually impaired (Goodglass and Kaplan 1972); similar subtle impairment of comprehension can be found in reading.
The traditional Broca’s area, established in the original cases, is the posterior part of the inferior frontal gyrus. An associated ideomotor apraxia of the non-dominant hand may be found depending upon the extent of subcortical damage. Some patients will show quite striking dysarthria and associated orofacial dyspraxia.
Two distinct clinical patterns of Broca’s aphasia have been described (Mohr et al. 1978), depending on the size of the lesion. Lesions confined to Broca’s area and subcortical white matter, are usually due to embolic strokes in the anterior branches of the left middle cerebral artery, and are associated with rapid recovery of expressive speech. Patients with occlusions of the middle cerebral artery, sparing the territory of the inferior division which supplies the temporal lobe, or patients with occlusion of the internal carotid, have a more widespread lesion which renders them globally aphasic initially, and often unable to comprehend, together with a dense hemiparesis. However, over the subsequent months of recovery, comprehension improves and a residual Broca’s aphasia remains.
The majority of patients with Broca’s aphasia have suffered strokes, but the syndrome may also be found with tumours, although in a less pure form. Some cases of selective left hemisphere degeneration may also present with a non-fluent speech, as in primary progressive aphasia (Mesulam 1982), and some patients with degeneration of the frontal lobe, such as occurs in Pick’s disease, may develop a striking orofacial dyspraxia with speech impairment (Tyrrell et al. 1991).
Lichtheim had originally proposed a model of cortical concept centres for words which were connected with the motor centre or word sound centre by transcortical pathways. Theoretical syndromes based on this model and involving disconnections between the centres were postulated for conduction, transcortical motor and transcortical sensory aphasias. In transcortical motor aphasia patients make frequent errors of speech production with a very low output and frequent phonemic paraphasias. Repetition is, however, intact. Transcortical motor aphasia is seen most commonly with anterior cerebral artery lesions with an associated ideomotor apraxia of the left hand and a right hemiparesis affecting the leg more than the arm.
By contrast with transcortical motor aphasia patients with conduction aphasia have a profound impairment of repetition with frequent phonemic paraphasias. This was explained as a disconnection between intact comprehension and intact motor centres which would allow for relatively normal spontaneous speech. Anatomically, this was attributed to lesions of the arcuate fasciculus which indeed are often associated with conduction aphasias.
Speech production requires the correct selection and ordering of phonemes, impairment of which gives rise to the characteristic phonemic errors seen with a conduction aphasia. A pattern of deficit has also been recognized due to impairment of the motor coordination required for phoneme production, so called kinetic speech production impairment. These are often associated with lesions in the inferior precentral gyrus (Lecours 1976). These disturbances of phoneme selection and expression can be distinguished from dysarthrias in which there are characteristic impairments in swallowing and generation of meaningless sounds which require the same motor apparatus.
Intact speech is dependent upon appropriate word retrieval. Patients with impaired word retrieval may be relatively fluent but their speech appears empty with frequent circumlocutions. Clinically this can be tested by confrontational naming when abnormalities may be apparent, particularly for low frequency words, that are less obvious in spontaneous speech. Word finding difficulties are found quite frequently in neurological practice, but can occur as a relatively isolated finding in patients with left temporal lobe lesions. The study of word retrieval has proved to be a fertile area for theoretical modelling and a number of important clinical observations have been made. First, naming may be modality specific, for example, patients may be unable to name when presented with the object visually but are able to do so when presented to touch, so called optic aphasia. In addition, patients have been described in whom a tactile naming impairment is confined to the left hand, and such cases are most easily interpreted as disconnection syndromes involving lesions of the corpus collosum (Geschwind and Kaplan 1962). Another distinction has been drawn between patients whose failure at naming is consistent, and patients in whom the failure varies between different testing sessions and appears to be sensitive to the precise timing of confrontation. Different names are failed on different occasions and an object may be correctly named, but not if immediately shown again. The latter has been interpreted as an impairment of access to the word store, so called semantic access dysphasia (Warrington and McCarthy 1983). This syndrome of impaired access can be contrasted with patients in whom confrontational naming is impaired because they have lost their verbal semantic memory; in these instances the same words tend not to be named and patients can quite often verbalize their loss of comprehension.
One of the striking clinical features of word finding difficulty is the phenomenon of category specificity, namely that certain categories of words are more impaired than others. In some instances, the specificity is so striking as to have been recognized as a distinct syndrome, for example, colour anomia in patients who are unable to name but can adequately match colours; letter naming or letter anomia, and body part naming, or autotopagnosia. Many additional dissociations have been demonstrated, for example, between action naming and object naming, living and inanimate objects etc. These category-specific dysphasias provide important theoretical insights into language organization and have been proposed to depend upon the association of the word with various attributes at the time meaning is acquired. Thus, for example, words which are associated with a strong visual component, of which colour would be the most striking, can be contrasted with those, such as tools and manipulable objects, which would depend on a major proprioceptive input when the word acquires its meaning (Warrington and McCarthy 1987). Such an account would accord well with current concepts of parallel distributed processing across neural networks. These examples within the verbal domain reflect how concepts and meaning may be organized across all domains and deficits in verbal, visual, and possibly other sensory domains can be seen in semantic dementia (Section 34.6.4).
Shortly after Broca’s description, Karl Wernicke outlined the features of a fluent aphasia which in many respects provided the clinical counterpart of a Broca’s aphasia. The striking feature is that such patients speak fluently but the speech is often empty of meaning with frequent semantic paraphasias. At times the paraphasias may be profound with frequent neologisms, so called jargon aphasia. Comprehension is invariably impaired as is reading. Writing reflects the language impairment with frequent semantic paraphasias and spelling errors. Repetition, as with Broca’s aphasia is impaired. Wernicke’s aphasia is commonly due to a vascular lesion and the acute onset of a jargon aphasia is usually due to an embolus to the inferior division of the middle cerebral artery. The area involved is the posterior superior temporal gyrus, often extending into the inferior parietal area. By contrast to Broca’s aphasia, Wernicke’s aphasia is often unaccompanied by neurological deficit on examination which to the unwary can lead to faulty diagnosis of a psychotic disturbance. A right superior quadrananopia may be found if carefully sought.
Intact comprehension requires intact speech perception and patients may be seen with so called pure word deafness. A number of these patients, with bilateral temporal lobe lesions, have been shown to have impairment of auditory temporal acuity (Auerbach et al. 1982). However, some patients have impairment of phoneme discrimination which can be associated with left temporal lobe lesions.
As the counterpart to transcortical motor aphasia, Lichtheim proposed the syndrome of transcortical sensory aphasia in which patients are able to repeat, and whose speech is fluent, but is associated with impaired comprehension and paraphasias. The model postulated that the word recognition centre was intact, as shown by an intact repetition, but dissociation from a central meaning system resulted in impaired comprehension. This syndrome is now interpreted as an impairment of verbal semantic memory. It can be seen with posterior border zone infarcts but more commonly in frontotemporal degeneration where it is the major feature of the clinical syndrome of semantic dementia (Section 34.6.4). Rarely patients may be seen with isolation of the speech area who are neither able to speak nor to understand but are able to repeat (Geschwind et al. 1968).
Patients with Broca’s aphasia often have impairment of the normal rhythm of speech, so called dysprosody. Sometimes this may be so pronounced as to be referred to as the ‘foreign accent syndrome’ (Blumstein et al. 1987). Impairment of the emotional expression and comprehension of speech is often found with right hemisphere lesions and attempts have been made to seek comparable dysphasia syndromes to those found with left hemisphere lesions (Ross 1981).
Dysphasias are classically associated with cortical lesions but subcortical damage is increasingly being recognized as a cause of dysphasia. To some extent these mimic the classical dysphasia syndromes depending upon their location, for example, anterior lesions resulting in a non-fluent aphasia. In many instances reduced metabolism can be demonstrated on positron emission tomography scanning in the appropriate cortical area and are presumed to reflect impaired projection systems. Other syndromes have been described, for example, ischaemic lesions of the head of the caudate nucleus and associated internal capsule present with striking orofacial dyspraxia, dysarthria, and non-fluent dysphasia (Naeser et al. 1982). Left thalamic haemorrhages frequently give rise to an aphasia, often with fluctuations in arousal with concomitant fluctuation in language function.
34.4.5. Disorders of speech production and dysarthria
Dysarthria as a disorder of articulation does not involve any disturbance in the proper construction and use of words. In the dysarthric patient, symbolic verbal formulation is normal: only the mechanism of verbal sound production is faulty. When so severely affected that the patient is totally unable to articulate, it is referred to as anarthria. Dysphonia is applied to local disturbance of the larynx and may also render the patient mute. As well as structural abnormalities of the larynx, impaired innervation of laryngeal muscles can lead to dysphonia. A ‘bovine cough’ is a simple clinical sign of inability to close the larynx.
The articulatory muscles on each side appear to be innervated by both cerebral hemispheres. Hence a unilateral corticospinal lesion, for example in the internal capsule, may cause temporary but not permanent dysarthria. However, an extensive unilateral lesion involving the motor cortex may cause persistent dysarthria, especially when the dominant hemisphere is involved, in this case the dysarthria is often associated with some degree of Broca’s aphasia. Dysarthria is consistently produced, however, by bilateral corticospinal lesions, due, for example, to congenital diplegia, vascular lesions of both internal capsules, degeneration of both corticospinal tracts, as in motor neurone disease, and lesions such as tumours involving both corticospinal tracts together in the midbrain. With such lesions, the articulatory muscles are weak and spastic and the tongue appears smaller, firmer, and less mobile than normal. The jaw-jerk and the palatal and pharyngeal reflexes are exaggerated. Speech is slurred and often explosive, production of consonants, especially labials and dentals, being severely affected. Spastic dysarthria is usually associated with dysphagia and often with impairment of voluntary control over emotional expression, the syndrome of ‘pseudobulbar palsy’.
With lesions of the corpus striatum, articulation is impaired, partly, at least, as a result of muscular rigidity. Thus in Wilson’s disease and in Parkinsonism, articulation is slow and slurred owing to immobility of the lips and tongue and the pitch of the voice is monotonous. In the dystonias and Huntington’s disease, dysarthria is common; indeed in severe cases speech may be unintelligible. In these diseases irregular respiration may also contribute to the dysarthria.
The co-ordination of articulation suffers severely when the cerebellar vermis is damaged and also when lesions involve the cerebellar connections in the brainstem. Speech in such cases is often explosive with slurring and undue separation of individual syllables; scanning or syllabic speech. Ataxic dysarthria of this character is seen after acute cerebellar lesions and in multiple sclerosis and the hereditary ataxias.
Lower motor neurone lesions cause wasting and weakness, and often fasciculation, of the muscles of articulation; a true bulbar palsy. In the early stages, the pronunciation of labials suffers most. Later, progressive weakness of the tongue impairs the production of dentals and gutterals, and weakness of the soft palate gives the voice a nasal quality. There is often associated dysphonia and finally total anarthria. Motor neurone disease is the commonest cause, but paresis of the bulbar muscles may also be seen in syringobulbia, bulbar poliomyelitis, cranial polyneuritis, and brainstem tumours.
Combinations of these varieties of dysarthria are common; for example, in multiple sclerosis the articulatory muscles may be both spastic and ataxic and in motor neurone disease, a combination of upper and lower motor neurone lesions may be present.
Diseases of the muscles, such as myasthenia gravis, polymyositis, and muscular dystrophy involving facial muscles, lead to a dysarthria similar to that resulting from lesions of the lower motor neurones. In myasthenia, fatigability may cause increasing slurring if the patient is asked to count aloud. In the myotonias, impaired muscular relaxation may add a spastic quality to the speech.
Palilalia is a rare disorder of speech which, as its name implies (Gk: palin, again; lalein, to chatter), is characterized by repetition of a phrase which the patient reiterates with increasing rapidity. Palilalia most frequently occurs in post-encephalitic Parkinsonism, in general paresis, frontotemporal degenerations, and in pseudobulbar palsy due to vascular lesions. In echolalia the patient repeats or echoes words or brief phrases spoken by the examiner. It is often seen in frontotemporal degenerations and in autism.
34.4.6 Agraphia, alexia, and acalculia
The majority of aphasic syndromes are associated with impairment of writing or dysgraphia. This is such a frequent association clinically that sparing of writing with impaired speech usually indicates that the speech impairment is due to a disruption of speech production rather than a pure dysphasic syndrome. Similarly, some patients may demonstrate dysgraphia with intact speech. Agraphias have been broadly divided into those which affect the processes of spelling and those which affect writing. The latter can be seen as a particular type of ideational dyspraxia, although patients are described in whom praxis is otherwise preserved. Disorders of spelling as such have also been subdivided and have allowed the generation of theoretical models similar to the informational processing models for reading (Shallice 1981b). Dysgraphias are typically associated with posterior dominant parietal lesions.
Acquired disorders of reading, or dyslexias, are commonly found with dysphasias but can present in isolation. These were originally classified by Dejerine into two broad groups, those with and those without dysgraphia. In clinical terms this distinction has stood the test of time. Dyslexia with dysgraphia is commonly seen with lesions of the left angular gyrus. This type of dyslexia is often seen together with agraphia, acalculia, and anomia and has been described as a distinct syndrome by Gerstmann, although this is only an observed clustering and these are not dependent on each other (Benton 1961). In the syndrome of alexia without agraphia, patients are unable to read but are able to write even though they cannot read their own writing. This is often found with colour anomia and patients usually have a right hemianopia. It is most commonly seen with lesions of the left parieto-occipital area, often involving the splenium of the corpus callosum. The classical interpretation of this syndrome has been that of a disconnection of visual information in the intact left field from the left angular gyrus. However, this does not readily explain a striking feature of these patients, which is the ability to read using a letter by letter strategy. Information-processing models have now largely replaced the neurological models of reading (Marshall and Newcombe 1966). Using these models, alexia without agraphia can be interpreted as a word form dyslexia supported by the fact that these patients are more impaired on reading script than print (Warrington and Shallice 1980). It is argued that following initial word form recognition, analysis may proceed either by a phonological route or by a sight vocabulary route. For further discussion of the information processing models see McCarthy and Warrington (1990).
Impairment of arithmetic ability is relatively common and is seen frequently with aphasia. However, it can be recognized as a selective lesion and most commonly is found with left parietal lesions. Dyscalculia commonly arises as a consequence of dyslexia or dysgraphia and so-called spatial acalculia due to visuospatial disorganization when written arithmetic calculations are performed.
34.4.7 Disorders of memory
Memory is the ability to store and subsequently retrieve past experience and is central to many cognitive functions, and the maintenance of an autobiographical memory is central to personal identity.
It is clear that memory is not a unitary function and there is a profusion of different terms. It is usual, however, to draw a distinction between short term or primary, and long term or secondary memory. Neurologists often use ‘short-term’ memory to describe memory for recent autobiographical events but it is preferable to confine this term to the concept of ‘immediate’ memory, developed by neuropsychologists. We use short-term or immediate memory to remember a telephone number, and is tested at the bedside using the digit span. A normal person can usually retain a maximum of seven or eight digits with rapid forgetting over some 30s unless rehearsed. Although less commonly tested at the bedside, patients may also have a selective impairment of short-term visual memory. The original simple model that memory involved entry into the short-term store before consolidation into a long-term store ‘secondary memory’ is no longer tenable as patients with impaired digit span may have normal learning and secondary memory. Current theories of the role of primary memory range from a component of the working memory model of Baddeley (1986), to involvement in language fluency or as a safety backup resource (Shallice and Warrington 1970). From the neurologist’s point of view, reduced digit span is commonly seen with impairment of attention but as an isolated finding can be related to lesions of the inferior dominant parietal lobe where it often occurs with dyscalculia.
Disabling memory impairments arise when individuals lose the ability to maintain an autobiographical memory. This can occur in a variety of clinical situations such as dementia and confusional states, but it is the patients with otherwise intact cognition who have provided the main basis for study. Such patients typically have two components to their impairment, an anterograde amnesia, which is a deficit in acquiring new memories following the illness, and a retrograde amnesia, a loss of recall for events prior to the illness. The patient HM, who had bilateral medial temporal lobe resections extending back some 8 cm from the temporal poles, has been intensively studied and provided important insights into amnesia. These studies demonstrate a profound impairment of both verbal and non-verbal learning with intact immediate recall as evidenced by normal digit span (Scoville and Milner 1957; Milner et al. 1968). Subsequent similar cases of amnesia have followed this pattern. The status of remote memories has been less secure. So-called Ribot’s ‘law’ states that there is a direct relationship between the strength of a memory and its recency, i.e. old memories being better preserved, and indeed this is often observed at the bedside. However there are problems of interpretation since it is difficult to match the saliency of the remembered events and the apparent preservation of old memories probably just reflects a small stock of overlearned anecdotes. The preservation of these overlearned episodes are likely to engage semantic memory systems as evidenced by the better recall of recent as opposed to distant events in semantic dementia. Despite the profound memory loss in HM and other similar cases, there is preservation of certain types of learning, for example improved performance on the recognition of fragmented letters can be demonstrated and, most strikingly, a retained ability to acquire new motor skills often without recollection of having done so.
In the case of HM, impaired learning of both verbal and visual material was found, but these can be selectively impaired. Group studies indicate that patients with left hemisphere damage have impaired verbal memory and the converse for non-verbal or visual memory. Often these material-specific memory impairments do not present clinically, but rather are found on specific testing. On occasions, however, some do present to the neurologist, the most striking being a topographical memory impairment in patients who are unable to recall familiar routes or buildings (Patterson and Zangwill 1945).
Studies of amnesia had previously focussed on failure at various putative stages of memory in terms of input, storage, and retrieval. Impairments of input and consolidation suggested that the strength and endurance of a memory depended on the extent of processing and thus consolidation (Craik and Lockhart 1972). This interpretation of amnesia in terms of impaired storage had argued that consolidation and retrieval mechanisms were intact but that there was an increased rate of forgetting. More recently, however, attention has focussed on the dissociations between preserved and impaired memory functions, observations which cannot easily be accommodated within a simple unitary model of memory with consolidation and retrieval models. Cohen and Squire (1980) contrasted procedural learning, which reflects ‘knowing how’, and declarative knowledge, the ‘knowing that’ memory. This describes the situation of patients acquiring new motor skills often without explicit knowledge of having done so. One patient for example, was able to learn a new piano tune without any recollection of having done so, and replay if prompted with the initial bars (Starr and Phillips 1970). However, the dimension of declarative memory does not easily explain the deficits seen in patients such as HM in whom memory for words, part of declarative knowledge, is well preserved. Tulving (1973) drew attention to the difference between episodic memory, such as for day-to-day events, and semantic memory. Other approaches have looked at the dynamic processes involved rather than observed dichotomies, for example the processes involved in implicit and explicit learning, which are those variably dependent upon the degree of conscious recall.
Causes of amnesia
A large variety of diseases may be associated with amnesia (Kopelman 2002). Most commonly memory impairment is seen with confusional states or dementia, but in these instances the amnesia is part of a wider spectrum of cognitive impairment (see below). Diseases affecting the medial temporal lobes and other structures on the limbic circuit may cause amnesia. Thus midline tumours in the region of the third ventricle, such as craniopharyngiomas, colloid cysts, massive pituitary tumours (Williams and Pennybacker 1954), thalamic gliomas, and tumours of the splenium of the corpus collosum, believed to be due to involvement of the fornix (Rudge and Warrington 1991) can all cause severe amnesia. Inflammatory disorders such as sarcoidosis and other granulomatous lesions in the same areas and limbic encephalitis as a paraneoplastic phenomenon (Henson and Urich 1982) are also associated with amnesia. A profound memory impairment is also commonly seen with herpes encephalitis due to the selective involvement of the medial temporal cortex. Vascular events of the posterior cerebral artery which supplies medial temporal lobe and hippocampus can cause amnesia (Benson et al. 1974). This often occurs with bilateral damage in association with basilar artery syndromes, but can occur with unilateral cerebral artery occlusions particularly in the elderly, which may be due to pre-existing contralateral hippocampal damage.
The Korsakoff syndrome
This is a striking amnesia which usually follows a Wernicke’s encephalopathy (Section 34.5). Patients present with a profound amnesia and are quite unable to remember events even within the last half an hour but may be shown to have implicit learning, for example of motor skills. Other tests of cognitive function are well preserved in the pure form of Korsakoff syndrome but in clinical practice a spectrum may be seen with the more generalized cognitive impairment of alcoholic dementia at one end and patients with a pure Korsakoff syndrome at the other (Cutting 1978). It is, however, the striking contrast between the profound amnesia and the relatively minor additional cognitive defects that characterizes Korsakoff’s syndrome.
Transient loss of memory
This is also a common clinical problem with both anterograde and retrograde amnesia, the latter shrinking on recovery leaving a gap in memory for the period of anterograde memory impairment subsequent to the onset. Temporary memory loss may occur with a variety of conditions which result in either generalized cerebral dysfunction or with selective disturbance of the medial temporal lobe and diencephalon, such as in temporal lobe epilepsy. Cerebral tumours may cause episodic memory loss which may also be on an epileptic basis (Lisak and Zimmerman 1977). Head injury and drugs, especially alcohol (Goodwin et al. 1969) and benzodiazepines, are common causes. Transient memory impairment may also occur as a feature of transient ischaemic episodes in posterior cerebral territory. A picture resembling transient global amnesia may also occur with migraine but this is usually with a clinical history of previous migraine attacks and the episodes are normally followed by headache (Caplan et al. 1981). Psychogenic amnesia and hysterical fugue states, a not infrequent topic of newspaper stories, are discussed below.
Transient epileptic amnesia
In addition to the transient memory loss associated directly with seizures, patients with transient epileptic amnesia suffer recurrent episodes of amnesia and report gaps in their autobiographical memory for which they have no recall (Zeman et al. 1998) A sleep EEG may be required to demonstrate temporal lobe epileptiform discharges. Patients with transient epileptic amnesia have been shown to have an accelerated rate of forgetting (Manes et al. 2005).
Transient global amnesia
This is a striking syndrome affecting the middle aged and the elderly. The history is obtained of sudden onset of impairment of episodic or autobiographical memory. The attacks are frequently reported to have been triggered by sexual intercourse or sudden cold; winter bathing in the elderly being a classic history (Fisher 1982). The attacks last from 1 to 24 h and the patients may repeatedly ask questions and appear anxious but otherwise able to drive home and there have been reports of virtuoso musical performances during an attack. Testing during an attack reveals profound loss of episodic memory with a variable retrograde component. Investigations are usually normal (Quinette et al. 2006) and a full recovery can be anticipated, although some patients are left with mild memory impairment (Mazzucchi et al. 1980). Recurrences are rare but do occur in a small proportion (Shuping et al. 1979). A vascular cause may underlie the syndrome of transient global amnesia (Fisher and Adams 1958), although supportive evidence has been difficult to establish and epidemiological studies have suggested a closer link to migraine (Hodges and Warlow 1990). Venous ischaemia has been suggested as a mechanism due to observed triggers which can be associated with a Valsalva manoeuvre (Winbeck et al. 2005).
Confabulation, the production of memories without any basis in real events, can accompany amnesia and is most commonly observed in Korsakoff’s syndrome. However, confabulation can be seen in patients with adequate performance on routine memory testing and is therefore more appropriately considered as a paramnesia (Stuss et al. 1978). Two classes of confabulation have been distinguished (Berlyne 1972). Momentary or provoked confabulation occurs in response to questions and requests for specific information that the patient might reasonably be expected to know. More florid is fantastic confabulation in which the patient will spontaneously produce bizarre accounts often far in excess of what might be required in response to the situation. Confabulation is found most commonly in association with frontal lobe lesions, particularly in medial frontal lobe lesions (Stuss et al. 1978; Damasio et al. 1985).
Reduplicative paramnesia (Pick 1903) describes a behavioural disturbance in which the patient transposes or reduplicates places. For example, he might claim that his home is not his normal home but a very similar building in which he is staying or alternatively that the hospital in which he has been admitted is next door. Such patients usually have bifrontal or right frontal lesions (Kapur et al. 1988). A similar syndrome is the Capgras syndrome in which patients refuse to recognize people, often close relatives who are familiar to them, claiming them to be impostors. Capgras’ syndrome is usually seen in association with right hemisphere lesions (Alexander et al. 1979). Patients with the Fregoli syndrome believe that persons are all the same but adopting disguises. Reduplicative paramnesias are often seen in dementia with Lewy bodies.
34.5 Wernicke–Korsakoff syndrome
In 1887, Korsakoff reported a syndrome of mental changes, predominantly of memory impairment in association with polyneuropathy. The tendency to confabulate was noted, as was the link with alcohol abuse, but it was also reported with typhoid fever and prolonged vomiting. Six years earlier, Wernicke had described an acute illness of ataxia, ophthalmoplegia, polyneuropathy, and a confusional state. It was later observed that these syndromes often occurred sequentially in the same patient. Now the majority of cases are associated with alcohol abuse and thiamine deficiency plays a key role in Wernicke’s encephalopathy (Section 5.2.3).
Wernicke’s encephalopathy presents with an acute or subacute confusional state together with oculomotor disturbance and ataxia. The confusional state involves inattention and disorientation but can progress to drowsiness and even to coma and death if the underlying thiamine deficiency is not recognized and treated. The examination may reveal nystagmus, VI nerve palsies, conjugate gaze palsies, and ataxia. Criteria reflecting the classic triad of encephalopathy, oculomotor disturbance and ataxia have been developed (Caine et al. 1997). The occurrence of any two of the following: dietary deficiency, oculomotor palsies, cerebellar dysfunction, and altered mental state, can provide high diagnostic accuracy.
Korsakoff’s syndrome emerges as the Wernicke’s encephalopathy resolves and the confusional state clears to reveal a profound amnesia with both an inability to recall recent events and to learn new facts (Kopelman 1995). It may emerge gradually without a prominent preceding encephalopathic stage. The key component is the impairment of memory out of proportion to other cognitive domains. The deficit relates to event or episodic memory with sparing of semantic memory, and implicit learning can be demonstrated. Classically, patients also confabulate and will easily confuse the temporal sequence of memories that are recalled; this is believed to relate to additional frontal damage and indeed, many patients lack insight and initiative indicative of a frontal syndrome. However, more widespread cognitive deficits may be seen along with a clinical picture which merges with ‘alcohol dementia’ (Cutting 1978). Some have suggested that Korsakoff’s syndrome and alcohol dementia are all part of the same spectrum but memory impairment of the former does set it apart as does involvement of diencephalic structures. Bilateral haemorrhagic lesions in the areas of the third and fourth ventricle and aqueduct are characteristic of Wernicke’s encephalopathy and the diencephalic lesions are critical to the emergent amnesia of Korsakoff’s syndrome. The original proposal that damage to the dorsal medial nucleus of the thalamus was the minimal lesion (Victor et al. 1989), has been considered too specific and anterior and medial thalamic and mammillary body involvement are also implicated. Thiamine deficiency is believed to underlie the pathogenesis of the disorder and explains its occurrence in other disorders such as prolonged vomiting, nutritional deficiency, and hyperemesis gravidarum. In patients who abuse alcohol, there is considerable variability in susceptibility to Wernicke–Korsakoff syndrome suggesting not only subtle differences in diet but also potential genetic factors.
The key to the treatment is to make the diagnosis which should be considered in all patients presenting acutely with unexplained cognitive impairment or coma. Treatment is with intravenous thiamine, at least 100 mg daily. In the acute situation it is important to give thiamine before intravenous glucose as a sudden glucose load may exhaust the thiamine required as a cofactor in the pentose phosphate shunt. (Heye et al. 1994).
34.6 The Dementias
34.6.1 Approaches to a differential diagnosis
The term dementia refers to the clinical syndrome of impairment in multiple domains of cognitive function, which must include impairment of episodic memory, in a patient who remains alert with normal arousal. This serves to distinguish patients with dementia from those with confusional states or delirium, who have abnormal arousal, and from those with a single discrete cognitive deficit such as a dysphasia. This definition has been used to create operational criteria, such as those of the Diagnostic and Statistical Manual of the American Psychiatric Association, DSM-IV. An important feature of these definitions is that the dementia must be sufficiently severe to interfere with social and occupational function. There is clearly no simple cut-off from normality and whether this criterion is met will depend upon premorbid function and on the patient’s social and occupational demands. This is particularly relevant to the elderly in whom some decline of cognitive function, particularly memory, is commonplace. Attempts have been made to distinguish patients with a progressive dementia, normally due to Alzheimer’s disease, from less severe memory impairment associated with ageing. The terms benign senescent forgetfulness, age-associated memory impairment, and age-associated cognitive decline have been used but it is clear that many patients presenting in late life with memory complaints will be in the early stages of Alzheimer’s disease even if not fulfilling the formal criteria of dementia. The term mild cognitive impairment was introduced to reflect this group of patients who had a memory impairment but were not demented (Petersen et al. 2001). Patients with this amnestic mild cognitive impairment progress to fulfil criteria for Alzheimer’s disease at a rate of 10–15 per cent per year. With the recognition that mild cognitive impairment may be heterogeneous with non-amnestic presentations and multiple domain involvement, the concept has been expanded beyond only memory (Winblad et al. 2004; Jicha and Petersen 2007).
The definition of dementia is a broad one and it is not surprising, therefore, that the syndrome can be associated with a large variety of diseases (Table 34.1). All of these may be associated with widespread cognitive impairment but the clinical patterns vary and can lead to characteristic features. A broad distinction has been drawn between subcortical and cortical dementias (Albert et al. 1974; Cummings 1986). The term subcortical dementia was originally applied to the cognitive deficits seen in progressive supranuclear palsy and Huntington’s disease, and is characterized by a marked slowness in cognition with additional impairments of motivation and attention. Indeed if the patient is allowed time then performance on routine neuropsychological testing may improve, but performance in everyday life remains severely compromised. The diseases that are most commonly found with this type of dementia are those affecting the basal ganglia and frontal connections. Dysphasia, dyspraxia, and agnosia are not prominent in these patients, by contrast to those with cortical dementia, in whom the memory impairment is generally not improved by cues, and the speed of cognition is relatively normal. The prototypic cortical dementia is Alzheimer’s disease and the characteristic clinical pattern reflects damage to the cortical association areas (Table 34.2).
Table 34.1 Illustrative causes of adult-onset dementia
Primary cerebral degenerations
Down’s syndrome and Alzheimer histopathology
Progressive supranuclear palsy
Frontal lobe degeneration
Dementia with motor neuron disease inclusions
Parkinsonism–dementia complex of Guam
Parkinson’s disease and dementia
Dementia with Lewy bodies
Calcification of the basal ganglia with neurofibrillarytangles
Progressive myoclonic epilepsy
Cerebral Infections and Inflammatory Disorders
Viral encephalitis esp Herpes simplex
Progressive multifocal leucoencephalopathy
Subacute sclerosing panencephalitis
Subacute rubella encephalitis Viral, bacterial, and fungal meningitides
Disseminated encephalomyelitis Multiple sclerosis
Multiple cortical infarcts
Multiple lacunar infarcts
Congophilic angiopathy including hereditary
Thrombotic thrombocytopoenic purpura
Subacute diencephalic angioencephalopathy
Dutch amyloid angiopathy Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
Cranial arteritis Cerebral arteritides inc polyarteritis nodosa, systemic lupus erythematosis, thromboangiitis obliterans, and granulomatous angiitis
Metabolic and toxic causes
These generally present as confusional states
Hyper- and hypocalcemia
Hypo- and hypernatremia Uremia
Chronic hepatic encephalopathy
Drugs, poisons, heavy metals
Vitamin B12 deficiency
Malabsorption syndrome and celiac encephalopathy
Sporadic and familial Creutzfeldt–Jakob Disease
Iatrogenic Creutzfeldt–Jakob Disease
Variant Creutzfeldt–Jakob disease Familial fatal insomnia
Meningiomas Gliomas especially callosal Parapituitary tumours Pineal and midbrain tumours Cerebral lymphoma Cerebral metastases Carcinomatous meningitis Paraneoplastic syndromes including limbic encephalitis
Inherited metabolic and storage disorders
Metachromatic and adrenoleucodystrophies
Normal pressure hydrocephalus
Open and closed head injuries
Post cerebral irradiation
Table 34.2 Cortical and subcortical dementias Derived in part from Cummings (1986)
Mild to moderate
More severe earlier in course
Speed of cognition
Normal but frequent errors
Memory impairment, recall aided by cues
More severe memory impairment unaided by cues
Dysphasia, dyspraxia, agnosia
Depression less common
Prominent changes in striatum and thalamus
Of the many diseases listed in Table 34.1 some are very rare, and in others dementia is only an occasional clinical feature. The cognitive impairment may vary from minor deficits found only on specific testing to a more prominent dementia. Vascular dementia, for example, subsumes a large variety of different pathological entities, with a variable cognitive profile.
Only a minority of patients with dementia are found to have a treatable disease in published series, the most common being the subcortical dementia of depressive illness, but other treatable diseases include benign neoplasms, infections, vitamin deficiencies, and normal pressure hydrocephalus. However, the proportion of patients with reversible dementia seen by neurologists has lessened with earlier and better assessment (Clarfield 2003). In view of the profound consequences of dementia and the emerging treatment possibilities, a comprehensive approach to investigation and early diagnosis is justified, although clearly the extent of investigations will be determined by the clinical features and age of the patient. Both European (Waldemar et al. 2007) and US (Doody et al. 2001) guidelines on investigation and management of patients with dementia have been published. It would be inappropriate to undertake intensive investigation in a very elderly patient with multiple systemic illnesses and cognitive impairment; by contrast, the young or atypical patient requires exhaustive investigation. All patients presenting with dementia should undergo a careful neuropsychological assessment. This will establish whether the patient does indeed have a generalized cognitive impairment and will help to detail the pattern of deficits. Routine biochemical and haematological determinations, which should include an ESR, thyroid function, syphilis and Borrelia serology, and autoantibody screen, will identify many of the potentially remediable causes. Vitamin B12 is often found to be low but rarely implicated as a cause of dementia. At-risk individuals with a subcortical dementia may require HIV testing. Chest X-ray and ECG complete the general assessment which will also serve to identify comorbid illnesses which may contribute to the cognitive impairment. Other blood tests, for example, genotyping, will depend upon the clinical features.
All patients should have neuroimaging, either CT scanning or MRI. Tumours and hydrocephalus can be excluded by both imaging modalities but MRI has the additional advantage of more detailed imaging of white matter disease in demyelination and vascular disease. Increasingly, MRI can also provide information on regional atrophy, such as the selective atrophy of hippocampi in Alzheimer’s disease, which is of value in differential diagnosis (Jack et al. 1999). Serial MRI may also demonstrate rates of atrophy in degenerative disease outside the normal range (Fox and Schott 2004). Positron emission tomography, PET, can also identify regional deficits of blood flow and cerebral metabolism in degenerative dementia, using either 15-oxygen or fluorodeoxyglucose scanning. Thus, a characteristic feature of Alzheimer’s disease is posterior biparietal bitemporal hypometabolism (Frackowiak et al. 1981) which can be contrasted with frontal deficits in the frontotemporal degenerations (Silverman et al. 2001). The use of single photon emission tomography is more readily available and although it lacks the quantitative information provided by positron emission tomography scanning can also contribute to the identification of regional deficits, most useful in frontal degeneration where atrophy may be difficult to identify on structural images. The EEG may identify patients with subclinical seizure activity and the characteristic changes of the spongiform encephalopathies; in addition it can assist in the distinction of patients with Alzheimer’s disease, with early slow wave changes, from patients with frontotemporal degenerations in whom the EEG is relatively well preserved (Chan et al. 2004). Examination of the cerebrospinal fluid is important in patients in whom one suspects an inflammatory or infective cause and increasingly CSF protein markers are useful such as Aβ1–42 and tau in Alzheimer’s disease (Blennow 2003). A relatively specific protein marker, P14-3-3 is found in cerebrospinal fluid in Creutzfeldt–Jakob disease (Lemstra 2000). Tissue biopsy, of muscle to detect mitochondrial cytopathy, of skin for Kufs disease, or of tonsil for variant Creutzfeldt–Jakob disease (Hill et al. 1999) may be diagnostic. In rare instances meningeal and cerebral tissue biopsy will be necessary, and may be the only way to establish a diagnosis of isolated cerebral vasculitis (Warren et al. 2005).
The majority of the diseases causing dementia which are listed in Table 34.1 are discussed elsewhere. In general, most cause a largely subcortical picture. In many of these instances there will be other clinical clues. The primary degenerative dementias give rise to a dementia with few other neurological findings in the early stages and these are dealt with in detail here.
34.6.2 Alzheimer’s disease
In 1906, Alois Alzheimer described a 51-year-old lady with dementia and senile plaques and neurofibrillary tangles at autopsy. Originally Alzheimer’s disease was viewed as a rare pre-senile dementia. However, clinicopathological studies in the 1960s demonstrated an overall relationship between dementia and the presence of senile plaques in both young and elderly demented patients, (Blessed et al. 1968) and the view emerged that Alzheimer’s disease and senile dementia of the Alzheimer type was a single disease. Nevertheless, within the broad group of Alzheimer’s disease cases, clinical and pathological heterogeneity can be observed. This originally focused on the age at onset with subtle distinctions being made between early and late onset disease. At a neuropathological level, distinctions have been drawn between cases that consist predominantly of neurofibrillary tangles and those that consist predominantly of senile plaques. However, the most robust biological categorization relates to cases with a clear family history. Up to 40 per cent have a family history of an affected first degree relative (Farrer et al. 1990); rarely there is a clear autosomal dominant history. Pathogenic mutations in three different genes have been identified in this group, namely presenilin 1 and 2 and amyloid precursor protein, APP, genes which account for the majority of the autosomal dominant familial Alzheimer’s disease cases described. Inheritance of an E4 allele of the apolipoprotein E gene is associated with an increased risk of developing Alzheimer’s disease (Corder et al. 1993).
It is now recognized that Alzheimer’s disease is the major cause of dementia. Epidemiological studies indicate a doubling of the prevalence of dementia with each decade above 65 years to a prevalence approaching 50 per cent in those aged 85 and above (Evans et al. 1989). Approximately 70 per cent of cases of dementia will be due to Alzheimer’s disease, either alone or in combination with vascular disease. Moreover vascular risk factors per se are also associated with a higher incident rate of Alzheimer’s disease in longitudinal studies.
Alzheimer’s disease is a disorder of middle and late life. Early onset cases are described in the fourth and fifth decade but these are rare and almost exclusively familial. The clinical features of familial Alzheimer’s disease associated with mutations in the APP and presenilin genes are broadly similar to sporadic disease apart from the age at onset. However, cases with mutation at APP 692 have more amyloid angiopathy with cerebral haemorrhages and thus, share similarities to hereditary cerebral haemorrhage with amyloidosis of the Dutch type due to mutations at APP 693, and some preenilin 1 mutations are associated with a spastic paraparesis (Crook et al. 1998).
The classical presentation of Alzheimer’s disease is with memory impairment. In some patients there may be a relatively prolonged course with isolated memory deficits until late into the disease (Hodges 2006). Patients who fulfil the criteria for mild cognitive impairment (Section 34.6.1) with an isolated memory impairment often progress to Alzheimer’s disease confirmed at autopsy or found to have neurofibrillary tangles suggestive of early Alzheimer’s disease (Petersen et al. 2006). The memory impairment primarily affects episodic and autobiographical memory, the patient forgets appointments, and mislays objects. Procedural memory and learning may be relatively preserved and, as with Korsakoff’s syndrome, patients may demonstrate procedural learning without apparent parallel declarative learning. It is often stated that remote memory is preserved but if specifically investigated remote memory is also disrupted. Language impairment can occur relatively early and emergence of verbal semantic memory impairment implicates involvement of temporal lobe structures, extending beyond the hippocampus. Alzheimer patients frequently complain of difficulty with people’s names which may reflect early impairment in the semantic memory system (Thompson et al. 2002). Dyspraxia is generally a late feature, although ideomotor dyspraxia is often found if specifically sought. Visuospatial and visuoperceptual deficits are also prominent and in some patients may be the presenting feature. Patients are quite often unaware of their cognitive deficits, often being brought to the attention of doctors by their relatives. The denial or anosognosia is not related to severity (Feher et al. 1991).
In addition to the classical presentation with impairment of episodic memory, some patients present with prominent frontal or language impairment (Galton et al. 2000). Patients with a biparietal presentation can be difficult to distinguish from corticobasal degeneration. Posterior cortical atrophy was a term used to describe patients with a variety of posterior parietal and parieto occipital features (Benson et al. 1988). The majority of such patients do have Alzheimer’s disease and are sometimes referred to as the visual variant; early on dorsal visual processing deficits are the most prominent (McMonagle et al. 2006). However, some patients can present similarly with dementia with Lewy bodies (Section 34.6.3), Creutzfeldt–Jakob disease (Section 34.6.5), and corticobasal degeneration (Section 40.3.10).
In addition to the cognitive deficits, patients with Alzheimer’s disease develop a number of neuropsychiatric features. Depression is very common and to a minor degree occurs in the majority of patients (Wragg et al. 1989) but needs to be distinguished from apathy. Psychosis is also common as the disease progresses, often with delusions of theft which can be difficult to manage for family members. Hallucinations do occur but if prominent should raise the possibility of dementia with Lewy bodies (Section 34.6.3). Agitation is also common as the disease progresses and is associated with increased burden of neurofibrillary tangles in the orbitofrontal and cingulate cortex (Tekin et al. 2001).
The general neurological examination is relatively normal in Alzheimer’s disease at presentation, although motor abnormalities of extrapyramidal type commonly emerge as the disease progresses. Many patients with additional bradykinesia are found to have dementia with Lewy bodies. Primitive reflexes such as the instinctive grasp reaction, rooting, and sucking occur late. Generalized seizures occur in 10–20 per cent over the total course of the disease and myoclonus is relatively common in familial Alzheimer’s disease.
Structural neuroimaging characteristically shows medial temporal lobe atrophy which can be seen on CT scan or more specifically, hippocampal atrophy on MRI (Scheltens et al. 2002) (Fig. 34.2). Functional imaging with single photon emission tomography or positron emission tomography reveals a posterior biparietal bitemporal pattern of hypometabolism. EEG shows slowing and loss of alpha rhythm relatively early in the disease. Routine CSF examination is normal but Aβ1–42 concentration is reduced and both total tau and phosphotau increased. The combination of the two results in high sensitivity and specificity in younger Alzheimer’s disease patients at least (Schoonenboom et al. 2004). The criteria for diagnosis of Alzheimer’s disease provide levels of probable and possible diagnosis; definite Alzheimer’s disease is reserved for those in whom histological confirmation of plaques and tangles is available (McKhann et al. 1984). Clinical diagnosis has steadily improved and, using these criteria, high sensitivity of 80–90 per cent but lower specificity of around 70 per cent are commonly reported (Knopman et al. 2001).
The histopathological hallmarks of the disease are neurofibrillary tangles and senile plaques. Neurofibrillary tangles are intraneuronal and found predominantly in the allocortex and temporoparietal neocortex (Fig. 34.3). There is a predilection for pyramidal cells to be involved, particularly in layers three and five of the neocortex, the CA1 layer of the hippocampus, subiculum, and layers two and five of the entorhinal cortex. Braak and Braak quantified regional tangle formation in normal elderly and mild to severe Alzheimer’s disease cases and suggested a staging system with progression of the disease from entorhinal cortex and hippocampus to neocortex (Braak and Braak 1991). This progression can be visualized in vivo by mapping the progressive atrophy in patients with familial Alzheimer’s disease using MRI (Scahill et al. 2002). Neurofibrillary tangles consist of paired helical filaments which can be seen under electron microscopy (Kidd 1963), with a filament diameter of 10 nm wound in a double helix with a periodicity of 160 nm. Neurofibrillary tangles are also found within the dystrophic neurites of senile plaques. The major component of the paired helical filament has been shown to be the microtubule-associated protein tau which is abnormally phosphorylated (Lee et al. 1991). All six tau isoforms are deposited in Alzheimer’s disease (Goedert et al. 1992) which distinguishes the tau pathology from that found in progressive supranuclear palsy, Pick’s disease, and the other tauopathies.
Senile plaques are also found predominantly in neocortical association areas and consist of glial processes, abnormal nerve endings or dystrophic neuritis, and a central core of β-amyloid; they vary between 25 and 200 microns in diameter. β-amyloid is also deposited in cerebral blood vessels. The β-amyloid protein has been isolated and shown to be derived from a much larger transmembrane molecule, the amyloid precursor protein (Kang et al. 1987). Diffuse plaques are not associated with dystrophic neurites and are believed to precede the classical mature plaque. The central amyloid core consists predominantly of the Aβ1–42 species which may act as a nidus for subsequent fibrillary amyloid deposition (Iwatsubo et al. 1995).
Neuronal cell loss is also maximal in the hippocampus and association areas of the neocortex. Cell loss also occurs in subcortical nuclei which include the amygdala and the origins of the subcortical projection systems, the nucleus basalis of Meynert, the nucleus raphe, and the locus coeruleus. The damage to the nucleus basalis and septal nuclei results in the cholinergic deficit, a consistent but not specific feature of Alzheimer’s disease. Replacement of the cholinergic deficit is the basis of current symptomatic treatment. There is an overall association between cell loss and the histological features of plaques and tangles and it is assumed that cells which contain neurofibrillary tangles are degenerating. Other histological changes found predominantly in the hippocampus include eosinophilic Hirano bodies and vacuolar changes in cytoplasm referred to as granulovacuolar degeneration. The severity of the histological changes of senile plaques and neurofibrillary tangles show an overall association with severity of dementia. They are not, however, specific to Alzheimer’s disease and neurofibrillary tangles in the hippocampus are found commonly in normal old age, as are limited numbers of senile plaques throughout the cortex. This has led to quantitative criteria for diagnosis based on neuritic plaques, the Consortium to Establish a Registry of Alzheimer’s Disease criteria now largely superseded by a combination with the Braak score of neurofibrillary tangle distribution, ‘the National Institute on Aging—Reagan Criteria’ (Newell et al. 1999).
The cause of Alzheimer’s disease is still not established but considerable advances have been made which identify a central role for amyloid deposition. This is best understood in patients with autosomal dominant familial Alzheimer’s disease. The rare mutations in the APP gene either increase the total amount of β-amyloid produced or alter the processing to favour amyloid deposition. The APP 670-671 mutation increases the total amount of β-amyloid peptide produced from the precursor protein and is similar in this regard to Down’s syndrome, where there is an increased amount of amyloid produced due to a gene dosage effect arising from the trisomy 21. The amyloid precursor protein is normally cleaved at putative β- and γ-secretase sites to release the 40 amino acid Aβ peptide whose physiological function is unclear. It can be measured as a soluble peptide in both plasma and CSF but will form fibrillary aggregates of β-amyloid in senile plaques. Mutations at APP 717, close to the γ-secretase site, result in a subtle increase in the proportion of molecules extended at the C terminus Aβ1–42 (Fig. 34.4). Aβ1–42 has a greater propensity to fibril formation and can act as a nidus for subsequent Aβ1-40 deposition. The familial Alzheimer’s disease cases associated with mutations in the presenilin 1 and 2 genes (Cruts and Van Broeckhoven 1998), also result in altered metabolism of APP resulting in a relative increase in Aβ1–42; and presenilin 1 is a component of the γ-secretase. ApoE4, also known to be an important genetic risk factor, is associated with enhanced amyloid deposition and may stabilize fibril formation.
These lines of evidence all support a central role for amyloid deposition and the ‘amyloid cascade’ hypothesis (Hardy and Higgins 1992). This model predicts that the neuronal loss and neurofibrillary tangle formation are secondary events, but as yet, it is not established how exactly neurodegeneration is triggered but protofibrils found early in the amyloid aggregation process are neurotoxic. Recent evidence for this central role is provided by transgenic mouse models arising from over expression of a human mutated APP gene, which result in senile plaque formation and can be prevented by immunization with Aβ1–42 (Schenk et al. 1999). The secondary role for neurofibrillary tangles in this pathogenic cascade does not diminish their potential importance as a final common pathway.
Advice, support, and a sensible prognosis for the carer should be available and information can be obtained from national Alzheimer’s Disease Societies and Alzheimer’s Disease International. Treatment of comorbid disease such as infections and heart failure are important as these may cause further deterioration in cognition and behaviour. Patients with dementia are very sensitive to the cognitive side effects of drugs (McKeith and Cummings 2005). Agitation and delusional symptoms may need to be treated but neuroleptic medication should be kept to an absolute minimum as there may be an increased risk of cerebrovascular adverse events. Atypical antipsychotics may be better but are still reported to be associated with a small increase in mortality (Schneider et al. 2005). Depression is a common early feature of Alzheimer’s disease and a trial of a selective serotonin reuptake inhibitor is indicated if there is a clinical suspicion of depressive symptomology. Tricyclics should be avoided because of anticholinergic side effects. Patients who hold a driving licence should inform the national driving authority at the time of diagnosis according to national guidelines but the decision of when to stop driving will depend upon their cognitive function (Waldemar et al. 2007).
There is no current treatment to affect the progression of neurodegeneration in Alzheimer’s disease but, following the effects of immunotherapy in transgenic models (Schenk et al. 1999), a number of trials of active and passive immunization are underway. One active immunization study had to be stopped due to development of meningoencephalitis. However, patients subsequently coming to autopsy had apparent clearance of amyloid (Nicoll et al. 2003). Inhibition of cholinesterase activity in the brain will enhance levels of acetylcholine and thus ameliorate the cholinergic deficit arising from degeneration of the ascending projections from basal forebrain to hippocampus and the neocortex. Donepezil, rivastigmine, and galantamine all have similar symptomatic effects which are modest but improvement in cognitive measures and activities of daily living is seen in 20–25 per cent of patients with mild to moderate Alzheimer’s disease over and above a placebo response (Cochrane database of systematic reviews: 2006). There is no evidence of any effect on disease progression. Memantine, a non-competitive N-methyl-D-aspartate, or NMDA, receptor agonist represents the second class of licenced drugs for Alzheimer’s disease, and is currently approved for moderate to severe disease. It may be combined with cholinesterase inhibitors (Tariot et al. 2004)
34.6.3 Dementia with Lewy bodies and Parkinson’s disease dementia
Terminological confusion has surrounded the group of patients with Parkinsonian features and dementia. It has been known for a long time that patients with Parkinson’s disease may develop cognitive impairment and such patients are found to have Lewy bodies, the pathological hallmark of Parkinson’s disease, throughout the cerebral cortex. With systematic autopsy studies, such cases have emerged as being common, perhaps constituting as many as 15–20 per cent in some series of older patients (Rahkonen et al. 2003). Series based on clinical diagnosis would suggest a similar proportion. However, there are overlaps in terms of both the clinical and pathological features with Alzheimer’s disease, for example, senile plaques found in dementia with Lewy bodies and Lewy bodies are found in classical Alzheimer’s disease, making assessment difficult. However, it is now sufficiently clear that there is a distinct clinical picture with management implications to justify its own nosological status (McKeith et al. 2004). Dementia with Lewy bodies is now the preferred term, but this condition has previously been, and still is referred to as cortical Lewy body disease, Lewy body dementia, senile dementia of the Lewy body type, and Lewy body variant of Alzheimer’s disease.
Cognitive impairment emerges in the majority of patients with Parkinson’s disease with time, typically after about 10 years, and if severe justifies the term Parkinson’s disease dementia. At the end stage dementia with Lewy bodies and Parkinson’s disease dementia will be indistinguishable. Conventionally dementia with Lewy bodies is reserved for cases in which the Parkinsonian syndrome follows or coincides with the cognitive syndrome. For research studies a maximum of 1 year before emergence of the dementia is allowable.
The characteristic clinical picture is that of a cognitive impairment which precedes or follows closely a symmetrical Parkinsonian syndrome although dementia with Lewy bodies may be unaccompanied by extrapyramidal failures. Tremor is rare compared with classical brainstem Lewy body Parkinson’s disease. The cognitive impairment is similar to Alzheimer’s disease except that executive, visuoperceptual, and visuospatial impairments are more prominent and the impairment of episodic memory less severe. The additional striking feature is marked fluctuation of cognitive function which can appear as a confusional state with impairment of attention. Reduplicative paramnesias and hallucinations complete the picture. In between these periods of worsening cognition, caregivers will often report episodes of lucidity. Hallucinations also occur late in Alzheimer’s disease, however, if present at an early and mild stage, this is a strong indicator of an underlying diagnosis of dementia with Lewy bodies (Ballard et al. 1999). The features were formalized into criteria in which in addition to the central feature of dementia two out of three core features of a Parkinsonian syndrome, fluctuations and hallucinations were required to be present. These criteria have been updated (McKeith et al. 2005) with added suggestive features of a rapid eye movement sleep behaviour disorder, severe neuroleptic sensitivity, and low dopamine transporter uptake by single photon emission tomography or positron emission tomography imaging. If one or more suggestive features occur with one core feature, then a diagnosis of probable dementia with Lewy bodies can be made. In some patients, the disorder is of an apparent subacute onset with rapid deterioration and myoclonus may occur prompting a diagnosis of Creutzfeldt–Jakob disease.
The EEG usually shows slowing. MRI may show atrophy with relative greater involvement of the parahippocampal gyrus than hippocampus in contrast to Alzheimer’s disease (O’Brien et al. 1997). Functional imaging shows the biparietal bitemporal pattern of Alzheimer’s disease, but in addition, more prominent occipital changes which may reflect the visuoperceptual problems and hallucinations (Albin et al. 1996). Dopamine transporter imaging, which is reduced in Parkinson’s disease and dementia with Lewy bodies, is spared in Alzheimer’s disease and so may prove a useful diagnostic marker (O’Brien et al. 2004).
Histologically the Lewy body in dementia with Lewy bodies is identical to that found in brainstem Lewy body Parkinson’s disease, consisting of eosinophilic inclusions. Alpha-synuclein is the major component of Lewy bodies (Spillantini et al. 1997) and immunohistochemistry not only shows the widespread distribution of Lewy bodies but also neuritic change in affected cells, so-called Lewy neurites (Fig. 34.5). Cases of Lewy body pathology can be classified according to whether brainstem, limbic/basal forebrain, or neocortical areas are involved. Limbic and neocortical involvement are the predominant patterns in dementia with Lewy bodies. Many cases have associated β-amyloid plaques but typically without the extensive tau-positive neuritic change found in Alzheimer’s disease. Many cases, however, will have additional neurofibrillary tangles and as the tangle load increases the probability that the pathological features are associated with a dementia with Lewy bodies phenotype is reduced (McKeith et al. 2004).
Management is difficult (McKeith et al. 2005). Treatment of the Parkinsonian syndrome may worsen the confusional state. Patients are exquisitely sensitive to neuroleptics which not only precipitate a profound extrapyramidal syndrome but also result in worsening cognition. There is some evidence that the atypical neuroleptics such as olanzepine and risperidone may be safer, but even here, there is a risk of worsening the clinical state and in general, all such drugs should be avoided if at all possible. Autopsy studies have demonstrated a cholinergic deficit comparable to or even greater than that found in Alzheimer’s disease, and cholinersterase inhibitors are of value. A trial of rivastigmine in patients with Parkinson’s disease dementia demonstrated cognitive improvement comparable to that seen in Alzheimer’s disease (Emre et al. 2004).
34.6.4 Frontotemporal degenerations
The frontotemporal degenerations are a group of disorders which are considered together as they all share the characteristic feature of a degenerative process affecting the frontal and/or temporal lobes (Snowden et al. 1996). The anatomical distribution determines the clinical features which may often be asymmetric. These disorders are characterized by disturbances of language, speech production, frontal dysexecutive, and behavioural features. Clinical descriptions of the prototypic syndromes, frontotemporal dementia, also referred to as frontal variant, progressive non-fluent aphasia, and semantic dementia have been published (Neary et al. 1998), but other presentations, for example, primary progressive prosopagnosia (Tyrrell et al. 1990) also occur. The neuropathological processes underlying these diseases are variable and include Pick’s disease, non-specific frontal lobe degeneration, hereditary tauopathies, corticobasal degeneration, and ubiquitin-positive tau-negative motor neurone disease type inclusions; Alzheimer’s disease and prion disease can also present with the features of a frontal syndrome. The difficulty in predicting the underlying neuropathology from the clinical features demands a clinical descriptive approach to the frontotemporal degenerations before considering the potential diseases defined neuropathologically. The nosology surrounding these disorders is confused further by the terminology relating to Pick’s disease. Originally, Pick described cases of focal atrophy with the clinical features of dysphasia and/or a frontal lobe syndrome. This purely descriptive clinical terminology has been championed by some who suggest the term Pick syndrome (Kertesz and Munoz 1998) but in parallel, the development started by Alzheimer, who observed the swollen Pick cells and argentophilic inclusions, Pick bodies, has defined a particular type of neuropathology. More recently, our understanding of the molecular pathology of Pick’s disease has further defined its nosological status.
Asymmetrical cortical degeneration is another term that was introduced by Caselli and Jack (1992) to refer to the group of slowly progressive focal degenerations. In a sense, all degenerative dementias start as a focal syndrome, even including Alzheimer’s disease, which initially is that of a memory impairment. Most of these focal cortical degenerations are subsumed within the frontotemporal degenerative group but primary progressive apraxia, often associated with corticobasal degeneration and posterior cortical atrophy (Benson et al. 1988), usually associated with Alzheimer’s disease, fall outside the general rubric of the frontotemporal degenerations.
Typically, the frontotemporal degenerations show structural or functional imaging changes indicative of frontotemporal degeneration. The EEG is characteristically normal by contrast to Alzheimer’s disease and CSF examination is usually unremarkable.
Management of the frontotemporal degenerations can be very difficult with no available treatment to stop the progression. A randomized trial of trazodone has shown some benefit on the behavioural disturbance (Lebert et al. 2004).
Although the term frontotemporal dementia has been retained as one of the prototypic clinical syndromes of frontotemporal degeneration (Neary et al. 1998), the clinical features are those of a frontal syndrome although the disease process does with time extend into the temporal lobes. An alternative term widely used is frontal variant of frontotemporal degeneration. It is the behavioural change as opposed to language or speech impairment, which characterize this group of patients. Social skills deteriorate early with difficulties at work, and the change in personality can be particularly distressing for the spouse. Some patients become disinhibited and overactive, reflecting predominant involvement of the orbitomedial frontal cortex, whilst others become apathetic, reflecting dorsolateral involvement. Patients who are at first overactive and at times aggressive, may become quieter as the disease progresses. Loss of empathy is common and distressing to the family (Gregory et al. 2002).
Other behavioural features include changes in food preference, usually towards sweet foods, ritualistic behaviours, and daily routines. Preservation of other cognitive skills means that the patient can go off walking in a stereotyped route, without ever getting lost. Dramatic failures on tests sensitive to frontal lobe function are apparent, although some patients may do well even on these tests, but fail on those of social cognition (Blair and Cipolotti 2000). Utilization behaviour may be observed. Speech in some gradually reduces with the features of a dynamic aphasia.
Some patients develop a frontotemporal degeneration in association with motor neurone disease. Characteristically, this involves the anterior horn cells as opposed to long tracts and fasciculation is seen characteristically in the proximal upper limb (Mitsuyama et al. 1979).
Progressive non-fluent aphasia
A non-fluent aphasia with relative preservation of comprehension results in non-fluent and effortful speech, although writing early on may be preserved (Grossman and Ash 2004). Comprehension is relatively preserved even as the disease progresses to mutism. At this stage, patients may travel alone or even drive a car without difficulty. Social skills are preserved early but with disease progression, behavioural changes do emerge. Structural imaging shows left perisylvian atrophy which can also be seen on functional imaging. (Nestor et al. 2003)
The third commonly encountered syndrome is referred to as semantic dementia and describes patients whose presenting feature is that of a verbal semantic memory impairment (Snowden et al. 1989; Hodges et al. 1992). Speech is fluent and on first encounter the disorder may be missed. However, more detailed examination soon reveals the naming and comprehension deficit. Speech production is spared but it does become progressively more empty and communication more difficult. A surface dyslexia is common, representing a dependence on a phonological as opposed to lexical route to reading; it is characterized by difficulty with irregular words, tending to ‘regularize’ their pronounciation. Thus to pronounce ‘pint’ to rhyme with ‘stint’ would be a regularization error. As the disease progresses, the semantic memory deficit may extend into the visual domain, and rarely this can be the presenting feature, with the appearance of a visual associative agnosia. Behavioural changes with altered eating and ritualistic stereotypes occur. The disease starts with language impairment, reflecting left temporal lobe involvement, but with involvement of the right temporal lobe, patients can develop a prosopagnosia and an inability to recognize emotional expressions, impairing further their ability to communicate. MRI and functional imaging reveal asymmetric left anterior temporal lobe atrophy involving the anterior hippocampus (Chan et al. 2001) (Fig. 34.6). In some patients, right temporal lobe atrophy predominates with more florid behavioural changes and in some, prosopagnosia is the presenting feature (Rosen et al. 2005).
Neuropathology of the frontotemporal degenerations
A variety of neuropathological changes are associated with the frontotemporal degenerations (Forman et al. 2006). Although particular syndromes tend to be associated with certain pathologies, there is overlap such that the underlying disease process cannot at present be predicted reliably from the clinical presentation alone. Moreover, it is not yet clear whether the apparent neuropathological entities do indeed represent distinct nosological entities or merely a spectrum of patterns of neuronal degeneration. Recent advances in molecular pathology are helping to clarify this complex group of disorders.
Tau-inclusions. In Pick’s disease, there is striking asymmetric focal atrophy usually with a distinct border. Affected gyri may be very thin with a ‘knife-edged’ appearance. The anterior temporal and frontal lobes are predominantly involved with the superior temporal gyrus characteristically spared, particularly posteriorly. Astrocytic gliosis is variable. The hallmark lesion is the presence of tau-positive, ubiquitin-positive argentophilic inclusions known as Pick bodies, which are widespread and typically prominent in the dentate gyrus; there may in addition, be ballooned neurons or Pick cells. The balloon cells are tau positive and Aβ crystallin positive, and can be identified in a number of cases of frontotemporal degeneration as well as in typical cases of corticobasal degeneration (Binetti et al. 1998). Recent studies have demonstrated that the tau inclusions consist only of tau isoforms which contain the three repeat microtubule-binding domains, ‘three repeat tau’; this now distinguishes Pick’s disease from the other tauopathies (Delacourte et al. 1996). A wider neuropathological substrate has been attributed to Pick’s disease in the past, but it is now considered a rare predominantly sporadic disorder. Pick inclusions or the features of corticobasal degenerations are a common finding at autopsy in patients with progressive non-fluent aphasia.
Hereditary tauopathies. Families with apparent autosomal dominant inheritance of frontotemporal degeneration have long been recognized. Many, but by no means all, are now linked to mutations in the tau gene (Poorkaj et al. 1998; Hutton et al. 1998). Neuropathologically these are associated with glial tau inclusions, tau positive ballooned neurons, ‘Pick cells’, and atypical Pick bodies. The clinical phenotype is variable and often includes an extrapyramidal syndrome and amyotrophy. Before the discovery of tau mutations, these cases were referred to as ‘frontotemporal dementia with Parkinsonism linked to chromosome 17’ (Foster et al. 1997).
Ubiquitin inclusions. Frontotemporal degeneration with motor neurone disease shows similar changes in the frontal lobe to those described under frontal lobe degeneration but with additional loss of motor neurones in the spinal cord. In addition, ubiquitin positive, tau negative inclusion bodies are found particularly in layer 2 of the frontal and temporal cortex. With improved immunohistochemistry an increasing number of cases are found to have ubiquitin positive, tau negative inclusions, which is a common finding in patients presenting with semantic dementia (Rossor et al. 2000; Davies et al. 2005). A proportion of cases of ubiquitin positive inclusions are familial and have characteristic intranuclear deposits, in some of these families mutations in the progranulin gene are found (Baker et al. 2006; Cruts et al. 2006). A large Danish family, with frontotemporal degeneration and ubiquitin inclusions, is associated with a mutation in CHMP2b, part of the ESCRT pathway involved in protein degradation (Skibinski et al. 2005).
Dementia lacking distinctive histology. Frontal lobe degeneration of the non-Alzheimer type (Brun 1993) lacks inclusion bodies or other hallmark features, and has also been referred to as ‘dementia lacking distinctive histology’, (Knopman et al. 1990) and non-specific dementia (Kim et al. 1981). Atrophy tends to be symmetrical in contrast to the asymmetry of Pick’s disease, but can be severe, affecting the frontal lobes. There is microvacuolation or mild spongiosis and astrocytic gliosis, particularly in cortical laminae 1–3. There is no abnormal tau immunoreactivity or inclusions, but some cases have been reclassified as ubiquitin positive inclusions. Some cases of frontotemporal degeneration are found to have neurofilament inclusions (Josephs et al. 2003) and rarely, cases with a phenotype of frontal lobe degeneration are reported in whom the underlying histopathology is that of Alzheimer’s disease or prion disease.
34.6.5 Prion diseases
The prion diseases (Section 42.8) also referred to as the spongiform encephalopathies, comprise Creutzfeldt–Jakob disease, variant Creutzfeldt–Jakob disease, Gerstmann Straussler–Schenker syndrome, Kuru and familial fatal insomnia; diseases that are now grouped together because they share a common disease mechanism involving aberrant protein folding (Prusiner et al. 1998). The novel disease mechanism which results in a disorder that can be both hereditary and transmissible, together with a threat of an epidemic of variant Creutzfeldt–Jakob disease consequent upon the bovine spongiform encephalopathy crisis in Europe, has focused considerable attention on these diseases despite their rarity.
The transmission of Kuru, the spongiform encephalopathy found amongst the Fore highlanders of Papua New Guinea, to non-human primates by Gajdusek led to the concept of a ‘slow virus’ although the transmissible agent remained elusive. Ultimately this was shown to be a protein devoid of nucleic acid—the prion protein PrP (Prusiner 1991). The transmissible prion protein, PrPSc, is derived from a normal cellular protein, PrPc, by post translational modification resulting in a high beta sheet content; the mechanism of the subsequent cellular degeneration is not established. The abnormal isoform of the protein, PrPSc, has the ability to induce aberrant folding of the host protein, hence the transmission which can occur either through cannibalism as in Kuru, or iatrogenically as with growth hormone derived from cadaveric pituitary glands and surgical interventions. Species differences in the PrP sequence make transmission of the disease across species inefficient. This species barrier can occur experimentally and is now believed to have occurred with variant Creutzfeldt–Jakob disease following the bovine spongiform encephalopathy epidemic. Mutations in the PrP gene are believed to facilitate the aberrant protein folding and underlie familial Creutzfeldt–Jakob disease, familial fatal insomnia and Gerstmann Straussler–Schenker syndrome. A common methionine/valine polymorphism at PrP 129 is a genetic risk factor for the disease (Palmer et al. 1991).
Prion diseases are multisystem central nervous system disorders with variable degrees of dementia, cerebellar, pyramidal and extrapyramidal features. Creutzfeldt–Jakob disease occurs world-wide with an annual incidence of about one per million. It is invariably fatal. The classical triad of dementia, myoclonus, and abnormal EEG with periodic or pseudoperiodic complexes is seen typically in patients between the ages of 50 and 70 years. It has a subacute onset; rarely the disease can be extremely rapid with death within 2 months whereas in others there is a slower progression of the disease over 1–2 years (Brown et al. 1986). The different clinical phenotypes in terms of progression have been related to different isoforms of the aberrant prion protein, PrPSc (Parchi et al. 1996). About 10 per cent of cases of prion disease are familial with autosomal dominant transmission due to mutations in the PrP gene. The phenotype can be varied, some mimicking Alzheimer’s disease and others Huntington’s disease; cases with the 144 base-pair insert tend to have a slow progression with a variable phenotype (Collinge et al. 1992). Patients with a prominent cerebellar component were originally described as Gerstmann Straussler–Schenker syndrome and familial fatal insomnia (Lugaresi et al. 1986) is characterized by insomnia with loss or dramatic reduction of slow wave and rapid eye movement sleep, together with autonomic disturbance.
Iatrogenic cases have been associated with corneal grafting, dura mater grafts, and in-depth electrode recording. The majority of iatrogenic cases have been associated with cadaveric pituitary derived growth hormone treatment, a practice which was discontinued in the mid-1980s. These cases have more cerebellar features and less dementia (Fradkin et al. 1991). Variant Creutzfeldt–Jakob disease has emerged in the United Kingdom and France in the last 10 years and is believed to have resulted from ingestion of contaminated food from bovine spongiform encephalopathy infected cattle and recently by blood transfusions from individuals harbouring the disease (Llewelyn et al. 2004). Recent incidence cases of Kuru suggest that incubation periods in excess of 40 years can occur with human to human prion disease transmission (Collinge et al. 2006). Variant Creutzfeldt–Jakob disease is associated with a characteristic PrPSc isoform (Collinge et al. 1996). The cases of variant Creutzfeldt–Jakob disease are younger than classical Creutzfeldt–Jakob disease, some even in their teens, with early depression, anxiety, and dysaesthesiae. Cerebellar and basal ganglia features are more prominent than cognitive impairment early in the disorder (Will et al. 2000).
The characteristic histopathology is the spongiform change, although this is variable; it is associated with neuronal intracytoplasmic vacuolation together with astrocytosis and gliosis. The abnormal prion protein, PrPSc, can be demonstrated on immunohistochemistry and can form plaques, especially in the cerebellum in Gerstmann Straussler–Schenker syndrome. Variant Creutzfeldt–Jakob disease is also associated with PrP plaques reminiscent of Kuru.
Blood tests are usually normal in prion disease, although there can be mildly abnormal liver function tests. PrP genotyping will identify mutations in the familial cases and cases of variant Creutzfeldt–Jakob disease reported to date have all been methionine homozygous at PrP 129. MRI may show increased signal in the basal ganglia and cortex in sporadic Creutzfeldt–Jakob disease, most readily seen with diffusion weighted imaging (Tschampa et al. 2005). In variant Creutzfeldt–Jakob disease a characteristic increase in MRI signal in the posterior thalamus, the pulvinar sign, is best seen with FLAIR images (Zeidler et al. 2000). Cerebrospinal fluid is unremarkable although P14-3-3, which probably reflects rapid neuronal disintegration, is found in most classical Creutzfeldt–Jakob disease cases. The EEG may be normal or non-specific early in the disease but in classical Creutzfeldt–Jakob disease pseudoperiodic or periodic complexes are seen. Pharyngeal tonsillar biopsy in variant Creutzfeldt–Jakob disease can reveal the specific PrPSc isoform (Hill et al. 1999).
At present there is no specific treatment for the prion diseases (Trevitt and Collinge 2006). The PrPSc is highly resistant to degradation and thus instruments cannot be routinely sterilized. Neurosurgical instruments must be quarantined and if the diagnosis confirmed, destroyed. There is no need to barrier nurse patients but disposable instruments should be used for invasive procedures, and all samples clearly indicate the suspected diagnosis.
34.6.6 Vascular cognitive impairment
Impairment of blood supply to the brain used to be considered to be the main cause of dementia in the elderly until it was recognized that such a mechanism is rarely, if ever, implicated. Multiple small strokes, referred to as multi-infarct dementia, were subsequently identified to be an important mechanism both clinically and at autopsy (Hachinski et al. 1974). In most early neuropathological and clinical series, vascular dementia accounted for some 10–20 per cent of dementia cases alone, but importantly is a major concomitant of Alzheimer’s disease in the elderly so called mixed dementia (Neuropathology group 2001). Moreover, up to 25 per cent of patients 3 months after a stroke were considered to have dementia using Diagnostic and Statistical Manual of the American Psychiatric Association, DSM-IV, criteria and up to 60 per cent had cognitive impairment (Pohjasvaara et al. 1997). The incidence of vascular dementia may be falling with better management of vascular risk factors. It is also believed that many cases of dementia with Lewy bodies were previously diagnosed clinically as vascular dementia. If cases of dementia where there is a vascular component are considered, then there is no doubt that vascular disease is a major cause or contributor to cognitive impairment (Hachinski and Bowler 1993). The term vascular dementia replaced multi-infarct dementia as it reflected the considerable heterogeneity of the condition and includes cases due to haemorrhage, small lacunar infarcts, large cortical infarcts, and vasculitides. However, the dependence of the term on the dementia criteria meant that only late cases would be included and the term vascular cognitive impairment is increasingly used (O’Brien et al. 2003).
Clinical criteria for the diagnosis of vascular dementia have been dominated by the development of criteria for Alzheimer’s disease. Thus, memory remains as a key component and yet may be relatively less important in vascular dementia (Bowler et al. 1997) in which executive dysfunction is prominent. Early criteria assumed that stepwise deterioration and motor abnormalities would be characteristic and from this was developed the Hachinski score. Patients with a score of 4 or less were considered likely to be degenerative by contrast to those with a score of 7 or more who were thought to have a multi-infarct dementia. This remains a useful guide and series have been pathologically verified (Moroney et al. 1997). Criteria (Roman 1998) have been developed which require the appearance of cognitive impairment within 3 months of a stroke or sudden onset and fluctuation of cognitive impairment. In view of the potential contribution of focal neuropsychological deficits from a discrete stroke, the cognitive criteria for dementia are that, there should be memory impairment plus at least two other affected domains. There should also be relevant vascular changes on imaging which are thought to be directly related. However, very different proportions of cases are diagnosed as vascular dementia depending upon the use of different consensus criteria. (Wetterling et al. 1996).
Various vascular pathologies are associated with vascular cognitive impairment: single discrete cortical infarcts, multiple infarcts or multi-infarct dementia, subcortical arteriosclerotic encephalopathy or Binswanger disease, hypoperfusion dementia, and haemorrhages. In reality, these may overlap.
Single discrete infarcts, for example, in right middle cerebral and posterior cerebral artery territories and thalamic infarcts, can present with a picture suggestive of dementia. Much more common however, are accumulation of deficits from multiple individual cortical and/or subcortical infarcts. Men are more commonly affected than women and there is usually a vascular history particularly of hypertension. There is a gradual accumulation of cognitive deficits with episodes of confusion or focal neurology but the onset may be insidious with gradual progression in the absence of stepwise deterioration. If there are mainly subcortical infarcts, patients tend to have a subcortical pattern of cognitive deficit with cognitive slowing and additional motor features. Some may develop an extrapyramidal syndrome and in others a pseudobulbar palsy can be prominent with pathological laughing and crying. Neuropathologically, multiple small subcortical infarcts appear to be more important in vascular dementia than single large infarcts (Esiri et al. 1997).
Subcortical arteriosclerotic encephalopathy: Binswanger’s disease
Binswanger originally described eight cases of periventricular demyelination and dementia. This was considered a rarity until the advent of neuroimaging and many patients with white matter changes on scanning acquired this diagnosis. Clinically, it is very similar to patients with multiple subcortical infarcts namely frontal and subcortical cognitive features, dysarthria, and pseudobulbar palsy. Gait impairment may occur early and is characterized by a wide-based shuffling gait in contrast to the narrower base seen in Parkinson’s disease (Thompson and Marsden 1987). Criteria have been suggested for the diagnosis of Binswanger’s disease (Bennett et al. 1990).
Much confusion has arisen from attempts to diagnose Binswanger’s disease from neuroimaging. Non-specific periventricular white matter abnormalities are common both in patients with dementia and in the non-demented elderly and the term leukoaraiosis has been proposed (Hachinski et al. 1987). Leukoaraiosis appears as low attenuation on CT scan particularly around the frontal and occipital horns and as increased signal on T2-weighted MRI (Fig. 34.7). Neuropathologically, there is demyelination, gliosis, and hyalinosis with fibrinoid necrosis of small blood vessels similar to that seen in hypertension. Minor degrees of white matter disease are also seen in pure Alzheimer’s disease.
Increasingly the term subcortical vascular dementia or subcortical vascular cognitive impairment is used to encompass both ‘Binswanger’s disease’ and the lacunar state as these normally co-exist. The subcortical cognitive impairment reflects the anatomical distribution of disease (Gold et al. 2005)
Treatment of vascular cognitive impairment is primarily that of management of vascular disease risk factors such as hypertension, smoking, diabetes, carotid stenosis, and heart disease. There have been few control trials of management of risk factors and its effect on cognition but, treatment of isolated systolic hypertension in the elderly may reduce the incidence of dementia (Forette et al. 1998). Statins may be less important as hypertension is a greater risk factor than hypercholesterolaemia for small vessel disease (Shepherd et al. 2002). Cholinesterase inhibitors are reported to be of some benefit but it is not clear how much may relate to coexistent Alzheimer’s disease (Bowler et al. 2003).
Other causes of vascular dementia
Significant cognitive impairment, sufficient to justify the criteria of dementia, can occur after subarachnoid haemorrhage, subdural haematomas, and global ischaemia following cardiac arrest with laminar necrosis and hippocampal cell loss, ‘hypoperfusion dementia’ (Sulkova 1987). A variety of vasculitides can also be associated with the early development of cognitive impairment and even present as a dementia; these include systemic lupus erythematosus (Section 36.3.1) and primary cerebral angiitis (Section 36.2.2) which is usually accompanied by headaches. Sneddon’s syndrome (Rebollo et al. 1983) is the association of livedo reticularis with cerebrovascular disease and can present with cognitive impairment. A number, but not all, are associated with anticardiolipin antibodies.
The rare cases of hereditary cerebral amyloidosis both of the Icelandic, the Dutch, and the Flemish type, can be associated with cognitive impairment although the salient clinical feature is that of recurrent cerebral haemorrhage. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, known as CADASIL (Dichgans et al. 1998) is characterized by recurrent subcortical ischaemic events with the subsequent development of a pseudobulbar palsy and cognitive impairment. Early symptoms include migraine-like headache and psychiatric disturbance. The MRI scan shows a striking leukoencephalopathy in addition to multiple small infarcts with characteristic signal changes in the temporal pole and external capsule. This condition, which is increasingly recognized is linked to mutations in the Notch 3 gene (Joutel et al. 1996). Most mutations are found in exons 3 and 4. Notch 3 deposition can be demonstrated in the smooth muscle of the arteriole wall, and skin and muscle biopsies can be highly specific although sensitivity is low (Markus et al. 2002).
34.6.7 Miscellaneous causes of dementia
Since cognition is so easily disrupted by diseases affecting the cortex and its subcortical connections, cognitive impairment or dementia is very common in neurological practice. In the majority of cases the other clinical features provide the diagnostic clues. These dementia-plus syndromes are numerous and include Huntington’s disease, some spinocerebellar ataxias, and a variety of inherited metabolic disorders, such as metachromatic leucodystrophy, Kuf’s disease, lysosomal storage disorders and mitochondrial cytopathies. Normal pressure hydrocephalus can present as the classic triad of dementia, incontinence, and gait disturbance, but has tended to be over-diagnosed (Section 26.4.5). The cognitive impairment is very much that of a subcortical impairment with cognitive slowing. Patients with prominent cognitive impairment are more likely to have a coexisting degenerative disease and rarely, if ever, respond to shunting. Multiple sclerosis patients will often develop cognitive impairment and in some this can be a prominent and even presenting feature.
Syphilis is the classic infection which can be associated with dementia (Section 42.5.1). However, late cases of Borrelia burgdorferi, Lyme disease, can also be associated with dementia (Krupp et al. 1991) (Section 42.5.2) and Whipple’s disease (Section 42.5.8) can rarely involve the cerebral cortex with cognitive impairment which responds to antibiotic treatment (Singer 1998). The other major infection associated with dementia is HIV encephalopathy and dementia can be a presenting feature (Janssen et al. 1992) (Section 43.3.5). The clinical features are those of a subcortical dementia: minor degrees of cognitive impairment insufficient to fulfil criteria for dementia are termed ‘HIV-associated minor cognitive/motor disorder’. Only a small proportion of such patients progress to frank dementia. There is evidence that dementia is becoming less common with antiretroviral treatment but the prevalence of minor cognitive impairment has remained unchanged, possibly because of prolonged survival (Cysique et al. 2004). Progressive multifocal leucoencephalopathy (Section 42.3.14) is frequently associated with cognitive impairment and occurs in a variety of immuno-suppressed patients as well as those with HIV.
One of the reasons for neuroimaging of patients with dementia is to identify tumours, the treatment of which can result in cognitive improvement. However, with malignant tumours irradiation itself may give rise to late cognitive impairment (Keime-Guibert et al. 1998) (Section 5.9.2). The paraneoplastic phenomenon of limbic encephalitis, usually associated with carcinoma of the bronchus, can result in a memory impairment that precedes diagnosis of the tumour by a number of years and can mimic Alzheimer’s disease (Section 38.4.2). However, examination of the CSF usually reveals oligoclonal bands and occasionally pleocytosis (Bakheit et al. 1990). Non-paraneoplastic limbic encephalitis has recently been associated with antibodies to the voltage-gated potassium channels (Vincent et al. 2004; Thieben et al. 2004). Drugs, particularly barbiturates, can lead to cognitive slowing as can heavy metals, such as lead, arsenic, manganese, and mercury. Workers in the felt hat industry who were exposed to mercury frequently developed a confusional state with cognitive impairment, hence the term ‘mad as a hatter’ (Section 5.7.5). Dementia pugilistica, arising from recurrent head injury, particularly in boxers, is associated with tangles and presents as a cognitive impairment with dysarthria and an extrapyramidal syndrome.
A variety of rare degenerative dementias are gradually being delineated although some, such as argyrophilic grain dementia (Braak et al. 1989) are really only diagnosed at autopsy. Kosaka (1994) described a series of patients with basal ganglia calcification on neuroimaging with neurofibrillary tangles but no senile plaques. The rare Worster–Drought syndrome, a familial disorder with dementia and spastic paraparesis is now recognized as a novel amyloidosis due to a stop codon mutation in the BRI gene (Vidal et al. 1999). The disease is now also referred to as familial British dementia. The MRI reveal deep white matter changes, lacunar infarcts, and prominent callosal atrophy (Mead et al. 2000). Patients with a frontotemporal dementia, Paget’s disease, and inclusion body myositis have mutations in the valosin-containing protein which is involved in ubiquitination and degradation of proteins (Schroder et al. 2005).
34.7 Acute confusional states and delirium
Acute confusional states are extremely common, especially in the elderly, and may occur in up to 25 per cent of those admitted to medical and surgical wards (Taylor and Lewis 1993). It is very common in intensive care units (McNicoll et al. 2003), and after heart bypass (Santos et al. 2004). By contrast to dementia, confusional states are usually short-lived and potentially reversible with prominent impairments of attention and arousal (Lipowski 1990). The term ‘acute confusional state’ tends to be most commonly used in Europe and the term ‘delirium’ to be used in the US. The terms toxic psychosis, acute brain syndrome, acute encephalopathy, and transient cognitive disorder are all synonymous (Lipowski 1990). Patients are likely to be elderly, although the very young are also vulnerable. The condition is often seen within the setting of systemic disease or multiple drug therapy. Disruption of attention, a loss of the ability to focus on specific stimuli, is a key feature. This consists of impairment of selective attention with the patient unable to attend to the examiner and being continually distracted by irrelevant environmental stimuli (Geschwind 1982; Inouye 1990). Arousal may be impaired with somnolence and descent into stupor, or alternatively agitation may occur. However, attention is impaired even if arousal is enhanced. These disturbances of selective attention and arousal result in marked disorientation in place and time, particularly of a sense of time of day, but as with dementia personal identity is normally preserved. The sleep–wake cycle is disrupted with patients being awake at night leading to the familiar feature of the patient wandering into the street in their night clothes. Memory is impaired, in particular short-term memory as assessed by the digit span, is greatly disrupted by the impairment of attention. This is not, however, specific to confusional states. There are frequent paramnesias such as reduplicative paramnesia and the Capgras syndrome (Section 34.4.7). Misperceptions, particularly with visual hallucinations are prominent, whereas auditory hallucinations should raise the suspicion of a functional psychosis. Patients may have bizarre and very frightening hallucinations often with image distortion, known as metamorphopsia, and these can occur particularly with drugs and toxins. Language is relatively preserved although the content is abnormal. Errors may relate to the disrupted thought processes and errors on naming may reflect visual misperceptions or reflect paramnesic errors; these disturbances on confrontational naming have been referred to as non-aphasic misnaming (Weinstein and Kahn 1952). As might be predicted, judgement is grossly impaired, particularly since anosognosia is the rule rather than the exception and may result in patients being combative and aggressive when being examined or if any attempt is made to restrain them. Mood lability is common and fluctuations in the cognitive state are frequent, such that the patient may be seen in a lucid interval when examined. The onset of a confusional state is acute or subacute over hours or days, in contrast to the common dementias, and fluctuation characteristic.
In addition to the cognitive features, clinical examination commonly reveals autonomic disturbance with tachycardia, hypertension, sweating, fever, and tachypnoea. Asterixis, myoclonus, increased tone, and carphologia, or plucking at the bedclothes, are often found. There may be evidence of systemic disease such as cardiac failure, respiratory failure or infections and these should be carefully sought.
Common difficulties with differential diagnosis include the functional psychoses (Lishman 1987). In general, patients with functional psychoses are orientated in time and place and not overtly dysphasic, although there may be a bizarre content. An abrupt onset in an older patient without a psychiatric history would be most unusual for functional psychosis. Similarly, any clouding of consciousness or disorientation suggests an acute confusional state, as does the predominance of visual over auditory hallucinations.
The distinction from dementia may be difficult with chronic confusional states. Moreover, the two often co-exist; acute confusional states may evolve into dementia, and patients with dementia are very prone to acute confusional states due to infections or drugs. Dementia with Lewy bodies (Section 34.6.3) may also present with features of a confusional state. Patients with dementia may also develop confusion with reduced or unfamiliar environmental cues, so called ‘sundowning’ at night. In general, when a patient presents with cognitive impairment suggestive of an acute confusional state with rapid onset and fluctuation, the more aggressive should be the investigation for reversible underlying causes.
The disturbance of arousal in acute confusional states can be attributed to dysfunction of the reticular activating system, and patients will have associated disturbances of the sleep–wake cycle and may deteriorate into stupor or even coma. Abnormalities of arousal, however, are not necessary to make a diagnosis of an acute confusional state in those instances in which impaired attention is prominent. Attention requires both disregard of irrelevant environmental stimuli and sustained attention on relevant stimuli. The association cerebral cortices provide the anatomical substrate of selective attention (Mesulam 1981) with particular involvement of the non-dominant parietal lobe as evidenced by the occurrence of acute confusional states with right middle cerebral artery infarcts (Mesulam et al. 1976). A disturbance of selective attention may also occur with frontal lobe lesions.
The disturbances that cause acute confusional states tend to be generalized and it has been proposed that the selective vulnerability of the systems that subserve arousal and selective attention is due to their polysynaptic characteristics. It has also been suggested that the ascending cholinergic system may be particularly vulnerable because of the prominent confusional state that can occur with anticholinergic drugs (Tune et al. 1981; Han et al. 2001).
The causes of acute confusional states are legion. Acquired metabolic disturbances, particularly hypoxia and hypoglycaemia are common and require prompt treatment. Thiamine deficiency should always be considered in patients who are admitted to accident and emergency departments without a clear history, since the administration of glucose can precipitate a Wernicke’s encephalopathy. Drugs are a very common cause, particularly in patients on multiple drug regimens (Carter et al. 1996). Anticholinergics, anti Parkinsonian, and benzodiazepine drugs, as causes of confusional states are commonly encountered in neurological patients (Foy et al. 1995; Jain 2001). Recreational drugs including alcohol, cocaine, ‘crack’, amphetamines and LSD are all well recognized causes. Acute confusional states commonly occur following surgery and are often due to a combination of drugs, hypoxia, electrolyte disturbance, and infection but may also be exacerbated by fragmented sleep. Confusional states are common after cataract surgery in the elderly and may relate to sensory deprivation (Summers and Reich 1979). Approximately 30 per cent of patients undergoing open heart surgery or coronary artery bypass grafting develop confusional states (Smith and Dimsdale 1989): recognition of a confusional state in the setting of an intensive care unit can be diagnostically challenging. Cerebrovascular disease can cause acute confusional states, particularly right middle cerebral artery infarcts (Mesulam et al. 1976), but also occur with posterior cerebral artery infarcts (Medina et al. 1974). Migraine attacks may rarely be associated with a confusional state, particularly in children. Epilepsy is a common cause both during the seizure and as a post-ictal phenomenon.
Investigation should be thorough and will in part be directed by the general medical examination. Not only will this include screening of blood sugar, electrolytes, liver function tests, and a search for infection, but where necessary a drug screen. Neuroimaging, EEG to detect diffuse slowing or low voltage fast activity, and examination of CSF may all be necessary.
Management and prognosis
Management depends upon treatment of the underlying cause and symptomatic measures should be directed towards the maintenance of constant environmental stimuli so as to avoid over and under-stimulation; a night-light may be valuable (Meagher et al. 2001). Drug therapy should be kept to an absolute minimum, but patients may rarely require a neuroleptic for marked agitation, atypical antipsychotics with low anticholinegic properties are preferable.
Although in general the prognosis is good, delirium can be life-threatening and is an important determinant of institutionalization (Cole 2004). Many elderly patients may have underlying degenerative disease which renders them vulnerable to confusional states, and in whom a stable cognitive deficit may emerge as the confusional state clears (Levkoff et al. 1992; Jackson et al. 2004).
Hallucinations are a common accompaniment of confusional states, but they can also occur in a variety of other disorders. A hallucination may be defined as a sensory perception occurring without an external stimulus. An illusion is defined as a misinterpretation of an external stimulus and can occur in normal people, particularly with fatigue. A delusion, by contrast, is an idea or thought, such as a false concept of persecution, which has no substance in fact; in contrast to visual and auditory hallucinations, it is purely a thought process with no sensory content. Hallucinations and delusions may occur together in various toxic or confusional states and in psychotic illnesses, such as schizophrenia.
The principal circumstances in which hallucinations may occur are:
♦ in dreaming and the hypnagogic state;
♦ in pathological disorders of sleep;
♦ as a result of disease of the peripheral sense organs;
♦ focal disturbance of the central nervous system and in neurodegenerative diseases;
♦ drug-induced hallucinations; and
♦ in certain psychoses.
Hallucinations are not uncommon in states of drowsiness and will occur in hypnagogic states, when falling asleep, and hypnopompic, on awakening from sleep, but to an exaggerated extent in patients suffering from narcolepsy. Visual hallucinations can occur particularly in the elderly with reduced visual acuity and can occur with lesions anywhere along the visual pathway, Charles Bonnet syndrome (Santhouse et al. 2000). Visual hallucinations are a core feature of dementia with Lewy bodies. Extracampine hallucinations in which there is a sense of a person outside the visual field also occur commonly in dementia with Lewy bodies (Chan and Rossor 2002). Auditory hallucinations, including music, may also occur following acquired deafness, and again may be more common in the elderly (Stewart et al. 2006). Hallucinations involving various sensory modalities, together with perceptual illusions and other disorders of consciousness are particularly liable to occur as a result of lesions of the temporal lobes. These may frequently occur as epileptic phenomena. The perceptual illusions include disordered visual perception, for example macropsia or micropsia, and a similar alteration in auditory perception, feelings of unreality of the self or the surroundings, and disturbances of awareness of the body. Visual hallucinations have been described in which the individual feels that he is observing his own body from outside his physical self; this unusual phenomenon has some affinity with sensations of intense depersonalization or unreality. Visual hallucinations also sometimes occur as a result of epileptic discharge arising in the posterior part of the temporal lobe or in the parieto-occipital region. Agitated delirium and visual impairment may, for example, result from medial temporo-occipital infarction (Medina et al. 1977). L’hermitte described peduncular hallucinosis with lesions of the upper part of the brainstem which was interpreted as a dissociation of the state of sleep. Hallucinations may also result from brainstem compression (Dunn et al. 1983) and elementary auditory hallucinations may occur with pontine lesions, so-called ‘pontine auditory hallucinosis’.
A variety of drugs may result in hallucinations, mescaline and lysergic acid, LSD, being notorious. However, withdrawal of alcohol can result in hallucinosis, which may become permanent particularly in established alcoholics. Hallucinations are an important diagnostic feature of the psychoses. They may occur with severe affective disorders, such as depression in which they are often associated with morbid features. Auditory hallucinations occurring in clear consciousness which are mood incongruent are very suggestive of schizophrenia. It is characteristic that such auditory hallucinations involve argument about the patient in the third person.
34.9 Psychiatric disorders in neurological practice
34.9.1 Mood disturbance
Affective disturbances commonly involve the neurologist, either because patients with a primary diagnosis of depression present with neurological symptoms, because the patient develops a depressive reaction to their neurological disability, or, less commonly, a depressive illness arises directly as a result of central nervous system disease.
A depressive illness is the commonest psychiatric diagnosis to be found in neurological practice (Kirk and Saunders 1977). The commonest presentations are headache, dizziness, and memory impairment. A careful history may unearth depressive symptomatology, such as persistent dysphoria, loss of appetite and libido, and disturbed sleep patterns with early morning waking. Suicidal ideation should be specifically sought. However, patients may not volunteer or may minimize mood symptoms, focusing instead on somatic complaints. Depressive pseudodementia (Caine 1981) is an important diagnosis since it is the main cause of a reversible dementia. The term ‘pseudodementia’ is not ideal, as these patients do have impaired cognition and probably share some of the neurochemical disturbances found in other dementias, namely deficits in the ascending monoaminergic projections to cerebral cortex. The clinical features are those of a subcortical dementia with marked slowing of cognition. The patients often complain of their memory disturbance and are clearly distressed by it. Patients give many ‘don’t know’ answers to questions, in contrast to patients with Alzheimer’s disease who will give incorrect or circumlocutary refutable answers. Effortful, as opposed to implicit memory function, is particularly affected. As a general rule, patients who spontaneously complain of memory loss should always raise the possibility of a depressive illness. Depression is, however, common early in Alzheimer’s disease and requires appropriate treatment.
A depressed mood as a reaction to neurological disability is commonplace and can be difficult to distinguish from persistent depression which may be more intimately related to the neurological disturbance itself. Diseases of the basal ganglia and connections to frontal lobe are particularly liable to cause depressive illness. Thus, frontal meningiomata were commonly misinterpreted as depressive illness particularly in the pre-scanning days. Depression is a common accompaniment of Parkinson’s disease that is not relieved by improvement in motor function following drug treatment (Mindham et al. 1976; Santamaria et al. 1986); this may indicate an overlap in the underlying biochemical disturbance of monoamine systems. Cerebrovascular disease is a frequent cause of mood changes with up to a third of patients developing depression after stroke. It is important for management since many patients may become depressed some months after their stroke and appropriate follow-up is essential (Wade et al. 1987). Some studies have suggested a high prevalence of depression with dominant hemisphere infarcts, particularly with more anteriorly located lesions (Starkstein and Robinson 1993). This has not been confirmed in other studies, although the high prevalence of depression is recognized (House et al. 1990). Hypomania and euphoria are much less common, but can occur with cerebral infarcts and with Huntington’s disease. It is often stated that patients with multiple sclerosis develop an euphoria and although this may be observed, depressive illness is still the major mood change (Schiffer 1987).
Anxiety is defined in the Diagnostic and Statistical Manual of the American Psychiatric Association, DSM-IV, as ‘The apprehensive anticipation of future danger or misfortune accompanied by a feeling of dysphoria or somatic complaints of tension. The focus of anticipated danger may be internal or external’. Both DSM-IV and ICD-10 classify anxiety disorders into a number of categories; the most relevant to neurological practice are generalized anxiety disorder, panic disorder, specific phobias, and post traumatic stress disorder. As with depression, patients may develop anxiety in response to their neurological illness and, in addition, patients with anxiety may present to the neurologist by virtue of their symptoms. Generalized anxiety may result in a number of symptoms of nervousness, fatigue, and loss of concentration. These are generally non-specific symptoms and the key features are the additional acute attacks of anxiety. These attacks are associated with nervousness and increasing panic which if severe, as in phobic-anxiety attacks, may result in intense sensations of depersonalization and fear of impending death. There may be a sense of being smothered together with dyspnoea and frequently palpitations, both of which may result in referrals to a cardiologist. Nausea, urinary frequency, and vertigo during attacks are common. Hyperventilation, by virtue of the reduction in pC02, will itself contribute to the sense of vertigo and result in paraesthesiae classically affecting the fingers and circumoral region. If sufficiently severe, this may result in tetany (Section 4.3.4).
Panic attacks may occur in relation to obvious precipitating factors particularly in relation to specific phobias, such as open spaces or heights. They are quite frequent following trauma and caffeine may precipitate anxiety in normal people and panic attacks in those who are susceptible. They may, however, occur in apparently unprovoked situations. Diagnostic confusion occurs with epilepsy, labyrinthine disturbance, essential tremor, and cognitive impairment. Anxiety and panic attacks usually present in patients in their twenties and are rare as an initial presentation after the age of 40. Forced hyperventilation for a period of 2–3 min may reproduce many of the symptoms aiding diagnosis, but care should be taken in the interpretation since many of the symptoms of paraesthesiae, vertigo, and derealization can be precipitated as a normal concomitant of forced hyperventilation.
Post traumatic stress disorder is usually associated with both anxiety and depression. Key diagnostic features are flashbacks to the original trauma which may be triggered by relevant stimuli. Patients characteristically avoid situations which might be associated with the original trauma. Such symptoms are common immediately after a traumatic event but are considered abnormal if persisting for more than a month.
34.9.3 Obsessive–compulsive disorders
Obsessions are recurrent, intrusive thoughts or images that are often repulsive to the individual. Compulsions are repetitive and stereotyped behaviours that are found in association with obsessions and are usually performed according to certain rules and may be used to neutralize obsessional thoughts. Commonest amongst the obsessive–compulsive disorders are ritual washing and cleaning, and ritual checking. Pure obsessive disorder with stereotyped thoughts, which are often of an illicit sexual or sacrilegious nature, are less common. A close association of obsessive–compulsive disorders with neurological disease has been recognized since the development of obsessive–compulsive behaviour was observed in association with post-encephalitic Parkinsonism, especially with oculogyric crises (Section 40.3.6). There is also a high prevalence of obsessive–compulsive disorder in Gilles de la Tourette syndrome (Robertson et al. 1988) (Section 40.6.3) in patients with Sydenham’s chorea (Swedo et al. 1989) (Section 40.5.7) and in paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (Swedo et al. 1998) and the Kleine–Levin syndrome (Arnulf et al. 2005) (Sections 32.3.3; 34.11). Neurological abnormalities are frequently found on examination in patients with obsessional slowness, and include speech and gait abnormalities, cogwheel rigidity and tics, together with frontal neuropsychological deficits (Hymas et al. 1991). This suggests dysfunction within the fronto-striatal connections, a view supported by focal hypometabolism on 15-oxygen positron emission tomography scanning in the orbital frontal, pre-motor, and mid-frontal cortex (Sawle et al. 1991).
34.10 Disorders of sexual behaviour
Disturbances of sexual behaviour, as opposed to disturbance of the mechanics of sexual activity arising from disease to the spinal cord and peripheral nerves (Section 29.5.2), is seen predominantly with diseases of the basal ganglia and frontal and temporal lobes. Sexual imagery may form part of the obsessive–compulsive disorder and disturbed behaviour may arise in association with post-encephalitic Parkinson’s disease. Similarly, cases of increased libido and paraphilia have been found in patients on treatment for Parkinson’s disease (Quinn et al. 1983). Disturbances in sexual behaviour in patients with frontal lobe lesions probably reflect disinhibition. Lesions of the temporal lobes are frequently associated with disturbances in sexual behaviour, found most commonly as part of the spectrum of temporal lobe epilepsy. Reduced libido with impotence as an inter-ictal phenomenon is common, but hypersexuality can occur as an immediate post-ictal phenomenon (Blumer 1970). In addition to hyper- or hyposexuality, the development of paraphilias can occur with temporal lobe lesions or temporal lobe epilepsy. The most famous case was that described by Mitchell et al. (1954) of a 38- year-old man who had experienced pleasure in looking at, and imagining, safety pins, since adolescence. Increasingly this would be associated with sexual arousal and on occasions would result in the precipitation of temporal lobe seizures. As the attacks became more frequent, he developed impotence. Post-ictally, he would occasionally dress in his wife’s clothing. He was found to have a left temporal lobe focus with increased EEG activity on looking at safety pins. He underwent left temporal lobectomy and at operation, gliosis was found. Following surgery, there was a resolution of his attacks, restoration of potency, and cessation of the paraphilia.
Sexual disinhibition can occur in all the common dementias (Alagiakrishnan et al. 2005) but is particularly common with frontotemporal dementia. This reflects the involvement of medial basal frontal cortex and amygdalae, structures commonly implicated in acquired hypersexuality or paraphilias (Miller et al. 1986). Malpositioned ventricular catheters affecting the septal area can also lead to hypersexuality (Gorman and Cummings 1992).
Finally, side effects of a variety of drugs in neurological practice may alter sexual behaviour. Neuroleptics, antihypertensives and anticonvulsants may reduce libido. Dopaminergic drugs can be associated with increased libido and rarely with emergence of paraphilias.
34.11 Eating disorders
Neuroendocrine control of feeding behaviour is carefully balanced and an increasing number of neurotransmitters, hormones, and receptors are now known to be involved, including neuropeptide Y, PYY, corticotrophin releasing factor, leptins, ghrelin, and insulin (Woods et al. 1998). These are primarily under hypothalamic control and eating disorders are commonly found with hypothalamic lesions. Anorexia and bulimia nervosa, classically considered psychiatric disorders, may relate to hypothalamic disturbance. These disorders are seen primarily in adolescent and young women. Anorexia nervosa is associated with a distorted body image and the fear of gaining weight and individuals have increased physical activity, reduced caloric intake and at times, dramatic weight loss. Bulimia nervosa involves episodic gorging followed by self-induced vomiting, laxative, and diuretic abuse (Yager and Andersen 2005).
Changes in eating behaviour can also be seen with the frontotemporal degenerations (Section 34.6.4) and a variety of drugs in neurological practice, for example, sodium valproate and steroids can lead to enhanced appetite.
The Kleine–Levin syndrome
This is rare and originally described in males, but can rarely be seen in females (Section 32.3.3). It typically starts in adolescence, often following infection or head injury, and may resolve with time. It is characterized by episodes, typically lasting from 4 to 7 days, of hypersomnia, hypersexuality, hyperphagia, and altered mood (Asnulf et al. 2005). The hyperphagia may herald the onset of an attack with the individual eating raw and cooked food with a voracious appetite (Critchley 1962), the same clinical syndrome has been reported with a localized diencephalic encephalitis.
Sleep-related eating disorder
This was first reported in 1955 as ‘night eating syndrome’ (Stunkard et al. 1955) and is linked to somnambulism. Patients develop nocturnal hyperphagia, insomnia, and subsequent obesity. It is more common in women than men and there is commonly partial or complete amnesia for the event. Low-dose pramipexole (Provini et al. 2005) and topiramate have been reported to be beneficial (Winkelman et al. 2003).
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