Symptoms associated with regional brain pathology
Assessment of the ‘neuropsychiatric patient’
Amnesia and amnestic syndromes
Other neuropsychiatric syndromes
Secondary or symptomatic neuropsychiatric syndromes
Neuropsychiatry comprises psychiatric disorders that arise from demonstrable abnormalities of brain structure and function. Cognitive impairments are the most prominent feature, especially in dementia and delirium, but behavioural and emotional disturbances are also common, and may be the sole manifestations.
The term neuropsychiatry is sometimes used interchangeably with organic psychiatry (see David, 2009a). However, the latter category is broader, including psychiatric disorders that arise from general medical disorders with their basis outside the brain (e.g. endocrine and metabolic disorders). These disorders are covered in Chapter 15. Moreover, the term organic has the fundamental problem that it wrongly implies that other psychiatric disorders do not have any such basis (see Chapter 2, p. 26); neuroscience increasingly shows the falsity of this dichotomy. Finally, both terminologies run the risk that psychological and social factors will be neglected because the disorder is considered to be ‘physical.’
In this chapter we cover the range of disorders conventionally considered under the heading of neuropsychiatry, which include:
• delirium—acute, generalized cognitive impairment in the setting of altered consciousness
• dementia—chronic, generalized cognitive impairment in clear consciousness. As with delirium, the syndrome of dementia can be caused by many separate disease processes (this chapter covers the clinical features and aetiology of dementia; its treatment and management are covered in Chapter 18)
• amnestic (or amnesic) syndromes—circumscribed deficits in memory
• head injury
• other neuropsychiatric disorders, including focal cerebral syndromes, infections, tumours, and multiple sclerosis
• secondary or symptomatic neuropsychiatric disorders—disorders such as depression and anxiety which in particular cases can be attributed directly to a neuropsychiatric cause (e.g. psychosis due to cerebral vasculitis). (Psychiatric disorders secondary to diseases elsewhere in the body are covered in Chapter 15.)
In ICD-10, organic psychiatric disorders are termed organic, including symptomatic, mental disorders, and in DSM-IV they are categorized as delirium, dementia, amnestic and other cognitive disorders. The two classifications are compared in Table 13.1. The main differences can be summarized as follows.
• The omission of ‘organic’ from the section title in DSM-IV led to rearrangement of the classification of some conditions formerly grouped under the heading ‘organic.’ Thus major depression with organic aetiology is classified under mood disorders either as secondary to a general medical condition, or as substance induced. As a result of these changes, DSM-IV avoided the problems within ICD-10 of the definition of the terms organic, symptomatic, and secondary (Spitzer et al., 1992).
• In both classifications the specific medical conditions causing cognitive disorder can be coded in addition to the latter disorder. In DSM-IV, this additional code is recorded on Axis III.
• In ICD-10, the section on organic disorder includes subcategories for mental disorders due to brain damage and dysfunction and to physical disease, and for personality and behavioural factors due to brain disease, damage, and dysfunction (e.g. ‘organic anxiety disorder, thyrotoxicosis’). In DSM-IV these conditions are classified under the relevant psychiatric disorder, with the addition of a code to indicate that the disorder is secondary to a medical condition.
• DSM-IV includes categories of substance-induced delirium, dementia, and amnestic disorders. In ICD-10 these conditions are recorded in the section on mental and behavioural disorders due to psychoactive substance abuse. Thus, for example, amnestic syndrome is coded in ICD-10 in this section, but amnestic syndrome due to alcohol (Korsakov’s syndrome) is classified as a psychoactive substance abuse disorder.
Table 13.1 Classification of organic mental disorders
Symptoms associated with regional brain pathology
Before considering the various syndromes, it is helpful to consider the characteristic features associated with lesions in different regions of the brain, and the neuro-anatomical basis of memory. Knowledge of the regional affiliation of neurological and psychopathological findings is relevant when attempting to localize neuropsychiatric conditions. However, the clinical features are not diagnostically specific, and the clinico-pathological correlations are often modest rather than strong. For a review of this subject, see David (2009a).
The frontal lobes, together with their reciprocal connections to other cortical and subcortical regions, have a crucial role in personality and judgement. Patients with a frontal lobe syndrome may present with a variety of clinical syndromes.
• They may be disinhibited, overfamiliar, tactless, and garrulous, make fatuous jokes and puns (Witzelsucht), commit errors of judgement and sexual indiscretions, and disregard the feelings of others.
• They may appear inert (abulic) and apathetic, with a paucity of spontaneous speech, movement, and emotional expressions.
• They may engage in obsessive, ritualistic behaviours, with perseveration of thought and gesture.
Measures of formal intelligence are generally unimpaired in frontal lobe disease. However, there may be difficulties in abstract reasoning (e.g. ‘How are glass and ice different?’) and cognitive estimates are typically inaccurate but precise (e.g. ‘364 miles from London to New York’). Concentration and attention are reduced, and insight is often markedly impaired. Verbal fluency, assessed using word generation by letter (e.g. number of words beginning with ‘s’ in one minute) and category (e.g. number of animals), is reduced, and unusual (low-frequency) examples may be volunteered. The patient has difficulty switching between tasks (perseveration), carrying out sequenced movements, and understanding rules. Utilization behaviour (e.g. donning several pairs of spectacles) may be evident.
Posterior extension of a dominant frontal lobe lesion may involve Broca’s area and produce an expressive (non-fluent) dysphasia. Encroachment on the motor cortex or deep projections may result in a contralateral hemiparesis. Other signs may include ipsilateral optic atrophy or anosmia, a grasp or other primitive reflexes and, if the process is bilateral or in the midline, incontinence of urine.
Lesions of the parietal lobe may cause various neuropsychological disturbances which are easily mistaken for conversion disorder (see p. 394). Involvement of the non-dominant parietal lobe characteristically gives rise to visuospatial difficulties, with neglect of contralateral space, and constructional and dressing apraxias. Lesions of the dominant lobe may be associated with receptive dysphasia, limb apraxia, body image disorders, right–left disorientation, dyscalculia, finger agnosia, and agraphia. Other signs may include contralateral sensory loss, astereognosis and agraphaesthesia, and (with more extensive lesions) a contralateral hemiparesis or homonymous inferior quadrantanopia.
Persistent unawareness of neurological deficit (anosognosia) is not uncommon, especially with non-dominant parietal lesions. In extreme cases, the patient may deny that a paretic limb belongs to him. This should be distinguished from denial due to a psychological unwillingness to recognize disability and its consequences.
The temporolimbic syndromes are characterized by complex and wide-ranging neuropsychiatric clinical pictures. There may be personality change resembling that of frontal lobe lesions, but more often accompanied by specific cognitive deficits and neurological signs. The relatively florid behavioural disturbances that characterize the frontotemporal dementias reflect the combined temporal and frontal involvement, and their interconnections.
Unilateral medial temporal lobe lesions, especially those involving the hippocampus, produce lateralizing memory deficits—left hippocampal damage impairs verbal memory (and semantic impairment and fluent dysphasia), whereas right hippocampal damage affects non-verbal (spatial) aspects of memory. Some evidence also suggests that left medial temporal lobe lesions are more likely to produce psychotic symptoms, and right-sided lesions produce affective ones.
Occipital lobe lesions rarely present to psychiatrists, but they may cause disturbances of visual processing which are easily misinterpreted as being of psychological origin. Such phenomena occasionally accompany migraine or occipital lobe seizures. Complex visual hallucinations may occur with lesions involving visual association areas, sometimes referred to a hemianopic field. These include multiple visual images (polyopia), persistent aftertraces of the features of an image (visual perseveration or palinopsia), and distortions of the visual scene (metamorphopsia). Lesions that impinge anteriorly on the parietal or temporal lobes may produce visual disorientation (inability to localize objects in space under visual guidance) with asimultagnosia (difficulty in perceiving the visual scene as a unity), or prosopagnosia (inability to recognize familiar faces). In patients with suspected occipital lobe pathology, the visual fields should be mapped using perimetry, and neuropsychological tests performed to delineate visual agnosias and other higher-order derangements of visual processing. Some patients who are blind due to occipital lobe damage deny that they are blind (Anton’s syndrome).
Corpus callosum lesions (classically, the ‘butterfly glioma’) typically extend laterally into both hemispheres. They then produce a picture of severe and rapid intellectual deterioration, with localized neurological signs varying with the degree and direction of extension into adjacent structures. Pure callosal lesions (usually iatrogenic, following surgery for intractable epilepsy) can be surprisingly difficult to identify, and require specialized neuropsychological testing to expose a ‘disconnection syndrome’, reflecting disruption of interhemispheric communication. These unique ‘split-brain’ patients raise intriguing questions concerning the mechanisms that normally bind the two hemispheres together to generate a consistent, unitary sense of the self (Gazzaniga, 2000). Callosal degeneration is a hallmark of the rare Marchiafava–Bignami syndrome, which is seen in severe alcohol dependence.
Subcortical structures and cortico-subcortical circuits
The regional cortical associations with cognitive, affective, and behavioural features reflect the classic ‘locationist’ approach to neurology and neuropsychiatry. Increasingly, this is being complemented, if not replaced, by a ‘connectionist’ approach, in which emphasis is placed on distributed neural systems in which cortical regions are linked with subcortical structures, and with the white matter pathways that connect them.
Mesulam (1998) described five networks:
• a right-hemisphere spatial awareness network including the posterior parietal cortex and frontal eye fields
• a left-hemisphere language network including Broca’s and Wernicke’s areas
• a memory–emotion network including the hippocampus, amygdala and cingulate cortex
• a working memory–executive function network including the prefrontal cortex and posterior parietal cortex
• a face and object recognition network in the temporoparietal and temporo-occipital cortex.
Another influential model is that of Alexander and Crutcher (1990), who proposed four parallel circuits linking different parts of the cerebral cortex with specific basal ganglia and thalamic nuclei. Each circuit mediates different functions. For example, the ‘limbic’ circuit, which is involved in emotional and motivational processes, links the anterior cingulate cortex and medial prefrontal cortex with the ventral striatum, ventral pallidum, and mediodorsal thalamus.
Thalamus, basal ganglia, and cerebellum
A variety of cognitive and psychiatric consequences have been described following lesions of subcortical nuclei. These structures, which were previously considered to be primarily involved in sensory processing (the thalamus) or in motor control (the basal ganglia and cerebellum) are now all known also to be integrally involved in cognition and behaviour, and lesions therein may present with psychiatric as well as neurological features (DeLong and Wichmann, 2007; Schmahmann and Pandya, 2008), and include disturbances of memory, language, and mood. Reduced initiation of actions is also characteristic of basal ganglia pathology, and impaired consciousness with thalamic lesions.
Behavioural disturbances frequently accompany lesions of the rostral brainstem. The most characteristic features are an amnestic syndrome (see below), hypersomnia, and the syndrome of akinetic mutism(‘vigilant coma’) or stupor.
As well as the corpus callosum, mentioned earlier, damage to other white matter tracts—both subcortical and periventricular—has important neuropsychiatric and behavioural consequences. For example, degeneration of the white matter (leukodystrophy) can produce a schizophrenia-like syndrome (Hyde et al., 1992), whereas multiple focal areas of white matter damage are associated with an increased risk of mood disorder and dementia. The clinical features of white matter pathology depend on the location of the damage and whether it is focal or diffuse. For a review of this subject, see Schmahmann et al. (2008).
Memory systems and their neuroanatomy
Clinical, neuropsychological, and brain imaging studies (both structural and functional) support the existence of multiple memory systems in the human brain. These functions may all be affected more or less selectively by brain lesions. The most basic division lies between implicit (i.e. procedural) and explicit (i.e. declarative) memory. The former includes a range of phenomena that are not usually subject to conscious analysis, such as motor skills, conditioned behaviours, and repetition priming. Explicit memory is subclassified into episodic (memory of autobiographical events) and semantic (knowledge of the world) functions.
The short-term store underpins working memory (e.g. when dialling an unfamiliar telephone number). Distinct anatomical substrates for short-term storage of verbal and visuospatial information, both controlled by a central executive, have been proposed. In neuropsychological terms, ‘short-term’ refers to immediate recall. By contrast, the concept of ‘short-term’ memory, as sometimes applied by clinicians to recall over minutes and days, does not correspond to an anatomical substrate.
Specific types of memories, such as faces and topographical information, may engage dedicated subsystems. Episodic memory has both anterograde (new learning) and retrograde (recall of past events) components. It appears to be mediated by a network of cortical and subcortical structures, which include the hippocampus, parahippocampal and entorhinal cortices, amygdala, mammillary bodies, fornix, cingulate, thalamus, and frontobasal cortex, whereas semantic memory may be subserved by a partly independent network overlapping the language areas. Broadly speaking, verbal memories are mediated by the left (dominant) hemisphere and non-verbal memories by the right hemisphere.
For a review of the classification and neuroanatomical basis of memory and its dysfunction, see Budson and Price (2005) and David and Kopelman (2009).
Assessment of the ‘neuropsychiatric patient’
The assessment of cognitive function was introduced in Chapters 1 and 3 as part of the general psychiatric assessment, and in this chapter the evaluation of amnesia, delirium, and dementia will be discussed. In this section, we introduce key aspects of the initial approach to the patient who has a suspected neuropsychiatric disorder. For a more detailed discussion, see Kipps and Hodges (2005) and David (2009b).
Before embarking upon the assessment, it is worth bearing in mind the range of major diagnostic possibilities. One question to be addressed early on is whether there is clouding of consciousness, as this defines delirium, and the assessment can proceed to determine its cause. If there is no impaired consciousness, the main diagnostic categories to consider are amnesia, dementia, or a ‘functional’ cause of cognitive impairment. The key feature of an amnestic syndrome is a specific deficit in episodic memory, as outlined above; although rare, amnestic syndrome needs to be considered in patients presenting with memory impairment, especially in those with alcohol dependence. A functional cause should always be considered, as memory impairment may occur secondary to many psychiatric disorders; in particular, depression in the elderly may present as pseudodementia (see Chapter 18, p. 503). Distinction between organic and functional causes requires positive evidence to be sought for both forms of disorder, and is an important distinction to make, as it has a significant impact upon treatment and prognosis. Once these other causes of cognitive impairment (delirium, amnestic syndrome, and functional disorder) have been ruled out, a provisional diagnosis of dementia can be made (assuming that the impairment is of sufficient severity), and attention can then turn to determining the type of dementia from which the patient is suffering, as discussed later.
History and mental state examination
Although physical examination and laboratory investigations play a much larger role than elsewhere in psychiatry, the history remains essential: ‘the difference between a good neuropsychiatrist and a mediocre one is a good history’ (David, 2009b). An informant is especially important, as the presence of impaired cognition or consciousness will necessarily limit the patient’s ability to provide a full and accurate history. Key points in the history include the onset, duration, and progression of the impairment—for example, an acute onset suggests delirium or, if it began after a fall, may indicate a subdural haematoma. The neurological, medical, and family history is important too, as many causes of cognitive impairment are secondary to pre-existing disorders, or have a genetic basis.
The physical examination needs to be comprehensive and careful, as signs may not be conspicuous. Particular attention should be paid to the nervous system, as well as to searching for peripheral stigmata of systemic disease and alcohol dependence. Specific signs may provide diagnostic clues (Cooper and Greene, 2005) (e.g. the Argyll–Robertson pupil of neurosyphilis, optic disc pallor in vitamin B12 deficiency, or cranial nerve signs in neurosarcoidosis).
The choice and extent of investigations will depend on the findings from the history, mental state examination, and physical examination, but usually includes a core set of tests, such as the cognitive tests and blood tests used in evaluation of dementias noted below. In difficult or atypical cases, and in younger patients, investigations may be extensive, and the opinion and assistance of a neurologist, physician, or neurosurgeon may be required.
Some examples of specialized investigations used in neuropsychiatric evaluation are listed below.
• Structural brain imaging with CT or MRI. Neuroimaging can detect focal and diffuse pathologies, and longitudinal scans can map progressive changes that mirror clinical decline. MRI is superior to CT for most purposes, including evaluation of white matter disease, and the ability to perform volumetric measurements. Functional brain imaging with fMRI, MRS, SPECT, or PET is a valuable research tool, but is not in widespread clinical use.
• Neuropsychological testing is less widely used than previously, in part because of the increasing availability of brain imaging. However, it can still play a valuable part in characterization of the cognitive impairment (e.g. the cognitive domains that are most affected), inferred localization of the lesion (see p. 313), and measurement of severity and progression (David, 2009b). Rating scales for the assessment of dementia are considered below.
• Electroencephalogram (EEG) studies retain a limited but valuable role in several situations where EEG findings are characteristic—for example, in delirium, prion disease, and detection of non-convulsive status epilepticus. They are also useful in the differential diagnosis of stupor, as a normal EEG would suggest a dissociative state.
• Cerebrospinal fluid (CSF) examination after lumbar puncture is essential if an inflammatory or infective process is suspected. It may also become more widely used in the evaluation of dementia, as different proteins are being found which have diagnostic or prognostic value.
• Genetic testing has a key role in the diagnosis (and prediction) of a very limited range of disorders in which the mode of inheritance, and the causative gene, are known (e.g. Huntington’s chorea).
• Brain biopsy, usually of the right frontal lobe, is occasionally indicated as a last resort in the diagnosis of unexplained cognitive impairment or in suspected prion disease. However, the risks of this procedure must always be weighed against the diagnostic and prognostic information that will be obtained from it.
Delirium is characterized by global impairment of consciousness (clouding of consciousness), resulting in reduced level of alertness, attention, and perception of the environment. A number of other terms, such as ‘confusional state’ and ‘acute organic syndrome’, have also been used, but delirium is the preferred term in both ICD-10 and DSM-IV.
For a review of delirium and its management, see Burns et al. (2004) and Meagher and Trzepacz (2009).
Delirium occurs in 15–40% of patients in general medical or surgical wards, and a higher proportion of patients in intensive-care units (Siddiqi et al., 2006). It is more common in the elderly and in other individuals with diminished ‘cerebral reserve’, notably those with preexisting dementia. Overall, about one in five general hospital inpatients develops delirium at some stage of their admission.
The cardinal feature is disturbed consciousness. It is manifested as drowsiness, decreased awareness of one’s surroundings, disorientation in time and place, and distractibility. At its most severe the patient may be unresponsive (stuporose), but more commonly the impaired consciousness is quite subtle. Indeed the first clue to the presence of delirium is often one of its other features, which include mental slowness, distractibility, perceptual anomalies, and disorganization of the sleep–wake cycle (see Table 13.2).
Symptoms and signs vary widely between patients (Meagher et al., 2007), and in the same patient at different times of day, typically being worse at night. For example, some patients are hyperactive, restless, irritable, and have psychotic symptoms, while others are hypoactive, with retardation and perseveration. Repetitive, purposeless movements are common in both forms. Thinking is slow and muddled, but often rich in content (‘dream-like’). Ideas of reference and delusions (often persecutory) are common, but are usually transient and poorly elaborated. Visual perception is often distorted, with illusions, misinterpretations, and visual hallucinations, sometimes with fantastic content. Tactile and auditory hallucinations also occur. Anxiety, depression, and emotional lability are common. The patient may be frightened, or perplexed. Experiences of depersonalization and derealization are sometimes described. Attention and registration are particularly impaired, and on recovery there is usually amnesia for the period of the delirium.
The main causes of delirium are listed in Table 13.3. Often more than one cause contributes. Old age, frailty, and previous medical and neurological disorders lower the threshold for developing delirium.
Table 13.2 Clinical features of delirium
Clouding of consciousness
Disorientation for time and place
Behavioural and other symptoms
Fluctuation over 24-hour period
Reversal of sleep–wake cycle
The pathophysiological basis of delirium is unclear. The severity of clinical disturbance correlates with the degree of slowing of cerebral rhythms on EEG, and the neurotransmitters dopamine and acetylcholine are implicated in a final common pathway.
Management of delirium
Delirium is a medical emergency. It is essential to identify and treat the underlying cause, and a range of investigations may be required (see Table 13.4). Diagnostic instruments, such as the Confusion Assessment Method, can also be valuable (Wong et al., 2010). As delirium is often caused by drugs (due to side-effects or withdrawal effects), these should always be suspected until there is evidence of another cause. As well as urgent investigations, general measures are necessary to relieve distress, control agitation, and prevent exhaustion. These include frequent explanation, reorientation, and reassurance. Unnecessary changes in the staff who are caring for the patient should be avoided. The patient should ideally be nursed in a quiet single room. Relatives should be encouraged to visit regularly. At night, lighting should be sufficient to promote orientation, while not preventing sleep. For a review, see Meagher and Trzepacz (2009).
Table 13.3 Causes of delirium
Alcohol withdrawal and delirium tremens
Any drug with anticholinergic properties
Febrile illness (e.g. urinary tract infection)
Organ failure (cardiac, renal, hepatic)
Hypo- or hyperglycaemia
Epileptic seizure (post-ictal)
Drug treatment of the underlying physical problem should be reviewed to ensure that it is the minimum required. Despite the above interventions, which should always be tried first, many patients with delirium require medication to control agitation and distress, and to allow adequate sleep.
There is a lack of good-quality trials of delirium treatment (Skrobik, 2010). In practice, the drug of choice is usually an antipsychotic. Haloperidol is conventionally used, in a dose carefully titrated to achieve the desired calming effect without excess sedation or side-effects. If necessary, the first dose can be given intramuscularly, followed by doses every 6 hours (typically 2–10 mg per day, although elderly patients may require less). Atypical antipsychotics are also increasingly used instead of haloperidol. Some causes of delirium require avoidance of antipsychotics, or particular caution when using them. This includes all patients with coexisting dementia, especially dementia with Lewy bodies, who are particularly sensitive to antipsychotics.
Table 13.4 Investigations for delirium
Full blood count
Urea and electrolytes
Renal function tests
Liver function tests
Random blood glucose
Arterial blood gas
MRI or CT brain scan
Antipsychotics should be avoided in delirium associated with alcohol withdrawal (delirium tremens, see p. 450) or with epilepsy, because of the risk of seizures. In delirium tremens, a reducing regimen of the benzodiazepine chlordiazepoxide is the standard treatment (see p. 459).
All sedative drugs should be used sparingly in liver failure because of the danger of precipitating hepatic coma.
Many cases recover rapidly. The prognosis is related to the underlying cause, and is worse in the elderly, and in those with pre-existing dementia or physical illness. There is an elevated mortality rate following delirium, with an estimated 25% mortality at 3 months, although published estimates vary markedly (Siddiqi et al., 2006). A recent meta-analysis of elderly patients found that an episode of delirium was robustly associated with a twofold increased risk of death in the next 2 years, as well as with increased risks of institutionalization and of a diagnosis of dementia (Witlox et al., 2010).
Amnesia and amnestic syndromes
Amnesia is loss of memory, and amnestic syndromes or amnestic disorders are those in which memory is specifically and persistently affected (see Table 13.5). An amnestic disorder is defined by DSM-IV as a specific impairment of episodic memory, manifested as inability to learn new information (anterograde amnesia) and to recall past events (retrograde amnesia), accompanied by ‘significant impairment in social or occupational functioning’, and with evidence of a general medical condition ‘aetiologically related to the memory impairment.’ Unlike dementia, the memory deficit occurs in the absence of evidence for generalized intellectual dysfunction. Korsakov syndrome (also called Korsakoff syndrome) is sometimes erroneously referred to synonymously with amnestic syndrome, but is in fact a specific form of it, as described below.
For a review of this subject, see Kopelman (2009).
Table 13.5 Causes of amnesia
Transient global amnesia
Transient epileptic amnesia
Post-traumatic stress disorder
Amnesia for criminal offence
Persistent (amnestic syndrome)
Posterior cerebral artery and thalamic strokes
The cardinal feature is a profound deficit in episodic memory. The full clinical picture is striking. There is disorientation for time, loss of autobiographical information (often extending back for many years), severe anterograde amnesia for verbal and visual material, and lack of insight into the amnesia. Events are recalled immediately after they occur, but forgotten a few minutes later. Thus the digit span, which tests the short-term memory store, is typically normal. New learning is grossly defective, but retrograde memory is variably preserved and shows a temporal gradient, with older memories being better preserved. Other cognitive functions are relatively intact, although some emotional blunting and inertia are often observed.
The other classic feature, seen particularly in Korsakov syndrome, is confabulation, in which gaps in memory are filled by a vivid and detailed but wholly fictitious account of recent activities which the patient believes to be true. The confabulating patient is often highly suggestible.
Aetiology and pathology
Amnesia results from lesions in the medial thalamus, other midline diencephalic structures, or medial temporal lobes (hippocampus and adjacent temporal cortex). Cases due to damage in the medial temporal lobe typically produce the ‘purest’ amnesia, with little in the way of disorientation or confabulation; these features are characteristic of thalamic and diencephalic lesions.
The commonest cause of amnestic syndrome is Korsakov syndrome, named after the Russian neuropsychiatrist (sometimes spelt as Korsakoff) who described it in 1889. The alternative term, Wernicke–Korsakov syndrome, was proposed by Victor et al. (1971), because the syndrome often follows an acute neurological syndrome called Wernicke’s encephalopathy, described by Wernicke in 1881, consisting of delirium, ataxia, pupillary abnormalities, ophthalmoplegia, nystagmus, and a peripheral neuropathy. Korsakov syndrome is usually caused by thiamine deficiency, secondary to alcohol abuse, although it occasionally results from hyperemesis gravidarum and severe malnutrition. The classic neuropathological findings are neuronal loss, gliosis and microhaemorrhages in the periaqueductal and paraventricular grey matter, the mammillary bodies, and the anterior and mediodorsal thalamus. Other causes of amnestic syndrome include tumours and infarcts in the medial thalamus (diencephalic amnesia), and encephalitis (see below).
For a review of Korsakov syndrome, see Kopelman et al. (2009).
Investigation and management
Alertness to the possibility of amnestic syndrome is essential; the patient may not fit the stereotype of chronic alcohol misuse associated with Korskov syndrome, and this is a potentially reversible condition. Useful findings from investigations include a reduced red cell transketolase level, which is a marker of thiamine deficiency, and an increased MRI signal in midline structures.
In practice, Korsakov syndrome should be assumed to be the cause of amnestic syndrome until another aetiology (see Table 13.6) can be demonstrated, and should be treated urgently with thiamine without awaiting the results of investigations. Thiamine is given parenterally in an acute presentation, together with rehydration, general nutritional support, and treatment of supervening alcohol withdrawal. Thiamine replacement should always precede administration of intravenous glucose-containing solutions. Close liaison with physicians and neurologists is important.
Table 13.6 Differential diagnosis of transient amnesia and other paroxysmal neuropsychiatric symptoms
Syncope (cardiogenic, vasovagal, reflex)
Transient ischaemic attacks
Epileptic seizure (ictal or post-ictal)
Transient global amnesia
Narcolepsy and other parasomnias
Tonic spasms of multiple sclerosis
Treatment-related complications in Parkinson’s disease
Medial temporal lobe tumour
Panic attacks and hyperventilation
Bipolar affective disorder
Aggressive outburst in personality disorder
Temper tantrums (in children)
Breath-holding spells (in children)
In the longer term, persistent amnestic syndrome may require substantial rehabilitation and support, as the condition markedly impairs normal activities and ability to provide self-care.
Course and prognosis
In the series of Victor et al. (1971), consisting of 245 patients with Wernicke–Korsakov syndrome, 96% of the patients presented with Wernicke’s encephalopathy. Mortality was 17% in the acute stage, and 84% of the survivors developed a typical amnestic syndrome. There was no improvement in 50% of cases, complete recovery in 25%, and partial recovery in the remainder. Favourable prognostic factors were a short history before diagnosis and prompt commencement of thiamine replacement.
The prognosis is poor in cases of amnestic syndrome due to encephalitis and other causes of irreversible bilateral hippocampal or diencephalic damage. However, amnestic syndrome due to head injury has a better outlook. Progressive amnesia suggests a slowly expanding structural lesion, such as a midbrain tumour.
Transient global amnesia
The syndrome of transient global amnesia is important in the differential diagnosis of paroxysmal neurological and psychiatric disturbance (see Table 13.6). It occurs in middle or late life. The clinical picture is of sudden onset of isolated, often profound, anterograde amnesia in a clear sensorium, generally lasting for between 15 minutes and 24 hours. Functional imaging studies during transient global amnesia have demonstrated localized transient hypo- or hyperperfusion consistent with dysfunction of circuits that mediate episodic memory.
The patient appears bewildered, and requires repeated reorientation, only to ask the same questions moments later. However, there is no disturbance of alertness, and (in contrast to psychogenic fugue) personal identity is retained. Procedural memory is spared—for example, the patient may carry on driving competently during the episode. Apart from the memory disturbance, the neurological examination is entirely normal.
Complete recovery, with amnesia for the period of the episode, is usual and recurrence is rare. However, investigation is always indicated, to exclude other causes of amnesia (see above and Table 13.6). Patients with transient global amnesia often present as emergencies to general practitioners and Accident and Emergency departments, and the syndrome may be misdiagnosed as a dissociative fugue.
For a review of this subject, see Quinette et al. (2006).
Dementia is an acquired global impairment of intellect, memory, and personality, but without impairment of consciousness (Burns and Illiffe, 2009a). It is usually but not always progressive. The syndrome of dementia is caused by a range of diseases (see Table 13.7), of which Alzheimer’s disease (accounting for 50–60% of cases), vascular dementia (20–25%), and dementia with Lewy bodies (15–20%) are the commonest. Only a small proportion (4% of cases in one large series) are currently potentially reversible (Hejl et al., 2002).
Although dementia is a global or generalized disorder, it often begins with focal cognitive or behavioural disturbances. However, both DSM-IV and ICD-10 definitions require impairment in two or more cognitive domains (memory, language, abstract thinking and judgement, praxis, visuoperceptual skills, personality, and social conduct), sufficient to interfere with social or occupational functioning. Deficits may be too mild or circumscribed to fulfil this definition, and are then called mild cognitive impairment (see p. 325).
In this section, the main features of the dementia syndrome are described, followed by the principles of assessment. We then discuss the clinical, aetiological, and neuropathological features of the major diseases that produce dementia. Note in Table 13.7 that many other neuropsychiatric disorders and some medical disorders can also include cognitive impairment; these conditions are considered later in this chapter and in Chapter 15, respectively. Dementia as a result of substance misuse, especially alcohol misuse, is discussed in Chapter 17.
It should be noted that the management of dementia, and the relationships between dementia and ageing, are deferred until Chapter 18.
Clinical features of dementia
The presenting complaint is usually of poor memory. Other features include disturbances of behaviour, language, personality, mood, or perception.
Table 13.7 Causes of dementia
Primary neurodegenerative disorders
Alzheimer’s disease*, dementia with Lewy bodies, Pick’s disease and other frontotemporal dementias,*Parkinson’s disease*, prion diseases*, Huntington’s disease*
Vascular dementia, multiple strokes, focal thalamic and basal ganglia strokes, subdural haematoma
Inflammatory and autoimmune causes
Systemic lupus erythematosus and other vasculitides with CNS involvement, Behçet’s disease, neurosarcoidosis, Hashimoto’s encephalopathy, multiple sclerosis
Severe head injury, repeated head trauma (‘dementia pugilistica’)
Infections and related conditions
HIV, iatrogenic and variant CJD (prion disease), neurosyphilis, post-encephalitic
Metabolic and endocrine causes
Renal failure, hepatic failure, hypothyroidism, hyperthyroidism (‘apathetic’ or masked), hypoglycaemia, Cushing’s syndrome, hypopituitarism, adrenal insufficiency
Intracranial space-occupying lesions, carcinomatous or lymphomatous meningitis, paraneoplastic limbic encephalitis
Acute and subacute radionecrosis, radiation thromboangiopathy
Severe anaemia, post-surgical (especially cardiac bypass), carbon monoxide poisoning, cardiac arrest, chronic respiratory failure
Vitamin and other nutritional deficiencies
Vitamin B12 deficiency, folate deficiency
Alcohol, poisoning with heavy metals, organic solvents, organophosphates
Normal-pressure hydrocephalus Leucodystrophy*
* Causes exist in genetically determined forms.
The clinical picture is much determined by the patient’s premorbid personality. People with good social skills may continue to function adequately despite severe intellectual deterioration. Dementia is often exposed by a change in social circumstances or an intercurrent illness. The elderly, socially isolated, or deaf are less likely to compensate for failing intellectual abilities; however, their difficulties may go unrecognized or be dismissed.
Forgetfulness is usually early and prominent, but may sometimes be difficult to detect in the early stages. Impaired attention and concentration are common and non-specific. Difficulty with new learning is usually the most conspicuous feature. Memory loss is more evident for recent than for more remote material. Disturbed episodic memory is manifested as forgetfulness for recent day-to-day events, with relative preservation of procedural memory (e.g. how to ride a bicycle) and, at least initially, general knowledge about the world at large. By contrast, words and, ultimately, the very objects to which they refer, lose their meaning for patients with semantic memory impairment (as in certain frontotemporal dementias).
Loss of flexibility and adaptability in new situations, with the appearance of rigid and stereotyped routines (‘organic orderliness’), and, when taxed beyond restricted abilities, sudden explosions of rage or grief (‘catastrophic reaction’) are frequent. As dementia worsens, patients are less able to care for themselves and they neglect social conventions. Disorientation for time, and later for place and person, is common. Behaviour becomes aimless, and stereotypies and mannerisms may appear. Thinking slows and becomes impoverished in content and perseverative. False ideas, often of a persecutory kind, gain ground easily. In the later stages, thinking becomes grossly fragmented and incoherent. This is reflected in the patient’s speech, with syntactical and dysnomic errors. Eventually the patient may become mute. Mortality is increased, with death often following bronchopneumonia and a terminal coma (Mitchell et al., 2009).
Behavioural, affective, and psychotic features often accompany the cognitive deficits during dementia. They appear to be part of the underlying biology of the disease process, although in the early stages, while insight is retained, they may also be a psychological response to the realization of cognitive decline. Mood disturbances are particularly common, together with distress, anxiety, irritability, and sometimes aggression. Later, emotional responses become blunted, and sudden, apparently random mood changes occur. Psychotic symptoms are also a common and fluctuating feature during dementia.
The balance of these core symptoms and signs, together with some additional features, forms the basis for the clinical differentiation between the various causes of dementia, as summarized in Table 13.8 and described in the following sections.
Subcortical and cortical dementia
A distinction is sometimes drawn between subcortical and cortical dementia, based upon their putative neuro-anatomical basis. Although the distinction is blurred, clinically and pathologically, the terms have descriptive utility (Turner et al., 2002). The key features are summarized in Table 13.9, and examples of the diseases are listed in Table 13.10. The term subcortical dementia is seen to refer to a syndrome of slowness of thought, difficulty with complex, sequential intellectual tasks, and impoverishment of affect and personality, with relative preservation of language, calculation, and learning. It contrasts with the spectrum of dysfunction (including early, prominent impairments of memory, word finding, or visuospatial abilities) that is seen in cortical dementias.
Table 13.8 Clinical features that help to distinguish between major causes of dementia
Presenile and senile dementia
Another traditional distinction was that made between dementia occurring in those under 65 years of age (prese-nile or earlyonset dementia) and dementia beginning later in life (senile or late-onset dementia). It arose in part because of the belief that the major causes were different—Alzheimer’s disease in the former, and vascular dementia in the latter. With the realization that Alzheimer’s disease is the commonest form of dementia in both groups, less attention is now paid to this categorization. However, presenile dementia does differ in certain respects from later-onset dementia (Sampson et al., 2004). Frontotemporal dementia and prion disease are relatively more common, vascular dementia is rarer, and a higher proportion of cases are due to genetic diseases. These factors influence management. Patients with presenile dementia are more likely to be referred to and investigated by neurologists, before psychiatrists become involved in their care. Investigations are more intensive and extensive because of the importance of making a definite diagnosis and providing a clear prognosis. The course tends to be more rapid.
Table 13.9 Features of cortical and subcortical dementias
Assessment of dementia
Assessment of a patient who is presenting with a complaint of cognitive impairment involves several stages. A key question to be addressed initially is whether the impairment is due to dementia. This involves ruling out other causes, notably delirium, amnesia, and depression. Other patients will have mild cognitive impairment.
Having established the probable diagnosis of dementia, its characteristics (including severity, symptom and behaviour profile, and associated risks) are considered, together with assessment of its cause, and identification of potentially reversible causes. In the study mentioned earlier, the latter consisted mostly of hydrocephalus and space-occupying lesions (Hejl et al., 2002).
Table 13.10 Examples of cortical, subcortical, and mixed causes of dementia
Focal thalamic and basal ganglia lesions
Dementia with Lewy bodies
Assessment of the severity and clinical profile
Screening tests are useful in the assessment of dementia and its severity, and for monitoring progression (Salmon and Bondi, 2009). Different scales are available to assess cognition, behavioural symptoms, global functioning and activities of daily living, and depression; the latter is useful because depression can coexist with dementia and worsen functioning. Some commonly used screening tests are listed in Table 13.11. For cognitive impairment, the benchmark is the Mini-Mental State Examination (MMSE), which has a sensitivity and specificity for dementia of around 80% when a cut-off score of 23 is chosen (Mitchell, 2009). The ‘seven-minute screen’ and clock test are valuable and brief alternatives. The ADAS-Cog is specifically designed for suspected Alzheimer’s disease, and is widely used in clinical trials to monitor treatment response. The CAMCOG is largely a research tool.
Careful evaluation of the behavioural symptoms of dementia is an integral part of the assessment, and needs to be repeated during the illness, since these symptoms are common and they pose as many difficulties for carers as the cognitive symptoms.
Assessment of the cause of dementia
Definitive diagnosis of the cause of dementia can usually only be made neuropathologically or, in rare cases, by identification of genetic mutations. However, the differing profiles of the various dementias allow ‘probable’ diagnoses to be made by experienced clinicians with reasonable accuracy. For example, Burns et al. (1990) found that 88% of cases of clinically diagnosed Alzheimer’s disease were confirmed at autopsy. The use of biochemical, radiological, and genetic investigations only modestly increases the diagnostic accuracy for common dementias, but is important for ruling out rarer and reversible causes. With regard to the latter, Heijl et al. (2002) found that about 4% of patients with dementia who were referred to a memory clinic had a potentially reversible form. Table 13.12 summarizes the investigations for dementia. An MRI or CT scan is recommended as routine in many guidelines, but in practice brain scanning, like most investigations, is used in some but not all patients. The extent to which investigations are carried out, as well as the addition of more specialized tests, depends upon the patient’s age and history, the results of the initial tests, and the subsequent differential diagnosis.
Table 13.11 Screening tests for dementia
Mini-Mental State Examination (MMSE)
Six-Item Cognitive Impairment Test
Clock drawing test
Hopkins Verbal Learning Test (HVLT)
Mental Test Score (MTS)
Alzheimer’s Disease Assessment Scale—cognitive
Cambridge Examination for Mental Disorders of the Elderly, cognitive section (CAMCOG)
Behavioural and psychological features
Cohen–Mansfield Aggression Inventory
Activities of daily living
Alzheimer’s Disease Functional Assessment and Change Scale
Disability Assessment for Dementia
Geriatric Depression Rating Scale
Clinical Dementia Rating (CDR)
Table 13.12 Investigations for establishing the cause of dementia
In primary care
Full blood count
Erythrocyte sedimentation rate
Urea and electrolytes
Liver function tests
Calcium and phosphate
Thyroid function tests
Vitamin B12 and folate
In secondary care
MRI or CT brain scan
Adapted from Burns and Illiffe (2009a).
Assessment of risk in dementia
Patients with dementia are at risk from self-neglect, poor judgement, wandering, and abuse. Their physical health is often a problem. Risks to others may occur because of aggressive or disinhibited behaviour. Fitness to drive is a specific issue to consider, and may be difficult to determine in the early stages (Breen et al., 2007); current UK regulations allow those with ‘sufficient skills’ and whose ‘progression [of dementia] is slow’ to continue to drive, subject to annual review. Thus risk assessment is part of a full assessment of dementia. A good history from carers and other informants is essential, and an occupational therapist has an important role to play in assessment of functional ability.
Early detection of dementia
Mild cognitive impairment
Increasing attention is being given to the earlier diagnosis of dementia in those with equivocal evidence, or subjective complaints, of worsening memory, in part driven by the research focus on developing treatments to delay or prevent progression to dementia. This intermediate category, which was introduced in ICD-10, is called mild cognitive impairment (MCI). However, its clinical significance remains unclear, as only 5–10% of patients convert to dementia each year, and the majority of MCI patients have not progressed to dementia 10 years later (Mitchell and Shiri-Feshki, 2009). The MMSE is of limited value in the MCI population (Mitchell, 2009). Neuropathologically, MCI is mainly associated with Alzheimer-type changes, and also with vascular pathology. For a review of MCI, see Petersen et al. (2009).
Presymptomatic diagnosis and biomarkers
There is increasing evidence that dementia, especially Alzheimer’s disease, can be detected premorbidly, long before overt symptoms of any kind are present. Longitudinal studies show that there are selective and characteristic neuropsychological impairments, detectable up to 20 years before the onset of symptoms, as well as functional brain changes (e.g. in regional glucose metabolism) and structural and neuropathological abnormalities that precede symptoms by several years. For example, hippocampal atrophy at the rate of about 2% per annum begins several years before the symptoms of Alzheimer’s disease appear. This contrasts with normal age-related decreases of 0.5% per year (Frisoni et al., 2010).
Brain imaging that is used in this way is an example of a biomarker—that is, a test or marker which is of value in diagnosis, prognosis, or prediction of the treatment response. A range of biomarkers are nearing clinical utility in Alzheimer’s disease and some other dementias, including measurements of proteins in the CSF and blood (Blennow et al., 2010), and PET detection of β-amyloid deposits in the brain (Jagust et al., 2009).
In 1907, Alois Alzheimer reported the case of Auguste D, a woman with presenile dementia whose brain exhibited unusual neuropathological features. It was Alzheimer’s colleague, Emil Kraepelin, who named the disease (Maurer et al., 1997). For many years the disease was thought to be rare and limited to presenile forms of dementia, but classic studies by Roth and colleagues (Blessed et al., 1968) suggested that it is the commonest cause of senile dementia, a conclusion which has been confirmed by many subsequent studies. About 60% of dementia is attributable to Alzheimer’s disease (Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study, 2001).
Prevalence rates for populations over 65 years of age are 2–7% for moderately or severely affected individuals. Age-specific prevalence rates approximately double with every additional 5 years of age, from about 1% at 65 years, rising to around 8–10% at age 80 years and 30–40% at age 90 years (Nussbaum and Ellis, 2003). Because of the ageing population, the projected numbers of cases, and their health costs, will increase substantially (Mebane-Sims, 2009).
For a general review of Alzheimer’s disease, see Burns and Illiffe (2009b) and Lovestone (2009a).
The main features of dementia have been described above, and Table 13.13 summarizes the clinical features of Alzheimer’s disease (strictly, ‘dementia of the Alzheimer type’, since formal diagnosis awaits neuropathology) (see also Table 13.8, and Lovestone, 2009a).
The first evidence of the condition is often minor forgetfulness which may be difficult to distinguish from normal ageing. The condition progresses gradually for the first 2–4 years, with increasing memory disturbance and lack of spontaneity. Memory is lost for recent events first. Language is usually affected early on, with difficulty in finding words or naming objects, and impairments in the ability to construct fluent and informative sentences. Visuospatial skills may be affected, with difficulties in tasks such as copying pictures or learning the way round unfamiliar environments (e.g. when on holiday or in an unfamiliar house). Disorientation in time gives rise to poorly kept appointments and changes in the diurnal pattern of activity.
Table 13.13 Key clinical features of Alzheimer’s disease
Memory impairment (amnesia), with gradual onset and continuing decline
Disturbance in executive functioning (e.g. planning, reasoning)
Behavioural symptoms (e.g. agitation, wandering)
The relationship between Alzheimer’s disease and depression is complex. Depression is a probable risk factor for the disease, may be confused with it, or may occur as part of the syndrome. Regarding the latter point, major depression occurs in about 10% of cases, with less marked episodes and symptoms occurring in over 50% of cases. Patients who experienced depression have greater decreases in serotonin and noradrenergic markers than other patients with Alzheimer’s disease.
Delusions and hallucinations occur in a significant minority of patients at some stage in the illness. Their prevalence is unclear, as many studies did not distinguish Alzheimer’s disease from dementia with Lewy bodies (see below). Recent estimates suggest rates of 10–50% for delusions and 10–25% for hallucinations. The commonest delusions are persecutory, concerning theft (however, as this idea often arises from the patient’s forgetfulness, it is questionable whether it is helpful to regard this as a true delusion).
Changes in behaviour are common, and are of particular concern to carers. The patient may be restless and wake at night, disorientated and perplexed. Motor activity may increase in the evening (‘sundowning’), and eventually the sleep–wake cycle may become completely disorganized. Aggression (both verbal and physical) is common, and often takes the form of resistance to help with personal care. Serious physical violence towards others is rare. Both increases and reductions in level of activity are common, involving varying degrees of purposefulness. Wandering can refer to a variety of different behaviours, but patients may place themselves at risk by going into unsafe environments. Patients with dementia may under- or overeat, with associated changes in weight and nutritional state. Changes in sexual behaviour occur, usually with a reduction in drive, although sexual disinhibition occasionally occurs.
Self-care and social behaviour decline, although some patients maintain a good social facade despite severe cognitive impairment, particularly if carers are able to assist with these functions.
In the early stages of Alzheimer’s disease, the clinical features are modified by the patient’s premorbid personality, and their traits tend to be exaggerated. In the middle and later stages of the illness, the cognitive impairments increasingly predominate, together with the neurological and behavioural features noted above. Incidental physical illness may cause a superimposed delirium, resulting in a sudden deterioration in cognitive function. Median survival from diagnosis is 5–7 years, and is slightly less in men than in women. Shorter survival is also associated with an older age of onset, and a rapid rate of cognitive decline.
The investigation of suspected Alzheimer’s disease follows the same principles as the investigation of dementia in general, outlined above. In addition, a comment on genetic testing is warranted. Such testing is indicated in the very rare cases of familial early-onset Alzheimer’s disease for which three causative genes are known (see below). Although the apoE4 allele of the apolipoprotein E gene is a major risk factor in all forms of Alzheimer’s disease (see Box 13.1 and also see below), routine testing for this variant in the differential diagnosis of dementia is not currently recommended, and there is no place for genetic screening of healthy subjects in order to predict future dementia. The scientific and ethical issues involved have been discussed by Green et al. (2009).
On gross examination the brain is shrunken, with widened sulci and enlarged ventricles. Brain weight is reduced. On microscopic examination, the cardinal diagnostic features are neurofibrillary tangles and senile plaques (also called amyloid plaques) in the cerebral cortex and many subcortical regions. The diagnostic criteria are based upon the abundance and distribution of plaques and tangles—the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria (Mirra et al., 1991). However, it should be noted that these features are also seen, to some extent, in some non-demented elderly people (e.g. Savva et al., 2009), and the relationship between clinical dementia and neuropathology is more complex than is sometimes assumed to be the case.
In addition to the tangles and plaques, there is selective loss of neurons in the hippocampus and entorhinal cortex, proliferation of astrocytes (gliosis), and loss of synapses. The latter is the strongest neuropathological correlate of cognitive impairment. Other histological findings include amyloid deposits in blood vessel walls (so-called vascular amyloid or congophilic angiopathy), Hirano bodies(intracellular, crystalline deposits) and granulovacuolar accumulation (vacuoles or ‘holes’ within neurons).
For a review of the neuropathology of Alzheimer’s disease, see Duyckaerts et al. (2009).
Progression of neuropathology
The disease starts in the entorhinal cortex, before spreading to the hippocampus, association areas of the parietal lobe, and some subcortical nuclei. Six neuropathological stages based upon β-amyloid deposition are recognized, called Braak stages, which correlate with clinical severity (Braak and Braak, 1991). The spread of pathology along cortico-cortical projections leads to an effective ‘disconnection’ between affected regions.
Senile (amyloid) plaques
Senile plaques are deposits of insoluble proteins, together with degenerating neurites (neuronal processes) and glia. They occur in the space between neurons (the neuropil). Both neuritic and diffuse plaques are recognized, depending on their appearance using silver stains; neuritic plaques have a dense-staining core, whereas diffuse plaques have been likened to cotton wool. The neuritic plaques are pathologically more significant. The protein at the heart of all senile plaques is β-amyloid (also called Aβ or A4), a 39–42 amino-acid peptide. This molecule and its encoding gene are central to the aetiology of the disease (see below).
Neurofibrillary tangles occur within the cell body of neurons, especially pyramidal neurons of the cerebral cortex and hippocampus. They are formed of paired helical filaments, which in turn are comprised of the microtubule-associated protein tau. The normal function of tau is in axonal transport and maintenance of the neuronal cytoskeleton. Tangles are thought to occur because tau becomes hyperphosphorylated, rendering it insoluble. The presence of a tangle causes dysfunction and death of the neuron.
Aetiology and pathogenesis
In rare families, usually those with an early onset of illness (before the age of 60 years), an autosomal-dominant mode of inheritance can be discerned. Causative mutations have been identified in three genes—amyloid precursor protein (APP, on chromosome 21), presenilin 1 (PS1, on chromosome 14), and presenilin 2 (PS2, on chromosome 1). Discovery of APP as the first ‘Alzheimer gene’ was a seminal event in psychiatry (see Box 13.1). These three genes together account for the majority of familial cases of the disease; equally, at least one other gene is likely to exist. Different mutations are known in each gene, and the age of onset, features, and progression of disease vary depending on the causative mutation.
Box 13.1 Discovery of APP gene mutations in familial Alzheimer’s disease
In 1984, the protein that accumulates in vasculature, senile plaques, and meninges in Alzheimer’s disease was discovered to be the β-amyloid peptide mentioned above. Knowledge of its amino-acid sequence allowed the encoding gene, called amyloid precursor protein (APP), to be identified and localized to chromosome 21. It was already known that there was a relationship between Alzheimer’s disease and Down’s syndrome (trisomy 21), suggesting that APP was a ‘candidate gene’ for Alzheimer’s disease. Researchers collected DNA from families with autosomal-dominant Alzheimer’s disease to test this hypothesis. The work culminated in the landmark discovery in 1991 of an APP mutation (a point mutation changing valine to isoleucine at position 717) which caused Alzheimer’s disease (Goate et al., 1991). Since then, different APP mutations have been found in other families. Any doubt that the APP mutations are causative for the disease was removed by the demonstration that transgenic mice containing a mutated APP gene become cognitively impaired and deposit β-amyloid (Games et al., 1995). APP mutations are pathogenic primarily because they affect metabolism of APP, promoting the formation of β-amyloid. APP mutations explain only a tiny fraction of cases of Alzheimer’s disease. However, mismetabolism of APP and β-amyloid, caused by a range of other factors, appears to be central to much if not all Alzheimer’s disease, as described in the text.
Despite the importance of these findings, the vast majority of Alzheimer’s disease is not inherited in a Mendelian fashion, and it is often termed ‘sporadic.’ However, first-degree relatives of patients with late-onset Alzheimer’s disease have an elevated risk of developing the disorder, and a genetic predisposition is now confirmed by studies showing an unequivocal association between polymorphisms in the apolipoprotein E (apoE) gene and all forms of Alzheimer’s disease. As discussed in Box 13.1, the apoE4 variant of this gene accounts for about 50% of the vulnerability to late-onset Alzheimer’s disease. Its main effect is to promote an earlier onset of disease, by about a decade. ApoE4 heterozygotes have a threefold greater risk, and homozygotes have an eightfold greater risk of the disease. Other data suggest that apoE4-positive cases may show some differences in pathology, course, and response to medication. In Caucasians, the apoE2 variant reduces the risk of Alzheimer’s disease (compared with the commonest apoE3 form), but this does not hold in African Americans. The (lack of a) role of genetic testing for apoE4 was mentioned above. It is stressed that apoE4 is not a determinant of disease; at least one-third of patients with Alzheimer’s disease are apoE4 negative, and some apoE4 homozygotes never develop the disease. It is not known how apoE4 elevates the risk of Alzheimer’s disease, but it is likely to reflect its interaction with βamyloid metabolism, cholesterol, and other cellular functions (Bu, 2009).
There is now statistically convincing evidence for several other susceptibility genes for Alzheimer’s disease, with acronyms such as CLU (APOJ), PICALM, CR1, and SORL1 (Jun et al., 2010). However, they remain less firmly established, and of much lesser importance, than apoE4.
Various environmental factors are associated with an altered risk of developing dementia in general, or Alzheimer’s disease in particular (see Table 13.14). However, for many of them, it is not clear to what extent they are causal, act independently, or interact with genetic predisposition.
With regard to non-steroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy (HRT) and statins, there is considerable evidence that people who have used these drugs have a significantly decreased rate of dementia and Alzheimer’s disease. In each case there is also a plausible biological explanation for this effect. On the other hand, randomized trials have in each case failed to find any beneficial effect in treating or preventing dementia (e.g. McGuinness et al., 2009). The significance of the observational data is therefore unclear (Henderson, 2010). The robust finding that levels of educational attainment (Caamano-Isorna et al., 2006), as well as cognitive and physical activity (Scarmeas et al., 2009), predict rates of Alzheimer’s disease, supports a ‘use it or lose it’ hypothesis, whereby such attributes increase cerebral reserve. A past history of depression has repeatedly been associated with an increased risk of Alzheimer’s disease and dementia, but the causality and the mechanism involved remain unclear (Geda, 2010). Diabetes mellitus and obesity are now known to be significant and independent risk factors (Profenno et al., 2010). Aluminium exposure was implicated, but the evidence base is weak, and it is not an established risk factor. Head injury and dementia are considered on p. 344.
The amyloid cascade hypothesis
The APP research summarized in Box 13.1 led to the ‘amyloid cascade hypothesis’, originated by Hardy and Higgins (1992), which remains the dominant molecular model for the disorder, and the basis for most ongoing therapeutic research (Citron, 2010). It proposes that the central, pathogenic event is increased formation and deposition of β-amyloid, particularly the 42-amino-acid variant. APP is a transmembrane protein, which can be cleaved by one of three enzymes, called secretases. Normally, α-secretase activity predominates, and this does not give rise to β-amyloid. However, in Alzheimer’s disease, more APP is processed via β- and γ-secretase pathways, leading to increased β-amyloid formation. The presenilins are part of the γ-secretase complex, emphasizing the common pathogenic effects of the genes that cause familial Alzheimer’s disease. The increased production of β-amyloid leads to disease because it tends to aggregate, becomes insoluble, and is toxic to synapses and neurons. Decreased removal of β-amyloid from the brain may also contribute. For an updated review of this hypothesis, see Hardy (2009). It is still controversial how the amyloid pathology relates to the tau protein and neurofibrillary tangles; the consensus is in favour of the latter being downstream, but other models are possible (Ittner and Götz, 2011).
Table 13.14 Risk factors for Alzheimer’s disease
Other genetice polymorphisms
Environmental and medical risk factors
Low educational attainment
Previous head injury
History of depression
High homocysteine levels
Herpes simplex virus
Cognitive and physical activity in mid-life
?Use of non-steroidal anti-inflammatory drugs (NSAIDs)
?Use of hormone replacement therapy (HRT)
?Use of statins
Neurotransmitter changes: the cholinergic hypothesis
Prior to the amyloid hypothesis, the prevailing view was the cholinergic hypothesis of Alzheimer’s disease, based on findings in the 1970s that there is a severe and widespread loss of acetylcholine in the cerebral cortex. The loss occurs because of pathology and atrophy in the cells of origin, in the nucleus basalis of Meynert. The findings led to the development of the current cholinergic therapies for the disease. However, although cholinergic deficits may well explain some of the cognitive impairment, they are no longer considered to have a primary causal role. For a review, see Francis et al. (1999). Cholinergic pathology may in fact be of more relevance in dementia with Lewy bodies, and it is possible that the earlier studies of Alzheimer’s disease included patients in this category.
Other pathogenic hypotheses
Additional hypotheses for the pathogenesis of Alzheimer’s disease include the role of oxidative stress, inflammation, apoptosis (programmed cell death), and disturbances of the cell cycle. For a review, see Querfurth and LaFeria (2010).
The dementia caused by cerebrovascular disease was in the past referred to as ‘atherosclerotic psychosis.’ Following the separation of distinct syndromes of psychiatric disorder in late life (Roth, 1955), it became apparent that dementia was often associated with multiple infarcts, and Hachinski et al. (1974) suggested the term multi-infarct dementia. Subsequent research has shown that these patients are a subgroup of a larger group of patients with dementia due to cerebrovascular disease, and the umbrella term of vascular dementia is now preferred. Other clinic-pathological subtypes include état lacunaire, leucoariosis, Binswanger’s disease, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Paralleling the clinical heterogeneity, the neuropathological findings are varied, and include large- or small-vessel arteriosclerosis, embolus, vasculitis, amyloid angiopathy, and intracranial haemorrhage; both subcortical and cortical-predominant forms occur (Jellinger, 2008).
Vascular dementia is the second commonest cause of dementia, of comparable prevalence to dementia with Lewy bodies. It is slightly more common in men than in women. The prevalence increases with age, approximately doubling every 5 years. There appear to be geographical differences, with high rates reported in China, Japan, and the Russian Federation.
For a review of vascular dementia, see Erkinjuntti (2009).
Onset is usually in the late sixties or the seventies. It is often relatively acute and follows a stroke (Leys et al., 2005). About 10% of people develop dementia after a first stroke, and more than one-third after recurrent stroke (Pendle-bury and Rothwell, 2009). Emotional and personality changes may appear first, followed by impairments of memory and intellect that characteristically progress in stages. Depression is frequent, and episodes of emotional lability and confusion are common, especially at night. Transient ischaemic attacks or mild strokes may recur from time to time. Insight is often maintained until a late stage. Behavioural retardation and anxiety are more common than in Alzheimer’s disease.
The course of vascular dementia is usually a stepwise progression, with periods of deterioration that are sometimes followed by partial recovery for a few months. About 50% of the patients die from ischaemic heart disease, and others from cerebral infarction or renal complications. From the time of diagnosis the lifespan varies widely. However, most studies show somewhat shorter survival than in Alzheimer’s disease.
The diagnosis is difficult to make with confidence unless there is a clear history of strokes or localizing neurological signs. Suggestive features are patchy psychological deficits, erratic progression, and relative preservation of the personality. On physical examination there are usually signs of hypertension and of arteriosclerosis in peripheral and retinal vessels, and there may be neurological signs such as pseudobulbar palsy, rigidity, akinesia, and brisk reflexes. The Hachinski scale is sometimes used.
It is assumed that vascular dementia results from the neuronal dysfunction and death which follow from the cumulative focal areas of ischaemia and necrosis. The risk factors for vascular dementia are essentially those of cerebrovascular disease, and prevention and optimal management of stroke would probably reduce the incidence (Pendlebury and Rothwell, 2009). Recent research also emphasizes similarities with the risk factors for Alzheimer’s disease (including diabetes and hyperhomocysteinaemia), consistent with the frequent co-occurrence of the two pathologies (Jellinger, 2008) and the emerging concept of mixed dementia (see below).
Dementia with Lewy bodies
Since the late 1980s, a new type of dementia with a relatively distinct pathology and clinical course has been described using various terms, including dementia with Lewy bodies, Lewy body dementia, cortical Lewy body disease, diffuse Lewy body disease, and Lewy body variant of Alzheimer’s disease. Dementia with Lewy bodies is now the consensus term. Arising mainly from research in Newcastle, neuropathological studies have found dementia with Lewy bodies in around 15–25% of all cases, suggesting that it is the second or third most frequent cause of dementia. As the name suggests, the cardinal feature consists of Lewy bodies in the cerebral cortex; it also has a characteristic clinical profile. The recent ‘discovery’ of dementia with Lewy bodies may reflect sampling bias in earlier studies (e.g. under-representation in patients coming to autopsy) and the fact that cortical Lewy bodies are difficult to see using routine stains.
For a review, see McKeith (2009).
The core clinical features are summarized in Table 13.15. The fluctuating level of dementia with recurrent delirium-like phases, together with Parkinsonism and visual hallucinations, is characteristic. Use of the criteria allows dementia with Lewy bodies to be diagnosed with good specificity and sensitivity. The average survival is 5–7 years. For a review, see McKeith et al. (2005).
The characteristic histopathological feature of Lewy body dementia is the presence of Lewy bodies in the cerebral cortex. As in Parkinson’s disease, they are also seen in the substantia nigra, and their composition is the same in both diseases. The key protein is c α-synuclein, although routine detection of Lewy bodies is currently based on the presence of another protein, ubiquitin. There is also a significant overlap with Alzheimer’s disease, with dementia with Lewy bodies often exhibiting abundant senile plaques and widespread reductions in choline acetyltransferase in the neocortex; however, neurofibrillary tangles are rare. Brain atrophy is less marked than in Alzheimer’s disease, especially in the hippocampus. For a review, see Dickson et al. (2009).
Table 13.15 Abbreviated clinical criteria for dementia with Lewy bodies
Progressive cognitive decline, especially in attention and visuospatial ability
Pronounced fluctuations in cognition and attention
Recurrent visual hallucinations, usually well formed and detailed
Motor features of Parkinsonism
Transient loss of consciousness
Adverse reactions to antipsychotics
Diagnosis made less likely in the presence of
Evidence of cerebrovascular disease or stroke
Evidence of other disorder sufficient to account for the clinical picture
Dementia with Lewy bodies is closely related to Parkinson’s disease, and both are characterized as ‘synucleinopathies’, reflecting the abnormal aggregation of; α-synuclein protein present in Lewy bodies. There is a modest familial aggregation (Nervi et al., 2011), and associations with some of the genes implicated in Parkinson’s disease (see below) have been reported. No environmental risk factors have been well established (McKeith, 2009).
Frontotemporal dementias are the second most common form of presenile dementia, and also underlie about 7% of late-life dementias. Presentation is usually between 45 and 70 years of age. The term was proposed in 1994 when the Lund–Manchester criteria were developed (these were later updated; see Neary et al., 2005). The grouping is based upon the shared clinical features (see Table 13.16) and regional neuropathology of a range of hitherto diverse clinical syndromes (see Table 13.8 on p. 323). The term frontotemporal lobar degeneration is the neuropatho-logical counterpart (Cairns et al., 2007).
Clinical features and subtypes
Frontotemporal dementia (also known neuropathologically as frontotemporal lobar degeneration) consists of a broader and more heterogeneous range of clinical presentations (see Table 13.17) than the other common dementias. The prominence of behavioural rather than cognitive features is emphasized. For a review, see Neary et al. (2005) and Gustafson and Brun (2009).
Frontal and temporal variants are recognized, reflecting the predominant features of pathology in the two lobes. Thus the frontal form presents with behavioural and personality change, whereas language disorder occurs in the temporal form. There is often asymmetry of cortical involvement, with left temporal atrophy associated with language deficits, and right-sided disease producing a behavioural disorder. Other subdivisions can be made based on familial versus sporadic cases, and on the presence of Parkinsonism, or features of motor neuron disease.
Table 13.16 Some clinical criteria for frontotemporal dementias
Insidious onset, slow progression
Early loss of insight
Early signs of disinhibition and lack of judgement
Stereotyped and imitative behaviour
Hyperorality (e.g. craving for sweet foods)
Distractibility and impulsivity
Language and speech features
Progressive decrease in speech output
Early primitive reflexes
Low and labile blood pressure
A family history is present in about 50% of cases, with about 10% being autosomal dominant. The proportion of family history-positive cases varies between the different frontotemporal dementia syndromes (Rohrer et al., 2009).
Arnold Pick described the disease which bears his name in 1892. The key clinical features that he noted were aphasia with dementia; the striking pathological findings were focal ‘knife-blade’ atrophy of the frontal and temporal poles, with ballooned neurons (Pick cells) that contained inclusions called Pick bodies. Pick bodies also occur in other areas, notably the hippocampus. They are composed of tau, ubiquitin, and other proteins. Features of Alzheimer’s disease are absent. Pick’s disease remains the archetypal frontotemporal dementia, and is sometimes referred to synonymously with it, but if defined properly (including the neuropathological features), it explains only a small proportion of cases.
Table 13.17 Diagnostic categories subsumed within frontotemporal dementia
Frontal lobe degeneration of non-Alzheimer type
Dementia lacking distinctive histology
Motor neuron disease with dementia
Progressive non-fluent aphasia
Progressive aphasic syndrome
Frontotemporal dementia with Parkinsonism
Progressive supranuclear palsy*
Parkinsonism–dementia complex of Guam*
* Not always included.
Semantic dementia refers to a syndrome distinguished by selective, progressive loss of meaning for verbal and nonverbal material, accompanied by striking difficulty in naming, categorization, and comprehension (Garrard and Hodges, 2000). It is usually considered to be a frontotemporal dementia, because it is associated with a reasonably selective, often left-predominant, anterior temporal lobe atrophy. Autobiographical memory is relatively preserved (although it may be difficult to access). When asked to demonstrate an object or action, the patient typically stares at the examiner uncomprehendingly, repeating the instruction as if it had been asked in a foreign language. Associated cognitive, psychiatric, or neurological signs are minimal in the early stages, and the increasingly severe semantic impairment may remain circumscribed for many years.
Differential diagnosis and investigations
A study conducted in 1993 found that 18 out of 21 patients with Pick’s disease had been misdiagnosed clinically as having Alzheimer’s disease. Although the situation has probably improved with the development of diagnostic criteria and greater awareness, frontotemporal dementia remains difficult to diagnose, reflecting its heterogeneity and its relative neglect by researchers. The behavioural features are more useful than the neuropsychological profile in distinguishing it from Alzheimer’s disease and other dementias. There are few investigations to aid diagnosis (Pasquier et al., 2003), although both neuroimaging and EEG may be helpful. There is focal, often asymmetrical atrophy of the temporal and frontal poles, without the medial temporal lobe atrophy of Alzheimer’s disease, and the EEG is usually normal in frontotemporal dementia but diffusely slowed in Alzheimer’s disease.
The classic features of Pick’s disease have been summarized above. Other forms of frontotemporal dementia lack such specific neuropathological correlates. All of them show the gross atrophy of the temporal and frontal lobes, with neuronal loss, gliosis, spongiform change in superficial layers of the cortex, and often ballooned cells and neuronal inclusions which stain for ubiquitin, tau, and phosphorylated neurofilaments. Recently, inclusions positive for TDP-43 (TAR DNA-binding protein) have become a key neuropathological finding (Cairns et al., 2007).
Neurochemically, frontotemporal dementia differs from Alzheimer’s disease in not showing cholinergic deficits. Dopamine also appears to be unaffected, but serotonin markers are reduced in affected brain areas (Huey et al., 2006).
The aetiology of frontotemporal dementias remains largely unknown, with the exception of the familial forms of the various syndromes, some of which can be attributed to mutations in progranulin (GRN), tau (in cases that are linked to chromosome 17), TDP-43, and C90RF72 genes (Seelaar et al., 2011). Other genes, and genetic factors in non-familial cases, are suspected. The disease process is thought to involve abnormalities in the functioning of these and other proteins (Sieegers et al., 2010). However, it remains unclear how the clinical heterogeneity of the frontotemporal dementias is related to the causative genes, and to the neuropathological variability (Seelaar et al., 2011).
Prion diseases are a unique category of diseases, which are grouped together because of the central role of a specific protein, called prion protein (PrP). They also share neuropathological features, including diffuse spongiosis (hence the older term, ‘spongiform encephalopathy’), neuronal loss, gliosis, and, in many cases, amyloid plaques. They can be inherited, or acquired infectiously or iatrogenically, while other cases are sporadic and idiopathic. Because of these unique properties, their interest and importance are out of all proportion to their rarity. In the UK, all cases of suspected prion disease should be referred to the National Surveillance Centre in Edinburgh.
For reviews of prion diseases, see Johnson (2005) and Collinge (2009).
Creutzfeldt–Jakob disease (CJD) is the main prion disease, with an approximate annual incidence of one case per million. A small number of cases are inherited as an autosomal-dominant disorder due to point or length mutations in the PrP gene (see below). Other cases have been transmitted iatrogenically, via pituitary-derived growth hormone, contaminated neurosurgical instruments or graft material, and possibly by blood transfusion. The incubation time in these cases can exceed 20 years. Because of the potential infectivity, no patients with dementia should be organ donors.
Sporadic CJD affects both sexes equally. Onset is typically between 50 and 65 years of age. It is usually heralded by memory impairment, which may be accompanied by prominent behavioural abnormalities or personality change, prompting initial referral to a psychiatrist. Visual symptoms, cerebellar signs, involuntary movements, myoclonic jerks, and other motor features are frequent. Seizures occur later in the course. There is usually a relentless and rapid progression to death, often within 6 months, but some patients have a more protracted illness. The EEG classically shows a triphasic 1–2 Hz discharge which, together with the history and rapid course, is diagnostically characteristic. The biochemical profile of the CSF, notably the presence of ‘14-3-3 proteins’, is also suggestive. However, definitive diagnosis in life requires a brain biopsy.
Variant Creutzfeldt–Jakob disease
Intense interest in prion disease followed the description of variant Creutzfeldt–Jakob disease (vCJD), which was first identified in the UK in 1996, with about 150 cases reported since then. This is linked with bovine spongi-form encephalopathy (BSE), which was epidemic in British dairy herds at that time. BSE and vCJD are caused by the same prion strain, and it is beyond reasonable doubt that vCJD occurred as a result of eating contaminated bovine products. A total of 176 cases had been identified by January 2012. The incidence peaked at around 2000; a handful of cases are still diagnosed each year, but it is now considered highly unlikely that a human epidemic will occur. There is a polymorphism at codon 129 of the PrP gene that encodes either methionine or valine; all vCJD patients except one have been homozygous for methionine (compared with 40% in the population), which suggests that this genetic subgroup is more susceptible to vCJD. For a review, see Collinge (2009).
Compared with other forms of CJD, vCJD has an earlier onset, slower course, and usually presents with psychiatric symptoms, including depression and personality change (Spencer et al., 2002); EEG abnormalities are less common. The ‘pulvinar’ sign on MRI (hyperintensity over the posterior thalamus) is a useful and non-invasive diagnostic sign. Diagnosis of vCJD is possible via tonsil biopsy, but the role of this in clinical practice remains unclear.
Other prion diseases
Kuru, described in the Fore tribe of New Guinea highlanders, was transmitted by ritual cannibalism; the disease has virtually disappeared since this practice was abolished in the 1950s. Transmission of kuru to monkeys in 1970 was the first experimental proof of the infectivity of prion disease.
Other inherited prion diseases are Gerstmann–Sträussler-Scheinker syndrome and fatal familial insomnia. Like familial CJD, both of these are caused by autosomal-dominant mutations of the prion protein gene. Both are extremely rare. For a review, see Johnson (2005).
The name ‘prion’ denotes proteinaceous infectious particles. It was coined in 1982 by Prusiner, who received the 1999 Nobel Prize for Medicine (Prusiner, 2001). As noted above, prion protein (PrP) is encoded by a gene on chromosome 20. The functions of ‘normal’ PrP (denoted PrPC) are unknown, but it is expressed by neurons and may serve as a receptor and influence synaptic properties. Prion diseases are caused when PrPC takes on an abnormal conformation, called PrPSc (named after scrapie, the prion disease that affects sheep). PrPSc is both the core molecular marker and presumed causative agent of prion diseases. Compared with PrPC, PrPSc is resistant to breakdown by proteases, and tends to self-aggregate and be deposited in the brain. PrPSc is also thought to promote synaptic and neuronal loss and gliosis, and to produce the resulting spongiform appearance of the brain.
In familial cases, the mutated PrP is assumed to be intrinsically more likely to self-aggregate. In forms that are acquired (either iatrogenically or through diet), it is postulated that the normal PrPC becomes ‘corrupted’ by the acquired PrPSc, which changes the conformation of PrPC into PrPSc, thus propagating ever more PrPSc. The molecular details of this remarkable process remain obscure. In the case of peripheral acquisition, PrPSc may spread via the nerves, lymphatics, and blood to reach the brain. Different PrP conformations and modifications (glycosylation patterns) give rise to various disease ‘strains.’ The aetiology of ‘sporadic’ prion disease is not known. It may result from spontaneous mutation or conversion of PrPC to PrPSc, or it may arise from occult environmental sources. It is not known why PrPSc is infectious, when other misfolded, amyloidogenic proteins (such as β-amyloid) are not. Prion diseases are not caused by ‘slow viruses’, as was formerly believed.
For a review, see Aguzzi et al. (2008).
Dementia due to HIV disease
See Chapter 15.
Dementia due to alcohol misuse
See Chapter 17.
Emerging concepts of dementia
Classification and clinical practice are based on the dementia syndromes described above. However, epidemiological and biological research is increasingly calling current diagnostic concepts into question.
The frequency and importance of ‘mixed dementia’ are becoming apparent, particularly the coexistence of Alzheimer’s disease and vascular dementia. This occurs in at least 20% of cases, and the coexistence worsens the severity of dementia (Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study, 2001). The clinical overlap is now complemented by the increasing evidence that risk factors for Alzheimer’s disease and vascular dementia overlap (Viswanathan et al., 2009).
Molecular classification of neurodegenerative diseases
There is further blurring of diagnostic boundaries at the molecular level, in that the same core biochemical process—misfolding and accumulation of proteins—appears to be central to all major neurodegenerative disorders (e.g. β-amyloid in Alzheimer’s disease, PrP in prion disease, and huntingtin in Huntington’s disease) (Love-stone and McLoughlin, 2001; Soto, 2003). Equally, it is apparent that there is not a one-to-one correspondence between protein and syndrome, as exemplified by the involvement of tau in both Alzheimer’s disease and frontotemporal dementia. These factors are leading to the molecular reclassification of dementias as ‘amyloidopathies’, ‘tauopathies’, and ‘synucleinopathies’ (Hardy and Gwinn-Hardy, 1998; Forman et al., 2004). These issues are likely to influence clinical thinking and practice in the near future, as their prognostic and treatment implications become clear.
Prevention of dementia
Mild cognitive impairment, and biomarkers for dementia, were mentioned earlier. The interest in these topics has been driven by the hope that disease-modifying or preventative treatments may be possible—for example, the promise of β-amyloid immunization against Alzheimer’s disease (Lemere and Masliah, 2010). Several of the known risk factors for dementia are also readily modifiable (Middleton and Yaffe, 2009), although it would be premature to introduce public health programmes in this respect (Kurth, 2010).
Disorders in which movement and coordination are the cardinal features are usually managed by neurologists. However, many of them also include prominent and clinically significant psychiatric features, including cognitive impairment, psychosis, and mood disorders. It is the psychiatric aspects that will be considered here. For a review of the neuropsychiatry of movement disorders, see Henderson and Mellers (2009).
The cardinal triad of idiopathic Parkinson’s disease is a rest tremor, cog-wheel rigidity, and bradykinesia (Jankovic, 2008). The main psychiatric consequences are cognitive impairment, depression, psychosis, and behavioural problems (see Table 13.18). For a review, see Aarsland et al. (2009). The differential diagnosis includes other Parkinsonian syndromes, and, of particular relevance to psychiatrists, the Parkinsonian side-effects of antipsychotic drugs. In clinico-pathological terms, Parkinson’s disease is part of the spectrum of Lewy body disease, discussed earlier (Dickson et al., 2009). Impaired olfaction is a neglected feature, and can pre-date other symptoms by several years (Ross et al., 2008).
Estimates of the prevalence of dementia in Parkinson’s disease vary widely, probably because different populations have been studied and diagnostic criteria have varied, and because of the increasing recognition of dementia with Lewy bodies. The convention is that the former category (‘dementia in Parkinson’s disease’) is used if the dementia begins more than 12 months after the onset of Parkinsonism (Mindham and Hughes, 2009). According to this definition, dementia occurs in up to 40% of cases of Parkinson’s disease, especially later-onset cases and those with severe bradykinesia. L-DOPA does not improve the dementia; however, cholinesterase inhibitors and memantine may do so. As well as a classic subcortical dementia, several other profiles of cognitive impairment are seen in Parkinson’s disease, notably a ‘dysexecutive syndrome’ in which planning and working memory are especially affected (Kehagia et al., 2010).
Table 13.18 Neuropsychiatric manifestations in Parkinson’s disease
Delirium, stupor (especially due to drugs, or intercurrent infection)
Cognitive decline (subcortical dementia, dysexecutive syndrome)
Depression, apathy, mania
Hallucinations (chiefly visual)
Sleep attacks, REM sleep behaviour disorder
Impulse control disorders, e.g. gambling (largely medication related)
The association of Parkinson’s disease with depression is well established; clinically significant depressive symptoms (including apathy) are present in 35% of cases, and a major depressive disorder in about 20% (Reijnders et al., 2008). Depression is most common in the early and the very advanced stages of the disease. The mechanism is uncertain; depression correlates poorly with degree of disability and disease duration, and may be related to frontal lobe abnormalities and disturbed dopaminergic mechanisms. Antidepressants must be used with care, to avoid exacerbation of cognitive impairment or induction of delirium. SSRIs and newer-generation agents, which have less anticholinergic activity, are preferable to tricyclic antidepressants.
Psychotic symptoms occur at some stage in around 20% of patients. Visual hallucinations are associated with dopaminergic medication, increasing age, disease duration and severity, depression, cognitive impairment, and reduced visual acuity. Delusions are less frequent and are usually paranoid in content. Anti-Parkinsonian drugs have been implicated as causes, and whenever possible these should be reduced. If antipsychotic medication is necessary, newer drugs, notably clozapine or quetiapine, should be used. For a review, see Friedman (2010).
Other neuropsychiatric manifestations
Excessive somnolence, a disordered sleep–wake cycle, sleep attacks, and REM sleep behaviour disorder are more common in Parkinson’s disease. As a result, patients with Parkinson’s disease must be counselled about the risks of driving, even in the absence of dementia. Pathological gambling and other impulsive behaviours are also a recognized feature, especially in patients treated with dopamine agonists.
Idiopathic Parkinson’s disease is a common disorder of later life, occurring in around 1% of the population over the age of 55 years (Nussbaum and Ellis, 2003). It results primarily from degeneration of dopaminergic neurons in the zona compacta of the substantia nigra, although the first site of pathology is in the IX/X cranial nerve nuclei, and it later extends to other dopamine pathways. The pathological hallmark is Lewy bodies (inclusions within dopaminergic and some other neurons). The composition of Lewy bodies was mentioned above. For a review, see Dickson et al. (2009).
Parkinson’s disease occurs in a rare autosomal-dominant form, caused by mutations in α-synuclein, UCHL1, NR4A2, and LRRK2 (dardarin) genes. There is also an autosomal-recessive form, due to mutations in the Parkin, DJ-1, and PINK1 genes. Sporadic Parkinson’s disease is associated with polymorphisms in LRRK2, a-synuclein, and glucocerebrosidase, and several other genes. For a review, see Lees et al. (2009). Environmental risk factors include exposure to some toxins, solvents, and possibly well water, whereas smoking and perhaps caffeine have a protective effect (Di Monte, 2003). Pathophysiologically, the disease process is thought to be due to impairment of mitochondrial and synaptic functioning, and oxidative stress (Shapira, 2008; Lees et al., 2009).
This disease, also called Huntington’s chorea, was described by the New England physician George Huntington in 1872 (reproduced in Huntington, 2003). It has a worldwide distribution, with an estimated prevalence of 4–7 per 100 000. Onset is typically in middle life, although adolescent cases are well recognized. There is relentless progression of cognitive and behavioural decline in most cases. The tell-tale choreiform movements may be subtle, taking the form of excessive, purposeless ‘fidgeting’ which the patient may attempt to disguise.
The disease may present to the psychiatrist, as these patients commonly become depressed early in the course of the disease, while insight is retained, and later often become withdrawn, ‘eccentric’, and socially isolated. The clinical features of Huntington’s disease are shown in Table 13.19. Depression is seen in about 50% of cases at some stage. Psychotic symptoms, both schizophrenia-like and affective in nature, occur in about 10% of cases. Cognitive impairment with subcortical features is invariable in the later stages, but its severity and progression vary widely. Distractibility is characteristic, with reduced ability to regulate attention and psychomotor speed, and apathy later in the course. A gaze apraxia and inability to sustain tongue protrusion (‘serpentine tongue’) are typically found.
For a review of Huntington’s disease see Walker (2007), and for a review of the psychiatric aspects see Jauhar and Ritchie (2011).
The pathological changes mainly affect the caudate nucleus and frontal lobes. The caudate nucleus is markedly atrophic and gliotic. Pyramidal neuronal loss occurs in the frontal cortex, with thinning of the grey matter. Polyglutamine nuclear inclusions are present within some cells, reflecting the causative mutation described below. Neurochemically, there are decreased concentrations of the inhibitory transmitter gamma-aminobutyric acid (GABA) in the caudate nucleus.
Huntington’s disease is one of the few single-gene, auto-somal-dominant disorders in psychiatry. Penetrance is complete (i.e. all carriers of the mutation develop the disease), and new mutations are very rare; most apparently sporadic cases reflect an incomplete family history, or lack of knowledge of true paternity. The gene, on chromosome 4p, encodes a protein called huntingtin. The mutation, identified in 1993, is a ‘triplet repeat’ or ‘tri-nucleotide repeat’ of the codon CAG, which codes for glutamine. Normal individuals have less than 30 repeats of this ‘polyglutamine’ sequence; disease occurs in those who have more than 36 copies. The expansion tends to increase in succeeding generations, leading to an earlier age of onset, a feature called anticipation, which is characteristic of trinucleotide repeat diseases. The normal function of huntingtin, and the pathogenic mechanism by which the mutation causes disease, remain unclear, but a range of molecular pathways leading to cell death and dysfunction are implicated (Ross and Tabrizi, 2011). Diagnostic and predictive genetic testing is now widely available. Because of the devastating implications for the sufferer and their descendants, genetic counselling is required (Harper et al., 2004).
Table 13.19 Features of Huntington’s disease
Decreased volitional movements
Difficulty eating, speaking, and swallowing
Behavioural and psychiatric symptoms
There is no specific therapy. Dopaminergic blockade may occasionally be required to suppress severe chorea if it is causing exhaustion or limiting mobility. Antidepressants are useful for major depressive symptoms. Cholinesterase inhibitors do not benefit the cognitive impairment.
Dystonias are uncontrolled focal muscle spasms that lead to involuntary movements of the eyelids, face, neck, jaw, shoulders, larynx, hands, and (rarely) other parts of the body. They are uncommon but disabling. The aetiology is uncertain. In the past, dystonias were regarded as conversion phenomena. However, there is now strong evidence that they are genetic, idiopathic, or drug-induced neurological disorders, and that psychogenic cases are rare. However, psychiatric factors may exacerbate symptoms and disability. Clinical types include blepharospasm, torticollis, writer’s cramp, and laryngeal dystonia. The most effective treatment is the injection of botulinum toxin directly into the affected muscles. Deep brain stimulation is also being used. Psychiatric symptoms secondary to the physical disorder can be treated with antidepressants or behavioural therapy. For a review, see Henderson and Mellers (2009).
Muscular problems are common among musicians, and may threaten to end their careers. There are many causes, including overuse injury, pressure on peripheral nerves, and focal dystonias. These problems should be assessed by a physician with experience in the field. Performance anxiety is also frequent, and may impair or prevent performance. Beta-blockers alleviate this symptom and are used by many musicians, sometimes without medical supervision. Anxiety management is effective in some cases. Other occupations also have characteristic dystonias (e.g. golfers’ ‘yips’).
Tics are purposeless, stereotyped, and repetitive jerking movements that most commonly occur in the face and neck (Zinner and Mink, 2010). They are much more common in childhood than in adulthood, although a few cases begin at up to 40 years of age. The peak of onset is about 7 years, and onset often occurs at a time of emotional disturbance. Tics are especially common in boys. Most sufferers have just one kind of abnormal movement, but a few people have more than one (multiple tics). Like almost all involuntary movements, tics are worsened by anxiety. They can be controlled briefly by voluntary effort, but this results in an increasing unpleasant feeling of tension. Many tics that occur in childhood last for only a few weeks; others last for longer, but around 80–90% of cases improve within 5 years. Tics in children are associated with a range of psychiatric disorders, notably obsessive–compulsive disorder, attention deficit hyperactivity disorder, and anxiety disorders. Tics can be treated with antipsychotics or alpha-2 adrenergic agonists; botulinum toxin can also be used (Shprecher and Kurlan, 2009).
Gilles de la Tourette syndrome
This condition was first described by Jean Itard in 1825 and subsequently by Georges Gilles de la Tourette in 1885. It is the most common tic disorder. The main clinical features are multiple tics beginning before the age of 16 years, together with vocal tics (grunting, snarling, and similar ejaculations). About one-third of affected individuals exhibit coprolalia (involuntary uttering of obscenities), but few of these are children. Around 10–40% exhibit echolalia or echopraxia. There may be stereotyped movements, such as jumping and dancing. The tics are often preceded by premonitory sensations. Associated features include overactivity, difficulties in learning, emotional disturbances, and social problems. Obsessive–compulsive symptoms frequently occur in these patients, and occur more often among the families of these patients than in the general population. Attention deficit hyperactivity has also been reported to be more frequent.
The reported prevalence of the condition varies according to the criteria for diagnosis and method of enquiry. Recent data suggest a prevalence in children of almost 1%. The disorder is three to four times more common in males than in females.
The aetiology of the syndrome is uncertain. There is a substantial genetic contribution, and an overlap with the genetic predisposition to obsessive–compulsive disorder. Altered dopamine function and aberrant cortico-striatal connectivity have also been implicated. In addition, autoimmune abnormalities are suspected in a subgroup. For a review, see Albin and Mink (2006).
Mild cases may not require specific treatment. Many treatments have been tried (Shprecher and Kurlan, 2009). Antipsychotics, especially haloperidol, have been widely used and are effective, but the side-effects can be troublesome. There are also randomized trials showing efficacy of clonidine and desipramine. Comorbid psychiatric disorders, such as obsessive–compulsive disorder and attention deficit hyperactivity disorder, are common, and should be treated.
There are few good outcome data. Clinical experience suggests that two-thirds of patients can expect an improvement or lasting remission in early adulthood, but the outcome is frequently poor. Coprolalia disappears in one-third of patients, but the tics and obsessive–compulsive symptoms may be lifelong.
For a review, see Kurlan (2010).
Epilepsy is the tendency to recurrent seizures, where a seizure consists of a paroxysmal electrical discharge in the brain and its clinical sequelae. The tendency to recurrent seizures, which defines epilepsy, must be distinguished from isolated seizures that may be provoked by many factors, including drugs, hypoglycaemia, and intercurrent illnesses. Epilepsy is managed primarily by neurologists, and for a full description the reader is advised to refer to a neurology textbook. However, epilepsy also has several important psychiatric aspects, reflecting its description as the ‘bridge’ between psychiatry and neurology:
• the differential diagnosis of episodic disturbances of behaviour (particularly ‘atypical’ attacks, aggressive behaviour, and sleep problems)
• the treatment of the psychiatric and social complications of epilepsy
• seizures caused by psychotropic medication
• the psychological side-effects of anticonvulsant drugs.
Table 13.20 Classification of seizures
Seizures beginning focally
Simple motor or sensory (without impaired consciousness)
Complex partial (with impaired consciousness)
Partial seizures with secondary generalization
Generalized seizures without focal onset
Types of seizures
The current classification of seizures was proposed by the International League Against Epilepsy in 1969, and later revised (Dreifuss et al., 1981). A simplified outline is shown in Table 13.20. The principal distinction is between focal-onset seizures, called partial seizures, and seizures which are generalized from the start. Since focal-onset seizures may become generalized, an accurate description of the onset is essential. It is also necessary to distinguish between types of epilepsy and types of seizure. Traditional terms such as ‘petit mal’ and ‘grand mal’ are ambiguous, and are best avoided. It should be remembered that an ‘aura’ is in fact a partial seizure; most so-called ‘absences’ and ‘petit mal’ are actually complex partial seizures, implying a focal rather than generalized disturbance, as in true absences.
A brief clinical description of the more common types of seizure follows.
Simple partial seizures
The content depends upon the site of the focus. Simple partial seizures include Jacksonian motor seizures and a variety of sensory seizures in which the phenomena are relatively unformed. Awareness is not impaired. Focal neurological or cognitive dysfunction may persist for a variable period following the seizure.
Complex partial seizures
Complex partial seizures are characterized by altered awareness of self and the environment, and include a wide range of ‘psychiatric’ features (see Table 13.21)—hence the earlier term ‘psychomotor epilepsy’—making them the form of epilepsy of most importance to psychiatrists, and frequently forming part of the differential diagnosis.
Consciousness is not lost, unless secondary generalization occurs. However, during this period the subject appears out of touch with their surroundings, and often has great difficulty in describing their experiences later. The seizures arise most commonly in the temporal lobe, reflecting the additional former term ‘temporal lobe epilepsy.’ However, that is not an appropriate term, as complex partial seizures can also begin in the frontal lobes and other sites. Seizures that originate in the latter region are particularly likely to be misdiagnosed as functional, as they are frequently accompanied by bizarre posturing and other semi-purposeful, complex motor behaviours. Complex partial seizures of temporal lobe origin are often heralded by an aura, which may take the form of olfactory, gustatory, auditory, visual, or somatic hallucinations. Particularly common is the ‘epigastric aura’—a sensation of churning in the stomach which rises towards the neck. The patient may also experience odd disturbances of thought or emotion, including an intense sense of familarity (déjà vu) or unfamiliarity (jamais vu), depersonalization or derealization, or, rarely, vivid hallucinations of past experiences (‘experiential phenomena’). The sequence of events during the seizure tends to be stereotyped in the individual patient, which is an important diagnostic aid. The whole ictal phase usually lasts for up to 1–2 minutes. After recovery, only the aura may be recalled. Non-convulsive status epilepticus may take the form of a prolonged single seizure, or a rapid succession of brief seizures. In such cases, a protracted period of automatic behaviour may be mistaken for a dissociative fugue or other psychiatric disorder.
Table 13.21 Clinical features of complex partial seizures
The key feature of an absence attack is loss of awareness which starts suddenly, without an aura, lasts for seconds, and ends abruptly. Simple automatisms (e.g. eyelid fluttering) often accompany the attack. There are no postictal abnormalities. For the purposes of diagnosis and treatment, it is essential to distinguish between absence seizures and complex partial seizures. The latter last longer, automatisms during the episode are more complex, recovery occurs more slowly, and the patient may subsequently recall an aura. Absence attacks in children were previously called ‘petit mal’, and are classically associated with 3 per second ‘spike-and-wave’ EEG discharges.
Generalized tonic-clonic seizures
This is the familiar epileptic convulsion with a sudden onset, tonic and clonic phases, and a succeeding period of variable duration (up to many hours) in which the patient may be unrousable, sleepy, or disorientated. Incontinence and tongue-biting or other injuries may occur during the seizure. During the post-ictal phase the patient may present with delirium, which may cause diagnostic uncertainty if the convulsion was not witnessed. Generalized tonic–clonic seizures may be initiated by a partial seizure, implying localized brain disease, which is often overlooked. This is an issue of importance, as primary and secondary generalized seizures differ in significance and management.
Myoclonic, atonic, and other seizure types
There are several types of seizures with predominantly motor symptoms, including myoclonic jerks and drop attacks with loss of postural tone. They are unlikely to present to the psychiatrist.
In the UK, general practice data indicate that the prevalence of epilepsy in adults is about 7 per 1000. About 1 in 30 people have a seizure at some stage. The inception rate is highest in early childhood, and there are further peaks in adolescence and over the age of 65 years. Epilepsy is usually of short duration, and only becomes a chronic condition in about 20% of subjects. This means that regular attenders at specialist clinics are a minority of all those with epilepsy, who are especially likely to suffer from its medical and social complications. Childhood epilepsies are more often associated with significant cognitive impairment.
Age at onset is an important clue to aetiology. For example, in the newborn, birth injury, congenital brain malformations, and metabolic disorders are common causes. Infantile febrile convulsions, especially status epilepticus, are classically associated with later complex partial epilepsy, via damage to the hippocampus (hippocampal sclerosis). About 30% of epilepsy is thought to have a primarily genetic basis. However, although many individual genetic mutations and copy number variants are being identified, to date they account for only a small proportion of cases. In adults, identifiable causes include cerebrovascular disease, brain tumours, head injury, autoimmune disorders, and neurodegenerative disorders. Overall, the aetiology of epilepsy in general is attributed to a combination of genes, developmental processes, and altered plasticity (Scharfman, 2007).
Patterns of alcohol and other drug use should always be established, particularly in young adults. Seizure threshold may be lowered by drug therapy, including antipsychotics and tricyclic antidepressants. Sudden withdrawal of substantial doses of any drug with anticonvulsant properties, most commonly diazepam or alcohol, can precipitate seizures.
Making the diagnosis
Epilepsy is essentially a clinical diagnosis that depends upon detailed accounts of the attacks provided by witnesses as well as by the patient. The background history, physical examination, and special investigations are directed towards establishing the aetiology. The extent of investigation is guided by the initial findings, the type of attack, and the patient’s age. Only an outline can be given here; for a full account the reader is advised to refer to a neurology or epilepsy textbook. An EEG can confirm but cannot exclude the diagnosis. It is more useful for determining the type of epilepsy and site of origin. The standard EEG recording may be supplemented by sleep recording, ambulatory monitoring, and split-screen video (telemetry) techniques. Although neuroimaging has an increasing clinical role, no specific brain abnormality (or other cause) is found in the majority of patients with epilepsy.
Epilepsy can be erroneously diagnosed as the cause of paroxysmal neurological and psychiatric symptoms, and it is important to keep in mind the extensive differential diagnosis (see Table 13.6). A clear description of the circumstances surrounding the episode and the mode of onset is fundamental. The most important differential diagnoses of generalized seizures are vasovagal syncope (commonly associated with involuntary movements, a fact not always appreciated) and cardiac arrhythmias. Hyperventilation (of which the patient is often unaware) and panic attacks frequently produce symptoms similar to complex partial seizures, and may lead to actual loss of consciousness if prolonged. Sudden changes in motor activity, affect, and cognition can occur in schizophrenia.
Factors that together suggest a seizure include abrupt onset, a stereotyped course lasting from many seconds to a few minutes, tongue-biting, urinary incontinence, cyanosis, sustaining injury during the attack, and prolonged post-ictal drowsiness or confusion. However, none of these alone is necessary or sufficient to make the diagnosis. Some forms of frontal lobe epilepsy are particularly likely to be misdiagnosed as psychogenic. If the diagnosis remains uncertain, and attacks are frequent, close observation in hospital, including video recording and EEG telemetry and ambulatory monitoring, may be worthwhile.
Non-epileptic attacks (‘pseudoseizures’) and dissociative states can be very difficult to distinguish from epilepsy. Indeed, up to 50% of patients who are referred to epilepsy services have non-epileptic attacks exclusively or in combination (Brown and Trimble, 2000). A detailed description and careful history of the background of the attacks is crucial (Mellers, 2005). Features that suggest non-epileptic episodes include identifiable psychosocial precipitants, a past history of physical or sexual abuse, a history of psychiatric disorder, an unusual or variable pattern of attacks, occurrence either only in public or only while alone, and the absence of autonomic signs or change in colour during ‘generalized’ attacks. The patient may be suggestible, or betray other evidence of retained awareness during the episode. Complex, purposeful behaviour is more often seen in dissociative states. Ambulatory EEG may be helpful. However, some types of seizure may not be reflected in the surface EEG and, conversely, EEG abnormalities occur in perhaps 3% of healthy individuals. Post-ictal serum prolactin levels are useful in a minority of cases (they are elevated after a generalized seizure), but should not be relied upon to make the distinction.
Psychiatric aspects of epilepsy
Psychiatric comorbidity is common in people with epilepsy, with overall rates increased by at least twofold, and higher among those in specialist care. Many different types of psychiatric disorder are associated with epilepsy, including cognitive, affective, emotional, and behavioural disturbances. They are usually classified according to whether they occur before, during, after, or between seizures (see Table 13.22). The relationship between epilepsy and psychiatric disorder may reflect any of the following factors:
• a shared aetiology or pathophysiology—for example, temporal lobe pathology appears to predispose to epilepsy and to psychosis
• the stigma and psychosocial impairments associated with epilepsy
• the side-effects of anti-epileptic drugs.
• For reviews of the psychiatric aspects of epilepsy, see Gaitatzis et al. (2004) and Hermann et al. (2008).
Increasing tension, irritability, and anxiety and depression are sometimes apparent as prodromata for several hours or even days before a seizure, generally increasing in intensity as the seizure approaches.
Ictal psychiatric disturbances (i.e. those directly related to seizure activity) are common and diverse, as noted above. During seizures, transient confusional states, affective disturbances, anxiety, automatisms, and other abnormal behaviours often occur (especially in partial seizures). On occasion, an abnormal mental state may be the only sign of non-convulsive (complex partial or absence) status epilepticus, and the diagnosis is easily overlooked.
Psychosis may occur as an ictal phenomenon. Clues to this possibility include sudden onset and termination of psychiatric disturbance, olfactory or gustatory hallucinations (especially with partial seizures), a relative lack of first-rank symptoms, and amnesia for the period of the disturbance.
Table 13.22 Associations between epilepsy and psychological disturbance
Psychiatric and cognitive disorders associated with the underlying cause
Behavioural disturbances associated with seizures
Pre-ictal: prodromal states and mood disturbance
Ictal: complex partial seizures (affective disturbances, hallucinations, experiential phenomena, automatisms); absence seizures (altered awareness, automatisms)
Post-ictal: impaired consciousness; delirium; psychosis;
Todd’s paresis (hemiparesis, dysphasia, other focal signs)
Epileptic pseudodementia (non-convulsive status)
Depression and emotional disorder
Suicide and deliberate self-harm
Crime and other antisocial behaviour
Ictal violence is extremely rare (less than 0.3% in one large series) (Delgado-Escueta et al., 1981), and crimes committed during epileptic automatisms are probably even rarer, which is an important medico-legal finding (Treiman, 1999; see also p. 713).
Psychiatric disturbances may occur during the hours following a seizure. Psychotic symptoms are seen in about 10% of cases, and are associated with bilateral and extratemporal seizure foci, long duration of epilepsy, and structural brain lesions (Alper et al., 2008). These transient psychoses are distinct from the inter-ictal psychoses described below. Diverse motor, sensory, cognitive, and autonomic dysfunction can also occur and, as with the psychoses, may occur as part of a delirium, or in clear consciousness.
Post-ictal violence is rare, although it is more common than violence during the seizure, and may be secondary to psychotic experiences. Extreme post-ictal violence may be recurrent, stereotyped, and more likely to occur in men, after a cluster of seizures (Gerard et al., 1998). There is usually amnesia for the episode.
In the nineteenth century it was widely believed, based on experience with institutionalized populations, that epilepsy was associated with an inevitable decline in intellectual functioning. However, it is now established that relatively few people with epilepsy show cognitive changes. When these do occur, they are likely to reflect concurrent brain damage, unrecognized non-convulsive seizures, or the effects of anti-epileptic drugs. A few epileptic patients show a progressive decline in cognitive function. In such cases, careful investigation is required in order to exclude an underlying progressive neurological disorder; this is a particular concern in paediatric practice.
The historical concept of an ‘epileptic personality’, characterized by egocentricity, irritability, religiosity, quarrelsomeness, and ‘sticky’ thought processes, has been discarded. Community surveys indicate that only a minority of patients have serious personality difficulties, and these probably reflect the adverse effects of brain damage on education, employment, and social life, rather than a specific association with epilepsy. It has been suggested that behavioural abnormalities (including hypergraphia) are particularly associated with medial temporal lobe lesions. For a discussion of this subject, see Mellers (2009).
Depression and emotional disorders
Depression is particularly common in people with epilepsy, for both biological and psychosocial reasons, and the rate of depression may be higher than in other chronic neurological disorders. Anxiety disorders are also common. The rate of mood disorder, especially unipolar depression, is increased severalfold, with reported prevalence rates of 22–77%. Many subjects meet the criteria for dysthymia rather than major depression, and the term interictal dsyphoric disorder is sometimes used. The risk factors for depression in epilepsy are summarized in Table 13.23. The relationship between epilepsy and depression may in fact be bidirectional, with depression preceding epilepsy as well as vice versa, and reflecting common pathogenic factors for the two conditions (Kanner, 2008). Assessment and treatment of depression in epilepsy have been reviewed by Barry et al. (2008).
Table 13.23 Risk factors for depression in epilepsy
Family history of mood disorder
Focus in temporal or frontal lobe
Fear of seizures
Pessimistic attributional style
Decreased social support
Anti-epileptic drugs, especially polypharmacy and high serum levels
The nature and prevalence of inter-ictal psychosis has long been controversial, including the fundamental question as to whether the two coexist more or less often than expected. Following the important study by Slater et al. (1963), the evidence supports the view that epilepsy is associated with an increased risk of psychosis, especially a schizophrenia-like presentation. Convincing data come from a Danish population study, which demonstrated a two- to threefold increase in schizophrenia and related psychoses among people with epilepsy (Qin et al., 2005). Religious and paranoid delusions appear to be particularly common, and affect tends to be preserved. Risk factors include complex partial seizures, especially with the focus in the mesial temporal or frontal lobe, a lesion which is prenatal in origin, and possibly in the left hemisphere more than the right one. For a review, see Mellers (2009).
Suicide and deliberate self-harm are more common among people with epilepsy than in the general population. Although estimates vary markedly between studies, a meta-analysis found a standardized mortality ratio for suicide of 3.3 (Bell et al., 2009). The rate appears to be higher in those with temporal lobe epilepsy (a 25-fold increase), and after surgical treatment for epilepsy (Harris and Barraclough, 1997). Suicide risk factors in epilepsy encompass the same range of risk factors as in the general population (see Chapter 16).
Social aspects of epilepsy
The consequences for quality of life correlate with the severity of the seizure disorder and the presence of structural brain pathology. The social implications and stigma attached to a diagnosis of epilepsy can be far-reaching, as is the unpredictability of seizure occurrence. When counselling patients and their families, it is important to be sensitive to these issues and to allay groundless fears and misconceptions. Restrictions on driving are a major burden for many patients, whose livelihood may be at stake. In order to obtain a UK driving licence, the patient must have had at least 1 year with no seizures while awake, whether or not they are still taking anti-epileptic drugs. Those who have seizures only while asleep may hold a licence if this pattern has been stable for at least 3 years.
Sexual dysfunction with reduced libido and impaired performance is common in patients with epilepsy, especially where there is a temporal lobe focus. This is thought to be mainly due to anti-epileptic medication, although psychosocial factors are also important, and rarely there may be a direct link to the cause of the seizures.
Epilepsy has been said to be associated with crime and violence. However, there is little evidence for either assertion. In meta-analyses, rates of epilepsy among prisoners were not increased (Fazel et al., 2002), nor was the risk of violence higher in people with epilepsy (Fazel et al., 2009b). The latter result emphasizes that ictal and post-ictal violence, mentioned earlier, are both very rare events.
Treatment of epilepsy
The drug treatment of epilepsy is usually undertaken by neurologists. Here the discussion will be restricted to some key points of psychiatric relevance. For reviews, see Barry et al. (2008), Mellers (2009), and Mittan (2009).
It is important to distinguish between peri-ictal and inter-ictal psychiatric disorders when planning treatment. For peri-ictal disorders, treatment is aimed at control of the seizures. Treatment of inter-ictal psychiatric disorders is similar to that in non-epileptic patients, although it should be remembered that psychotropic drugs may increase seizure frequency. Suitable antidepressants for use in epilepsy are the SSRIs or MAOIs, while amisulpride, risperidone, and haloperidol are appropriate antipsychotics. Conversely, anticonvulsant drugs can cause a variety of cognitive and psychiatric symptoms (Lagae, 2006), and are increasingly being used to treat psychiatric disorders (see Chapter 19). Finally, there are pharmacokinetic interactions between anti-epileptic, psychotropic and other drugs that can lead to toxicity or sub-therapeutic levels (Monaco and Cicolin, 1999). Close liaison between neurologist, psychiatrist, and general practitioner is recommended.
The psychiatrist is likely to see two main groups of patients who have suffered a head injury:
• a relatively small group with persistent, serious cognitive and behavioural sequelae
• a larger group with emotional symptoms and personality change.
The severity of non-penetrating (closed) head injury is best assessed by the duration of post-traumatic amnesia (PTA)—that is, the interval between the injury and the return of normal day-to-day memory. This measure has the advantage of being reasonably accurate even when assessed retrospectively (i.e. by asking the patient several months later what they remember of the immediate post-injury period). A PTA of less than 1 week is associated with a reasonable outcome (e.g. return to work) in the majority of cases, but a PTA of more than 1 month often results in failure to return to work. Retrograde amnesia (i.e. loss of memory of events prior to the injury) is much less predictive of outcome. An MRI scan is useful for defining the extent of brain injury, but a normal MRI scan does not preclude some degree of brain damage.
The vast majority of closed head injuries are due to acceleration and deceleration forces. When loss of consciousness occurs for a few seconds it is thought to be due to disruption of cholinergic transmission in the brainstem. With more severe injuries, haemorrhagic areas of damage, and diffuse axonal injury and shearing in white matter, are the two main pathological events. Both contribute to coma duration. Other complications include extra- and subdural haemorrhage and anoxia. Deposition of β-amyloid occurs in some cases, which may explain the link seen, at least in men, between head injury and later development of Alzheimer’s disease (Fleminger et al., 2003), and with dementia pugilistica (see below). There is some evidence that the apolipoprotein E4 (apoE4) genotype increases the risk of death or cognitive deficits after head injury (Zhou et al., 2007).
For a review of the psychiatry of head injury, see Kim et al. (2007).
Acute psychological effects
After severe injury, a phase of delirium may follow awakening from coma. Prolonged delirium may be accompanied by a transient confabulatory state. Occasionally, delusional misidentification or reduplicative paramnesia (see p. 307) is observed—for example, ward staff may be identified as old friends, or the ward may be identified as a duplicate in a distant town. Agitation and disinhibition (often sexual) are often present, and may take days or weeks to resolve.
Chronic psychological effects
Both primary and secondary (due to the effects of brain swelling and raised intracranial pressure) damage determine the neurological and cognitive deficits. The long-term outcome is also influenced by premorbid personality traits, occupational attainment, availability of social support, and compensation issues. Post-traumatic epilepsy may be a further significant complicating factor in more serious injuries. The risk of suicide is increased threefold after head injury.
After head injury, many patients describe a group of symptoms known as the post-concussional syndrome. The main features are anxiety, depression, and irritability, accompanied by headache, dizziness, fatigue, poor concentration, and insomnia. The duration and severity of these symptoms are highly variable. Most cases resolve without specific medical intervention.
Lasting cognitive impairment
The particular vulnerability of frontal and temporal lobes to closed head injury hints at the usual pattern of neuropsychological deficits, with memory and executive function being most affected. The patient may show significant impairments in these domains (e.g. organizing and planning activities) without an overall decline in performance in terms of IQ.
Personality change is common after severe injuries, particularly if there is frontal lobe damage, when there may be irritability, apathy, loss of spontaneity and drive, disinhibition, and occasionally reduced control of aggressive impulses. ICD-10 has a category of ‘organic per sonality disorder’ to describe this group. Management is difficult, demanding considerable social support and, in some cases, prolonged rehabilitation. Such resources are scarce and often unavailable. Fazel et al. (2009b) found an increased risk of violence after head injury.
Depression and emotional disorder
Depression, anxiety, and emotional lability are very common after brain damage. Persistent depression and anxiety occur in about 25% of cases, a frequency similar to that in other serious physical disorders (Jorge and Stark-stein, 2005). Left frontal lesions appear to be associated with a greater risk of depression, but an association with right frontal damage has been reported for penetrating injuries. Post-head-injury mania, also linked to right frontal damage, is much less common, and can be mistaken for personality change.
Transient psychotic symptoms are common during the delirium after head injury. However, it is unclear whether there is an increased risk of schizophrenia-like psychosis after this phase has passed. The classic study was undertaken by Davison and Bagley (1969), who found a two- to threefold greater risk of schizophrenia in survivors of war injuries. However, later studies do not support such an association (David and Prince, 2005).
Boxing and head injury
In 1969, Roberts drew attention to the tendency for professional boxers to develop a chronic traumatic encephalopathy, sometimes called punch-drunk syndrome or dementia pugilistica (Roberts, 1969), related to the cumulative extent of head injuries suffered during their boxing career. Subsequent changes to the rules of boxing, and more careful medical assessment, have been intended to reduce the incidence of the syndrome, which typically develops after retirement from the ring. The principal early features are executive dysfunction, bradyphrenia, mild dysarthria, and incoordination, followed by Parkinsonism, spasticity, and ataxia. The fully developed syndrome may consist of a range of motor features, cognitive deficits, and a variety of behavioural manifestations. Neuropathologically, there is loss of neurons in the cortex, substantia nigra, and cerebellum, together with neurofibrillary tangles and diffuse amyloid plaques (Roberts et al., 1990).
Treatment of head injury
Prospective studies have demonstrated that early assessment of the extent of neurological signs provides a useful guide to the likely pattern of long-term physical disability. Neuropsychiatric problems should be assessed and their impact anticipated, and a comprehensive social assessment is crucial. The clinical psychologist can sometimes contribute behavioural and cognitive techniques. Practical support is needed for the patient’s family and carers. Issues of compensation and litigation should be settled as quickly as possible.
Medication is often used to treat aggression, depression, apathy, psychosis, or concentration problems, but evidence (as for psychological treatments) is lacking. If drugs are considered to be necessary, always start with a low dose and choose agents that have less potential for seizure generation and anticholinergic or extrapyramidal side-effects. For a review of the management of head injury, see Fleminger (2009a).
Most improvement after a head injury occurs within the first year. Late deterioration should raise suspicion of a progressive or second event, such as a subdural haematoma or hydrocephalus, epilepsy, the development of a psychiatric disorder (e.g. depression), or drug toxicity.
Strokes may lead to vascular dementia, as described above (see p. 330). However, they have other neuropsychiatric implications, too. Overt strokes usually present as a neurological emergency, with hemiparesis, dysphasias, and other focal symptoms and signs. Subsequently, survivors may be left with these and other impairments, in addition to a range of psychiatric symptoms which depend largely on the site and size of the vascular event. For a review, see Fleminger (2009b).
Irritability, apathy, lability of mood, and occasionally aggressiveness may occur. Inflexibility in coping with problems is common, and may be observed in extreme form as a catastrophic reaction. These behavioural changes are often as disabling, and as distressing to carers, as residual hemiplegia or dysphasia. They are probably due more to associated widespread arteriosclerotic vascular disease than to a single stroke, and they may continue to worsen even when the focal signs of a stroke are improving.
After a stroke, some people become abnormally emotional, with mixtures of spontaneous laughter and crying, and the emotional display is frequently at odds with the patient’s apparent mood. Antidepressants are considered to be helpful.
Depressed mood is common after stroke and may contribute to the apparent intellectual impairment or impede rehabilitation (Robinson, 2003). The estimated prevalence is 12–64%. It has been claimed that the risk of depression is related to the location of the stroke, being associated with a left anterior or right posterior hemisphere stroke (Starkstein and Robinson, 1993), but the findings remain controversial. Post-stroke depression is associated with an increased mortality rate.
Treatment of post-stroke depression depends in part on active rehabilitation. A trial of an antidepressant is often used, but this should be undertaken cautiously, as side-effects are frequent. A systematic review found a small therapeutic benefit for medication but not for psychotherapy (Hackett et al., 2008). Patients who have suffered strokes are at increased risk of suicide (Stenager et al., 1998).
In the survivors of subarachnoid haemorrhage, cognitive impairment, personality change, and anxiety and depression are all common. The long-term outcome is poor, and psychosocial problems are often prominent. There are also anecdotal reports that a subarachnoid haemorrhage can be precipitated by emotionally stressful events. For a review, see Fleminger (2009b).
Inflammation of the cerebral vasculature, whether localized (e.g. temporal arteritis) or as part of a systemic disease process (e.g. Wegener’s granulomatosis), can produce a range of neuropsychiatric features. For a review, see Fleminger (2009b).
Subdural haematoma may follow a fall in elderly patients, especially in those with a history of alcoholism. However, a history of head trauma is commonly lacking. Acute haematomas may cause coma or fluctuating impairment of consciousness, associated with hemiparesis and oculo-motor signs. The psychiatrist is more likely to see the chronic syndromes, in which patients present with headache, poor concentration, vague physical complaints, and fluctuating consciousness, but often with few localizing neurological signs. It is particularly important to consider this possibility as a cause of accelerated deterioration in patients with a neurodegenerative dementia. Treatment is by surgical evacuation, which may reverse the symptoms.
Many intracranial infections cause cognitive impairment, and effective treatment is available for the majority of them. HIV infection is considered in Chapter 15. Unusual infections should always be considered as a cause of otherwise unexplained cognitive and psychiatric symptoms. For a review, see Dilley and Fleminger (2009).
Neurosyphilis, a manifestation of the tertiary stage of infection with the spirochaete Treponema pallidum, is now rare in Western countries. However, increasing numbers of cases have been reported in Eastern Europe and in association with HIV. Because of its protean manifestations, the possibility of neurosyphilis should be considered in all ‘neuropsychiatric’ patients, especially those with delirium or dementia, and appropriate blood or CSF serological tests ordered. Prior treatment with antibiotics may produce partial and atypical syndromes.
An asymptomatic stage precedes clinical disease with variable latency. Symptomatic neurosyphilis takes three forms.
• Meningovascular syphilis appears within 5 years of primary infection. It presents with strokes, or with personality changes, emotional lability, and headache. Dementia may occur subsequently, accompanied by psychotic symptoms.
• General paresis (also called general paralysis of the insane, or dementia paralytica) starts to develop about 20 years after infection. Presentation is with dementia, personality change, dysarthria, and motor symptoms and signs. Affective and psychotic symptoms may be florid, classically with euphoria and grandiose delusions. Discovery of the cause of general paresis was an important landmark in the history of psychiatry, stimulating a search for organic causes of other psychiatric syndromes.
• Tabes dorsalis is a degeneration of spinal cord pathways, and is unlikely to present to psychiatrists.
In the early stages, treatment with penicillin reverses the condition, and halts progression later in the illness. If the clinical disease is left untreated, death usually occurs within 5 years. For a review, see French (2007).
Encephalitis may occur with primary (generally viral) infection of the brain parenchyma, or as a complication of bacterial meningitis, septicaemia, or a cerebral abscess. A great many viral causes of encephalitis have been identified, notably herpes simplex. Effective treatment (intravenous acyclovir) is available. The sequelae of the untreated disease may be devastating. In the acute stage, headache, vomiting, and impaired consciousness are usual, and seizures are common. Presentation may be with delirium. The psychiatrist may be involved in initial diagnosis, but is more likely to see chronic complications which include prolonged anxiety and depression, a profound amnestic syndrome, personality change, or complex partial epilepsy. Other significant types of encephalitis in adults include those produced by arthropod-borne viruses and, especially in the immune compromised, varicella zoster.
Finally, antibodies against various neuronal proteins (NMDA glutamate receptors, potassium channels) have recently been recognized as being a common cause of limbic encephalitis, and often present floridly with delirium and psychosis, as well as with epilepsy and other neurological features (Dalmau et al., 2008). These include the paraneoplastic syndromes associated with ovarian and other cancers, but can also occur idiopathically.
A small outbreak of encephalitis lethargica (also called post-encephalitic Parkinsonism) was first reported in 1917 by Von Economo at the Vienna Psychiatric Clinic. The condition reached epidemic proportions in the 1920s, thought to be related to the influenza pandemic of the time. By the 1930s it had largely disappeared, but sporadic cases still occur. Parkinsonism is the most disabling complication; others include personality change with antisocial behaviour, and psychosis. Some patients develop a clinical state resembling schizophrenia. Sacks (1973) gave a vivid description of such cases, and the striking but temporary ‘awakening’ brought about in some by L-Dopa. Current speculation is that the condition is caused by anti-NMDA-receptor antibodies, mentioned above.
Many brain tumours cause psychological symptoms at some stage in their course, and a significant proportion present with such symptoms. Psychiatrists are likely to see patients with slow-growing tumours in ‘silent’ (especially frontal) areas. These produce psychological effects, but few neurological signs—for example, subfrontal meningioma or glioma of the corpus callosum. The nature of the psychological symptoms is influenced by the global effects of raised intracranial pressure, in addition to the tumour location. The rate of tumour growth is also important; rapidly expanding tumours with raised intracranial pressure can present as delirium, whereas slower-growing tumours are more likely to cause chronic cognitive deficits. Focal lesions give rise to a variety of specific neuropsychiatric syndromes; those near the frontal poles typically manifest initially as personality change. Craniopharyngiomas and other tumours around the hypothalamus are also often associated with personality changes and apathy. For a review, see Mellado-Calvo and Fleminger (2009).
Cognitive impairments in cancer
In addition to the direct effects of brain tumours, neoplasms both within and outside the cranium can impair cognition via a range of mechanisms (see Table 13.24). Occasionally, such complications are the presenting feature, but usually they arise during treatment, at which time the psychiatrist may be asked for a diagnostic and therapeutic opinion. For a review, see Khasraw and Posner (2010).
Table 13.24 Some causes of cognitive impairment in patients with cancer
Primary and metastatic brain tumours
Haemorrhagic change (especially melanoma, renal-cell carcinoma, choriocarcinoma)
Carcinomatous and lymphomatous meningitis
En plaque meningioma
Paraneoplastic limbic encephalitis
Acute and subacute radionecrosis
Accelerated cerebral atherosclerosis
Second malignancies (especially glioma, meningioma)
Opportunistic infections secondary to immunosuppression (herpes zoster, progressive multifocal leucoencephalopathy)
Other neuropsychiatric syndromes
Multiple sclerosis is the most common cause of chronic neurological disability in young adults in developed countries. Its consequences for work and relationships may be profound. The disease may be difficult to diagnose early in the course, and physical symptoms are sometimes misinterpreted as psychiatric. Psychological symptoms are rarely the presenting feature, but two-thirds of patients will experience them at some stage, especially depression (see below), euphoria, emotional lability, and fatigue. Such symptoms probably result both directly from the disease process, and from the disabilities associated with it. There is a several-fold increase in the risk of suicide.
Depression is more common in multiple sclerosis than in other neurological disorders, with a lifetime risk of 50%. It does not appear to be closely related to the severity of the clinical syndrome or the site of lesions. It can also be a side-effect of beta-interferon, which is used to treat multiple sclerosis.
Cognitive impairment is present in 40% of patients from community samples. It may be an early manifestation of the illness, and occasionally a rapidly progressive dementia occurs (Chiaravalloti and DeLuca, 2008). In most cases, however, intellectual deterioration begins later, is less severe, and progresses slowly. Well-practised verbal skills are often preserved despite deficits in problem solving, abstraction, memory, and learning. Cognitive impairment correlates with total lesion load and degree of callosal atrophy on MRI, and probably reflects axonal loss rather than demyelination per se.
For a review of psychiatric aspects of multiple sclerosis, see Ghaffar and Feinstein (2007).
Normal pressure hydrocephalus
The characteristic clinical triad in this condition (Adams et al., 1965) consists of a striking ‘gait apraxia’ (a broad-based, small-stepped gait with difficulty in initiation) on which supervenes a progressive frontal subcortical syndrome with bradyphrenia and, later, urinary incontinence. Frank dementia is rare. The prevalence is uncertain, but is reported to be 0–6% of cases of late-life dementia in published series. The condition is more common in the elderly, but sometimes occurs in middle life, and in children with congenital abnormalities.
The pathogenesis has been thought to be a block to CSF flow within the ventricular system due to aqueduct stenosis, or in the subarachnoid space. However, often no cause can be discovered. Ventricular pressure is generally normal or low, although episodes of raised pressure may occur, leading to the suggestion that the disorder should be renamed (Bret et al., 2002). Ventricular enlargement out of proportion to the degree of cortical atrophy, often with periventricular signal change, is the hallmark finding on brain imaging.
It is important to differentiate this condition from a degenerative dementia, and from depression with pseudo-dementia. Cases with a short history and prominent gait disturbance with relative sparing of intellect may be amenable to a neurosurgical shunt procedure to improve the circulation of CSF. However, the outcome is variable and difficult to predict. The presence of hippocampal atrophy on imaging suggests associated Alzheimer’s disease, and predicts a poor response to shunting.
For a review, see Finney (2009).
Anoxia, hypoglycaemia, and carbon monoxide poisoning
Anoxia (e.g. due to cardiac arrest), hypoglycaemia, and carbon monoxide poisoning produce similar patterns of brain injury. Cerebral and cerebellar atrophy may occur, and the hippocampus and globus pallidus are particularly vulnerable. Clinical experience suggests that the recovery trajectory is relatively brief compared with traumatic brain injury, and that neurological sequelae are less disabling. Parkinsonism is not infrequent after a latent interval. The commonest cognitive impairment is poor memory. For a review, see Auer (2004).
Carbon monoxide poisoning usually arises from deliberate self-harm by car exhaust fumes, and, more recently, from burning charcoal in the Far East. However, it can also occur accidentally as a result of badly ventilated gas boilers or fires. The prevalence of complications after carbon monoxide poisoning is unclear, with a wide range of figures reported. It is also unclear whether residual symptoms ever occur if the poisoning was insufficient to cause loss of consciousness, although complaints of problems with memory, concentration, fatigue, and headache are common.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) has neuropsychiatric manifestations in 20–75% of patients. The commonest of these is cognitive dysfunction, affecting all domains of memory, as well as poor attention and concentration, and reduced psychomotor speed. Mood disorder is also common, and psychosis affects up to 8% of cases. SLE is an autoimmune disorder, and anti-NMDA receptor, anti-phospholipid and other antibodies are implicated. For a review of neuropsychiatric SLE, see Mak et al. (2009).
Secondary or symptomatic neuropsychiatric syndromes
All of the disorders discussed in this chapter so far are either defined by their underlying pathology (e.g. the dementias) or have an undisputed biological basis (e.g. epilepsy). However, by convention, neuropsychiatry also includes disorders that are not usually included in this category (i.e. are ‘functional’ or idiopathic), but which can on occasion be explained in the same fashion. They are described as secondary, symptomatic, or organic (see p. 26). ICD-10 and DSM-IV code these disorders in different ways and use differing terminologies (see Table 13.1). As noted earlier, in this book we cover psychiatric disorders secondary to brain diseases in this chapter, whereas those resulting from systemic diseases are covered in Chapter 15. Examples of secondary neuropsychiatric disorders are listed in Table 13.25. See also Lovestone (2009b).
The clinical features of these secondary disorders are generally indistinguishable from those in the equivalent primary psychiatric disorder. Thus recognition of a secondary syndrome depends on the associated features. The following suggest that the disorder is secondary to a physical condition:
• evidence of cerebral disease, damage, or dysfunction, or of physical disease, known to be associated with one of the listed syndromes
• a temporal relationship (of weeks or a few months) between the development of the underlying disease and the onset of the psychiatric syndrome
• recovery from the psychiatric disorder following removal or improvement of the presumed cause
• absence of evidence suggesting an alternative ‘psychological’ cause of the psychiatric disorder (e.g. in the case of depression, no evidence of a family history of mood disorder, relevant personality traits, previous episodes of mood disorder, recent life events, etc.).
Table 13.25 Some causes of symptomatic or secondary psychiatric syndromes
David AS, Fleminger S, Kopelman M et al. (2009). Lishman’s Organic Psychiatry, 4th edn. Wiley Blackwell, Oxford. (The definitive textbook on neuropsychiatry—an essential reference.)
Yudofsky SC and Hales RE (2007). Essentials of Neuropsychiatry and Behavioural Neurosciences, 2nd edn. American Psychiatric Press, Washington, DC. (An American equivalent to ‘Lishman.’ Includes chapters on the underlying neuroscience.)