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Neuropsychiatric disorders 

Neuropsychiatric disorders
Chapter:
Neuropsychiatric disorders
Author(s):

Mervi L.S. Pitkanen

, Tom Stevens

, and Michael D. Kopelman

DOI:
10.1093/med/9780199204854.003.2604
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date: 29 January 2020

Essentials

Neuropsychiatry is concerned with disorders of affect, cognition, and behaviour that arise from overt disorder in cerebral function, or from indirect effects of extracerebral disease.

The clinician needs to have a practical approach to the assessment, investigation, and management of patients manifesting cognitive and behavioural change, and to be aware of the specific cerebral and extracerebral disorders that commonly involve or are accompanied by cognitive or behavioural change.

In the assessment and classification of mental and behavioural disorders it is crucial to: (1) distinguish between acute and chronic disorders—particularly between delirium and dementia; (2) distinguish between cognitive and psychiatric disorder—misdiagnosis of depression presenting as a ‘pseudodementia’, or of delirium as psychosis, are errors that can have dire consequences for the patient; (3) determine whether cognitive impairment is specific or generalized—specific impairments are more likely to be due to a focal brain lesion; and (4) determine whether any underlying condition is reversible or irreversible.

Acute cognitive and behavioural disturbance

Delirium—can be caused by a very wide range of conditions and needs to be distinguished from acute psychosis, which can be difficult. Features that support the diagnosis of delirium are: (1) deficits of attention that may range from distractibility and inability to follow complicated conversations, through an almost complete inability to register information or to concentrate (manifest poor performance on serial subtraction test), progressing in the extreme case to diminished consciousness and coma; (2) attentional difficulties that tend to have a sudden onset and to fluctuate over time; (3) muddled thinking and speech showing considerable perseveration; (4) illusions and hallucinations that tend to include a strong visual component, although auditory hallucinations and misperceptions are common; and (5) delusions are usually simple, persecutory in nature, fluctuating, and transient.

Psychiatric disorders—a past history of psychiatric contact or treatment should be sought in all those with behavioural disturbance. In patients with an underlying psychiatric disorder there is usually a background of insidious behavioural disturbance or personality change. Delusions in psychotic disorders tend to be complex, bizarre, and consistently held, visual hallucinations are rare, and marked attentional and memory deficits are not typical (see Chapter 26.5.7).

Alcohol and substance misuse—about one-quarter of all male medical admissions have a current or previous alcohol problem, and such patients are vulnerable to a large number of complications that may precipitate delirium.

Clinical approach—it is necessary to consider a wide range of factors and medical conditions that can both predispose to and precipitate delirium. A history of alcohol and/or illicit substance misuse is of particular importance. Although not always easy, a thorough physical examination with particular attention to the neurological system is essential. A routine screen—including full blood count, electrolyte, and γ‎-glutamyl transferase (GGT) measurements, liver and thyroid function tests, glucose estimation, and C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR)—is required, as this might indicate delirium where the diagnosis is in doubt. Infection is implicated in around one-third of hospital inpatients who are delirious, and a midstream urine sample (MSU) and chest radiograph are usually warranted. Relevant history and findings on physical examination determine the need for more specific investigation, e.g. brain CT, lumbar puncture, malarial blood film.

Management—delirium is a medical emergency. Management consists of treating the underlying causes and containment of any behavioural disturbance with general measures in the first instance, including nursing in a bright, simple room with minimal changes in staff and good lighting at night. Where sedation is required, then a regular oral antipsychotic such as haloperidol can be administered (see Chapter 26.3).

Chronic and subacute cognitive and behavioural disturbance

The diagnostic challenges in this group of patients are exemplified by the complex differentiation between dementia and depression or ‘depressive pseudodementia’.

Dementia—this is a progressive neurodegenerative syndrome involving a pervasive impairment of higher cortical functions resulting from widespread brain pathology. Reversible causes must be excluded. A typical diagnostic screen will include a full blood count, electrolyte and metabolic screen, thyroid screen, vitamin B12 and folate levels, syphilis serology, urinalysis, chest radiography, electrocardiography, and CT/MRI brain imaging. In some cases, lumbar puncture, electroencephalography, and (rarely) brain biopsy will be required. Functional brain imaging is likely to assume greater importance in the future.

Focal cognitive disorders—a variety of neuropsychiatric syndromes may arise from regional cerebral impairments of diverse cause and may present in the absence of generalized cognitive impairment: frontal lobe, temporal lobe, parietal lobe, and diencephalic syndromes are recognized.

Organic comorbidity in psychiatric disorders

Missing an underlying ‘organic’ diagnosis remains a continuing concern for clinicians responsible for the assessment and treatment of new cases of an apparent psychiatric disorder. (1) Organic psychotic disorder—debate remains over the degree of investigation appropriate at the onset of psychosis. Patients with cognitive impairment, abnormal neurological signs, atypical illnesses not responding to treatment, or other indications from the history, certainly warrant further investigations. Where appropriate, this should include neuroimaging, electroencephalography, syphilis serology, and other investigations indicated by the clinical picture. (2) Organic mood disorder—a variety of medical conditions are associated with prominent affective disorder. (3) Organic personality disorder—insidious changes in personality may reflect frontal lobe pathology.

Introduction

Neuropsychiatry is concerned with disorders of affect, cognition, and behaviour that arise from overt disorder in cerebral function, or from indirect effects of extracerebral disease. The term has largely replaced the earlier expression ‘organic psychiatry’, which originated in the classification of mental disorders as either ‘organic’ or ‘functional’ on the basis of the presence or absence of pathological changes in the brain. The latter distinction has become increasingly ambiguous as a result of the development of new methods for detecting abnormal brain pathology and pathophysiology in so-called ‘functional’ disorders such as depression and schizophrenia. Indeed, the most recent version of the Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV, American Psychiatric Association) states, ‘the term organic mental disorder is no longer used in DSM-IV because it incorrectly implies that ‘nonorganic’ mental disorders do not have a biological basis’. Nevertheless, a creative conflict has always pertained between neurological and psychological theories of behaviour and, in the absence of satisfactory alternatives, these terms have retained a place in clinical practice. In part, this serves to demarcate the uneasy and shifting boundary between disorders predominantly diagnosed and managed by physicians and psychiatrists, respectively.

In this chapter, we provide a consideration of practical issues related to the assessment, investigation, and management of patients manifesting cognitive and behavioural change, and we discuss specific cerebral and extracerebral disorders that commonly involve or are accompanied by cognitive or behavioural change. Our intention is to help in the identification of possible diagnoses causing particular behavioural features, and also to alert clinicians to the likely neuropsychiatric sequelae of specific medical disorders.

Assessment and differential diagnosis of patients with cognitive and behavioural change

The assessment and classification of mental and behavioural disorders is a frequent source of misunderstanding and confusion for clinicians, the process being undermined by the absence of robust clinical and laboratory markers for these conditions. Moreover, the clinical terminology used to describe certain symptoms and signs (such as ‘confusion’) is often unsatisfactory and unreliable. Although the major systems of classification are broadly similar, they continue to use different terminology: e.g. the World Health Organization’s International statistical classification of diseases and health-related problems, 10th revision (ICD-10) retains the term ‘organic disorders’, whereas DSM-IV uses the broad grouping ‘delirium, dementia, amnesic, and other cognitive disorders’. In addition, some of the operational diagnoses may have little validity in assisting the clinician to determine the appropriate investigation and treatment, e.g. the ICD-10 ‘unspecified organic personality and behavioural disorders due to brain disease, damage, and dysfunction’. Kopelman and Fleminger proposed a few principles that should be considered in revising ICD-10 and DSM-IV: the existing classification should be simplified; new syndromes should be incorporated where they have pathological justification; links to other specialist diagnostic classifications should be made; a broader range of ‘neuropsychiatric disorders’ should be incorporated, including alcohol-related organic disorders, head injury, sleep disorders, and if possible also ‘psychogenic syndromes’; progressive, degenerative disorders need to be clearly distinguished from nonprogressive syndromes, and some gradation of severity needs to be built; and finally the definitions need to be concise and accurate. Nevertheless, there is consensus on the essential clinical features of these disorders, and in this section we shall describe their assessment on the basis of a number of core features underpinning the differential diagnosis.

Acute versus chronic disorder

The differentiation of acute and chronic cognitive disorder essentially determines the boundary between delirium and dementia. This distinction should be apparent from the history and mode of presentation, although difficulties may arise where a clear history is lacking due to disturbed communication or the absence of an adequate informant. However, they can usually be distinguished on the basis that conspicuous impairment of attention is typical of an acute disorder, together with a fluctuating course and prominent perceptual disturbance, but the ‘acute vs chronic’ disorder—where there is a delirium superimposed on a chronic cognitive disorder— should not be overlooked. Caution is also needed in patients in hospital where protracted periods of delirium exceeding 6 months have been reported.

Cognitive versus psychiatric disorder

The distinction between a cognitive and a psychiatric disorder is not always easy. It is important to recognize that an apparent cognitive abnormality may be seen in psychiatric disorders such as schizophrenia and depression. In depression, impairment of memory and concentration together with somatic complaints may lead to a misleading impression of dementia, so-called ‘pseudodementia’ or ‘reversible dementia’. Likewise, the distinction between acute psychotic disorders and delirium can be difficult where both conditions show behavioural disturbance and disturbed communication. The risks associated with the wrongful categorization of delirium as psychosis are high: delirium is a medical emergency with high morbidity and mortality, and it is potentially reversible. Likewise, the attribution of a psychiatric disorder as delirium or dementia bears costs in terms of performing unnecessary investigations and pursuing the wrong therapy in an inappropriate setting, thereby compounding any illness behaviour.

Specific versus generalized cognitive impairment

If cognitive impairment is identified, it needs to be determined whether this is generalized to many cognitive functions or affects a specific function such as memory, planning, perception, language, or attention. Identification of a specific impairment, such as the amnesic syndrome, offers important clues as to the aetiology and management, and is more likely to result from a focal brain lesion (as opposed to an extracerebral disorder).

Reversible versus irreversible

The range of causes for any psychiatric or cognitive impairment needs to be fully assessed. In particular, it is essential that those conditions that can be reversed or arrested should be specifically considered. Also, it is important to note that many of the psychiatric and cognitive disturbances caused by underlying organic conditions have a time window for their reversibility, which is usually only in the early phases of the disease, although recent studies suggest that true reversibility of cognitive impairment in the older patient is actually very uncommon.

Acute cognitive and behavioural disturbance

A wide range of disorders may cause acute emotional and behavioural disturbances (Box 26.4.1). One of the most problematic aspects of assessment is the distinction between an acute psychotic episode and delirium. The clinical features of delirium (also known as ‘acute organic brain syndrome’ or ‘acute confusional state’) and of the ‘functional’ psychoses typical of schizophrenia or affective disorder share a number of characteristics. First, both involve a pervasive disruption of thought, cognition, communication, and behaviour in the patient, hence presenting particular difficulties in assessment. Second, both conditions may involve abnormalities of perception in the form of hallucinations or illusions; abnormalities of belief, in the form of delusions or overvalued ideas; psychomotor abnormalities, including hypo or hyperactivity; disturbance of the sleep–wake cycle; and emotional disturbance encompassing the range from depression to irritability and euphoria. These similarities cause practical difficulties in diagnostic differentiation, and they also hint that an absolute distinction between ‘functional’ psychosis and ‘medical’ delirium is probably untenable.

Delirium

A thorough history of the antecedents and onset of any behavioural and mental disturbance, as well as details of any past medical or psychiatric disorder, will yield important clues as to the likelihood of an organic aetiology to behavioural change. A drug history should be sought, in particular regarding use of anticholinergic agents.

The uncooperative or mute patient presents a particular challenge as important historical details may not be forthcoming, such as head injury, substance misuse, foreign travel, diabetes, or other medical disorders. Furthermore, accurately eliciting a mental and cognitive state is problematic, and it is in this group that a history from an informant, ward staff, or relatives is especially important. The diagnosis of delirium should be suspected where the history of behavioural disturbance is of recent onset, fluctuating, and there is evidence of deterioration at night. Difficulty in communicating with a patient is frequently the first indication of an underlying delirium.

Older people and general hospital inpatients are particularly vulnerable to delirium and there is an expanding literature advocating prevention through early detection and assertive management of risk factors including dehydration, sensory impairment, immobility, sleep deprivation, and cognitive impairment (Box 26.4.2). A prevalence of between 10% and 20% has been identified in hospital inpatients. Any change of environment such as a recent admission to residential care or pre-existing cognitive impairment will heighten this vulnerability. Among inpatients the problem is compounded by inadequate information, impersonal environments, and confusing exposure to a myriad of different professionals. It is common for the diagnosis to be missed where there is no overt agitation or antisocial behaviour.

Behavioural changes seen with delirium include irritability, repetitive purposeless movements, and disorganization or difficulty performing routine tasks such as undressing. It is important to recognize that patients may be both overactive and noisy or inactive and slow.

The predominant clinical feature of delirium has been described as ‘clouding of consciousness’ or ‘clouding of the sensorium’. There are no consensus definitions for these terms and they are not clear in practice, but have traditionally been used to describe a combination of orientation, attention, and memory deficits. Consequently, deficits of attention are stressed in diagnostic criteria, which in the delirious patient may range from distractibility and inability to follow complicated conversations, through an almost complete inability to register information or to concentrate, progressing in the extreme case to diminished consciousness and coma. Furthermore, such attentional difficulties tend to have a sudden onset and to fluctuate over time. Thinking tends to be muddled and speech may show considerable perseveration. The illusions and hallucinations associated with delirium tend to include a strong visual component, although auditory hallucinations and misperceptions are common. Delusions are usually simple, persecutory in nature, fluctuating, and transient.

It should be noted that if delirium and cognitive impairment are simply assessed by orientation in time, place, and person, then ‘mild’ or ‘early’ delirium may be missed, and it is therefore important to use additional tests of concentration and memory. All patients should be screened with a small battery of bedside cognitive tests that include specific tests of concentration such as serial subtractions and an assessment of memory for recent events and new information. The Mini-Mental State Examination (MMSE), is often used, but should be supplemented with a few additional memory and other tests.

Psychiatric disorder

The characteristic clinical features of psychiatric disorders are covered in Chapter 26.5.7. Here we will discuss the features of acute behavioural disturbance that are suggestive of a psychotic illness or other psychiatric disorder. This issue is especially important in the emergency medical setting where such patients may be perceived as ‘time-wasting’ and ‘not medical’, and their medical needs may be crucially neglected.

A past history of psychiatric contact or treatment should be sought in all those with behavioural disturbance, as this is an indicator of putative psychiatric causation. In those with an underlying psychiatric disorder there is usually a background of insidious behavioural disturbance or personality change, and this will often become apparent from any informant. Delusions in psychotic disorders tend to be complex, bizarre, and consistently held, but this may not be so in early cases. Visual hallucinations are rare in psychosis. Marked attentional and memory deficits are not typical of psychosis, although more subtle attentional problems and a range of other cognitive deficits may be present. Distractibility as a consequence of internal experiences may give the impression of confusion and attentional impairment, but careful cognitive assessment will usually indicate preserved function.

Delirium in those with psychiatric disorder

The diagnosis of delirium is particularly difficult in those with a history of severe psychiatric disorder and/or learning disability. Difficulty in communicating with and examining such patients, who may have baseline cognitive impairment, means that delirium is particularly likely to be overlooked. Patients with severe mental illness will often attend for emergency consultations where the initial impression is of deterioration in their mental state, often coupled with a recent history of failing to comply with prescribed treatment or a disengagement from services provided. It should always be remembered that there is a high rate of undiagnosed physical illnesses in this population, and their risk of delirium is also raised because of serious side effects from psychotropic medication, including neuroleptic malignant syndrome and lithium toxicity that can result in a deteriorating mental state. In addition, other aspects of these patients’ behaviour place them at risk of physical illness, such as coexisting substance and alcohol dependency.

Alcohol and substance misuse

About one-quarter of all male medical admissions have been found to have a current or previous alcohol problem. Such individuals commonly attend accident and emergency departments in a state of withdrawal or intoxication that engender negative attitudes from clinical staff. Often there is an expectation that the behavioural disturbance is due to intoxication or a withdrawal syndrome, without adequate assessment of any other physical pathology. Alternatively, such patients may attempt to minimize their alcohol and drug history so that the contribution of these to their complaints may not be immediately apparent.

Patients with a history of excessive alcohol consumption are vulnerable to a large number of complications that may precipitate delirium (Box 26.4.3) and care is needed to assess all of these possibilities. The onset of hallucinations may be mistakenly labelled as a consequence of delirium tremens without consideration of other ‘organic’ or ‘functional’ disorders.

Delirium tremens carries a mortality risk of about 5% and there is a danger that a withdrawal or intoxication syndrome may mask the emergence of other complications of alcohol and substance misuse. A history of recent blackouts or seizures should alert the physician to the possibility of hypoglycaemia or epilepsy. A careful assessment of the mental state is needed to differentiate ‘functional’ disorders, such as alcoholic hallucinosis, from schizophrenia as treatment of a mental disorder may be overlooked. Physical examination should include a careful assessment for signs of cirrhosis or acute hepatic encephalopathy, and Wernicke’s encephalopathy should always be considered since it may be seen in up to 3% of all admissions for alcohol complications (see Chapter 26.7.1).

Investigation

It is necessary to consider a wide range of factors and medical conditions that can both predispose to (Box 26.4.2) and precipitate (Table 26.4.1) delirium. A history of alcohol and/or illicit substance misuse may offer important indicators of aetiology. Although not always easy, a thorough physical examination, with particular attention to the neurological system, is essential in the assessment of all patients with acute disturbance. In addition, a routine screen—including full blood count, electrolyte and γ‎-glutamyl transferase (GGT) measurements, liver and thyroid function tests, glucose estimation, and C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR)—is required, as this might indicate delirium where the diagnosis is in doubt. Infection is implicated in around one-third of hospital inpatients who are delirious, and a midstream urine sample (MSU) and chest radiograph are usually warranted in addition to routine blood testing in these patients.

Table 26.4.1 Precipitants of delirium

Infection

Pneumonia, urinary tract infection, septicaemia, any other infection, e.g. HIV, malaria, encephalitis etc.

Iatrogenic

Drug toxicity—anticonvulsants, psychotropics, anticholinergics, opiates

Vitamin deficiencies

Thiamine, nicotinic acid, and vitamin B12 deficiency

Epileptic

Complex partial seizures, postictal states, petit mal epilepsy

Metabolic

Hypoxia, hypercapnia, electrolyte and acid–base disturbances, liver disease, uraemia, hypothermia, hyperthermia, and porphyria

Endocrine

Hypoglycaemia, hypo- and hyperthyroidism, addisonian crisis, hypo- and hyperparathyroidism, hypopituitarism

Trauma

Head injury, acute post-traumatic psychosis

Vascular

Cerebrovascular accident, subarachnoid haemorrhage, hypertensive encephalopathy

Toxic

Alcohol and drug withdrawal and intoxication, carbon monoxide poisoning

Relevant history and findings on physical examination usually guide more specific investigation. Encephalitis and intracerebral haemorrhage sometimes present with acute disturbance and cognitive impairment with no additional abnormalities in the history or clinical examination. An urgent CT or MRI of the head is indicated where the immediate cause of acute cognitive impairment is not apparent or there are focal neurological signs. Appropriate tests for infectious diseases such as malaria, trypanosomiasis, typhoid fever, and typhus will also need to be considered when there is a history of foreign travel. An EEG with evidence of progressive cortical slowing may suggest a delirium and the need for more extensive investigations where the diagnosis is in doubt.

Management

Delirium is a medical emergency and management essentially consists of treating the underlying causes. Containment of any behavioural disturbance should involve general measures in the first instance, rather than psychotropic drug treatment, although sedation is necessary in some cases. Careful and repeated explanation of the diagnosis, investigations, and treatment to the patient and relatives is important. The patient should be nursed in a bright, simple room with minimal changes in staff and good lighting at night to reduce perceptual disturbance. Drugs, especially psychoactive and anticholinergic agents that may exacerbate confusion, should be reduced to a minimum. Where sedation is required, then a regular oral antipsychotic such as haloperidol can be administered, although the clinician should be alert to the powerful antidopaminergic side effects of these drugs (see Chapter 26.3 for further discussion of these issues).

Chronic and subacute cognitive and behavioural disturbance

In the assessment of patients with a more insidious onset of cognitive and psychiatric disturbances there can again be uncertainty as to the relative aetiological roles of organic or behavioural factors. This may lead to unnecessary investigations at both considerable expense and discomfort to the patient, with attention diverted from appropriate management. Moreover, failure to consider a treatable cerebral disorder such as a space-occupying lesion may lead to avoidable and irreversible brain damage. Box 26.4.4 outlines a list of cognitive and psychiatric disorders that may exhibit evidence of cognitive impairment.

The diagnostic challenges in this group of patients are exemplified by the complex differentiation between dementia and depression or ‘depressive pseudodementia’, where there are changes in behaviour, mood, intellectual functioning, and cognitive performance. Differentiation is complicated by the fact that depressed mood is a frequent prodrome for an emerging dementia such as Alzheimer’s. Furthermore, depression is a common complication or consequence of Alzheimer’s and other dementias. It is therefore essential in the clinical setting that the relative contributions of behavioural and pathological factors in any given case are considered, and that assessment includes a thorough physical, neurological, and psychiatric examination.

Dementia

Dementia is a progressive neurodegenerative syndrome involving a pervasive impairment of higher cortical functions resulting from widespread brain pathology, the extent of which is best determined by formal neuropsychological assessment using instruments such as the revised Wechsler Adult Intelligence Scale (WAIS-R or WAIS-III), as well as standard memory and executive tests. The aetiology and characteristic clinical features of dementia are described in detail in Chapters 24.4.2 and 29.2, summarized in Table 26.4.2, and the most important causes are shown in Table 26.4.3.

Table 26.4.2 Clinical features of dementia

Behaviour

Disorganized, inappropriate, and distractible behaviour. Lack of interest and initiative. Personality change, antisocial behaviour, sleep disturbance, incontinence. Self-neglect

Mood

Anxiety, agitation, irritability, and depression. Lability of mood.

Thinking and perception

Delusions, illusions, and hallucinations

Cognition

Disorientation, recent and remote memory impairment, deficits in language; comprehension, production, recognition. Apraxia and agnosia

Insight

Impaired

Table 26.4.3 Causes of dementia

Degenerative

Alzheimer’s, cerebrovascular disease, Pick’s disease, Creutzfeldt–Jakob disease, Parkinson’s disease, multiple sclerosis, normal-pressure hydrocephalus

Infection

HIV, neurosyphilis, Whipple’s disease

Metabolic

Renal dialysis (aluminium toxicity), liver failure, metachromatic leukodystrophy

Endocrine

Hypothyroidism

Vitamin deficiency

Vitamin B12 and folate deficiency, pellagra

Space-occupying

Subdural haemorrhage, tumour

Traumatic

Punch-drunk syndrome

Genetic

Wilson’s disease, Huntington’s chorea

Autoimmune

SLE, APS

Anoxia

Respiratory failure, cardiac arrest, CO poisoning

Toxic

Alcohol dementia, heavy metal poisoning (lead, arsenic, mercury, and thallium)

APS, antiphospholipid antibody syndrome; SLE, systemic lupus erythematosus.

In the investigation of dementia it is essential to identify or exclude reversible causes: this should therefore include a full blood count, electrolyte and metabolic screen, thyroid screen, vitamin B12 and folate levels, syphilis serology, urinalysis, chest radiography, and electrocardiography. Imaging techniques are continually improving and are crucially important in the diagnosis of dementia (see section on ‘Focal disorders’). In some cases, EEG and cerebrospinal fluid examination are essential. Brain biopsy can be of additional assistance when justified by the clinical setting. However, one should keep in mind that choosing the appropriate investigation is dependent on the nature of clinical presentation: e.g. any suggestion of sporadic Creutzfeldt–Jakob disease (CJD) would make an EEG essential; focal neurological signs would indicate the need for early neuroimaging to exclude a space-occupying lesion; a known history of HIV infection may warrant a lumbar puncture; evidence of extrapyramidal disturbance should alert the clinician to the possibility of Wilson’s disease, necessitating serum copper and caeruloplasmin level investigation and slit lamp examination for Kayser–Fleischer rings.

The presence of a family history of early-onset cognitive impairment may raise the possibility of predictive and diagnostic genetic testing after appropriate counselling. These can be used in Huntington’s disease (huntingtin or HTT gene), familial Alzheimer’s disease (FAD) (three genes responsible for autosomal dominant FAD have been identified: amyloid precursor protein gene (APP), presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene), as well as in familial frontotemporal dementia (MAPT gene). However, a number of risks to such testing need to be considered, including psychological effects (i.e. depression, plans of suicide), prenatal diagnosis and testing of children, impact on insurances and employment, legal aspects, possible third-party coercion, and an understanding of the test limitations (see Chapter 24.17 for further discussion of these issues).

Focal cognitive disorders

Focal degenerative disorders were described long ago by Pick and others, but little recent attention was given to the reports of focal or lobar atrophy until Mesulam reported about primary progressive aphasia in 1982. A variety of neuropsychiatric syndromes may arise from regional cerebral impairments of diverse cause and may present in the absence of generalized cognitive impairment. However, classifying these syndromes has been difficult and the terminology remains confusing. Broadly, the frontal variant and temporal lobe variants of frontotemporal dementia have been distinguished, and—within the temporal lobe variant—progressive aphasia may be ‘fluent’ (as in ‘semantic dementia’) or nonfluent. However, the underlying histopathology has been shown to be very heterogeneous even within these broad lobar variants.

Frontal lobe syndromes

Particular neuropsychiatric interest is attached to the consequences of damage to the anterior regions of the brain. These are frequently neurologically ‘silent’, but they can also result in remarkable alterations in behaviour and personality, with preservation of spatial skills as well as cognitive functions such as memory and intelligence. Thus, neuropsychiatric manifestations may be the only signs of frontal brain disease, and psychiatric disturbance may be an impediment to medical management. Two clinical syndromes (which frequently coexist) are recognized. The first is characterized by emotional blunting, lack of empathy, indifference, and loss of initiative and motivation with impoverished speech and communication to the extreme of mutism. The second is characterized by decline in social conduct, loss of social awareness, disinhibition, impulsivity (occasionally with aggression), poor attention and concentration span, and decline in personal hygiene and grooming: in general, such patients are excessively talkative and may confabulate spontaneously. In addition, mental rigidity, fixed ideation, and stereotyped behaviours—including mannerisms or ritualistic preoccupations—are common. Both of these syndromes have been subsumed under the term ‘dysexecutive syndrome’ (also known as ‘strategy application disorder’), which attempts a unitary cognitive psychological perspective on the condition. Interesting parallels have been drawn between the clinical frontal lobe syndrome and features of neurological conditions such as Parkinson’s disease and psychiatric disorders such as the negative syndrome in schizophrenia: in both these examples it is thought that impaired dopaminergic neurotransmission in prefrontal brain regions gives rise to the particular symptomatology.

Temporal lobe syndromes

A variety of syndromes are recognized following temporal lobe damage depending upon the particular area affected. Personality disturbance may be seen, although usually with neurological impairments. A particular variant of this is Klüver–Bucy syndrome following bilateral lesions to the medial and lateral temporal lobes: this results in placidity, hyperorality, bulimia, abnormal sexual behaviour, and visual agnosia. It is a rare neurobehavioural condition but can be seen in patients with extensive temporal lobe damage as a result of post-traumatic, postinfectious, and degenerative (dementias) disorders.

Hemisphere specific, language dominant temporal lobe lesions may produce aphasia, ‘surface’ dyslexia, and/or dysgraphia, frequently accompanied by neurological impairments on the contralateral side. Progressive aphasia can be fluent or nonfluent. Nondominant lesions may particularly affect facial, spatial, or autobiographical memory, or may appear to be cognitively ‘silent’. There is a recognized association between temporal lobe lesions, particularly those giving rise to epileptic activity, and psychosis, which may bear striking similarities with that seen in schizophrenia or affective disorder. Severe bilateral mediotemporal lobe damage usually gives rise to a profound amnesic syndrome, with an almost complete loss of the ability to learn new material (anterograde amnesia) and a variable degree of retrograde loss of memory. Pathology in the left inferior and lateral temporal gyri can produce severe deficits in semantic memory as seen in progressive fluent aphasia.

Parietal lobe syndromes

The parietal lobes play a critical role in numerous cognitive functions such as attention, spatial representation, working memory, mental calculation, eye movements, and the guidance of actions. However, perhaps the main role of the parietal lobes is in determination of what is attended and what is ignored, in the representation of space, and in the aspects of sensorimotor conversions. Balint’s syndrome, caused by bilateral parietal damage, is a particularly striking disorder characterized by gaze apraxia, optic ataxia, and simultanagnosia. It causes impairment in space representation, while visual processing of basic perceptual features (colour and form) is spared.

Damage to the inferior parietal region may result in a profound neglect, which is thought to be an attentional impairment, not a perceptual deficit, although it can be difficult to fully distinguish between the two. Theories about inferior parietal lobe involvement in attentional processing suggest that either (1) it is involved in the disengagement of attention—patients with unilateral parietal damage have difficulty disengaging spatial attention from the ipsilesional visual field, making it difficult to direct attention to contralesional stimuli—and/or (2) it participates in the detection of salient items embedded in a rapid sequence of events and in maintaining or controlling attention over time.

The posterior parietal cortex plays a critical role in multimodal spatial integration and in the fusion of different coordinates into a unified representation of space.

Hemisphere differences between right and left also appear to be important: right inferior and temporal parietal lobe lesions commonly lead to neglect, whereas damage to the homologous region in the left hemisphere can lead to an apraxic syndrome.

Diencephalic syndromes

Lesions to the deep midline structures of the thalamus, the anterior nucleus, and mamillary bodies, as well as the degeneration of key fibre tracts connecting the limbic structures, are associated with amnesic syndrome, particularly exemplified by the Wernicke–Korsakoff syndrome. The crucial pathology here is thought to involve neuronal loss, gliosis, and microhaemorrhages that produce disruption of complex mammilothalamic circuits. Pathology in the paraventricular and periaqueductal grey matter, and in the frontal lobes, is also common. Clinically the condition is characterized by profound anterograde amnesia relative to any generalized cognitive impairment, and is usually associated with disorientation in time. Typically, these patients also perseverate when faced with shifts in the task demands. An interaction between ethanol neurotoxicity and thiamine deficiency has been postulated, contributing to the development of behavioural alterations and cerebral damage. An amnesic syndrome can also be caused by herpes simplex encephalitis, carbon monoxide poisoning, cerebral anoxia, thalamic infarction, subarachnoid haemorrhage, head injury, deep midline space-occupying lesions, or tuberculous meningitis.

Investigation

Cognitive assessment

Neuropsychological tests require the patient’s cooperation and may fail to discriminate reliably between a cognitive and a psychiatric disorder. However, they may furnish important indications of localized cerebral dysfunction, and they assist the clinician in monitoring the (treatment) progress of any cognitive impairment; they give valuable information about daily functioning; and they help in planning rehabilitation and intervention programmes. A wide range of tests is available to evaluate patterns of disability.

Brain imaging

Also important in investigating suspected neuropsychiatric disorders are brain imaging techniques, the technology and application of which has expanded greatly in recent years. For structural imaging, CT is able to reveal most cerebral lesions, but should nowadays be reserved for the investigation of symptoms of acute onset, where time is of essence and management decisions must be made rapidly. In more insidious, less acute contexts, the structural brain imaging of choice is MRI, which allows both a higher spatial resolution with fine anatomical detail and a choice of endogenous/exogenous tissue contrast modalities, producing greater diagnostic yield. MRI is more sensitive than CT in identifying small vascular lesions or demyelination, but less sensitive in detecting calcified lesions. Sequential estimation of cerebral atrophy and quantitative approaches can facilitate the accurate assessment of disease progression. More sophisticated techniques, such as serial volumetric imaging and voxel compression subtraction, with emphases on a quantitative approach, have been developed to reveal changes over time. However, the time consuming nature of these procedures prevents their widespread use as diagnostic tools. Diffusion tensor imaging MRI (DTI) can be used to determine the integrity of subcortical fibre tracts in vivo, but is generally restricted to research settings.

The past decade has also seen an enormous expansion in functional brain imaging that allows assessment of brain regional engagement during cognitive processing. Changes in regional cerebral blood flow using positron emission tomography (PET), or in regional haemoglobin oxygenation status using blood oxygenation level dependent (BOLD) functional MRI (fMRI), can be measured during cognitive performance. Magnetic resonance spectroscopy (MRS) allows noninvasive in vivo analysis of neurochemicals and their metabolites, and over the last two decades has been performed in patients with a range of neurological and psychiatric disorders to help understand the underlying pathological mechanisms, to monitor long-term changes with or without drug therapy, and to identify differences between diagnostic groups. More recently, changes in MRS measures have been correlated with cognitive performance in normal populations and in patients with cognitive disorders. Magnetic resonance perfusion (MRP), magnetic resonance diffusion (MRD) weighted imaging, and single photon emission computed tomography (SPECT), can help to identify subtle pathophysiological changes in the brain, before structural changes are present, thereby offering the potential for accurate and early diagnosis. Even though these functional imaging techniques are mainly used in research settings at present, they may well offer clinical value to diagnostic classification in the future (see Chapter 24.3.3 for further discussion).

Neurophysiology

The EEG is frequently employed in the investigation of neuropsychiatric disorder as it is both widely available and a sensitive, if relatively nonspecific, indicator of cerebral dysfunction. Focal abnormalities are characteristic of epilepsy that may, in turn, reflect vascular change. Diffuse slowing (i.e. a shift to lower frequency ranges) is a sensitive indicator of brain dysfunction arising from metabolic and degenerative processes that correlates with the degree of cognitive impairment, although with relatively little specificity. Characteristic EEG changes are associated with Huntington’s disease (pronounced flattening of traces), sporadic Creutzfeldt–Jakob disease (repetitive and triphasic spike discharges), and in association with specific drugs. Medial temporal slowing can be suggestive of early Alzheimer’s dementia (see Chapter 24.3.2 for further discussion).

Organic comorbidity in psychiatric disorders

Missing an underlying ‘organic’ diagnosis remains a continuing concern for clinicians responsible for the assessment and treatment of new cases of an apparent psychiatric disorder. The diagnosis of secondary psychotic/affective/personality disorder is used according to DSM-IV if the psychopathology is comparable to that of idiopathic disorder but caused by an organic brain disease. However, in many cases the causal relationship between the organic dysfunction and the psychiatric symptoms remains unclear. Therefore, instead of using the ‘organic’ diagnosis, the concept of comorbidity is widely used. Table 26.4.4 outlines some common brain disorders causing psychiatric disorder.

Table 26.4.4 Neuropsychiatric causes of psychiatric disorders

Intracranial disorder

Cerebrovascular stroke, head injury, Parkinson’s disease, multiple sclerosis, brain tumour, epilepsy, Huntington’s disease, postencephalitic

Endocrine disorder

Hypothyroidism, hyperthyroidism, hyperparathyroidism, hypopituitarism, Addison’s disease, Cushing’s disease, hypoglycaemia, diabetes mellitus

Systemic disorder

Hepatic failure, renal failure, pernicious anaemia, rheumatoid arthritis, systemic lupus erythematosus, malignant neoplasia, viral infection (particularly infectious mononucleosis, influenza)

Pharmacological causes

Corticosteroids, oestrogens (e.g. hormone replacement therapy), oral contraceptives, l-DOPA, clonidine, methylphenidate, withdrawal from stimulant agents, e.g. amphetamines

‘Organic psychotic disorder’

Clinical experience and numerous case reports attest to the wide range of disorders that may emerge following the initial diagnosis of a ‘functional’ psychosis. One follow-up study of a sample of patients with first-episode schizophrenia found that 15 out of 268 had a neurological disorder that appeared relevant to the mental state, with 13 out of these 15 having salient features in the medical history or neurological signs that could have alerted the clinician to the underlying disorder, the two exceptions both having a diagnosis of neurosyphilis. HIV is increasingly prevalent in this population and one recent cohort identified a known diagnosis of HIV in about 6% of the patients, with many subjects not tested. An assessment of risk factors for HIV is therefore required in all the new cases of psychotic disorder. Overall, the literature suggests that the risk of missing underlying medical or neurological disorder is relatively low, provided that a thorough clinical assessment is performed.

Some debate remains over the degree of investigation appropriate at the onset of psychosis. Patients with cognitive impairment, abnormal neurological signs, atypical illnesses not responding to treatment, or other indications from the history, certainly warrant further investigations. Where appropriate this should include neuroimaging, electroencephalography, syphilis serology, and other investigations indicated by the clinical picture. Increasingly, neuroimaging provides important information relevant to the management of the particular case, although in the absence of specific indications the identification of treatable neurological disease is low.

‘Organic mood disorder’

A variety of medical conditions are associated with prominent affective disorder, including anxiety, elation, and depressive symptoms. In many of these there appears to be a direct relationship between the presence of brain disease and depression, and the latter does not just seem to reflect the disabling social consequences of chronic disease, although the ‘psychological reaction’ to the disablement may well be an important contributory factor, e.g. there is accumulating evidence suggesting that depression in Parkinson’s disease is secondary to the underlying neuroanatomical degeneration, rather than simply a reaction to the psychosocial stress and disability. Furthermore, the severity of depression may correlate with the ‘objective’ disability or the prognosis of the disorder or cognitive impairment, and in some disorders, such as multiple sclerosis, can be associated with either euphoria or depression, or mood swings between the two extremes.

‘Organic personality disorder’

‘Organic personality disorder’ is an unhappy term employed in ICD-10 to denote acute or (more typically) insidious changes in personality, defined as a significant alteration in the habitual disposition and behaviour of a patient from their premorbid state. The syndrome is well recognized, although often in retrospect, and may often reflect frontal lobe pathology. Most prominently affected is the degree of emotional expression and levels of activity in the absence of pronounced cognitive alterations, except where ‘higher level’ functions such as planning complex actions or anticipation of social and emotional consequences are affected. Table 26.4.5 outlines some of the common causes.

Table 26.4.5 Causes of ‘organic personality disorder’

Intracerebral insult

Cerebrovascular stroke, head injury, tumour (frequently frontal/sphenoidal meningioma), abscess, encephalitis (frequently herpes encephalitis, which has a recognized tropism for frontotemporal brain regions), subdural haematomas (chronic)

Neurodegenerative conditions

Huntington’s disease, Wilson’s disease (hepatolenticular degeneration), Pick’s disease, Creutzfeldt–Jakob disease, subcortical dementias

Advances in brain imaging have led to a progressive increase in studies focusing on structural markers of human personality. These suggest a relationship between personality change and atrophy, particularly in the frontal lobes, but also in supplementary motor area grey matter, right anterior cingulate cortex, or the whole brain. Functional imaging studies have identified a number of personality traits supposedly associated with alterations in central metabolism, neurotransmitter function, or cerebral blood flow. However, these findings have not yet been closely related to neuropsychiatric symptoms.

Specific conditions giving rise to neuropsychiatric symptoms

This section attempts to address two aspects of neuropsychiatric problems associated with medical conditions: (1) to prompt the recognition and exploration of psychiatric abnormality in ‘high risk’ conditions where such associations are well recognized; and (2) to encourage appropriate medical examination and investigation in the presence of outwardly psychiatric abnormality.

Psychological or psychiatric disorder may become manifest as an adjustment reaction to medical disability, malaise, and handicap, and this can affect not only the patient, but also family members, who often bear the practical burden of care. Psychiatric disorder may also result from a specific compromise of cerebral function, either directly or systemically mediated. For example, postoperative psychiatric disturbance is common and usually the result of infective, metabolic, or drug-induced delirium. However, the circumstances of operation may lead to the precipitation of disorientation in the presence of an insidious dementia, or a withdrawal syndrome in an alcohol-dependent individual. Furthermore, the emotional reaction in response to life-threatening and life-altering circumstances may be profound following major surgery. These factors interact, and the ultimate expression of mental disturbance depends upon a particular patient’s premorbid disposition and social circumstances, as well as specific illness factors. Nevertheless, the recognition and specific ascertainment of the presence of mental disturbance in certain conditions has profound diagnostic and prognostic importance.

Neurological disorders

Cerebrovascular disorders

The psychiatric complications associated with stroke illustrate the relevance of a neuropsychiatric perspective. Early studies recognized distinct emotional reactions associated with cerebral damage. These include the catastrophic reaction (often extreme or disproportionate emotional outburst to small demands), an indifference reaction (associated with fatuous mood, indifference to failures, and unilateral neglect and anosognosia), and pathological laughter/crying reaction (also known rather pejoratively as ‘emotional incontinence’, where emotional displays occur seemingly spontaneously or to trivial provocation). The mood consequences of stroke are often disproportionate to the objective disability and it is important to screen for depression and anxiety in the first months after a stroke. The relationship between mood disorder and lesion location has been contentious, although there is an emerging consensus that anterior lesions are more associated with depression.

Cerebral tumours

Cerebral tumours are frequently associated with neuropsychiatric disability, ranging from understandable reactions to the diagnosis to frank syndromes resulting from impaired brain function. Minor psychological disturbance including anxiety, depression, and occasionally hysterical symptoms may be seen before the medical diagnosis is made, and specific signs of cerebral pathology need to be excluded in this group of patients. The regional syndromes outlined above are notable in cases of primary or secondary cerebral tumours, in particular when the tumour is rapidly progressive or where multiple brain regions are involved with metastases.

The most common adult-onset primary tumour is the ostensibly ‘benign’ meningioma, which is notoriously slow growing (estimates of growth indicate that at diagnosis it has often been present for some 10 to 15 years) and hence cerebral function is only slowly compromised. Coupled with their propensity for a frontal location, in which there may be few frank neurological signs, this can lead to tragic cases where the cause of progressive personality deterioration is missed.

More dramatic impairments of cerebral function are particularly associated with rapidly progressive tumours in which raised intracranial pressure, irritative epileptic phenomena, and an overall distortion in brain structure may combine to produce delirium and dementia.

There can be remote effects of malignant disease on cerebral function: hypercalcaemia may present with an acute confusional state or with other psychological/psychiatric manifestations, and some forms of lung carcinoma (in particular) secrete growth factor/endocrine hormones that result in neurodegenerative changes and a dementia-like picture. Furthermore, both episodic and prolonged confusional states have been reported in malignant disease in the absence of a clear metabolic disturbance or focal brain involvement, e.g. in diffuse leptomeningeal disease. Recent studies suggest that cognitive function is an important outcome measure in patients with brain tumours and is an independent prognostic factor in the survival of glioma patients. Moreover, cognitive deterioration may be the first indicator of progressive disease following treatment.

Head injury

Head injury often leads to impairment in personality, affect, and social/occupational function that is more prominent than the objective dysfunction would suggest. The wide range of neuropsychiatric sequelae recognized after head injury are outlined in Box 26.4.5. The most disabling and distressing problems for both patients and carers are often the emotional and behavioural effects and, in particular, personality change. This may reflect the vulnerability of the anterior temporal poles, frontal polar regions, and the orbitofrontal cortex to closed head injuries. After traumatic brain injury the risk of suicide increases threefold, with around 15% attempting suicide in the first 5 years after injury.

Impairment of consciousness is characteristic after all but the most mild head injuries and features of delirium are often seen after severe injuries. The period of post-traumatic amnesia represents the time that elapses between the moment of injury and the restoration of continuing memory for everyday events. This remains an important predictor of outcome, correlated with personality change as well as intellectual impairment and neurological disorder. By contrast, memory loss for the events of the trauma itself sometimes appears to protect against the development of post-traumatic stress disorder.

Cognitive impairment following head injury is usually more apparent after a post-traumatic amnesia exceeding 24 h, and testing reveals that Performance IQ is more vulnerable to the effects of trauma than Verbal IQ. Penetrating and localized injuries tend to result in more focal cognitive deficits dependent on the site of injury. Dysexecutive syndrome and anterograde memory impairment are commonly seen. In rare cases head injuries may predispose to Alzheimer’s disease.

Personality change is particularly common after severe head injury and frontal lobe damage, including irritability, impatience, apathy, and lability of mood. There is also an inability to learn from experience, with poor judgement and lack of initiative. Aggression and sexual disinhibition may necessitate high levels of subsequent care and are predicted by early agitation after head injury. Delusional disorders are frequently observed in the early stages of recovery and may reflect the persistence of disordered cognition; mood and anxiety disorders are also often seen. Premorbid alcohol misuse may have predisposed to the trauma and alcohol tolerance can decline markedly after severe injury. Problems with heavy drinking are common in this group, which may reflect poor insight and drinking in response to stressful circumstances. Caution is needed to exclude chronic subdural haematoma and post-traumatic epilepsy before ascribing emotional and behavioural change to a psychiatric diagnosis.

Complex rehabilitation strategies are often needed to manage this group of patients and novel pharmacological managements are being assessed.

Epilepsy

In assessing epilepsy it is important to establish the extent of underlying cerebral damage giving rise to the epileptic discharge, as well as the nature and severity of any cognitive impairment. While compatible with normal intelligence, epilepsy is more common in patients with a learning disability, and is related to its severity, presumably as both epilepsy and a learning difficulty arise from underlying cerebral dysfunction. Thus, the capacity of individuals to manage their epilepsy is highly variable and poses an important problem for management. Furthermore, there can be a relationship between emotional state and epileptic seizures, indicative of an important brain–mind correlation.

The neuropsychiatric consequences of epilepsy are best considered in terms of peri-ictal and interictal disorders, which are outlined in Table 26.4.6. This has important implications for management in which the focus should be on optimal control of seizures. Psychotropic medication can decrease the seizure threshold and possible interactions with anticonvulsants should be considered. The S2-D2 (refers to antagonism of atypical antipsychotics at the dopamine type 2 receptor and the serotonin type 2A receptor) or atypical neuroleptics are current first-line treatments for psychosis and are also used in aggression and irritability; olanzapine, risperidone, and quetiapine are particularly recommended. Selective serotonin reuptake inhibitors (SSRI) are generally agreed to be safe treatments for depression in patients with epilepsy (see Chapter 24.5.1 for further discussion).

Table 26.4.6 Neuropsychiatric complications of epilepsy

Ictal and peri-ictal disorders

  • Prodromal states

  • Complex partial seizures

  • Tension, irritability, and depression may be seen Automatisms, distortions of perception, hallucinations, déjà vu, unusual disturbances of memory, thinking

  • Sudden changes in affect.

  • Interictal disorders

  • Nonepileptic seizures

  • Cognitive impairment

  • Seen in about one-third of those attending specialist epilepsy centres. Associated with physical and sexual abuse.

  • This usually reflects underlying brain damage, and developmental consequences of repeated seizures and treatment with anticonvulsants. Associated with duration and frequency of previous seizures

Personality

Probably only related to severe epilepsy where there is underlying brain damage.

Schizophrenia-like psychosis

Associated with temporal lobe epilepsy.

Depression

Suicide is four times more frequent in epileptics: those with adverse social factors and temporal lobe epilepsy are particularly at risk

Subacute encephalopathies

A well recognized manifestation of acute cerebral infection or encephalitis is a dramatic behavioural disturbance that may involve violence and delirium. This is a relatively common diagnostic problem, and it is clearly of vital importance to make a correct diagnosis. Of particular note are, firstly, that the particular groups relatively predisposed to the development of encephalitis are alcohol and drug misusers, where attitudes of medical staff may exert a pejorative effect, and secondly, that the disordered behaviour may be sufficiently extreme to render medical examination and management difficult.

Herpes simplex encephalitis is particularly implicated in such presentations, perhaps as the most common encephalitis and also because of tropism of the virus to frontal and temporal regions. Damage in these areas may lead to psychosis, abnormalities in cognitive or social processing, or a syndrome resembling autism, particularly early in the course of disease. However, these presentations rarely persist in isolation and are less common than paresis or seizures. Furthermore, it is quite common that frontotemporal damage in these patients causes persistent behavioural deficits.

Other forms of encephalitis can also produce striking behavioural change, e.g. Epstein–Barr virus may lead to visual metamorphosis (‘Alice in Wonderland’ syndrome; an unusual syndrome characterized by visual hallucinations and bizarre perceptual distortions of form, size, movement, and colour, where objects appear larger or smaller than their actual size, associated with an abnormal sense of time or place), occasionally with persistent complications.

Intracranial infections

Neurosyphilis

Neurosyphilis can result in several different syndromes from infection of the brain, meninges or spinal cord. While its incidence is still rather low, neurosyphilis has become more common due to an increased prevalence of immunosuppression. The presentation can be subtle, atypical, often monosymptomatic, and it can present with psychiatric symptoms alone. Patients with neurosyphilis may show a normal MRI head scan, or bilateral mesiotemporal T2 hyperintensity, or meningeal thickening. A wide range of neuroimaging findings can resemble those found in herpes simplex encephalitis, mesial temporal sclerosis, leukoaraiosis, normal pressure hydrocephalus, and glioblastoma multiforme. However, neurosyphilis most commonly adopts either a meningeal form (leptomeningeal granulomas that may also occur intra-axially) or a vascular form (typically presenting with cortical and subcortical infarcts), which often occur together. CSF findings can vary from positive oligoclonal IgG bands and high IgG index to pleocytosis with or without CSF venereal disease research laboratory test (VDRL). Clinicians should be aware that dementia in young patients with temporal lobe atrophy and/or vascular damage can be caused by syphilis, and therefore these findings necessitate CSF and syphilis testing (see Chapter 24.11.4 for further discussion).

Human immunodeficiency virus

Human immunodeficiency virus (HIV) is a neurotropic virusthat enters the brain within 2 weeks of initial infection. Combination antiretroviral therapies have changed the course of the illness, but many patients with HIV still show signs of associated neurocognitive dysfunction. The clinical features of HIV-associated neurocognitive impairment are thought to reflect widespread synaptodendritic problems in the fronto-striato-thalamo-cortical circuit. Patients typically have problems with executive functions (e.g. abstraction, processing speed, verbal fluency, decision making, and attention) as well as with learning new information. It has also been postulated that prospective memory is particularly affected, i.e. ability to execute a future intention. The severity of cognitive decline can increase with age and in association with high viral loads and reduced CD4+ cell counts, as well as in association with age-related decline in functioning of fronto-striato-thalamo-cortical circuitry. Cognitive impairment can predict mortality, independent of clinical stage or CD4+ cell counts.

There is also an overall increased susceptibility of patients with HIV to develop a major psychiatric disorder: new-onset psychosis is reported in up to 15% and can occur without encephalopathy. The putative involvement of subcortical dopaminergic systems, particularly basal ganglia structures, is supported by high rates of antipsychotic-related extrapyramidal symptoms and neuropathological studies in HIV-infected patients.

Mood disorders are common in patients with HIV and effective treatment may result in considerable health and economic benefits. Depressive disorders are reported among 20 to 40%; they are commonly unrecognized but respond to appropriate treatment interventions in 80 to 90% of cases. Mania without pre-existing bipolar disorder or family history is found in 8% of patients in the late stages of disease, typically in the context of dementia and CNS involvement; early in HIV infection, episodes of mania are more commonly related to pre-existing bipolar disorder or family history (see Chapter 24.11.4 for further discussion).

Variant Creutzfeldt–Jakob disease

Variant Creutzfeldt–Jakob disease (vCJD) appears to present in a much younger population (mean age at death is 29 years) than the sporadic variant (mean age at death is 63). Difficulties occur in diagnosis because the early symptoms of vCJD are often nonspecific, such as anorexia, mild insomnia, apathy, mood swings, and personality changes, and prominent neurological signs are lacking. Neurological examination in the early stages is usually normal, but subsequent neurological decline is characterized by progressive ataxia, paraesthesia in legs and face, unusual aches and pains in hands, feet, face and lumbar region, and cognitive impairment. Careful clinical assessment remains the most important element in the early detection of symptomatic disease.

The most useful noninvasive investigation in advanced cases has been MRI imaging, particularly fluid attenuated inversion recovery (FLAIR) sequence. The pulvinar sign (a symmetrical region of signal hyperintensity in the pulvinar nucleus of the thalamus) has been reported to have sensitivity of up to 95% in the appropriate clinical context. EEG generally does not show the typical appearances of sporadic CJD. Definitive diagnosis of vCJD is based on neuropathological findings, obtained by brain biopsy, and supplemented by prion protein (PrP) immunohistochemistry and molecular strain typing by Western blotting of human brain tissue. Because PrP immunoreactivity is present in the tonsils of vCJD patients, tonsil biopsy has been proposed as a less invasive alternative to brain biopsy. The WHO published diagnostic criteria for sporadic CJD in 2001, suggesting that neuropathological examination (biopsy) is not mandatory for the confirmation of the diagnosis (see Chapter 24.11.5 for further discussion).

Neurodegenerative conditions

Multiple sclerosis

Affective disorders are common in multiple sclerosis (MS) and have been divided into four categories; depressive disorder, bipolar affective disorder, euphoria, and pseudobulbar affect. Both bipolar affective disorder and depression are more common in patients with MS than in the general population, with the lifetime prevalence for the latter being 50%. Euphoria is more common in patients with advanced disease, with a median prevalence of 25%. Pseudobulbar affect is found in about 10% of MS patients.

It is important not to dismiss these symptoms as they all are associated with significant morbidity and mortality. Furthermore, a strong association between affective disorder and cognitive impairment (40–65%) is recognized in MS. Depression can exert particularly adverse effects on the executive component of working memory. Cognitive functions in progressive MS subtypes are likely to decline across time, particularly on tasks requiring concurrent multiple abilities, i.e. visuospatial ability and processing speed or working memory and processing speed. Cognitive impairment in MS may reflect several underlying defects such as lesion severity, changes in neuronal signaling caused by axonal degeneration, and demyelination. Neurotransmitter changes are also recognized, e.g. a decline in choline acetyltransferase activity, and there are a number of studies showing benefits with acetylcholine esterase inhibitors. MS can also occasionally present as a cortical variant alone, with significant psychiatric complaints prior to sensory and motor presentations.

Parkinson’s disease and movement disorders

There are four particular aspects of neuropsychiatric disturbance relevant to the consideration of idiopathic and atypical parkinsonian syndromes, including multisystem atrophy:

  1. 1 A prodromal period without frank movement disorder is well recognized and may be typified by sleep disturbances, depression, as well as sensory and autonomic dysfunction, possibly reflecting the non-dopaminergic-cell dysfunction. Interestingly, these nonmotor symptoms are also prominent in advanced stages of the disorders.

  2. 2 Dopaminergic replacement therapy, whether with cholinergic antagonists, dopamine agonists, or levodopa (l-DOPA), is associated with a substantial incidence of psychosis and delirium. However, the neuronal degeneration of the pedunculopontine nucleus, locus coeruleus, and the dopaminergic raphe nuclei may also play a role.

  3. 3 There is a strong association between Parkinson’s disease and depression (10–50%), with possibly a more significant biological than purely reactive basis. Depression is characterized by a feeling of guilt, lack of self-esteem, sadness, and remorse.

  4. 4 Many patients develop ‘diffuse’ (extranigrostriatal) Lewy body disease, characterized by a progressive dysexecutive syndrome with impairment of visuospatial abilities and memory against a background of loss of response to dopaminergic drugs.

Particular mention should be made here of the iatrogenic movement disorder attendant upon antipsychotic and antidepressant medication. The mechanisms underlying this drug-induced movement disorder are largely unclear, but drug-induced movement disorders are generally reversible once the medication is removed, suggesting that the drugs produce an interference with neuronal function (see Chapter 24.7.2 for further discussion).

Learning disability

Although beyond the immediate scope of this chapter, the diverse conditions that give rise to learning disorders have been the subject of intense recent interest. In particular, their strong associations with attention deficit-hyperactivity disorder (ADHD), fetal alcohol syndrome, and autism have underscored a probable neuropsychiatric basis. Interestingly, studies suggest a critical role of the prefrontal cortex and its connections to the parietal cortex and striatum in children with ADHD in divided attention tasks, in inhibiting distraction and prepotent responses, and in maintaining the information ‘on line’ in working memory. From a neurodevelopmental perspective, attention deficit in children is strongly linked to conduct disorder and may have diverse consequences in adulthood, providing a precursor for some instances of personality disorder, traditionally not viewed in neuropsychiatric terms (see Chapter 24.18 for further discussion).

Another relevant area of interest is the concept of behavioural phenotypes, where consistent behavioural abnormalities are associated with distinct genotypic abnormalities. For example, the frequently occurring chromosomal disorders of Down’s syndrome, Turner’s syndrome, and Klinefelter’s syndrome have distinct and consistent neuropsychiatric aspects, albeit of variable degree. In Turner’s syndrome, overall IQ is variable but distinct difficulties in visuospatial function give rise to large Verbal-Performance IQ deficits.

Extracerebral disorders

Endocrine disorders

Endocrine disorder has an important influence on mental function and there are characteristic associations with neuropsychiatric disorder. The use of ‘routine’ blood tests of endocrine function has resulted in the earlier detection of problems, such that florid states are now rarely seen. The focus of clinical interest in this area is upon ‘preclinical’ endocrine dysfunction, the complications arising from the disorder, and treatment.

Diabetes mellitus

The neuropsychiatric aspects of diabetes mellitus (DM), both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) forms, may be considered in four aspects:

  1. 1 The syndrome itself and the constraints of optimal management have a considerable impact on the lives of people with the disorder. The disorder is stigmatizing, especially in the young, and is associated with significant morbidity and mortality. There is a risk of impaired psychological development, personality difficulties, and affective disorder. There is clear evidence of a relationship between ‘stress’, emotional disturbance, and impaired glycaemic control, although whether this is mediated directly or indirectly (through neglect of diet and treatment) is unclear.

  2. 2 Increased prevalence of psychological disturbance has been reported, particularly with IDDM. Anxiety disorder has been linked to poor glycaemic control, which in turn relates to fear of hypoglycaemia. IDDM-associated hypoglycaemic episodes can also cause frank automatisms.

  3. 3 Cognitive dysfunction in diabetic subjects has been recognized since the early 20th century. Both IDDM and NIDDM are associated with slowing of mental speed and diminished mental flexibility, and NIDDM is also associated with deficits in actual learning and memory processing. Several studies have shown that the rate of cognitive decline is accelerated in older people with NIDDM. There are several proposed pathophysiological mechanisms linking diabetes to changes in the brain and cognitive decline, including atherosclerosis (macroangiopathy, increased risk of stroke), microvascular disease (microangiopathy, small vessel disease), glucose toxicity (advanced protein glycation and oxidative stress, ‘advanced aging’), and insulin mediated changes (increased secretion and decreased breakdown of the amyloid). Neuroimaging studies suggest that the appearances of the brain in patients with diabetes resemble that of normal aging, but appear to develop at a younger age than in normal population.

  4. 4 The incidence of dementia is higher in people with diabetes compared with the normal population. However, the risk factors and mechanisms underlying the association between diabetes, accelerated cognitive decline, and vascular dementia still need to be identified.

Thyroid disorder

It is rare for classical presentations of thyroid disease to be missed in clinical practice, but interesting to note that surveys reveal that more than 5% of attendees at psychiatric consultations have an abnormality in thyroid function. While not all of this group would benefit from treatment for thyroid disease, it underscores the insidious nature of thyroid dysfunction. The rule should be to exclude this whenever suspicions are aroused. In particular, hypothyroidism may commonly manifest as apathy, depression, memory impairment, and dementia with prominent cognitive slowing: the condition may be reversible if recognized and treated early, but rarely so in long-lasting cases of hypothyroidism. Neonatal hypothyroidism or ‘cretinism’ is now rare as a result of routine screening, but this indicates the importance of adequate thyroid function for cerebral development. Occasionally, adult hypothyroidism may be associated with psychosis (most commonly a delirium with prominent agitation), famously termed ‘myxoedema madness’.

Hyperthyroidism is commonly associated with a subjective feeling of tension, irritability, and high arousal. Initially this may be confused with anxiety, but in more severe cases behaviour can be frankly disturbed, although the individual concerned generally retains insight. However, it should be noted that studies show no clear association between anxiety or depression and serum concentration of thyroid hormones. In a similar way, no strict relationship has been found between severity of symptoms of hyperthyroidism and degree of elevation in thyroid hormones concentrations. Hypomania is rare but has been reported. Thyroid ‘crises’ with delirium are occasionally seen following radioiodine treatment.

Both hypothyroidism and hyperthyroidism are common consequences of lithium treatment in bipolar affective disorder. This introduces the possibility of confusing a thyroid disorder with the recurrence of an affective disorder, although it should be effectively excluded by the routine monitoring of lithium treatment.

Hashimoto’s encephalopathy is an uncommon condition of presumed autoimmune aetiology characterized by the presence of high titres of antithyroid microsomal/peroxidase antibodies. The condition can follow a relapsing and remitting course, with features including confusion, cognitive decline, hallucinations, stroke-like episodes, myoclonus, or seizures. Thyroid function is typically normal. Treatment with corticosteroids is almost always effective.

Cushing’s syndrome

It is estimated that more than 70% of patients with Cushing’s syndrome can present psychiatric problems, ranging from anxiety and agitated depression to psychosis. Some degree of psychiatric disturbance frequently persists even after treatment. Furthermore, impairment in anterograde memory and cognition is common and can persist for at least a year after treatment. These effects are associated with a reduction in apparent brain volume, particularly in the hippocampal formation, which have been shown to be only partially reversible after correction of hypercortisolaemia. Exogenous steroids have also been shown to reduce hippocampal volume and to impair declarative memory.

Phaeochromocytoma

Phaeochromocytoma can mimic endocrine, cardiovascular, and neurological, as well as psychiatric conditions. The latter include panic and anxiety disorder, depressive disorder, and substance misuse. Common symptoms include dizziness, tremulousness, palpitations, and the subjective feeling of intense fear, leading to confusion with anxiety and panic attacks. The diagnostic feature is the elevation of blood pressure during an attack, and if such attacks are reported, routine testing for adrenergic metabolites should be conducted. Attacks are occasionally of sufficient intensity to lead to confusion and delirium.

Pituitary disorder

Panhypopituitarism with consequent adrenal failure produces a characteristic neuropsychiatric picture with apathy, fatigue, weight loss, inability to attend and concentrate, and memory impairment. The disorder may be confused with chronic fatigue, depression, or even dementia, and the weight loss has been confused with anorexia nervosa, although neither appetite disturbance nor distorted body image is usually found. Acromegaly can also result in a rather characteristic apathy and lack of concern, with occasional depression and irritability, perhaps reflecting a degree of global hypopituitarism.

There are two other particular neuropsychiatric issues that arise in consideration of a pituitary disorder. First, cerebral irradiation of pituitary tumours may give rise to collateral damage to adjacent brain structures, and there are reports of memory impairment, perhaps reflecting diencephalic and/or hippocampal damage. Second, endocrine replacement therapy following pituitary ablation may be suboptimal, indeed replacement of sex steroids is occasionally omitted because of their propensity to release sexual drive, which may be inappropriate.

Gonadal dysfunction

Contrary to previous beliefs, the menopause is not necessarily associated with psychological problems in healthy women. However, the following risk factors have been associated with affective disturbance: psychiatric problems; poor social, educational, occupational, and health status; stressful life events; high body mass index (BMI); cigarette smoking; as well as negative attitudes towards menopause and ageing. Successful treatments for mood disturbance include hormone therapy and psychological interventions, particularly cognitive behavioural therapy. Furthermore, increasing evidence supports the hypothesis that oestrogen treatment can have positive effects on cognitive performance in aging. The initiation of oestrogen treatment at the time of menopause, or soon after ovariectomy, is considered to provide a window of opportunity for the protection of memory in women. Imaging studies provide evidence of the neuroprotective role of oestrogen, particularly on the hippocampal volume in aging, and that it may lose its effectiveness after a specific period of time.

While significant advances have been made in our understanding of the modulatory effects of ovarian hormones on cognition in women, relatively little attention has been directed towards understanding the role of gonadal steroids on the modulation of cognitive functions in men. However, there are some studies which suggest that low premorbid testosterone levels are associated with a higher risk for Alzheimer’s disease. Furthermore, it may be that low testosterone has a selective effect on memory consolidation. Preliminary data suggest that replacement therapy can modify the deficits. However, one should note that the adverse effects the low testosterone levels have on mood, arousal, and attention may also indirectly affect higher cognitive functions.

Neuropsychiatric systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS)

Neuropsychiatric SLE is becoming an increasingly prevalent manifestation of SLE, estimated to affect 14 to 75% of patients and able to cause chronic irreversible brain injury. The American College of Rheumatology has recently revised its definition of neuropsychiatric SLE, distinguishing 12 types of central neurological involvement. There is no single diagnostic test that is sensitive or specific, hence the diagnosis depends on the combination of rheumatological examination, immunoserology, and brain imaging as well as psychiatric and neuropsychological tests in the presence of lupus disease activity. Recent neuropsychological investigations suggest that patients with SLE have particularly poor performance on verbal and memory tests. Furthermore, about 10 to 40% of patients have depression, for which risk factors are thought to include direct brain damage, concomitant neuropsychiatric disorders, steroid administration, and the patient’s response to the burden of the disease.

The clinical antiphospholipid antibody syndrome (APS) is found in 30% of patients with SLE or may occur in isolation. It is characterized by venous and arterial thromboses and neurological disease in the presence of antiphospholipid antibodies.

Voltage-gated potassium channel antibody-mediated syndromes

In the last few years, the role of channelopathies has been recognized in acute or transient neuropsychiatric disorders. Evidence has accumulated that voltage-gated antibodies to potassium channels are involved in certain limbic syndromes, and in some patients with subacute onset of unexplained epilepsy. Voltage-gated potassium channel (VGKC) antibodies were initially identified in patients with Isaac’s syndrome, which is an acquired syndrome of peripheral nerve hyperexcitability. Patients may present with myokymia and often have hyperhidrosis. Subsequently, two VGKC antibody syndromes have been described with CNS manifestations: limbic encephalitis and Morvan’s syndrome. Limbic encephalitis is an inflammatory disorder affecting prominently the mesial temporal lobes and characterized by confusion, disorientation, amnesia, personality change, and seizures. Patients develop acute or subacute memory loss and confusion, progressing over days or weeks to temporal lobe/partial complex epileptic seizures. Cognitive impairment is typically profound, with significant retrograde and anterograde amnesia. MRI usually shows high signal in the hippocampal region(s). In Morvan’s syndrome, the peripheral and the CNS manifestations of the VGKC antibody syndromes coexist, characterized by severe and persistent insomnia, autonomic instability, lability of affect, cognitive impairment, hallucinations, and peripheral hyperexcitability. Patients with limbic encephalitis or Morvan’s syndrome may improve spontaneously over time, but this is unusual. Treatment usually consists of immunotherapies similar to those employed for myasthenia gravis and other autoimmune disorders.

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