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H. Sanuyem, M.B. B.CH. B.A.O., M.B.B.Ch., Ph.D.

Professor, Indiana Wesleyan University

Occasionally, however, a normal record may be obtained even in the presence of advanced dementia. Atrophy of the heads of the caudate nuclei may be clearly apparent, with loss of the normal convex bulging into the lateral walls of the frontal horns. Various linear measures have been proposed for establishing this feature as an aid to diagnosis, but they are not sufficiently specific to be of value in the individual case (Shoulson & Plassche 1980). This, being more widely available, is likely to find clinical application in uncertain cases. For the past 10 years she had shown a slowly progressive dementia, along with increasing motor disorder by way of a stiff unsteady gait, writhing of the hands and choreiform movements of the face. The antecedent family history was at that time uncertain, but her sister in New Zealand was known to suffer from an entirely similar illness. Doubts about the diagnosis were further reinforced when vigorous efforts to trace the family history revealed longevity in the parents and their many siblings, with no evidence of dementia or movement disorder in any of them. It was therefore concluded likely that the illness represented a recessively inherited dementing disorder, with adventitious movements attributable to the neuroleptics that had been administered for many years. Muscular rigidity and tremor are commoner than choreiform movements, the mental deterioration tends to be rapid, and epileptic fits occur in more than half of the cases. After developing normally the child begins to fail at school and shows difficulties with concentration. The absence of chorea readily leads to other diagnoses even in families known to harbour the disease. When a change of personality is the predominant manifestation, this may all too easily be ascribed to external factors, especially when the onset is at the approach of adolescence. He showed ataxia, tremor, dysarthria and muscular rigidity, but these were thought to be due to the neuroleptics he had been given. His mother insisted that he had been a bright and inquisitive child, and that until the age of 11 he had progressed well at school. From then on he had shown unwillingness to work and increasingly aggressive behaviour. On leaving school he obtained simple labouring jobs, and was repeatedly arrested for thefts and other misdemeanours. During several hospital admissions thereafter he had been variously regarded as psychopathic or mentally subnormal, and was treated with a variety of neuroleptics. Detailed review 2 years later showed a parkinsonian gait, dysarthria and markedly increased tone in the limbs. He spoke only monosyllabically, but proved to be fully orientated in time and place. Course and outcome the course after the first definitive manifestations is generally much longer than with other primary dementing illnesses. This puzzling feature now finds an explanation from recent discoveries in molecular genetics. The infant mortality is also high, and Oliver and Dewhurst suggest that this may be partially due to undiagnosed cases occurring even in infancy. Epilepsy, schizophrenia, mental defect and a variety of other degenerative brain diseases have been reported. How far these may represent common genetic determinants remains to be established. It is possible that to some extent assortative mating between patients from Huntington families and those with other physical and psychiatric handicaps may contribute to the frequency of such disabilities. Minski and Guttmann (1938) noted a variety of psychopathological features in the relatives of cases, particularly a personality characterised by explosive irritability and readiness to take offence. Suicide has been reported to be frequent even among members unaffected directly by the disease (Bickford & Ellison 1953). It is unclear how far this may be due to endogenous mental illness or the result of knowledge of the consequences of the condition.

The commonest mental disturbance is progressive torpor and drowsiness with the insidious development of intellectual impairment. Further neurological manifestations include a myopathy, similar to that seen in hyperparathyroidism. Investigation of uraemic encephalopathy Blood urea is raised and electrolyte disturbances including hyponatraemia, hyperphosphataemia, hypocalcaemia and hyperkalaemia are common. There is generalised slowing, most marked frontally with an excess of delta and theta waves. Bilateral spike-andwave complexes in the absence of clinical seizure activity have been reported in up to 14% with chronic renal failure. The most constant change is scattered neuronal degeneration, with chromatolysis and vacuolisation of nerve cells. Aetiology of mental disturbances Although mental and neurological changes become commoner with increasing elevation of blood urea, it is widely accepted that urea cannot be responsible for all or even the majority of the symptoms. Considerable improvement can follow dialysis when urea is present in the dialysis fluid, and experimentally urea has not been found to have a strong neurotoxic effect. Other abnormalities must therefore play a direct aetiological role, with the level of blood urea serving mainly as an indicator of the severity of overall metabolic disturbance. In renal impairment the cerebral metabolic rate is reduced, with an associated decrease in cerebral oxygen consumption. These changes, which occur in the presence of normal levels of high-energy phosphates, have been attributed to a reduction in neurotransmission. Endogenous opiates have also been investigated: circulating levels of -endorphin are elevated in renal failure and there are reports of naloxone reversing encephalopathy in chronic renal failure (Mattana et al. Arterial hypertension also contributes to the clinical picture, as verified by the pathological findings, causing transient neurological disturbances, fits and headache. In many cases a part is played by raised intracranial pressure, altered permeability of small blood vessels and anaemia. Erythropoietin therapy is associated with an improvement in cognitive function, with improvements in the speed and accuracy of information processing and an increase in the event-related P300 (Nissenson 1989). Other derivatives of protein such as uric acid may play a part, as may other toxins so far unidentified. The rapidity of the shifts appears to be the essential factor, whether this is in the direction of normality or abnormality (Tyler 1968). Drugs have been strongly incriminated as a cause of mental disturbance in patients with chronic renal failure, accounting for over one-third of the episodes in some series (Richet & Vachon 1966; Richet et al. Other causes of neuropsychiatric disturbance in patients with chronic renal failure also need to be considered. The risk of intracranial infection is increased in uraemia, especially when immunosuppressive drugs are used after renal transplantation; encephalitis due to herpes simplex or cytomegalovirus may be hard to diagnose in the prodromal stages, leading to behavioural disturbance and change of personality. Low-grade meningitis can lack the typical physical signs and present as depression with chronic headache. Endocrine Diseases and Metabolic Disorders 669 the use of anticoagulants in maintenance haemodialysis may result in a subdural haematoma. Dialysis-related disturbances the psychological stresses associated with haemodialysis or transplantation bring a range of problems of their own. Salmons (1980) has reviewed the problems inherent in such management of chronic renal failure, with disruptions in work, daily life and family relationships. Not surprisingly there is a high incidence of depression, anxiety and disturbed sexual functioning among such patients.

Children and adults with autism have been shown to be impaired on a variety of executive function tasks [148]. The Weak Central Coherence model is based on the bias in autism to process details that result in enhancement of segments of information at the expense of context (reviewed in section "Sensation/Perception"). Although all of the major cognitive models of autism have been associated with underlying neural systems, they are largely descriptive and none explains all of the clinical symptoms. All are important, however, as frameworks within which to advance research and develop treatment interventions. Some newer explanatory models incorporate development and underlying neural mechanisms. Brock has proposed a temporal binding deficit which postulates that many features of autism, such as superiority in processing of detail (local processing) and disadvantage in global processing necessitating integration of information either over space (visuo-spatial perception) or context (integration of words into meaningful sentences), can be explained by a failure of temporal integration, or binding, between cortical areas [157]. A related and promising model of abnormal functional connectivity based on developmental neuroanatomic findings is considered by some to be a logical extension of the "weak central coherence" model [146, 75, 158] and may provide an explanatory base for many of the neuropsychological and social deficits in autism. Abnormal brain overgrowth in early development (discussed in the previous section) may result in abnormal white matter under- and over-connectivity [74, 75, 84, 76]. Excessive short-distance and reduced long-distance pathways that would result in a failure to integrate processing across brain systems could predict many of the neuropsychological processing abnormalities to be discussed below. There is growing evidence in support of such abnormal functional connectivity in autism. The first of these studies was conducted by Horwitz and colleagues more than two decades ago [159]. These authors were the first to suggest the failure of integrated long-distance communication in the autistic brain. Just and colleagues found decreased functional connectivity during a language task among brain region pairs including mid-range (occipito-temporal, occipito-parietal) and long-distance. The findings suggest weak functional connections between frontal cortex and other cortices which is consistent with longrange under-connectivity [160]. Theta band coherence in this study was consistent with short-range over-connectivity, (particularly in left hemisphere frontal and temporal cortex) which is also consistent with increased short-range fibers [167] and may reflect a local processing bias in autism [75]. Cognitive Profiles Attention Attentional dysfunction is a prominent feature of autism, first noted by Kanner in his early descriptions of the disorder [1]. Although individuals with autism have performed in the normal range on standardized tests that measure some static aspects of attention [168, 169], experimental tasks requiring dynamic manipulation of attention have typically found attentional dysfunction manifested in numerous ways, review: [170]. Disruption of basic attentional mechanisms may underlie clinical symptoms of autism such as language acquisition and social communication. Courchesne and colleagues found that adolescents with autism were slow to shift attention between auditory and visual information [174]. Akshoomoff examined these same attentional skills in children with acquired cerebellar damage and found similar results [175]. While typically developing children were able to shift attention between auditory and visual information almost instantaneously, children with autism (and those with cerebellar lesions) required more than 2 s to re-orient attention. However, a functional imaging study using a task patterned after the Courchesne et al. Slowed manipulation of attentional resources would particularly interfere with dynamic social interactions. Interestingly, a recent study has demonstrated that slowing facial movement and vocalizations significantly improved emotional expression recognition and imitation in autistic children [181].

Occasionally, complete investigation will leave one with probabilities rather than certainties, and it will then be necessary to see what course the disorder takes with time. Lack of clear confirmation of the diagnosis will mean that it is essential to keep the patient under regular review, with readiness to investigate anew if later developments are in any way unusual. History Family history can be of prime importance in early-onset cases and when the presentation is atypical. A marked family history of affective disorder may occasionally help towards the identification of depressive pseudodementia. Even slight head injury can lead to a subdural haematoma, especially in elderly, arteriosclerotic or alcoholic subjects. Normal-pressure hydrocephalus may likewise be 590 Chapter 9 traceable to prior head injury, subarachnoid haemorrhage or meningitis. Recent fits, faints or episodes of collapse will indicate the possibility of a cerebral tumour, cerebral infarction, episodic hypoglycaemia or an undiagnosed myocardial infarction that has led to cerebral anoxia. Previous episodes of transient neurological disturbance will raise the question of vascular dementia or multiple sclerosis. Special care must be taken whenever there is a previous history of anaemia, heart disease or chronic pulmonary disorder which may now be leading to cerebral anoxia. The recent administration of an anaesthetic may be significant, or any episode of carbon monoxide poisoning or prolonged coma due to drug overdosage. Recent illnesses must be viewed in relation to their effects on cerebral function, in particular hepatic or renal disease which may have led to metabolic disturbance, or infective processes that may have resulted in a cerebral abscess. Dietary neglect may have produced vitamin B or folic acid deficiency, either as a primary aetiological factor or as a complication of the dementing process. A history of gastrectomy may be especially significant in relation to vitamin B12 deficiency. Some patients with dementia and vitamin B12 deficiency do improve after correction of the deficit and those that do may have a somewhat different neuropsychological presentation (Osimani et al. Drug abuse should be suspected when the picture fluctuates from time to time or when there is a history of similar episodes in the past. Headache, visual disturbance or vomiting will raise the possibility of a spaceoccupying lesion. Other complaints that may indicate focal rather than diffuse cerebral disease include special difficulty with language, trouble in recognising people or objects, or inability to carry out habitual acts and manipulations. The abrupt onset, if known, will give the clue, likewise the preservation of memory and topographical orientation. Malaise, loss of energy and anorexia will suggest anaemia, uraemia or occult malignant disease. A cough of recent onset and severe loss of weight will suggest carcinoma of the lung, which can sometimes present with dementia in the absence of secondary cerebral deposits. Sensitivity to cold will immediately raise the possibility of myxoedema, and excessive thirst or bone pain may suggest parathyroid disorder. Separate note must be taken of the nature of the principal early difficulties, the duration up to the time of presentation, the certainty or uncertainty of onset, and the steadiness or otherwise of progression. Any onset with symptoms other than memory disturbance should always raise suspicion. In most primary dementing illnesses the symptoms are of long duration, usually of many months by the time the patient presents for attention. Caution should be paid when interpreting apparently sudden onset as the suddenness may simply represent infrequency of contact between the patient and the informant, especially in the elderly. Anecdotally, onset is not infrequently at national holidays, Christmas and Easter for example, when the elderly person with an early but as yet unrecognised dementia may have more contact with family members, may have more cognitive and functional tasks to perform. A definite date for the onset is also rarely obtained in the primary dementias, which tend to begin so insidiously that neither the patient nor family can give a precise timing to the earliest manifestations. In contrast, with cerebral tumours there is usually some episode or symptom that can later be recalled as the first indication of the illness. This information can be important in tumours that are unaccompanied by headache or other evidence of raised intracranial pressure, or for example in frontal meningiomas which can present with global dementia and lack all focal signs. Marked fluctuations from time to time must therefore immediately suggest that one may be dealing not with a chronic but an acute organic reaction, or at least with an acute component superimposed on the basic dementing process. Considerable difficulty can sometimes be encountered in differentiating between a subacute organic reaction and dementia, especially multi-infarct dementia. The elderly are unusually vulnerable to the effects of anoxia or metabolic derangements, and the responsible somatic disease may not be very obvious.