Northgate and Prudhoe NHS Trust, Prudhoe Hospital, Prudhoe, Northumberland NE42 5NT
See editorial pp.
1011, this issue.
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ABSTRACT |
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Aims To explore some of the newer developments in biological research into autism.
Method A review of recent publications and presentations.
Results The concept is shifting from the narrow perception of aloof autism, described by Kanner, to a wider one that includes a spectrum extending to a broader, subclinical phenotype. The genetic basis has been established; now we need to discover the location and interaction of the relevant sites. There is considerable interest in the bowel as a pathogenetic agent, particularly in the effects of exogenous opioids and multiple viral infection (the latter posing a public health problem). Also of concern is the role of (potentially treatable) epilepsy, analogous to the Laudau-Kleffner syndrome.
Conclusions In the absence of a cure, the implementation of ideas will continue to outstrip factual evidence. Clinicians are challenged by the availability of information (and misinformation), particularly on the internet.
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INTRODUCTION |
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DIAGNOSTIC CATEGORIES AND SUBTYPES |
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The concept of autism, and consequently its diagnostic criteria, continues to evolve. For example, one of the original members of Wing's definitive triad of symptoms, limited imagination, has been re-defined and the existing criterion of restricted, repetitive and stereotypic behaviour is being challenged (Tanguay et al, 1998). The loss of the latter criterion would leave autism defined by defective social communication but might also make it indistinguishable from a dissocial personality disorder. The appraisal of other symptoms, such as abnormal perception and conation, is hindered by their subjective nature.
Milder and more subtle characteristics are being recognised in the relatives of those with full-blown autism the broader phenotype (Bailey et al, 1998b). As symptoms are dimensional rather than categorical entities, the result is a continuum that entails uncertainty as to where the cut-off from normality actually falls. Although this leaves the core disorder untouched, it encourages the inclusion of a much wider population under the diagnosis. The effect will be to change our perception of autism, particularly in areas such as outcome and the need for specialist resources. As a result, and coupled with a greater public awareness, autism is becoming less of a specialist topic and more an everyday subject for mainstream services. Despite evidence that the prevalence of core autism remains constant (Fombonne et al, 1997), there is speculation that an increase, perhaps in subtypes, may be taking place, for reasons which vary from selective immigration (Arvidsson et al, 1997) to measles, mumps and rubella (MMR) immunisation (Wakefield et al, 1998c). This possibility is not easy to test, because changing criteria, increased awareness and the recognition of subtler variants make it hard to maintain a constant diagnostic threshold. It is especially difficult in certain groups such as those where a profound learning disability obscures or mimics the syndrome. Outside developmental psychiatry other diagnoses may be made, particularly of obsessive-compulsive or dissocial personality disorders, or even schizophrenia.
Asperger syndrome has been demarcated as potentially distinct from autism. It was initially defined by the presence of useful speech, normal ability and clumsiness, but in 1992 ICD-10 restricted it to those in whom there was an absence of early speech delay. The question of whether the two disorders are really separate or simply the poles of a single continuum echoes other psychiatric debates. It has proved difficult to assemble a series of cases on the new criteria, controlling for both age and ability, but those studies that have succeeded suggest that there are differences in cognitive profile, social interest and, perhaps, abnormal preoccupations (Kugler, 1998). Some characteristics, such as motor incoordination and delay, have proved elusive (Ghaziuddin & Butler, 1998), while other potential criteria, such as the qualities of insight and humour and the desire for social interaction, have been suggested.
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DIFFERENTIAL DIAGNOSIS |
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There is a risk of the diagnosis of autism being extended to include anyone whose odd and troublesome personality does not readily fit some other category; such over-inclusion is likely to devalue the diagnosis to a meaningless label. For the same reason, it is important to remain alert to the possible existence of other diagnostic groups. Newson has identified such a group with the label of pathological demand avoidance syndrome after its predominant characteristic. Children in this group have, at most, a mild learning disability and a high degree of social awareness, although many have enough in common with autism to attract the diagnosis (Newson & Maréchal, 1998). Pathological demand avoidance syndrome forms a long-standing and expensive disorder, persisting into adulthood and posing considerable problems in its management. The description is based on a series of 200 children but replication has been hindered by the lack of more formal publication.
Autism and epilepsy
Epilepsy occurs in up to 30% of those with autism and can amplify their
symptoms. There is much to suggest that epilepsy might cause or mimic autism.
For example, behavioural changes similar to those of autism can occur in the
Laudau-Kleffner syndrome (acquired epileptic dysphasia) in which clinical
seizures may be absent in as many as 30% of sufferers, the diagnosis of
epilepsy being based on an electroencephalogram (EEG). It is difficult to know
the significance of the paroxysmal activity that has been found in the sleep
EEGs of 50% of children with developmental dysphasia, even where there is no
history of seizure (Picard et al,
1998). A similar figure has been obtained for autism
(Kawasaki et al,
1997). A paroxysmal EEG has a statistical association with
autistic regression, the emergence of autism after a period of apparently
normal development (Tuchman & Rapin,
1997). However, a paroxysmal EEG is present in only a minority of
the children, being more frequent the later the regression
(Chez & Buchanon, 1997).
Such results raise the possibility of an epileptic basis for some cases of
autism and of using the EEG as a routine investigation. This is not something
to be done lightly. A recording would need to include both light and slow-wave
sleep, which can be difficult to achieve. Furthermore, it is only justifiable
where the results might affect clinical management: it is difficult to dismiss
a paroxysmal abnormality as an epiphenomenon that, in the absence of seizures,
might be ignored. Yet treatment is far from straightforward, with only five
published cases where autism has responded to an anti-epileptic drug, usually
valproate (Gillberg & Schaumann,
1983; Nass & Petrucha,
1990; Plioplys,
1994). Nevertheless, in some of these cases the disorder had been
established for up to a decade, and it is possible that better results might
be obtained with earlier, more vigorous or more persistent treatment at a
younger age and by exploring a wider range of drugs, possibly including
steroids. The last may be treating some other or more fundamental process. A
successful response was reported in a six-year-old child who had developed
autism at 22 months (Stefanatos et
al, 1995). In the absence of seizures or any focal or
paroxysmal EEG abnormalities, steroids were given on the basis of an abnormal
auditory evoked response. Treatment trials (whether using antiepileptic drugs
or corticosteroids) will be hampered by the difficulty of enrolling children
soon after the onset of the disorder.
Any evaluation of outcome needs either some form of untreated comparison or a better picture of the natural history: which children show autism from birth, which deteriorate in early childhood, how abruptly and in what areas of function. In particular, how often is there a clear autistic regression? These data need to be related to the outcome, for we need to know which are the children who will improve, particularly shortly after onset. Early remission may have meant that they failed to reach the psychiatrist and the diagnosis of autism. Others may have been segregated as suffering from disintegrative disorder, an overlapping group with a boundary that is becoming increasingly indistinct (Mouridsen et al, 1999). Earlier identification should come with greater public awareness something that the Checklist for Autism in Toddlers (CHAT) might bring (Baron-Cohen et al, 1992). The CHAT promises to be a very specific primary care screening instrument, but one that is very insensitive when used within the first two years of life.
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COMORBIDITY |
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The relationship of autism to learning disability is confusing. The increase in the prevalence of autism with increasing severity of learning disabilities leads to the following questions. First, how far does autism, which produces early social and communicative deprivation, cause learning disabilities? Second and conversely, can learning disability, with its widespread deficits, result in an autistic presentation is there a real distinction between severe learning disabilities with autistic features and autism? Third, are some of the medical disorders that cause learning disabilities particularly likely to produce autism?
Most studies have looked at populations with either learning disabilities or autism, rather than controlling for both. Hence, the high prevalence of autism in Cornelia de Lange syndrome probably reflects the severity of learning disability associated with that disorder (Berney et al, 1999). Once social anxiety had been disentangled from social impairment, fragile-X syndrome did not appear to have a greater claim on autism than other disorders producing similar degrees of disability, although it is associated in its own right with a pattern of behavioural symptoms which has some similarity. Tuberous sclerosis is linked and although the combination of epilepsy and severe disability may contribute the association also appears to relate to the siting of the tubers (Bolton & Griffiths, 1997).
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THE PATHOLOGY OF AUTISM |
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Another area that lends itself to exploration is the effect of motivation on the ability to initiate automatic (as opposed to voluntary) behaviour. The ability to perform fluently only when relaxed or very aroused (whether from fear or excitement) is well recognised and may relate to cerebellar function. This forms the basis for facilitated communication that, although effective (Simon et al, 1994), is so inconsistent and unreliable as to be discredited.
As neuroimaging improves so does its potential as a powerful research tool. Better definition allows the measurement of volume rather than just cross-sectional area. Still new is the measurement of the proportions of the brain of ratios (of one functional area to another) rather than absolute values. Such ratios are likely to be gender-specific and to vary over time and with developmental phase. They may well identify syndromic differences, although the scope for permutation might reduce this to a numerological hunting-ground.
As promising as neuroimaging is functional magnetic resonance imaging, which can pinpoint an area by the changes in blood flow that accompany activation as the subject attempts various tasks tasks that are being increasingly tightly defined (Baron-Cohen et al, 1997). It is this precision which holds out the most hope of relating clinical attributes to their neurology and physiology. One result might be to show some tangible distinction between various clinical subtypes, not just Asperger syndrome and high-functioning autism, but also other groups such as those characterised by repeated violence, compulsive routines, and the various forms of sociability (Attwood & Wing, 1987).
Positron emission tomography, using labelled compounds, can track the uptake of specific neurotransmitters, while magnetic resonance spectroscopy allows the measurement of the concentration of individual compounds. An example is a pilot study that has shown a localised abnormality of the metabolism of the prefrontal cortex which correlates with the neuropsychological and language deficit of autism (Minshew et al, 1993).
Magnetoencephalography identifies electrical changes by their effect on the magnetic field rather than the smeared voltage changes of the conventional EEG. Its very high temporal and spatial resolution promises to deliver what brain mapping could not.
The use of these newer investigative techniques will be limited by their expense, the skills required for valid and reliable results, and the level of cooperation and consent needed for what may be a demanding procedure.
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AETIOLOGY |
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Turner syndrome, with only one sex chromosome but derived from either parent, lends itself to a study of the effects of imprinting. A simple and elegant design has demonstrated marked impairment of sociability in those who get their X chromosome from their mother (Skuse et al, 1997), although the sex chromosomes have not otherwise been associated with autism. This implies the potential for localising the areas and systems relevant to sociability.
The opioid theory
The opioid theory proposes that autism arises from the early, long-term
overload of the central nervous system by opioids, which are probably
exogenous and possibly largely derived from incompletely digested dietary
gluten and/or casein (Reichelt et
al, 1991). Although difficult to substantiate, this theory
draws together a number of disparate findings
(Sahley & Panksepp, 1987). In essence, the theory is one of deficient barriers, the fault lying in the
bowel mucosa, in the blood-brain barrier, or in the failure of the intestinal
and circulating peptidases that should convert opioids to innocuous
metabolites. The defective barrier may be either inherited or secondary to
adversity. For example, a mucosal barrier might be affected by defective
sulphation, the latter being an incidental finding in a study of dietary
migraine (Alberti et al,
1999). Other therapists, blaming intestinal candidiasis, are using
a combination of dietary and antifungal treatments.
More tangible has been the discovery of lymphoid hyperplasia near the ileo-caecal junction in children who had been selected on the basis of an autistic regression together with current bowel symptoms (Wakefield et al, 1998c). The regression occurred immediately after immunisation in only one-third of the subjects, but nearly all the biopsy specimens showed evidence of measles infection (Wakefield et al, 1998a). This suggests that measles might act in conjunction with another factor, whether genetic predisposition, intercurrent infection or multiple immunisation, to trigger a chronic inflammatory response. Another study by the same group implicates coincident mumps infection in the origin of inflammatory bowel disease (Montgomery et al, 1999). These results raise several issues that have become conflated. Is there a link between measles and autism, between measles and inflammatory bowel disease or between autism and inflammatory bowel disease? If so, are all autistic children vulnerable to measles infection or to the polyvalent nature of MMR? It would be helpful to know whether lymphoid hyperplasia occurs in the bowel of those who have had autism from birth or do not have bowel symptoms. Lymphoid hyperplasia is clearly distinct from Crohn's disease (Walker-Smith, 1998) and there is no evidence of the latter being associated with autism (Fombonne, 1998). Immediate post-immunisation gastrointestinal symptoms do not forecast autism (Peltola et al, 1998). In Gothenburg, a review of the 74 children diagnosed with autistic spectrum disorder over a 10-year period (Gillberg & Heijbel, 1998) included the introduction of MMR immunisation in 1982. If anything, they showed the incidence declined although this is not entirely consistent with their impression that the incidence of autism is increasing over time (Arvidsson et al, 1997). A study of the onset of autism in 498 cases in London did show an increase in prevalence, but showed neither the superimposed surge with the introduction of the polyvalent vaccine nor the temporal link with diagnosis that might be predicted (Taylor et al, 1999). Unfortunately, any conclusions are limited by the possibilities of changing diagnostic practice and catch-up polyvalent immunisation of those born earlier than the critical period.
While neither study (Gothenburg or London) can exclude the possibility that autism might be caused or triggered by polyvalent measles immunisation, they indicate that it does not account for more than a small proportion of cases. It will need a much larger study, with greater statistical power, to disprove a hypothesis that is already reducing MMR uptake and herd immunity.
A conbination of open case studies and media support has led to excitement about the effect of secretin, a pancreatic enzyme that triggers peptidase release. This interest is unlikely to be dimmed by the failure of five placebo-controlled trials to find a convincing response in their preliminary, unpublished presentations. However, the trials did identify the difficulties of measuring change in autism and the extent of natural fluctuation in its symptom patterns. Popular demand has led to the resumption of secretin production despite the lack of evidence of efficacy or safety in repeated dosage, let alone a treatment licence. Nevertheless, the reports invite a closer scrutiny of the role of the intestinal peptidases as well as of gastrin, the polypeptide upstream to secretin, which requires sulphation to become biologically active.
Dietary exclusion of gluten and casein has been incorporated into a number of approaches, even those that focus on child-rearing. Although there have been a number of positive reports about its effectiveness, systematic trials have come from only two centres, one working with children in a residential school (Knivsberg et al, 1998) and the other monitoring children living at home (Whiteley et al, 1999). The results are mixed, and insufficient to gauge how far success balances against partial or transient responses, a failure to respond, or natural remission. However, the evidence warrants further studies, especially placebo-controlled trials.
Naltrexone provides a pharmacological means of blocking opioid action. Its proponents describe a therapeutic U-shaped curve and emphasise that it is effective only in very low dosage (Scifo et al, 1991). It is therefore unsurprising that other, more definitive studies should fail to find anything other than modest and mixed effects at higher dosages (Campbell et al, 1993; Willemsen Swinkels et al, 1996; Kolmen et al, 1997). These studies leave naltrexone in an equivocal position, except for the general agreement that it does reduce hyperactivity an important property in a condition where stimulants can increase stereotypy (Campbell et al, 1996).
There are many treatments for autism, each advocated with a zeal that undoubtedly makes for effectiveness. Unfortunately, such enthusiasm also makes it more difficult to evaluate how these treatments would perform in the hands of less charismatic practitioners. Most approaches depend on open, uncontrolled case reports and series that make little allowance for natural developmental change. The exception is the reporting of Lovaas's intensive behavioural technique (McEachin et al, 1993), although this too is under fire (Boyd, 1998; Gresham & MacMillan, 1998). Other home-based programmes are being shown to be effective (Ozonoff & Cathcart, 1998). Although some focus on one aspect of the child's deficit and can be applied without the need for the wholesale conversion of the family, most programmes demand the substantial sacrifice of time, attention and funds.
With inconsistent measures and differing populations it is difficult to make a coherent whole of a large number of observations. Cost-effective progress needs a greater coordination of efforts across a number of fields, using a variety of instruments and techniques, in order to get a multi-point fix an approach that has been pursued by the Tours group for some years (Adrien et al, 1989). As in 19th-century exploration, well-mapped areas are out-weighed by the unknown, from which emerge travellers' tales of strange practices and exotic cures.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication July 12, 1999. Revision received September 30, 1999. Accepted for publication October 1, 1999.