Neurologic Basis Of Autism:
Differential Diagnosis And Management

Isabelle Rapin, M.D.
Isabelle Rapin, M.D. is a Neurologist with the Albert Einstein College of Medicine, Bronx NY.

Introduction

Autism is a behaviorally defined life-long disorder of higher cortical function, with onset in early childhood, that affects sociability, language and communication, play, and range of interests and activities. Its severity is very variable, so that it is appropriate to speak of the autistic spectrum (referred to as pervasive developmental disorder or PDD in the Diagnostic and Statistical Manual of Mental Disorders - DSM IV) to encompass all cases, from the most severe to those with mild autistic traits. Its prevalence is much higher than previously supposed: at least 1/1000 for classic autism, and another 2-4/1000 for mildly affected individuals with autism (including pervasive developmental disorder not otherwise specified [PDD-NOS] and Asperger syndrome).

Etiology And Diagnosis

Etiologies

Autism has a number of etiologies, as it is what systems in the brain are involved rather than the etiology of their involvement that is responsible for its symptomatology. In children without a discernible etiology such as a congenital infection, brain malformation, tuberous sclerosis, phenylketonuria or other metabolic disorder, fragile-X, Angelman and Cornelia de Lange syndromes, and a host of other causes for brain maldevelopment, genetics appears to play a major role. The most recent evidence is that inheritance may be polygenic, and that what is inherited may, at least in some children, be susceptibility to some environmental insult such as a nondescript infectious illness or a psychologic trauma that other children would weather without permanent consequences.

Autistic Regression

Whereas in the majority of cases symptoms of autism may be discernible in the first or second year of life, about a third of children undergo a regression, at a mean age of 21 months, that involves language, sociability, play, and cognition. Some children were developing normally before the regression whereas others already had signs of autism that got worse as a consequence of the regression. The causes of autistic regression are unknown, but it is suspected that subclinical epilepsy may play a role in some children. In other genetically susceptible children, an infectious or even emotionally-taxing event may serve as triggers. Until an adequate number of children have been referred for investigation close in time to the regression, its causes will remain speculative. The course of the regression is a more or less prolonged developmental plateau, with or without fluctuations, then improvement, but almost never full recovery. By adolescence, a third of children with autism will have had at least two unprovoked clinical epileptic seizures, but prolonged sleep EEGs that include stages III and IV sleep reveal subclinical epilepsy in a greater number of children. All seizure types can occur.

Language And Communication

In early life all children with autism are dysphasic: some have mixed receptive/expressive deficits that impair phonologic decoding. This precludes or impairs all subsequent language operations, to the point where some are mute and comprehend little or no language; others have higher order processing deficits that result in an atypically organized lexicon, word retrieval difficulties, inadequate comprehension of open-ended questions and discourse. Echolalia and the use of memorized scripts are compensatory mechanisms in children who rely on an excellent verbal memory to circumvent difficulty in word retrieval, responding to open-ended questions, and the organization of coherent discourse. What is universally impaired in autism and distinguishes autism from specific developmental language disorders is very impaired pragmatics, that is, the conversational use of language. Except for mildly affected children with so-called Asperger syndrome, children with autism acquire language late. Those who remain nonverbal tend to have persistent severe comprehension deficits and to be mentally deficient.

Other Symptoms

Children with autism may have motor deficits such as hypotonia, clumsiness, toe walking, and repetitive stereotyped movements and activities, as well as sensory symptoms such as atypical perception of somatosensory, visual, auditory, gustatory, and olfactory signals. Some children engage in distressing self-injurious behaviors. Perseveration, rigidity, and obsessions may be prominent. Many have prominent sleep disorders. Disorders of attention may consist of too long an attention span for favorite activities and unusual tolerance of monotony, often paradoxically associated with a very short attention span for other activities. Some children are frankly hyperactive and disorganized and may be mistaken from children with primary attention deficit disorders with hyperactivity. A universal deficit is difficulty or inability to pay joint attention to an activity introduced by another person. Severely deficient joint attention is a prime indication for such educational approaches as one-on-one discrete trial training.

Cognition

Cognition is not a defining feature of autism, and an increasing number of individuals with mild autism and high intelligence are being recognized. The majority of children have mild to moderate cognitive deficits, with a characteristically very uneven cognitive profile. Verbal scores are generally inferior to performance scores, with rote memory and spatial skills disproportionately high. The opposite pattern with verbal IQ higher than performance IQ is seen, especially but not exclusively in some high functioning children of the Asperger type. Cognitive flexibility, organization and planning, and the ability to make inferences are typically low, even in persons with autism who have normal or superior cognitive abilities. Insight into other peoples' affect and intentions, and into the impact of one's behavior on others, is universally impaired.

Neuropathology

The neurologic basis of autism is currently under intensive investigation. Thus far, world-wide, less than 40 brains have been examined post-mortem with the findings published. Cellular maldevelopment in the neocerebellum and limbic cortical and subcortical areas was described by Bauman and Kemper. They were surprised not to find no anatomic evidence of neocortical involvement despite a great deal of functional evidence for its existence. Examination of six more brains by Bailey and colleagues corroborated the cerebellar findings but not the limbic abnormalities. In four brains there were cortical migration defects in the cerebrum not found by Bauman and Kemper. No brain has yet been examined with the most modern histochemical and immunochemical methods. If anything, the mean weights and volumes of autistic brains are greater than in controls, which corroborates a developmental rather than a destructive origin of autism. Because there are many biologic causes of autism, it is anticipated that a variety of anomalies will be found when an adequate number of brains have been examined with modern neuropathologic techniques. There is an urgent need for tissue donations of both affected and control brains, of which parent groups are just becoming aware and which needs to be emphasized by physicians who care for these patients.

Neurochemistry

Studies so far have focused on neurotransmitters and neuromodulators, but a coherent theory has yet to emerge. Dopaminergic deficits have been suspected because of the effectiveness of dopamine receptor blockers like haloperidol and the phenothiazines, and because of similarities between some of the symptoms of autism and those of schizophrenia (now viewed as another developmental disorder of brain function), in which abnormality of the mesolimbic dopamine system has been implicated. Abnormalities of opiate systems, perhaps explaining a high threshold for pain in some individuals, and of oxytocin related to a blunted need for social interaction have been invoked. Currently the searchlight is on serotonin, especially as a mutation in a serotonin transporter has been found and specific serotonin uptake inhibitors seem to be effective in some children and adults.

Clinical Investigation

Clinical investigations need to include a thorough medical/neurologic examination, seeking evidence by history or physical findings for a potentially treatable or diagnosable etiology for the autism. A definitive test of hearing is indicated in all young children with inadequate language, as the presence of hearing loss does not preclude the coexistence of autism. In all children with a history of regression and in those with very poor language, a prolonged sleep EEG is indicated. In the absence of any suspicious findings, neuroimaging and extensive metabolic tests have an extremely low yield. Chromosome studies are indicated in families who desire more children or in whom there is a suspicion of a diagnosable condition, but again, the overall yield is low. Detailed neuropsychologic and language evaluations are mandatory prior to entry into school because the findings will be very useful for parents and educators as they will indicate strengths that can be used to compensate for deficits, with the caveat that not all psychologists are adept at testing children with autism. A questionnaire to parents about how the child functions is not a substitute for quantitative testing. Equally important, though, is to keep in mind that psychologic testing in early childhood is descriptive of current level of functioning, but that its predictive validity for later cognitive ability is limited.

Intervention

Prognosis And Interventions

Because autism is generally the consequence of a static developmental abnormality, prognosis for improvement, but not full recovery, is good, provided children are provided with appropriate intervention at the earliest possible age. Intervention must address both the communication and the behavioral disorders and must be systematic, intensive, and individualized. Especially in children who are not severely cognitively compromised, appropriate early intervention may enable some of them to enter the educational mainstream, or at least require a less restrictive educational placement. Parents must be taught that providing structure in everyday life, making firm demands and sticking to their guns is extremely important.

Medication

Epilepsy calls for adequate anticonvulsant medication, but what to do in children with autism who have subclinical epilepsy with an epileptiform EEG without clinical seizures is controversial. The role of psychotropic medications in autism is being explored, with serotonin uptake inhibitors currently in fashion. The choice of medication has to target a particular behavior, as shotgun approaches do not work. By no means does every child with autism require medication, even though it may be very helpful (not curative!) in some cases. Long term use of drugs with potentially irreversible side-effects such as the dopamine receptor blockers must be avoided, as well as drugs with sedative side-effects. Some individuals with autism can function independently in adult life, but others will require some life-long assistance. The most severely affected may require institutional placement.

Education

The most effective treatment to date is early educational intervention. Applied behavior analysis (Lovaas) method consists of day-long one-on-one intervention with an adult. It is quite effective in severely withdrawn otherwise unavailable children but does not provide much opportunity for socialization with peers and is not the panacea in educational treatment of autism. The TEACCH method, which has been adopted by the State of North Carolina, is also highly structured but is center-based rather than home based. Therapeutic nurseries must also be very structured but they rely on more conventional social reinforcements to foster behavioral progress. The goal of special education is to return less severely affected children to ordinary classrooms, with whatever accommodations may be needed.

Unproven Treatments

The selective efficacy of sensory integration training, facilitated communication, and auditory integration training is dubious, or at least unproven. There is little or no empirical evidence on the efficacy of special diets, megavitamins, other dietary supplements, treatments for alleged yeast infections, and many other medical treatments. Secretin has been shown recently to be no more effective than placebo, both of which resulted in minor improvement.

SELECTED REFERENCES

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  2. Bailey A, et al. A clinicopathological study of autism. Brain. 1998;121:990-905.
  3. Catalano RA., Ed. When Autism Strikes: Families Cope with Childhood Disintegrative Disorder. New York, Plenum. 1998. (A sobering view of the medical profession through the eyes of parents of children with disintegrative disorder.)
  4. Chugani DC, et al.: Altered serotonin synthesis in the dentatoru-brothalamocortical pathway in autistic boys. Ann Neurol. 1997; 42:666-669. (Preliminary evidence for lateralized abnormality of serotonin metabolism in autism.)
  5. Cohen DJ, Volkmar FR. (Eds.). Autism and Pervasive Developmental Disorders: A Handbook. New York: John Wiley & Sons. 1997. (The most up-to-date and comprehensive book on autism. Covers all aspects, including investigation and intervention.)
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March, 2000/ Jacksonville Medicine

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