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RESEARCH LETTERS

tube or its coiling in the mouth. By using the swallowing Group Boys (n) Cases of ASD (%)
reflex the tube was successfully placed at the first or second
General population5 ~7746 73 (0·94)
attempt in 19 of 20 trials. The only failure occurred in a Normocephalic 362 2 (0·55)
patient with a left MCA infarction in whom the swallowing Macrocephalic 306 9 (2·94)*†
reflex could not be provoked. No serious complications, *General population rate versus macrocephaly (p=0·003).5 †Normocephalic
such as severe coughing—with the potential risk of versus macrocephalic (p=0·03).
inducing an increase of the intracranial pressure—or Frequency of autism spectrum disorders (ASD) in boys
respiratory distress were noted. The procedure was well
tolerated by all patients. These conditions are collectively referred to as autism
Our study confirms that the placing of nasogastric tubes spectrum disorders. Macrocephaly (head circumference
by inducing the swallowing reflex is a useful alternative if >97th centile) occurs in 25–30% of autism spectrum
the conventional method fails. Our new method is much disorder cases and is considered to be a consequence of
less distressing for the patients than direct placement of the megalencephaly.2 The risk of a macrocephalic child
nasogastric tube (with the help of a laryngoscope and developing an autism spectrum disorder has not yet been
Magil forceps), which requires sedation of the patient and established. We compared the rates of autism spectrum
which is usually recommended for such patients.5 disorders in an epidemiological sample of boys with and
However, our procedure may not work in patients who without infantile macrocephaly.
have had a brainstem infarction because they are prone to The Cambridge and Huntingdon Health Authority
lack a sufficient swallowing reflex. child-health surveillance programme has systematically
collected data from GP and health-visitor checks on all
1 Mann G, Dip PG, Hankey GJ, Cameron D. Swallowing function children born since 1991 and living in the health-authority
after stroke—prognosis and prognostic factors at 6 months. Stroke area. From 1993 onwards all contacts with community
1999; 30: 744–48.
health services (paediatric, child psychiatry, and speech
2 Smithard DG, O’Neill PA, Park C, et al. Complications and
outcome after acute stroke—does dysphagia matter? Stroke 1996; 27: therapy services) have also been recorded. We identified all
1200–04. boys born between May 1, 1991, and December 31, 1993,
3 Nakajoh K, Nakagawa T, Sekizawa K, Matsui T, Arai H, Sasaki H. and selected those that had macrocephaly at the GP and
Relation between incidence of pneumoniae and protective reflexes in health-visitor’s 8-month check, usually conducted between
post-stroke patients with oral or tube feeding. J Int Med 2000; 247:
39–42. 20 and 52 weeks of age (n=307). In addition, we identified
4 Teramoto S, Matsuse T, Fukuchi Y, Ouchi Y. Simple two-step all normocephalic boys (head circumference 25th–75th
swallowing provocation test for elderly patients with aspiration centiles) (n=1239) and selected children listed sequentially
pneumonia. Lancet 1999; 353: 1243. in the database (excluding those with medical disorders
5 Dyer I, Ashton WB. How to pass a nasogastric tube. Br J Hosp Med known to give rise to developmental problems) as
1991; 45: 45–46.
age-matched controls (n=362). The macrocephalic
Department of Neurology, Universitätsklinikum Münster, 48129 children were more likely than their normocephalic
Münster, Germany (Rainer Dziewas MD, Peter Lüdemann MD, counterparts to come from higher social grades (social
Carsten Konrad MD, Florian Stögbauer MD) grading was derived from postcodes with the ACORN
classification system, collapsing grades 1+2, 3+4, 5+6).3
Correspondence to: Dr Rainer Dziewas
The number of macrocephalic and normocephalic children
(e-mail: dziewas@uni-muenster.de)
in each social grade was 159 versus 131 grade 1+2, 99
versus 156 grade 2+3, 49 versus 75 grade 4+5 (p<0·0001
by Fisher’s exact test).
The autism screening questionnaire4 was posted to parents
of all the children. 308 (46·4%) parents replied and
Association between idiopathic confirmed that their child had no known handicapping
medical disorder. Seven children had scores above threshold
infantile macrocephaly and autism that indicated a possible diagnosis of an autism spectrum
spectrum disorders disorder. Macrocephalic children were more likely to have
suprathreshold scores than normocephalic children (7/162 vs
Patrick F Bolton, Melanie Roobol, Lucy Allsopp, Andrew Pickles 0/146, respectively; Fisher’s exact test p=0·02). To take
account of any response biases, further analyses were
We conducted a case-controlled, catch-up study of a cohort of undertaken with complex survey analysis methods
boys born with macrocephaly in order to determine (STATACorp, 1999). These confirmed the higher rates of
whether infantile macrocephaly is a risk marker for the suspected autism spectrum disorders in the macrocephalic
later development of autism spectrum disorders. Our results group (p=0·004; data weighted for non-response by strata
show that infantile macrocephaly was associated with an defined by social grade, macrocephaly status, and age).
increased risk of developing autism spectrum disorders Clinical records of all children referred to paediatric or
(odds ratio 5·44, 95% CI 1·11–52·15; p=0·03). These findings child psychiatry services were also examined (158/669
suggest that neurobiological differences during infancy may children). Nine had a diagnosis of idiopathic autism
predict behavioural manifestations of autism spectrum spectrum disorder according to ICD-10 criteria (one autism,
disorders. three atypical autism, and five Asperger’s syndrome). Four
of these nine cases had also been identified by the
Lancet 2001 358: 726–27 questionnaire survey. There remained, therefore, three
Autism is a disorder that becomes manifest in the first children with high autism screening questionnaire scores
3 years of life, but it remains unclear when the who had not been clinically diagnosed with an autism
neurobiological abnormalities that may underpin it begin. spectrum disorders. Parents of two of these children agreed
Genetic factors are important in its aetiology and create a to further assessments. Both were confirmed as having an
liability for a broad range of social and communication autism spectrum disorder (one had atypical autism and the
impairments that includes Asperger’s syndrome and other other Asperger’s syndrome) with the Autism Diagnostic
forms of autistic-like pervasive developmental disorder.1 Interview—Revised and Observation Schedule. The third

726 THE LANCET • Vol 358 • September 1, 2001

Copyright © 2001 All Rights Reserved

For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS

undiagnosed child with a suspected autism spectrum Positron-emission tomography of


disorder had been noted to have developmental problems
and macrocephaly by paediatric services, but the family was vector-mediated gene expression in
not available for further evaluation and so he was excluded
from the study. Overall, there were more macrocephalic
gene therapy for gliomas
children (9/306) than normocephalic children (2/362) with a A Jacobs, J Voges, R Reszka, M Lercher, A Gossmann, L Kracht, Ch
confirmed ICD-10 diagnosis of an autism spectrum disorder Kaestle, R Wagner, K Wienhard, W D Heiss
(odds ratio [OR] 5·44, 95% CI 1·11–52·15; p=0·03).
Moreover, the rate of idiopathic autism spectrum disorders In clinical gene-therapy trials for recurrent glioblastomas,
in the macrocephalic children was also higher than that transduction of the herpes simplex virus type-1 thymidine
expected in the general population (binomial test, p=0·003) kinase (HSV-1-tk) gene with subsequent prodrug activation by
based on a recent UK prevalence study of autism spectrum ganciclovir was found to be safe, but clinical response was poor.
disorders in children in this age range (general population We used positron-emission tomography (PET) with I-124-
prevalence rate=62·6/10 000; male to female ratio=4:1.5 By labelled 2’-fluoro-2’-deoxy-1-D-arabino-furanosyl-5-iodo-uracil
contrast, the rate of autism spectrum disorders among the ([124I]-FIAU)—a specific marker substrate for gene expression of
normocephalic children was no greater than expected HSV-1-tk—to identify the location, magnitude, and extent of
(binomial test, p=0·8). The higher rate of autism spectrum vector-mediated HSV-1-tk gene expression in a phase I/II
disorders in the macrocephalic children remained after clinical trial of gene therapy for recurrent glioblastoma in five
stratifying by social grade (OR 5·61, 95% CI 1·13–54·55; patients. The extent of HSV-1-tk gene expression seemed to
p=0·03). Seven of the nine children with infantile predict the therapeutic response. The expression of an
macrocephaly and a diagnosis of an autism spectrum exogenous gene introduced by gene therapy into patients with
disorder were still macrocephalic in later childhood. The gliomas can be monitored non-invasively by PET.
remaining two children had head circumferences on the 75th
and 85th centiles. Computed tomography or magnetic- Lancet 2001; 358: 727–29
resonance imaging brain scans in five macrocephalic children The design of effective gene therapy strategies relies on
with confirmed autism spectrum disorders did not reveal an concerted research to define the genetic and
identifiable medical cause for the macrocephaly. pathophysiological alterations causing the disease so that the
Many of the children in the survey (39%) had been in biological characteristics of the target tissue can be
contact with speech therapy, paediatric, or child psychiatry understood. A safe vector and expression system can then be
services and so most (68·5%) had been screened for autism developed to achieve efficient, targeted, and regulated
spectrum disorders either through contact with clinical alteration of specific therapeutic gene expression. In clinical
services or by our questionnaire survey. Most cases of autism gene-therapy trials for recurrent glioblastomas, transduction
spectrum disorders in these cohorts were likely, therefore, to of the herpes simplex virus type-1 thymidine kinase (HSV-1-
have been identified. tk) gene with subsequent prodrug activation by ganciclovir
This study reports the rate of autism spectrum disorders in was found to be safe, however, clinical responses were
a population-based sample of children with infantile observed only in a few patients with small brain tumours.
macrocephaly. We have found that the association between One of the most important issues for making gene therapy
macrocephaly and the development of an autism spectrum widely applicable to human beings is the development of
disorder is evident in infancy, well before the emergence of technology for non-invasive monitoring of the location,
clear signs of the disorder. Our findings suggest that in some magnitude, and duration of vector-mediated gene expression
children with autism spectrum disorders neurobiological in vivo.1–4 Prompted by the death of a patient with liver-
differences are present before exposure to putative causal directed adenovirus vector-mediated gene therapy, the
environmental factors. The results also indicate that infantile Recombinant DNA Advisory Committee of the National
macrocephaly may be an early marker of risk and could be Institutes of Health, USA, called for better assays for
of use in prospective longitudinal studies of the early measuring transgene expression in cells and tissues.
development of autism spectrum disorders. Further research Non-invasive localisation of gene expression (molecular
will be required to clarify when the neurobiological imaging) relies on the transduction of marker genes that
differences first emerge and how brain growth proceeds in encode enzymes or receptors that lead to a regional
children with autism spectrum disorders. accumulation of radiolabelled or paramagnetic marker
substrates or receptor binding compounds. These substrates
1 Bailey A, Luthert P, Dean A, et al. A clinicopathological study of or compounds can then be detected by radionuclide or
autism. Brain 1998; 121: 889–905.
2 Fombonne E, Roge B, Claverie J, Courty S, Fremolle J.
magnetic-resonance imaging (MRI).1–4 I-124-labelled 2-
Microcephaly and macrocephaly in autism. J Autism Dev Disord 1999; fluoro-2-deoxy-1-D-arabino-furanosyl-5-iodo-uracil ([124I]-
29: 113–19. FIAU), a specific substrate for HSV-1 thymidine kinase
3 Morgan M, Chinn S. ACORN group, social class, and child health. (HSV-1-tk), and positron-emission tomography (PET) have
J Epidemiol Community Health 1983; 37: 196–203. been successfully used for the non-invasive localisation of
4 Berument S, Rutter M, Lord C, Pickles A, Bailey A. Autism screening
questionnaire: diagnostic validity. Br J Psychiatry 1999; 175: 444–51.
retroviral,1 adenoviral,2 and herpes viral4 vector mediated
5 Chakrabarti S, Fombonne E. Pervasive developmental disorders in HSV-1-tk gene expression in rodent models. We used the
preschool children. JAMA 2001; 285: 3093–99 same method in a prospective gene-therapy trial to investigate
the safety of intratumourally infused liposome–gene complex
Autism Research Centre and Developmental Psychiatry Section, (LIPO-HSV-1-tk) followed by ganciclovir administration.
University of Cambridge, Cambridge CB2 2AH, UK Vector-mediated HSV-1-tk gene expression was followed
(P F Bolton FRCPsych, M Roobol MRCPsych, L Allsopp MRCPsych); and School by PET and [124I]-FIAU in five patients (age range 49–67
of Epidemiology and Health Science and Centre for Census and years) with recurrent glioblastomas. After biopsy sampling of
Survey Research, University of Manchester, Manchester the tumour, one or two catheters were stereotactically placed
(A Pickles PhD) within the tumour and subcutaneously connected to a port.
This allowed targeted intratumoural infusion of the cationic
Correspondence to: Dr Patrick Bolton liposomal vector DAC-30 (3  (N-N, N-dimethyl-
(e-mail: pfb1000@cam.ac.uk) aminoethane-carbamoxyl-cholesterol/1,2 dioleoylphospha-

THE LANCET • Vol 358 • September 1, 2001 727

Copyright © 2001 All Rights Reserved

For personal use. Only reproduce with permission from The Lancet Publishing Group.