Department of Psychiatry and Community Mental Health, University of Nottingham
Department of Psychology, University of Hertfordshire
SANE Research Centre, Warneford Hospital, Oxford
Correspondence: Dr S. J. Leask, University of Nottingham Department of Psychiatry, Duncan Macmillan House, Porchester Road, Nottingham NG3 6AA, UK. Tel: +44 (0) 115 969 1300, extension 40784; fax: +44 (0) 115 955 5352; e-mail: stuart.leask{at}nottingham.ac.uk
Declaration of interest Educational grants from SANE, the Theodore and Vada Stanley Foundation and Lilly Industries.
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ABSTRACT |
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Aims To investigate possible associations of adult-onset psychosis with neurological soft signs and common infectious illnesses in childhood.
Method Using data from the UK National Child Development Study, a longitudinal general population sample, odds ratios were calculated for clinical diagnoses of common childhood viral illnesses and later adult psychotic illness, childhood epilepsy and a range of neurological soft signs.
Results The number of illnesses per individual did not relate either to the number of soft signs, or to any particular adult outcome. Schizophrenia, affective psychosis and epilepsy were not associated with common childhood illness but were associated with neurological soft signs and an increased, but small, frequency of previous meningitis and tuberculosis.
Conclusions Overall the data support the notion of neurological soft signs as markers of disordered neurodevelopment in schizophrenia (but the early neurological abnormalities are not caused by infectiousillness) and an association between meningitis or tuberculosis in childhood and a small proportion of cases of epilepsy, affective psychosis and schizophrenia.
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INTRODUCTION |
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METHOD |
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Neurological soft signs
Systematic medical examinations were carried out on over 12 000 members of
the cohort at the ages of 7 and 11 years, and neurological
measures were recorded by school medical officers during these examinations,
from parents, teachers and a standardised medical examination
(Table 1). Some of these
measures were coded as ordered categoricals, e.g. question: "Child has
poor hand control"; answer "Certainly applies",
"somewhat applies", and "not at all". Where possible
this information was retained in the analysis.
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Epilepsy
The NCDS is one of the few epidemiological studies that has used systematic
research criteria for diagnosing epilepsy
(Kurtz et al, 1998).
Details about diagnostic criteria are provided by Kurtz et al
(1998).
Psychotic illness
Cohort members discharged from psychiatric hospitals between 1974 and 1986
were identified using information from the now defunct national database, the
Mental Health Enquiry. Their case notes were obtained and a Present State
Examination (PSE) schedule completed. These were then analysed using the
CATEGO computerised diagnostic program from which diagnostic classes were
obtained (Wing et al,
1974). Cases were identified achieving a diagnosis of
narrow schizophrenia (PSE S+) and affective psychosis (unipolar
or bipolar mood disorder with psychotic features;
Done et al, 1991).
Data analysis
Logistic regression was performed to explore associations between childhood
illnesses, neurological soft signs and adult outcomes in terms of odds ratios.
All analyses were performed using the Computer package SPSS for Windows
v8.0.
Follow-back designs such as this use a case-finding model unlikely to be biased by direct effects of the exposures. Likelihood of psychiatric admission as an adult will not be directly affected by illnesses or soft signs recorded in childhood, and the majority of cases of severe mental illness, such as psychosis, will be admitted to hospital. Thus power is limited by the number of cases, but not obviously bias. The calculated power varies with rates in cases and the population. Thus, it was felt that odds ratios with 95% confidence intervals would adequately demonstrate both effect size and uncertainty, as well as inform future power calculations in this field.
Wald statistic-derived odds ratios (with 95% confidence intervals) were
felt to be valid in the context of a large sample size
(Tabachnik & Fidell,
1996). Given the exploratory nature of this analysis, overall
trends were judged to be more informative than any individual test, and any
odds ratios the 95% confidence intervals of which excluded unity (95% CI1)
were examined in terms of the consistency of the size and sign of the effect
for that factor. That is, did a given exposure result in similar effects,
overall, across outcomes?
For the analysis of neurological soft signs we used factor analysis, as the numerous soft signs were deemed to be manifest measures of a smaller number of latent neurological abnormalities. Data on similar measures of neurological dysfunction gathered at the age of 7 years were used to explore the stability of the factor structure over time. Gender and social class were treated as covariates.
Given the lack of information on duration or onset of the childhood illnesses, no attempt was made to analyse with respect to degree of exposure or development of neurological effects over time. Similarly, a path analysis was not appropriate given that soft signs and illnesses up to this point were effectively measured simultaneously. It seemed appropriate to simply explore associations and consistency between the three strata: childhood illness; neurological soft sign; and adult outcome. Associations consistent between these might suggest a causal pathway, or a common underlying deficit with both neurological (soft signs) and immunological (illnesses) markers.
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RESULTS |
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Distribution of illnesses and soft signs for the population and outcomes are shown in Table 1. Note that, for all measures, the numbers of cases that had data in childhood varies. However, this attrition was felt to be independent of measure and outcome, and not to bias the findings.
Associations between total number of soft signs and illnesses were
investigated using linear regression and were not significant (standardised
ß= -0.004, P=0.65). Associations between gender and social class
and the total numbers of illnesses and soft signs were small but significant
(number of illnesses v. gender Z=- 2.4, P=0.016;
v. class 2=46.3, P<0.001; and number of
soft signs v. gender Z= - 13.8, P<0.001;
v. class
2=46.3, P<0.001). Higher social
class was associated with a greater number of illnesses. Significantly
increased numbers of soft signs were seen for schizophrenia (Z= -
2.04, P=0.042) and epilepsy (Z= - 6.1, P<0.001),
but not for affective psychosis (Z=0.89, P=0.37). None of
the adult outcomes was associated significantly with the aggregate measure of
total number of illnesses recorded.
Given continuing interest in individual illnesses and soft signs, an attempt was made to simplify the data while retaining the real measures.
None of the common childhood illnesses was associated with adult schizophrenia, although the rare illnesses meningitis and tuberculosis were both associated significantly with odds ratios of 7.8 (95% CI=1.0-59) and 15 (95% CI=2.0-120), respectively. In general, common childhood illness was not associated with affective psychosis, although a reduced risk of chicken pox (OR=0.33, 95% CI=0.2-0.7) is noteworthy. As with schizophrenia, affective psychosis is associated with meningitis and tuberculosis.
For common childhood illnesses, only whooping cough was associated with
increased risk of neurological soft signs (small positive effects for seven of
the eight significant associations between whooping cough and adult
outcomes/neurological soft signs; see Table
2) although even this association disappears as soon as a more
conservative criterion for statistical significance (e.g. 0.01) is
adopted. As expected, meningitis (large positive effects for all 12
significant associations; see Table
2) and tuberculosis (large positive effects for all six
significant associations; see Table
2) do show robust associations with neurological soft signs.
Factor analysis of the soft signs yielded seven factors consisting of more than one measure (percentage variance explained in parentheses): (1) left preference (12.4%); (2) clumsy and unsteady (11.1%); (3) hand control and speech problems (8.4%); (4) general coordination and neurological (7.5%); (5) tics/twitches (7.2%); (6) speech problems (6.0%); and (7) incontinence (5.8%). These factors do in general represent meaningful clusters of related soft signs, suggestive of common neurological origin (see Table 2).
Associations between these soft sign factors and adult outcomes were investigated using analysis of variance. Children who later developed schizophrenia had increased loading on all soft signs factors, significant for factors 3 and 4. Table 2 also shows a consistent pattern of raised levels of neurological soft signs (i.e. OR>1) in this group. Children who later developed affective psychosis showed a statistically significant increase of soft signs in factor 4 only. Cases of childhood epilepsy,, as expected, had increased loadings on all seven soft signs factors, significant for factors 2-5. Logistic regression confirmed that the fit of the outcomes of both schizophrenia and epilepsy on soft signs remained little altered after the effects of tuberculosis and meningitis had been removed.
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DISCUSSION |
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Limitations
Validity and reliability of diagnosis of childhood illness is uncertain.
Information regarding the more common viral illnesses was obtained from the
parents, diagnoses which even today can confuse health professionals in the
absence of serology. For example, more illnesses were found in higher social
classes. One possible explanation is that better parental education improves
ability to remember or differentiate between common illnesses. The finding
contrasts these data total number of different illnesses noted
with a measure of total exposure to disease, which one would expect to
decrease with increasing social class (cf. the number of soft signs).
Similarly, meningitis cannot be subdivided further, for example
into viral or bacterial.
Information on duration, severity and timing of illness is lacking. The lack of data on timing of illnesses could obscure any effects on neurodevelopment that only occur during a critical window of development, and the development of any soft signs could precede or follow an illness.
The diagnosis of epilepsy was made by age 11, and thus might not include cases of partial epilepsy that commonly might not manifest until young adulthood.
Neurological soft signs measures come from medical, school and parental reports. The measures, while signs of non-localised neurological deficits, have to be seen in the context of the developmental literature of the time and will only indirectly reflect current concepts (Schroder et al, 1991). However, given the variety of sources of information, exploratory factor analysis of the measures at 7 and 11 years was performed and showed consistency in the factor structure over time, suggesting reliability of the measures as well as validity of the constructs.
Neurological soft signs and adult outcomes
Our findings confirm earlier reports of raised levels of neurological soft
signs during childhood in individuals who later develop schizophrenia
(Table 1). There is also a
significant, but more modest, increased risk in those individuals who later
develop affective psychosis. This suggests that some soft signs reflect a more
general, latent neurological dysfunction. For example, the first
and third factors of the factor analysis reinforce the notion of soft signs as
markers of disordered neurodevelopment. It is noteworthy that of the
significant odds ratios (95% confidence intervals that do not
include unity) all represent increased frequency of soft signs associated with
adult outcomes.
The number of cases of schizophrenia identified lies within confidence limits that could be expected were the case-finding complete (Done et al, 1991). However, the percentage of cases of affective psychosis that are admitted to hospital is going to be a function of accepted practice, social acceptance of psychosis and illness severity, and milder cases are probably not represented. Differential attrition occurring because of measures in the study could include the removal of severe or complicated cases of childhood illness or soft sign (by death), leading to an extreme exposure but no outcome, with a resultant loss of study power.
Attrition at the level of case-finding reflects medical record keeping rather than characteristics of the patient per se. The clear exceptions to this are the tendency of those with chronic psychosis to social and geographical drift, as well as greater inconsistencies in recording personal details (e.g. names). This could lead to under-representation of more severe cases. Overall, the mixing of cases in the control population would decrease the power of the study. Any individual without data at 11 years was excluded from analysis.
Narrow schizophrenia, conforming mainly to the presence of first-rank symptoms, was used as it was felt to reflect the more neurodevelopmental features of schizophrenia, and therefore was more likely to be associated with other markers of disordered neurodevelopment. If this is seen as a more genetic form of psychosis, a lack of association with infectious illnesses might be expected, unless the diathesis is associated with immunological differences.
Illnesses and soft signs
Viral meningoencephalitis and bacterial meningitis, tuberculosis and more
rarely mumps can lead to central nervous system (CNS) involvement. For common
viral infections, autoimmune responses to the CNS (e.g. autoimmune
encephalitis) can be triggered by chicken pox, measles, scarlet fever and
rheumatic fever. Whooping cough can lead to punctate haemorrhages in the brain
following explosive coughing, and is sometimes followed by a related
post-tussis encephalitis. However, in this whole population
sample it appears that CNS involvement for the more common viral illnesses as
reflected in neurological soft signs is negligible, except for a possible
small association with whooping cough. For meningitis and tuberculosis, there
is evidence of a similar increase in soft signs in the population as a
whole.
Overall, then, infections that can directly cause CNS insults are associated with increased soft signs, whereas those mediated through autoimmune mechanisms are not. Whether the infection is viral or bacterial appears secondary to this consideration. Infectious hepatitis serves as a nominal control for general effects of illness in these data (infection but no CNS involvement). However, this observation does not extend either in specific illnesses or in total number of illnesses to the adult outcomes, with the exception of epilepsy (see below).
Illnesses and adult outcomes
An association between death rates from bronchopneumonia and dates of birth
of individuals with adult schizophrenia in two data-sets has been claimed
(O'Callaghan et al,
1994), as well as an association between schizophrenia and
childhood CNS infection (including meningitis) in prospectively gathered data
in a Finnish cohort (Rantakallio et
al, 1997). Here the risk for schizophrenia was associated
with viral CNS infection and the risk for other psychoses
associated with bacterial meningitis. Our data do not distinguish viral from
bacterial meningitis, but the associations between meningitis and both
schizophrenia (OR 7.8, 95% CI 1.0-59) and affective psychosis (adjusted OR
7.7, 95% CI 1.0-58) are clearly compatible with this work but each association
is based upon a single case.
The trends of association between tuberculosis, and psychosis and epilepsy are confounded by the association between tuberculosis and meningitis: 5 out of 40 cases of tuberculosis were also recorded as cases of meningitis. At the time of the measures (1969), cases of tuberculosis might have included cases of tuberculous meningitis which were not distinguished in the records.
Although there is a lack of effect of common illnesses on adult outcomes, the protective effect (OR=0.33, 95% CI=0.2-07, P=0.004) of chicken pox on adult affective psychosis is unexpected. Although this could be an artefact of multiple comparisons, this finding survives Bonferroni correction.
Is the excess of soft signs in schizophrenia caused by childhood
illness?
Although some childhood illnesses are associated with increased rates of
neurological soft signs, there are few consistent associations between the
childhood illnesses and adult psychiatric disorder.
Our findings show the typical pattern of a highly significant statistical association between neurological soft signs and schizophrenia but no statistically significant association between early infectious illness and schizophrenia. Despite the association between infectious illness and neurological soft signs in the population as a whole, it has to be concluded that neurological soft signs in schizophrenia arise from some cause other than childhood illness.
The link between meningitis and epilepsy is clear but accounts for few cases. This effect (and the similar trend with tuberculosis) is unrelated to social class. The weaker relationships of meningitis with schizophrenia and affective psychosis (each dependent upon a single case) are clearly no explanation for the increase in soft signs in these groups. Thus, the increase in soft signs in psychosis is independent of the effects of these rare illnesses in childhood. Within the limitations of the present data, exposure to common childhood illnesses at any age up to 11 years joins prenatal viral infection and complications of pregnancy and birth as candidate environmental factors in psychosis aetiology of small effect and doubtful significance. The excess of soft signs associated with psychosis must be assumed to reflect on the nature of the deviation in the trajectory of brain development in psychosis and its presumably genetic origin.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Erlenmeyer-Kimling, L. & Cornblatt, B. (1987) The New-York high-risk project. Schizophrenia Bulletin, 13, 451-462.[Medline]
Gupta, S., Andreasen, N. C., Arndt, S., et al (1995) Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. American Journal of Psychiatry, 152, 191-196.[Abstract]
Johnston, J. D. A., Strachan, D. P. & Anderson, M. D.
(1998) Effect of pneumonia and whooping cough in childhood on
adult lung function. New England Journal of Medicine,
338,
581-587.
Jones, P. B., Rodgers, B., Murray, R. M., et al (1994) Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet, 344, 1398-1402.[Medline]
Kurtz, Z., Tookey, P. & Ross, E. (1998)
Epilepsy in young people: 23 year follow up of the British National Child
Development Study. BMJ,
316,
339-342.
Malla, A. K., Norman, R. M., Agullar, O., et al (1997) Relationship between neurological soft signs and syndromes of schizophrenia. Acta Psychiatrica Scandinavica, 96, 274-280.[Medline]
McGorry, P. D., McFarlane, C., Patton, G. C., et al (1995) The prevalence of prodromal features of schizophrenia in adolescence: a preliminary survey. Acta Psychiatrica Scandinavica, 92, 241-249.[Medline]
Mednick, S. A., Machon, R. A., Huttunen, M. O., et al (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic. Archives of General Psychiatry, 45, 189-192.[Abstract]
O'Callaghan, E., Sham, P. C., Takei, N., et al (1994) The relationship of schizophrenic births to 16 infectious diseases. British Journal of Psychiatry, 165, 353-356.[Abstract]
Pollock, J. I. & Golding, J. (1993) Social epidemiology of chickenpox in two British national cohorts. Journal of Epidemiology and Community Health, 47, 274-281.[Abstract]
Power, C. & Peckham, C. (1990) Childhood morbidity and adulthood ill health. Journal of Epidemiology and Community Health, 44, 69-74.[Abstract]
Rantakallio, P., Jones, P., Moring, J., et al (1997) Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up. International Journal of Epidemiology, 26, 837-843.[Abstract]
Schroder, J., Niethammer, R., Geider, F. J., et al (1991) Neurological soft signs in schizophrenia. Schizophrenia Research, 6, 25-30.[CrossRef][Medline]
Tabachnik, B. G. & Fidell, L. S. (1996) Using Multivariate Statistics (3rd edn), pp. 598-599. New York: HarperCollins.
Westergaard, T., Mortensen, P. B., Pedersen, C. B., et
al (1999) Exposure to prenatal and childhood infections
and the risk of schizophrenia. Archives of General
Psychiatry, 56,
993-998.
Wing, J. K., Cooper, J. E. & Sartorius, N. (1974) The Measurement and Classification of Psychiatric Symptoms: An Instruction Manual for the PSE and CATEGO Program. London: Cambridge University Press.
Received for publication October 18, 2001. Revision received July 23, 2002. Accepted for publication July 31, 2002.
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