Download Infection in childhood and neurological diseases in adult life

Infection in childhood and neurological diseases
in adult life
C N Martyn
MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton, UK
Other chapters in this issue discuss the evidence that implicates infection during
infancy and childhood in the aetiology of respiratory disease. Here I argue that
experience of infection in early life may also be involved in the aetiology of some
diseases of the adult nervous system.The descriptive epidemiology of three
neurological diseases is compatible with the hypothesis that they are delayed
consequences of childhood infection. It is not difficult to imagine that the effects of
an infection which results in loss of cells from an organ system, like the central
nervous system, whose cell populations have lost the capacity to replace themselves
by mitotic division could remain hidden until unmasked by ageing. Such a
mechanism may be important in the aetiology of motor neuron disease and
Parkinson's disease. Age-related differences in host response, which may be partly
related to a maturing immune system, are known to influence both short- and longterm outcome for several infections. Perhaps the immune response to infection with
Epstein-Barr virus, or another common micro-organism with similar epidemiology,
in adolescence or early adult life is sometimes directed at antigens that are also
present in the central nervous system. At present, the evidence that supports these
hypotheses is largely circumstantial. But it may be possible to devise ways of testing
them both epidemiologically and in the laboratory.
Time trends in infant and maternal mortality
Over the past hundred years, expectation of life for people living in the
western world has improved dramatically. The improvement has
occurred in all age groups but it is most striking for expectation of life
at birth. A large part of the reason for this, of course, is the steady fall in
Correspondence to- i n r a n t mortality that began around 1900 (Fig. 1). In the first decades of
DrCN Martyn, the century, death in infancy was commonplace. At that time, infant
MRC Environmental mortality was dominated by post-neonatal mortality—that is deaths
Epidemiology Umt, o c c u r r i n g between the ages of 1 month and 1 year. The main causes were
Southampton General
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Hospital, Southampton respiratory and gastrointestinal infections which were associated with
SO76 6YD, u« adverse conditions, such as poor sanitation, contaminated water supplies
©The British Counal 1997
Bntiih Medical Bull.hn 1997,53 (No 1) 24-39
Childhood infection and later neurological disease
6-
175
r
Maternal mortality
-150
Infant mortality
-125
Infant
mortality
-100
per
1,000
live
. 75 births
Maternal
mortality
per
1,000
births
-50
-25
***^
Fig. 1 Time trends in
maternal and infant
mortality, 1891-1981.
•••V
0J
1891 1901 1911 1921 1931 1941 1951 1961 1971 1981
and over-crowding. In 1920 in Britain, for example, infant mortality was
80 per 1,000 live births; today the corresponding figure is 6.2.
The decline in maternal mortality has been even steeper than the fall in
infant mortality. But it did not begin until several decades after infant
mortality had started to fall (Fig. 1). In 1935, levels of maternal
mortality (caused mainly by toxaemia of pregnancy, inter partum
haemorrhage and post partum sepsis) were little different from those of
1835 — about 4 per 1,000 births. Yet now in Britain, maternal deaths
are so rare that their occurrence provokes a confidential enquiry. In
1993, only 27 such deaths occurred in England and Wales — a rate that
is 40 times lower than in 1935.
A corollary of the decline in maternal and infant death rates is that
there have been huge changes in the sort of environment in which
fetuses, infants and children grow and develop. Foremost among these
changes is a differing experience of infection in infancy and childhood.
People born later in this century are likely to have had fewer and less
severe infectious illnesses and will have had them at an older age than
people born earlier. In this chapter, I suggest that some degenerative
neurological diseases of adults have their origin in early life and point to
epidemiological evidence that indicates how three of these diseases,
Parkinson's disease, motor neuron disease and multiple sclerosis might
be linked to experience of particular infections.
Bnhtb Medical BuMefin 1997,53 {No 1)
25
Fetal and early childhood environment: long-term health implications
Parkinson's disease
Parkinson's disease is an extra-pyramidal movement disorder characterised pathologically by neuronal loss from the substantia nigra and
reduced concentrations of dopamine in the striatum. Its causes are
poorly understood. Despite several large case-control studies, no strong
environmental risk factors for Parkinson's disease have been identified.
Positive associations of the disease with rural residence, drinking water
from wells, and exposure to herbicides and pesticides have been
reported, but the associated relative risks were small and the findings
of different studies have not always been consistent1. Nor has the search
for powerful genetic determinants of the disease yet been very successful.
The prevalence of the condition in first-degree relatives of cases is not
significantly different from controls 2 and concordance rates in monoand dizygotic twins are similar3. Although the CYP2D6 allele associated
with slow metabolism of desbrisoquine is over-represented in patients
with Parkinson's disease, its prevalence is low and the proportion of
cases that can be attributed to this polymorphism is small4.
A possible reason for the lack of success in the search for environmental
risk factors for Parkinson's disease is that most epidemiological studies
have been focused on exposures occurring in adult life. If, as has been
suggested, Parkinson's disease results from the combination of an
environmental insult and the subsequent age-related loss of dopaminergic
neurons, the initial event that leads to the disease may occur many years
prior to the onset of symptoms. A few investigators have studied
environmental factors encountered during childhood, infancy or fetal life.
Associations between recall of several common viral infections of
childhood and risk of Parkinson's disease have been reported but only a
negative relation with recall of measles and a positive relation with croup,
diphtheria and rheumatic fever were statistically significant5'6. None of
these relations was strong. One study investigated whether birth weight or
growth during the first year of life, as indicated by weight at 1 year of age,
influenced risk of Parkinson's disease but found no relation6. However, an
analysis of mortality data from England and Wales concerning deaths from
Parkinson's disease that occurred in the period 1950-1992 provides
evidence that people born at the beginning of the century are at unusually
high risk of the disease. An old idea about the aetiology of Parkinson's
disease—the cohort hypothesis—deserves re-evaluation.
The cohort hypothesis of Parkinson's disease
In 1963, Poskanzer and Schwab reviewed nearly 1000 cases of a
Parkinsonian syndrome seen at the Massachusetts General Hospital 7 .
26
Bnhih MtdKal Bu/I.t.n 1997,53 (No 1)
Childhood infection and later neurological disease
The mean age of cases diagnosed between 1955-1959 was 27 years older
than that of cases diagnosed between 1920-1924. They suggested that
the increase in age of patients at the time of the onset of symptoms could
be explained if Parkinsonism was a condition which affected the cohort
of people aged between 5-59 years in 1920 and proposed the pandemic
of encephalitis lethargica that occurred between 1919-1926 as a likely
aetiology. A Parkinsonian syndrome is a recognised complication of
encephalitis but only 11% of their cases could be linked to an overt
encephalitic illness. To account for the majority of cases of Parkinsonism
without a history of an encephalitic illness, they conjectured that, while a
severe, clinically apparent episode of encephalitis was often followed by
a rapidly developing Parkinsonian syndrome, milder, subclinical and
undiagnosed attacks of the same infection might lead to Parkihsonian
symptoms only after an interval of many years.
This hypothesis, as the authors frankly admitted in the published
report, was devised post hoc. At the time, it was largely dismissed by
neurologists, partly because a delayed sequel to a subclinical viral
infection was considered an implausible pathogenetic mechanism and
partly because postencephalitic Parkinsonism and idiopathic Parkinson's disease were believed to be separate entities that could be
distinguished clinically by their different signs and symptoms and
histologically by their different pathological features8-9. Later reports of
the time trends of Parkinson's disease in several countries10"13 have been
consistent with an increase in the disease following the pandemic of
encephalitis lethargica, but the hypothesis has remained largely
unnoticed.
Age specific mortality rates from Parkinson's disease for England
and Wales for the period 1950-1992 are shown in Figure 2.
Mortality has declined in younger age groups while increasing 5-fold
in those 80 years and older. Age-period-cohort analysis proved
helpful in the interpretation of these diverging trends. This is a
statistical technique that attempts to dissect the trends in mortality
data into three components — the separate effects of age at death,
time period of death and cohort of birth. The method is described in
detail elsewhere14. Its purpose is to provide a more profound insight
into the influences that determine changes over time than could be
gained by a simple inspection of age-specific death rates. Diseases in
which long intervals elapse between exposure to the cause of the
disease and death from that disease tend to show changes between
successive generations. Such changes are known as birth cohort
effects. Diseases whose causes operate with a shorter latency are
likely to affect all age-groups more synchronously, even if different
age-groups are affected to a different extent, and reveal themselves
as period of death effects.
Bntt.fi Mtdical Builthn 1997,53 (No 1)
27
Fetal and early childhood environment: long-term health implicationt
Men
Women
Age at Death
2000 -g
1000 -i
85+
Q—B
80-84
V V
o—e
A- A
75-79
70-74
65-69
Mortality
Rate
60-64
3
•
»
•
55-59
100 (per
million
person
years)
10 -
Fig. 2
Age-ipecific
mortality from Parkinson's
disease, 1 9 5 0 - 1 9 9 2 , for
men and women, in
England and Wales.
1 J
1950
1960
1970 1980
1990
1950
Year of Death
1960
1970 1980
1990
Year of Death
The independent effects of age at death, time period of death and cohort
of birth in these data for Parkinson's disease are summarised in Figures
3-5. Mortality rises exponentially with age in both men and women
until the oldest age groups (Fig. 3). At all ages, mortality for women is
about a third less than mortality for men.
1000-,
Age
Effect
(Mortality
rate
per
million
person
years)
Fig. 3 The effect of
age, independently of the
effects of age of death
and cohort of birth, on
mortality from Parkinson's
disease for men and
women during the period
1950-1992 in England
and Wales
28
100-
10 J
55
60
65
70
75
80
85
Age at Death
Brrfish Mmdical BulUhn 1 9 9 7 , 3 3 (No 1)
Childhood infection and later neurological disease
2
15
1
Period
Effect
Tig. 4 The affect of
period of death,
independently of the
effects of age and cohort
of birth, on mortality from
Parkinson's disease for
men and women during
theperiodl950-1992in
England and Wales.
°
5
0.1 -I
1950
1960
1970
1980
1990
Year of Death
The effect of time period of death is shown in Figure 4. The decline in
magnitude from 1950 to 1980 parallels that seen in other chronic
diseases. It is likely to be due to gradual improvements in general
medical care and perhaps also to the introduction of levodopa for the
treatment of Parkinson's disease in the late 1960s. The rise that began
around 1980 coincided with the introduction of the 9th revision of the
International Classification of Diseases and may be partly artefactual.
Independently of the effects of age and period of death, risk of death
from Parkinson's disease increases steeply in successive birth cohorts
from 1869-1878 to a peak in the cohorts born 1889-1908 and then falls
equally sharply (Fig. 5). People born around the turn of century
experienced an unusually high risk of death from Parkinson's disease.
They were 2-3 times more likely to die from Parkinson's disease than
people born before 1888 or after 1924. The birth cohort effect is
sufficiently large to provide an explanation for the diverging trends in
mortality from Parkinson's disease in younger and older age groups.
One problem in interpreting these time trends concerns the validity of
mortality data. Parkinson's disease is under-reported on death certificates at present and the degree of under-reporting may have been more
severe in the past15. But as Marmot has pointed out11, it is unlikely that
the observed birth cohort effect could be a result of inadequacies in
death certification. To produce such an effect, medical practitioners
Snhih MmdKal BuH.hn 1997^3 (No. 1)
29
Fetal and early childhood environment: long-term health implications
2
15
1
Cohort
Effect
The effect of
cohort of birth,
independently of the
effects of age and cohort
of birth, on mortality from
Parkinson's disease for
men and women during
the period 1950-1992 in
England and Wales.
°
5
Fig. 5
01 J
1860
1870
1880
1890
1900
1910
1920
1930
1940
Year of Death
certifying deaths in the 1950s and 1960s would have to have been biased
towards a diagnosis of Parkinson's disease in a 60 year old person but
against it in a 80 year old. By the 1980s, this bias would need to have
been reversed. Previous analyses of mortality data for England and
Wales, carried out over a decade ago, produced evidence of a birth
cohort effect in Parkinson's disease11-12. Analysis of an additional 10
years of data confirms the strength of the effect and identifies the cohort
at greatest risk more precisely.
Since 1950, more than 76,000 deaths from Parkinson's disease have
been recorded in England and Wales. Modelling these data as functions
of age at death, time period of death and cohort of birth reveals that
patterns of mortality in these countries are dominated by the influence of
cohort of birth. People born around 1900 experienced a risk of death
from Parkinson's disease twice as high as people born around 1920 and
5 times higher than people born around 1930. This finding supports a
hypothesis, first formulated by Poskanzer and Schwab over 30 years ago,
that the majority of cases of Parkinson's disease are the result of a cause
that acted intensely in the early part of the twentieth century but whose
effect rapidly declined. Encephalitis lethargica is one candidate for this
aetiological factor.
The cause of encephalitis lethargica has never been determined,
although circumstantial evidence links it to the preceding epidemic of
influenza that swept the world in 1918 and 191916-17. Contemporary
30
Bnhih Mtdical Bu/I.t.n 1997^3 (No. 1)
Childhood infection and later neurological disease
accounts indicate that encephalitis lethargica affected men more often
than women. The incidence was greatest in adolescents and young
adults. The birth cohort effect present in mortality data for Parkinson's
disease from the last 4 decades and the relative rates in men and women
are both compatible with the idea that exposure to the causal agent of
encephalitis lethargica is part of the aetiology of Parkinson's disease. If
the hypothesis is correct, it follows that Parkinson's disease will become
rarer as members of the exposed birth cohorts die. Projections from the
age period cohort model predict that numbers of deaths from
Parkinson's disease in England and Wales are about to reach their peak
and that before the year 2000 they will begin to decline rapidly.
Poliomyelitis and motor neuron disease
Motor neuron disease is a condition, usually occurring in late adult life,
in which there is progressive loss of first and second order motor
neurons. It is almost invariably fatal within a very few years of the onset
of symptoms. A small proportion of cases are familial and, in some of
these families, the disease has been linked to a mutation of the SOD1
gene. But, for the large majority of cases which are sporadic, the
aetiology is unknown. The possibility that there might be a connection
between infection with poliovirus and motor neuron disease has been
discussed by neurologists for more than a century. The idea is attractive
because of the similarities in some of the clinical and pathological
features of the two diseases; however, the fact that the majority of
patients with motor neuron disease cannot recall ever having suffered
from paralytic poliomyelitis in the past is usually considered an
insurmountable objection.
But this objection fails to take account of the nature of poliovirus
infection. Only a very small proportion of non-immune individuals
exposed to the virus develop neurological symptoms and, even in those
that do, the severity of the illness is very variable. It ranges from a mild
aseptic meningitis through transient weakness of a limb to generalised
paralysis and death. In primates, neuronal and inflammatory lesions can
be found in the nervous systems of animals that have never shown signs
of infection. It is quite possible that similar subclinical forms of
poliomyelitis exist in humans. Such individuals would, in all probability,
never have been diagnosed as having poliomyelitis but, nevertheless,
they might have lost substantial numbers of motor neurons. If so, motor
neuron disease might be a delayed sequel either because of further
neuronal loss through ageing or as a result of a second insult.
Bnfu/)AWico/Su//«hnl997;53(No.1)
31
Fetal and early childhood environment: long-term health implications
Table 1 Correlations of infectious disease notification rates (1931-1939, both sexes) with mortality
from motor neuron disease (1968—1978, aged 55-74, both sexes) in 142 local authority areas of England
and Wales
Infectious disease
Numbers of cases notified
Correlation coefficient
PoliomyetlHi
6,463
946,648
506,398
8,548
16,981
147794
12,887
3,226
42,198
14,948
0.42
-0.20
- 0 30
- 0 03
Scarlet fever
Dipntneno
Smallpox
Enteric fever
Erysipelas
Cerebrospinal fever
EncephaGhs lethorgica
Ophttiatmia neonatorum
Puerperal fever ( 1 9 3 1 - 1 9 3 7 )
011
-018
- 0 08
011
- 0 02
0.06
One way to examine this idea further is to compare the geographical
patterns and time trends of the two conditions. If there is an aetiological
link, current patterns of motor neuron disease should mirror the
epidemiology of poliomyelitis half a century earlier. Studies in both the
UK and in the US have shown that mortality from motor neuron disease
approximates closely to its incidence. Mortality can, therefore, be used
to examine current patterns of motor neuron disease. Poliomyelitis
became a notifiable disease in 1911 in the UK and information about
notification rates in individual counties and • county boroughs was
included in the Registrar General's annual reports from 1921 onwards.
These data can be used to explore past patterns of poliomyelitis.
Table 1 shows the correlation coefficients between mortality from
motor neuron disease in the period 1968-1978 and notification rates for
poliomyelitis in the period 1931-1939 for the 142 counties, county
boroughs and London boroughs for which notification rates of infectious
diseases are available separately in England and Wales. A positive
relation between the two diseases is present. The relation is specific:
correlation coefficients between motor neuron disease and other
notifiable infectious diseases are either very small or negative. Table 2
shows that this specificity is maintained when other current causes of
death are correlated with rates of poliomyelitis in the 1930s.
The time trends of the two diseases also run in parallel. Figure 6 shows
that mortality from motor neuron disease at all ages has increased in
successive birth cohorts from 1900 onwards. Rates of poliomyelitis also
increased over the first half of the century. The epidemiology of
poliomyelitis is unique amongst infectious diseases in that it becomes
commoner rather than rarer as hygiene and social conditions improve.
The explanation is found in the changes in the age of first exposure to
poliovirus that accompany rising standards of living. In conditions
where hygiene is poor, infection invariably occurs during the first few
32
Bnhsfc MeoW Bul/ehn 1997^3 (No 1)
Childhood infection and later neurological disease
Table 2 Correlations of leading cautes of death (1968-1978, ages 55-74 yean, both
sexes) with notifications of poliomyelitis (1931-1939, < 25 age years, both sexes) in 142
areas of England and Wales
Cautei of death
Correlation coefficient
AH cauies
-0.57
-0.50
-0.50
-0.49
-0.48
0.28
0.34
0.42
Fkonchrtu and •mphyierna
Stroll.
Uchaemic heart daaase
Cancer of* Stomach
Ovary
Breast
Motor neuron daeaie
months of life at a time when the infant is still partially protected by
maternal antibody. The virus remains confined to the lymphoid tissue of
the gastrointestinal tract because the viraemic phase necessary for it to
reach the central nervous system is inhibited by circulating antibody. As
conditions improve, age of first exposure to the virus increases. The child
is no longer protected by maternal antibody and the incidence of
paralytic disease increases. In the population, the pattern of disease
changes from one of low rates of endemic infantile paralysis to recurrent
epidemics of acute paralytic poliomyelitis affecting children and young
adults. Over the first 50 years of this century, the UK and other countries
of the developed world experienced a striking increase in the incidence of
15 -,
Females
Males
10 -
. 1915
1915
/
/ 1905
1925
1925
Rate
(per
100,000
person
years)
10 -
1905
1
/
1
5 --^ 1895
1935 I If
5 -
1945 J
Fig. 6
/
/
1895
^
1885
^1875
1
Mortality from
motor neuron disease for
men and women in
England and Wales,
1958-1989 by cohort of
birth
Bnrufi Medical Butfifin 1997^3 (No 1)
0 30
0 -1
40
5 0 6 0
70
8 0 9 0
A
100
3 0 4 0 5 0 6 0
70
8 0 9 0 1
9 e At Death (years)
33
Fetal and early childhood environment: long-term health implications
paralytic poliomyelitis. Studies in the UK, the US and Norway have
recently shown that motor neuron disease is now behaving in a similar
way18"21.
The hypothesis that past infection with poliovirus is causally linked to
risk of motor neuron disease is compatible with the current geographical
and social patterns of motor neuron disease. It is able to account for the
gradual increase in mortality from motor neuron disease over the past
two decades. Time will tell if the hypothesis is right. If it is, rates of
motor neuron disease will continue to increase for the next 10-15 years
until the first cohort of people to have been immunised against poliovirus
in childhood reach the age at which motor neuron disease usually
presents. If there is a causal link with poliovirus infection, a fall in
incidence of motor neuron disease can be expected around the year 2010
and it will occur in the youngest age-groups first.
Multiple sclerosis
Multiple sclerosis has been the subject of a large number of
epidemiological investigations in many parts of the world and, although
gaps in our knowledge remain, we have a fairly clear account of the
patterns of occurrence of the disease. The disease is rare in the tropics
and common in temperate regions. In the continents of North America
and Europe, rates of the disease tend to be higher in the north than in the
south, while in the southern hemisphere, this gradient is reversed. The
most important exception to the general pattern of increasing rates of
multiple sclerosis with increasing distance from the equator is Japan,
where surveys have shown multiple sclerosis to be uncommon. The
disease is probably rare in other countries of the Far East too, but
information for these countries is less reliable.
How migration affects risk of multiple sclerosis has also been
extensively studied. Two consistent patterns can be discerned in the
results of migrant studies. The first of these patterns can be seen clearly
in Figure 7, which shows changes in prevalence of the disease after
migration. Migrants who have moved from a country of origin where
multiple sclerosis is common to a host country where the disease is rarer,
show a decrease in rate of disease. Only one study, of migrants to
Hobart, Tasmania, from the UK, is an exception to this rule. The second
pattern concerns migrants whose journey has been in the opposite
direction. Here the evidence is less secure because fewer studies have
been carried out but, as can be seen in Figure 8, this pattern contrasts
with the first. People who have moved from a place where multiple
sclerosis is rare to a place where the disease is commoner experience
34
British Med.ro/Bu//»/m 1997;53 (No 1)
Childhood infection and later neurological disease
Migration from High to Low
S Europe to S Australia (crude)
• Country of origin
•e—•
UK to S Australia (crude)
o Country of destination
••--
Europe to Queensland, Aust. (crude)
Migrants' change
in risk
UK/Ireland to Queensland, Aust. (crude)
Europe to Hobart, Tasmania
Europe to Newcastle, Australia
Europe to Perth, Australia
England to Hobart, Tasmania
O*—
Europe to Queensland, Australia
o
England to Perth, Australia
O A--
England to Queensland, Australia
S Europe to Israel (crude)
N & C Europe to Israel (crude)
UK to South Africa
Fig. 7 Change in
prevalence of multiple
tclerosil with migration
from country of high risk
to country of lower risk
O
O
o
50
100
150
Prevalence rate
per 100,000
little change in risk of the disease. Instead, it seems that they retain the
low risk of their country of origin.
These patterns though, do not persist into the second generation. Risk
of multiple sclerosis in the offspring of immigrants is very similar to that
in the population of the host country. Although migrants from high-risk
European countries to Israel were found to have a much higher
prevalence of multiple sclerosis than migrants from low-nsk Afro-Asian
countries, there seemed to be little difference in prevalence between
native Israelis whose fathers were born in Europe and those whose
fathers were born in Afro-Asian countries22'23. A recent update of this
survey reported that age-adjusted incidence and prevalence of the disease
was between 1.2-1.6 times higher in Israelis whose fathers were born in
Europe or America than in those whose fathers were born in Afro-Asian
countries24. This difference is much smaller than the difference in rates
between first-generation immigrants from these countries25. The
narrowing of the difference appears to be due to an increase in risk
among second-generation Afro-Asians rather than a decrease in risk for
second-generation Europeans and Americans. In the UK, immigrants
from the West Indies, the Indian subcontinent and Africa retain their low
risk of multiple sclerosis after migration26-27. But studies of the UK-born
children of such immigrants have shown that their risk of developing the
disease is at least as high as that of the white UK-born population28-29.
Brtlah Medico/ BuH.rm 1997,53 {No 1)
35
Fetal and early childhood environment: long-term health implications
Migration from Low to High
Africa & Atia to Jerusalem, Israel
»•
O
• Country of origin
Africa & Asia to Israel
•
o Country of destination
O
*• Migrant's change
in risk
N Africa to Israel (crude rates)
Fig. 8
Change in
prevalence of multiple
sclerosis with migration
from country of low riik to
country of higher risk.
50
100
150
Prevalence rate
per 100.000
What sort of aetiological agent could account for these patterns in the
occurrence of multiple sclerosis? The explanation cannot be the
straightforward one that the cause operates at a high level in places
where multiple sclerosis is common and at a low level in places where
the disease is rare. While this would account for the lowering of risk in
migrants moving from an area where multiple sclerosis is frequent to an
area where it is uncommon, it cannot explain why migrants moving in
the other direction retain their low risk. The patterns can however, be
explained by postulating a protective factor which operates in early life
in places where the disease is rare and confers life-long protection.
One theory which combines both protective and causal effects
concerns age at infection. If multiple sclerosis were a rare sequel to
delayed exposure to a common infectious agent, the consistent patterns
of migrant studies can be explained. The host response to many
infections varies with the age at which the infection occurs. One example
of this is hepatitis B; infection with this virus during early childhood
commonly results in a chronic antigen carrier state, but rarely causes an
overt hepatitic illness; in contrast, when infection is delayed until adult
life, the chronic carrier state is rare but hepatitis common. Several
studies suggest that age of infection with some of the common
communicable diseases of childhood tends to be older in cases of
36
Bnhth M»dKal Bullehn 1997,53 (No 1)
Childhood infection and later neurological disease
multiple sclerosis than in controls30'31. Most of these reports concern
measles, but there is some evidence that age of infection may also be
higher with mumps and rubella. There have also been suggestions that
delayed infection with Epstein-Barr virus is involved in the aetiology of
multiple sclerosis32"34. Infection with Epstein-Barr virus in early childhood is not associated with the typical symptoms of infectious
mononucleosis, whereas if infection is delayed until late adolescence or
young adult life, about 50% of people develop symptoms. In many
countries of the developing world there is a high rate of seroconversion
to Epstein-Barr virus before adolescence and consequently a low
incidence of classical infectious mononucleosis. The results of several
studies that show an association between multiple sclerosis and
infectious mononucleosis provide further evidence that common
infections are acquired late in cases of the disease. Further, the high
relative risk of multiple sclerosis associated with symptomatic EpsteinBarr virus infection raises the possibility that this virus is specifically
involved in the causation of the disease and not simply a marker for
delayed infection generally. This suggestion has received further support
from a cohort study in Denmark that exploited the nationwide Danish
multiple sclerosis registry and centralised records of serological testing
for Epstein-Barr virus35. In this study, people with serologically
confirmed late Epstein-Barr virus infection had a nearly 3-fold increase
in risk of developing multiple sclerosis.
As Warner and Carp pointed out more than 15 years ago, a link
between delayed infection with Epstein-Barr virus and the development
of multiple sclerosis is compatible with the broad epidemiological
features of the disease32. In developing countries where multiple sclerosis
is rare, early infection with Epstein-Barr virus is almost universal. By
contrast, in those areas of the world in which infectious mononucleosis
is common and where, by implication, first exposure to Epstein-Barr
virus is often delayed beyond the early years of childhood, the prevalence
of multiple sclerosis is high.
Acknowledgements
I am grateful to Mike Murphy, John Charlton and Tim Devis at ONS for
making mortality data on Parkinson's disease available and to Alistair
Shiell at the MRC Environmental Epidemiology Unit for his help in
analysing these data.
Bnhi/i /Medico/ Bulletin 1997;53 (No. 1)
37
Fetal and early childhood environment: long-term health implications
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