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Encephalitis and aseptic meningitis Olmsted County Minnesota 1950Ц1981 I.

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Encephahtis and Aseptic
Meningitis, Olmsted County, Minnesota,
1950-1981: I. Epidemiology
Ettore Beghi, MD,"t Alfred0 Nicolosi, MD,S Leonard T. Kurland, MD, DrPH,"
Donald W. Mulder, MD,§ W. Allen Hauser, MD,S and Lynne Shuster, BA"
All cases fulfilling stated criteria for encephalitis and aseptic meningitis in Olmsted County, Minnesota, for the period
1950 through 1981 were identified. This is, to our knowledge, the first such incidence and trend study in a delineated
population, providing rates per 100,000 person-years of 7.4 for encephalitis (189 cases) and 10.9 for aseptic meningitis
(283 cases). These are about twelve and six times higher, respectively, than the rates reported by the Centers for Disease
Control. The rates have been stable over successive 5- or 10-year periods except for a recent increase in aseptic
meningitis. Both conditions were more common in the summer months, in childhood, and among males. Viral
identification using conventional laboratory tests has improved with time; in the period 1970 through 1981, virus type
was specified in about one-fourth of the cases. The most common agents identified were California and mumps viruses
in encephalitis, and enter0 and mumps viruses in aseptic meningitis. Antecedent andlor concurrent infections were
noted in 42 and 35% of encephalitis and aseptic meningitis cases, respectively. No case due to mumps, measles, or
rubella viruses has occurred since 1972, reflecting the impact of immunizations. Recovery was reported at the end of the
acute phase in 95% of patients with aseptic meningitis, and there were no deaths. Seventy-eight percent of encephalitis
patients recovered completely; the case fatality rate was 3.8%. Of the encephalitis cases, 2% were diagnosed initially
postmortem.
Beghi E, Nicolosi A, Kurland LT, Mulder DW, Hauser WA, Shuster L Encephalitis and aseptic meningitis,
Olmsted County, Minnesota, 1950-1981: I. Epidemiology. Ann Neurol 16:283-294, 1984
Published reports describing epidemiological features
of viral infections of the central nervous system (CNS)
are fragmentary and largely derived from microbiological case lists [l, 19, 20, 231 or hospital series [lo, 1315, 2 1, 2 51. The former are selective for cases in which
laboratory investigations were performed, and the latter are influenced by the hospital's admission practice
and the clientele it serves. Severity and complications
of the illness are also determinants of admission, so that
cases from a hospital may not be a complete reflection
of the frequency within a community or the clinical
spectrum of cases. Furthermore, the diagnostic criteria
in different studies often are not comparable and the
clinical patterns may vary over time as well as with age
and season. Finally, temporal trends of CNS infections
may be evident only if studied over one or more decades. To evaluate incidence and to avoid the mentioned biases, it is preferable to assemble and analyze
all case Reports for a delineated population to provide
the most reliable picture of the impact of these disor-
From the "Department of Medical Statistics and Epidemiology and
the §Department of Neurology, Mayo Clinic and Foundation,
Rochester, MN, and the $Gertrude H. Sergievsky Center, Columbia
University, New York, NY.
ders. Such a population-based study has the following
advantages in furthering our understanding of such infectious disease processes:
1. The same criteria can be used in different areas or
2.
3.
4.
5.
over a span of time to ensure uniformity of case
inclusion.
Incidences can be determined SO that trends and
recognized epidemics can be described.
Comparisons by age, sex, residency, and other characteristics can be provided for different degrees of
CNS involvement.
Cases of known cause can be identified, and the
impact of different causative agents can be evaluated.
The effectiveness of vaccination and such other preventive measures as vector control can be assessed.
Our aim was to conduct an incidence study of viral
infections of the CNS as they occurred in the popula-
tPresent address: Mario Negri Institute of Pharmacological Research, Milan, Italy.
Received N~~ 10, 1983, and in revised form jan2 5 , 1984. ~~~~~~~d
for publication Jan 26, 1984.
Address reprint requests to Dr Kurland.
283
tion of Olmsted County, Minnesota, over a 32-year
period (1950 through 1981).This population is recognized as an excellent resource for descriptive studies,
because virtually all residents are seen for any
significant medical problem at the Mayo Clinic and its
affiliated hospitals or other local facilities, all of which
participate in a centralized diagnostic indexing system.
The system includes diagnoses based on findings from
outpatient visits to the Mayo Clinic and the Olmsted
Medical and Surgical Group, emergency room and inpatient care at the affiliated hospitals, house calls, Iaboratory data, and postmortem studies. A detailed description of this resource is presented elsewhere tl6,
171.
Materials and Methods
For local residents during the years 1950 through 1981, all
medical records identified in the centralized index with a
diagnosis of encephalitis, meningoencephalitis, postimmunization encephalitis, encephalomyelitis, encephalopathy, viral
or aseptic meningitis, and other infections of the CNS (excluding poliomyelitis) were reviewed as part of a comprehensive study of the incidence and outcome of C N S infections in
Olmsted County (A. Nicolosi and colleagues, unpublished
data, 1983). Only cases fulfilling the diagnostic criteria for
“encephalitis” or “aseptic meningitis” are discussed in this
report.
A case was included in the encephalitis group only if the
following criteria were satisfied:
Acute or subacute onset of symptoms
Presence of neurological symptoms or findings (clinical
or laboratory-microbiological, electroencephalographic,
computed tomographic, etc.) indicative of involvement
of the brain parenchyma, such as coma, seizures, focal
neurological findings, or mental function impairment
Absence of evidence of other diagnoses, including
noninflammatory conditions, and no microbiological or
other laboratory findings suggestive of a nonviral infection
Mild impairment of consciousness, febrile convulsions, or
mental dysfunction associated with higher fever alone were
not accepted as definite evidence of encephalitis. The absence of meningeal signs or the presence of normal cerebrospinal fluid (CSF) findings did not preclude acceptance of the
case if the other criteria were satisfied.
Cases were classified as “definite” or “possible.” The former were either pathologically definite (based on biopsy or
postmortem findings) or clinically definite. Although a diagnosis would be regarded as confirmed only if a virus were
isolated postmortem or at biopsy, virus isolation from the
CNS is rarely practical. Consequently, a case was classified as
clinically definite in the absence of evidence favoring another
diagnosis and in the presence of an inflammatory disease of
acute or subacute onset-generally with fever, meningeal
signs, and CSF pleocytosis of more than 5 cells per cubic
millimeter associated with evidence of brain involvement evident on the neurological examination and/or diagnostic tests
such as electroencephalogram and computed tomographic
scan. In a few cases postmortem examination provided infor284
Annals of Neurology
mation on histological features or virus identification. Patients with acute or subacute onset and ill-defined neurological symptoms such as blurred vision and dizziness, and
patients in whom a different disease could not be excluded or
confirmed, were classified as having “possible encephalitis.”
Aseptic meningitis was defined, following Wallgren [ 32)
and Adams and Victor 123, as a benign, self-limiting disease
of known or suspected viral cause consisting of fever, headache, and signs of meningeal irritation, without evidence of
brain parenchymal involvement, and a lymphocytic and
mononuclear pleocytosis of the CSF. Although clinical features similar to those found in aseptic meningitis may also be
noted in bacterial or fungal meningitis or, on occasion, in
noninflammatory diseases, in this report the term aseptic meningitis indicates meningitis of known or suspected viral cause.
Patients with stiff neck and/or meningeal signs associated
with a febrile viral illness and in whom a spinal tap was not
performed were classified as having “possible meningitis.”
Patients falling into the “possible” category were considered
separately and were not included in the incidence calculations.
In only a few instances was there an effort to isolate virus
from the cerebral tissue. If successful, it was considered proof
of viral cause. The causative agent was presumed to be viral
when (1) a virus was cultured from CSF, (2) complement
fixation o r hernagglutination inhibition revealed a fourfold
change in serum or CSF antibody titer between the acute and
convalescent stages, or (3) counterimmunoelectrophoresis
was positive.
Individuals had to have been residents of Olmsted County
at the time of diagnosis in order to be accepted into the study.
The sex and age distribution of the 1070 United States white
population was used for incidence adjustment, and these
rates are presented using as the denominator 100,000 person-years of experience. All tesrs of statistical significance
were made assuming a Poisson distribution, except when frequencies were large enough to adopt the normal approximation [27].
For all the Olmsted County patients fulfilling these criteria
for encephalitis and aseptic meningitis and satisfying the criteria for residency, the following data were abstracted:
1. Demographic information: age, sex, residence at onset,
and date of last follow-up o r death
2. Data on the disease: diagnosis, date of onset of symptoms,
date of diagnosis, symptomatology, and clinical course and
outcome, including review of postmortem examination reports when applicable
3. Data on recent illnesses, diagnoses, immunizations, and
the like collected from the clinical history, with special
emphasis on the month preceding the onset of current
symptoms
4. Results of laboratory investigations, with special attention
to microbiological tests
5. Results of neurophysiological (electroencephalographic)
and neuroradiological examinations
6. Information concerning hospitalization and any reporting
of the case to the County Health Department for the stare
and the Centers for Disease Control (CDC).
Results were determined for the entire study period as
well as for the selected time periods 1950 through 1959,
Vol 16 N o 3 September 1984
females, and 8.1 for both sexes combined (Table 1).
The age- and sex-adjusted rate was 7.4. For aseptic
meningitis the crude rates were 15.1 for males, 9.6 for
females, and 12.2 for both sexes combined (Table 2).
The age- and sex-adjusted rate was 10.9. The differences between the two sexes were statistically significant for both encephalitis (p < 0.05) and aseptic
meningitis (p < 0.001).
The incidence of encephalitis over the four time intervals showed no significant trend (Table 3; Fig 1).For
aseptic meningitis there were fluctuations in the first
three intervals and there was a significant rise in the
most recent interval, 1975 through 1981 (Table 4; Fig
2). The incidences of both diseases were higher among
rural residents than city residents (8.4 versus 7.3 for
encephalitis; 13.3 versus 11.1 for aseptic meningitis),
but the differences were not statistically significant.
The age-specific incidences of encephalitis are presented in Table 1. Children under the age of 10 years
were the most frequently affected group: the incidence
was 22.5 in those less than 1 year of age, 15.2 in the age
group 1 through 4 years, and 30.2 among those aged 5
through 9 years. From ages 10 through 39, incidences
were lower and almost constant (5 cases per 100,000
person-years). The rates decreased further in those 40
years of' age and older.
The highest incidence of aseptic meningitis (82.4)
was observed in patients less than 1 year of age (see
Table 2). The rate was 16.2 in the age group 1 through
4 years and ranged from 18.8 to 10.5 in the older
children and young adults. The rates were lowest in
those aged 40 and over (1.4 to 0.7).
Over the entire period of study, there was no trend
or change in the pattern of encephalitis occurrence in
any of the age groups, as shown in Figure 1 and Table
3. The incidence of aseptic meningitis similarly failed to
1960 through 1969, 1970 through 1975, and 1976 through
1981.
Results
Over the 32-year study period 1950 through 1981,
189 definite cases of encephalitis (107 in males, 82 in
females) were identified in the Olmsted County population. There were 11 deaths, 7 in patients with a diagnosis of encephalitis during life, of whom 6 were examined postmortem. These 6 cases were histologically
confirmed, and virus was also isolated in 1. There were
also 4 cases diagnosed as encephalitis only postmortem,
and these too were included as incidence cases. The
criteria for the clinical diagnosis of encephahtis were
met in all other cases. There were 283 cases (166 in
males, 117 in females) fulfilling criteria of definite
aseptic meningitis. In addition, 52 cases were classified
as possible encephalitis and 32 cases as possible aseptic
meningitis; these were not included in the incidence
calculations.
Among the patients of this series, 5 experienced
more than one episode. In one case of encephalitis the
clinical history documented a previous encephalitis incident occurring more than 30 years earlier. In a case of
aseptic meningitis, there was a diagnosis of encephalitis
20 years before. In each of these two cases, the first
disease occurred before 1950. After 1950, 3 other patients had recurrences of aseptic meningitis. The different episodes were far apart in time-the mean interval
between the first and the second episode was 8.5
years-and in none of the cases was the causative agent
or a predisposing condition identified.
lncidencef
The crude incidences of encephalitis per 100,000 person-years over the 32 years were 9.7 for males, 6.7 for
Table 1 . lncidences per 100,000 Person-Years of Encephalitis, All CaJes, in Olmsted County, 1950 through 1981, by Age and Sex
Females
No. of Cases
Age ( y d
~~~~
~
<1
1-4
5-9
10-19
20-29
30-39
40-59C
60 +
All ages
Adjusted rateb
95% confidence
interval
~~
7
13
28
14
9
7
2
2
82
Males
No. of Cases
Rate
-
~~~
27.7
13.5
23.4
6.6
4.1
4.5
0.9
1.2
6.7
6.3
4.9-7.6
Total
Rate
No. of Cases
Rate
17.8
16.9
36.6
5.9
4.4
4.5
2.8
6.0
9.7
12
30
74
26
16
14
8
9
189
22.5
15.2
30.2
6.3
4.2
4.5
1.8
3.2
8.1"
~
5
17
46
12
7
7
6
7
107
8.6
7.3- 10.0
7.42
6.35-8.49
"Crude incidence, 8.13 (95% confidence interval, 6.97-9.29).
bAdjusted to 1970 United Stares white population.
Beghi et al: Viral EncephalitisIMeningitis
285
Table 2. Incidences per 200,000 Person-Years of Aseptic Meningitii. All Cases,
in Olmsted County. 1950 through 1981, by Age and Sex
'
Females
Age (yr)
Total
Males
No. of Cases
No. of Cases
Rate
18
10
18
23
31
14
3
0
117
71.2
10.4
15.1
10.9
14.1
8.9
1.3
. . .
26
22
28
37
29
19
3
9.6
166
Rate
No. o f Cases
Rate
~~
<1
1-4
5-9
10-19
20-29
30-39
40-59
60 +
All ages
Adjusted rate"
L
8.7
7.2-10 3
9 5 p confidence
44
32
46
92.5
21.8
22.3
18.3
18.2
12.1
1.4
1.7
15.1
60
60
33
6
2
283
82.4
16.2
18.8
14.5
15.8
10.5
1.4
0.7
12.2"
10 9
9 65-12 23
13.1
11 1-15 1
Interval
-
"Crude incidence, 12 18 (95% confidence interval, 10 77-13 59)
'Adlusted to 1970 United States whire population
Table -3. Incidences per 100,000 Person-Years of Eniephalitis. All Cases.
i n Olmsted County, 1950 through 1981. by Age and Time Period
Age (yr)
1950- 195')
1960-1069
1070- 1975
1976-198 1
<l
1-4
5-9
10 +
All ages
26.1
12.5
24.7
2.9
6.7
20.8
15.3
32.5
5.1
9.7
20.7
19.0
35.7
4.6
9.5
21.8
15.4
25.1
3.1
6.1
6.0
8.3
4.0-8.0
6.4- 10.3
Adjusted rate'
95% confidence interval
8.8
6.4-11.3
6.3
4.2-8.5
"Adjusted to 1970 United States whire population.
show significant changes in the group over 10 years of
age and showed an inconsistent fluctuation among children 5 through 5) years old. A rising trend was noted in
children 1 to 4 years old, and a striking increase in
incidence was recorded among infants less than 1 year
of age (see Figure 2 and Table 4).
There was a seasonal pattern for both encephalitis
and meningitis (Table 5). In 89 patients with encephalitis (47%) and 188 patients with aseptic meningitis ( 6 6 q ) , the disease appeared in July, August, or
September. The peak incidence was in September for
encephalitis and in August for meningitis. In these
months the number of cases exceeded the number that
would have been expected if no seasonal variation were
present (p < 0.05). Aseptic meningitis occurred at
lower rates in other months of the year, whereas encephalitis showed another, lower peak in the winter.
Causation
Evidence of the presence of a virus was obtained in 29
of the 189 cases of encephalitis (15%) (Table 6).
286 Annals of Neurology Vol 1 6 No 3
California virus was detected in 12 cases, and mumps
virus in 6. Herpes simplex virus was isolated in one
postmortem examination and from CSF specimens of 2
patients. In 1 additional case the histological features
were consistent with the diagnosis of herpes encephalitis [ 5 , 12, 261. Evidence of a virus was also obtained in 33 of the 283 patients with aseptic meningitis
(129;). The most common were nonspecified enteroviruses (15 cases), mumps virus (7 cases), coxsackie-virus (4 cases), and California and echoviruses
(3 cases each).
Antecedent Disorders
Possibly relevant antecedent disorders recorded in the
four weeks preceding the onset of encephalitis or
aseptic meningitis are presented in Table 7. The large
majority of these disorders occurred in the week preceding onset of neurological symptoms. Nonspecific,
and presumably viral, illnesses were the most frequent
complaint before onset of the neurological symptoms
and consisted mainly of upper respiratory infections.
September 1984
0
0
40-
0
0"
E
30 -.
i
a
c
2 0 .-
d
---
1-4
10 -.
-
lot
Table 4. Incidences per 100,000 Person-Years of Aseptic Meningitis, All Cases,
in Olmsted County, 1950 through 1981, 6y Age and Time Period
Age ( y d
1750- 1757
1760- 1967
1970-1975
1976-1781
<1
1-4
5-7
10 +
13.0
8.9
28.5
7.7
11.6
31.2
16.7
7.3
7.2
9.0
5 1.7
16.3
25.5
6.8
10.5
337.8
27.7
16.7
11.7
18.7
All ages
Adjusted ratea
95% confidence interval
11.4
8.6-14.3
8.5
6.4- 10.6
9.5
6.9-12.0
17.8
14.3-2 1.3
"Adjusted to 1970 Unired States white population
Meningitis and encephalitis were preceded by respiratory infections, gastrointestinal illnesses, and otitis in
similar proportions of cases.
Viral infections preceded symptoms in 26 patients
with encephalitis (14%) and in 30 patients with meningitis (11%). All occurred within four weeks of the onset of neurological symptoms. Varicella was the most
common specific event preceding encephalitis (12
cases), followed by mumps (8 cases), measles (5 cases),
and rubella (1 case). Mumps was the only childhood
infection identified prior to the onset of aseptic meningitis (30 cases).
Vaccinations had been administered within three
weeks of onset of symptoms in 9 cases (6 of encephalitis, 3 of aseptic meningitis). Smallpox vaccine
alone was administered prior to onset of symptoms in 1
case, polio vaccine alone in 2 cases, and multiple vaccines in 5 cases. In one patient with aseptic meningitis,
N N e w Jersey '76 influenza vaccine had been adminis-
tered. There was also one patient who had received
mumps vaccine five weeks before onset of illness.
Hospitalizations
Of the patients with encephalitis, 88% (166) were hospitalized; the proportion was nearly 90% in those up to
age 9, 89% in those aged 10 through 39, and 100% in
those aged 40 years or more. Among the patients with
aseptic meningitis, 79% (224) were hospitalized, and
the proportion also varied with age: 73% in the age
group 0 through 9 years were hospitalized, 84% of
those aged 10 through 39, and 88% of those 40 years
of age or older.
The rate of hospitalization also varied with time. The
proportions of patients hospitalized decreased for each
of the diseases over the study period-for encephalitis
from 94% of patients in the period 1950 through 1959
to 73% in the period 1976 through 1981, and for aseptic
meningitis from 90% to 69% in the same srudy periods.
Beghi et al: Viral EncephalitisIMeningitis 287
701
/
S I
30
1-4
5-9
1 o+
1
1950-59
1960-69
1970-75
1976-81
Interval
Table 5 . Seasonal Distvibution of Otiset of Eni-ephalitti and
Aseptic Meningitij in Olnisted County. 1950 through 1981
Fig 2. Int.idencej of aseptic meningitlj fovfouv age groups by time
interval, Olmsted County. 1950 through 1981.
~
Cases of
Encephalitis
Month
No
Cases of
Aseptic Meningitis
No
P(
Y-
January
17
90
9
February
14
74
March
10
5
53
26
42
10
10
32
35
35
8
4
28
14
39
12 0
30 7
April
May
8
June
13
69
11
JULY
25
30
94
13 2
34
15 9
18 0
69
5 3
87
67
22
12
9
100 0
283
August
September
October
November
December
Total
13
10
10
189
53
21 7
78
42
32
100 0
Keports
Fifty-three percent of the definite cases of encephalitis
and 41V of the definite cases of aseptic meningitis
were reported to the health department. There has
been d decrease in reporting over time. For encephalitis there was a decline from 69% in the first
decade of the study to 1 8 F in the most recent six
years. For aseptic meningitis the proportion decreased
from 6 1 9 in the hrst decade to 1 3 p in the period
1976 through 1981
Outcome
ENCEPHALITIS. Among the patients with clinically
diagnosed disease, there were 7 deaths (caselfatality
288
Annals of Neurology
Vol 16 No 3
ratio, 3.8%). Of these, 6 were examined postmortem;
in 5 the examinations were confirmatory. In the sixth
case death occurred six months after the acute episode;
findings here were of an encephalopathy of undetermined cause, although the abnormalities were noted to
be consistent with a previous viral encephalitis. In 4
additional cases encephalitis was first diagnosed postmortem. Of the 10 patients in whom a pathological
confirmation was available, 2 had evidence of inflammation in the white matter, with demyelination of postinfectious type. Herpes simplex virus was isolated from
the brain of 1 patient; this case was 1 of 17 in which the
cell count and protein levels were within normal limits
at the time of the initial CSF examination. In another
case the characteristic necrosis and inclusion bodies of‘
encephalitis were recognized by the neuropathologist.
A fatal myocarditis and concurrent encephalitis were
found in a patient in whom a fourfold increase in the
hemagglutination inhibition titer was demonstrated for
coxsackievirus B4. In the remaining fatal cases a specific
agent could not be identified.
Patients with aseptic meningitis had a generally milder and briefer course, with 269
patients (95%) recovering completely and 14 patients
( 5 %) having mild residua.
ASEPTIC MENINGITIS.
Discussion
In classic clinical practice viral encephalitis and aseptic
meningitis are regarded as two distinct disorders. However, there is overlap in age at onset, seasonal distribution, antecedent illnesses, and the causative agents
September 1984
Table 6 Spelijied Causes of Encephalitis and AJeptic Meningitis in Olmsted Count>. 1950 through 1981
No of Cases of
Encephalitis
Virus
California
Mumps
Herpes simplex
Echo
Coxsackie
Entero (nonspecified)
Influenza
Rubella
12
Entero (nonspecified)
Mumps
Coxsackie
California
Echo
Herpes simplex
6
4
2
2
1
1
1
29
Total cases
Total cases
Table 7 . Events Antecedent t o Encephalitis and
Aseptic Meningitis in Olmsted County, 1950 througb 1981a
Subsequent
Cases of
Encephalitis
Subsequent
Cases of
Aseptic
Meningitis
Antecedent Event
No
v
NO
5f
Respiratory infections
(including influenza)
Acute gastrointestinal
illness
Otitis media
Childhood infectious
disorders
Varicella
Mumps
Measles
Rubella
Vaccinations
Smallpox
Poliomyelitis
Influenza
44
23.3
54
1Y. 1
5
2.6
10
3.5
4
2. I
4
1.4
12
8
6.3
4.2
2.6
0
30
0
...
10.0
...
0.5
0
...
3‘
1.5
0
3‘
1.5
2“
...
0.7
0.4
5
I
0
...
N o of Cases of
Aseptic Meningitis
Virus
1‘
“All antecedent events occurred within four weeks prior to onset of
symptoms.
‘With concurrent tetanus and typhoid vaccination in 1 case and concurrent diphtheria-pertussis-tetanus (DF’T) vaccination in another.
‘With concurrent DF‘T vaccination in 2 cases.
“With concurrent DPT vaccination in 1 case.
‘With concurrent herpetic stomatitis.
themselves. Nevertheless, we maintain the distinction
because the two diagnoses have different prognostic
implications [ 12].,The term meningoenrephalitis, even if
it is useful clinically, has been avoided, because in that
class cases with prominent involvement of the brain
parenchyma are not differentiated from those with meningeal involvement only. An effort was made in the
present study to develop specific and conservative criteria. Cases regarded as “possible” aseptic meningitis
and encephalitis were excluded from calculations of the
incidences, although age distributions, residence, and
seasonal trends were similar to those of the definite
cases.
15
7
4
3
3
1
13
It is uncertain if one attack of a viral CNS infection
predisposes to subsequent attacks of the same or another type of infection. Further, identification of the
causative agent is so infrequent that no conclusion can
be drawn as to whether the later infection is related to a
new virus or to the reactivation of a hypothetically
quiescent focus. Consequently, the few recurrences
recognized in this study were treated as independent
events for the incidence estimates.
From 1750 through 1981 the sex- and age-adjustecl
annual incidences per 100,000 population for encephalitis and aseptic meningitis wete 7.4 and 10.9,
respectively.
With the exception of the passive reporting system
at the CDC, all the published studies of encephalitis
and aseptic meningitis in the United States have been
derived from hospital series El, 6-8, 10, 13-15, 1721,23, 25, 31). According to the CDC reports, during
the period 1771 through 1980, the incidence of encephalitis ranged from 0.08 to 0.25 cases per 1d0,OOO
population, with a peak in 1975, the year of an outbreak of St. Louis encephalitis, in which 1.1 cases per
100,000 were reported. In the same period the incidence of aseptic meningitis ranged from 1.5 to 4.0
cases per 100,000 [;if. Our rates are about twelve times
greater for encephalitis and about six times greater for
aseptic meningitis. Although the rate might be higher
in Rochester than nationally, this possibility is most
unlikely; a more plausible explanation is the serious
underreporting in the passive system at the CDC.
The estimated rates calculated from the CDC data
are entirely dependent on the voluntary reporting of
these diseases through the local and state health departments. It is well known that many infectious disorders
are markedly underreported. The CDC, in its report
171, states that “dissimilar rates may . . . reflect dissimilar reporting practices and emphasis on epidemiologic
and laboratory investigations” and that “these data
[from the national surveillance program) should be interpreted with caution.” Marier [22), in his study of
Beghi et al: Viral Encephalitis/Meningitis
289
40 T
c
1 1
I
1
-1
I
,i
I
- 11 1
01
56
50
60
62
64
66
68
70
72
74
76
70
00
Year
F i g 3. Annual distribution of cases of encephalitiJ, Olmsted
County, 1950 through 1981.
discharge records of eleven hospitals in Washington,
DC, noted that only 11% of cases of diagnosed viral
hepatitis were reported, and that other selected reportable diseases were reported from 32 to 63%) of the
time. H e cited a survey of physicians’ attitudes about
reporting that found that many physicians did not
know the requirements or refused to report for various
reasons. At the Mayo Clinic, policy dictates that physicians who have failed to report a case to the health
department be notified by the clinic’s Department of
Medical Statistics and Epidemiology at the time of coding and indexing and asked to report it. The intensity of
this monitoring and its success have varied over the
period of study. In the 1950s and 1960s, 615% of the
cases of encephalitis and 63% of the cases of aseptic
meningitis were reported to the health authorities. The
rate dropped after computerization of the indexing was
introduced in 1975; for the period 1976 through 1981,
only 18% of the cases of encephalitis and 14% of the
cases of aseptic meningitis were reported. At another
medical facility in the community, which may be more
representative of practice in the country as a whole,
cases were rarely reported to the CDC. Furthermore,
the CDC lists depend on whatever diagnostic criteria
different physicians may have applied to their cases;
although the major deficit is in reported cases, this does
not mean that all those that were reported would have
fulfilled the criteria that we used.
A study in Israel based on hospitalized patients with
viral illnesses of the CNS [ 3 I] identified 1,350 cases of
“aseptic meningoencephalitis” for the period 1969
through 1970, giving a mean annual incidence of 21.6
cases per 100,000 population (adjusted to the United
States population in 1770). The Israeli rate approxi290 Annals of Neurology
VoI 16 No 3
mates the combined rate of 18.3 for encephalitis and
aseptic meningitis in the Olmsted County population,
but the rates may not be strictly Comparable. First, the
specific disease components in the two populations
may differ. Also, the Olmsted County population is
relatively homogeneous, whereas the Israeli population
comprises four major ethnic groups with different cultural and socioeconomic characteristics. The highestrate, 24.9 cases per 100,000 person-years, was found
among Jewish immigrants from Europe and America
and the native-born whose fathers came from those
same countries. The lowest rate, 4.4, was noted in the
Arab population, presumably a result of underreport-.
ing. The proportion of cases involving coma, seizures,
and paralysis in the latter group was twice that in the
Jewish groups, and mortality was more than five times
as high in the Arab group. It is very likely that those
with milder cases in the Arab population were nor
brought to the hospital, and this could also explain why
the number of cases of CNS infection identified among
the Arabs did not show the summer peak that was
present among the cases identified in the Jewish
groups. A comparison between the rates in Israel and
in Olmsted County would have to take into account
differences in climate and environment that might affect vectors or vehicles. Furthermore, the survey in
Israel covers a limited 2-year period and does not
include nonhospitalized patients, whereas that in
Olmsted County covers a 32-year period and includes
nonhospitalized as well as hospitalized patients.
In an epidemiological survey conducted from 194’5
through 1963 in Helsinki, Finland, the incidence was
estimated to be 2 to 3 cases per 100,000 population for
encephalitis and the number of cases of aseptic menin-
September 1084
40T
1
35
I
4
30
50
52
54
56
50
60
62
64
66
68
70
72
74
76
70
00
Year
F i g 4. Annual distribution of cases of aseptic meningitis,
Olmsted County, 19JO through 1981.
gitis was ten times that of encephalitis { 14). The major
limitation of this study relates to the restriction of case
finding to patients hospitalized at a single hospital that
admits an unknown portion of the patients with encephalitis and aseptic meningitis from Helsinki and the
surrounding area.
In Olmsted County the two diseases have similar
patterns of age distribution and maintain a relatively
high incidence up to the age range of 30 to 39 years.
The diseases reach their peaks at different ages, however: 5 to 9 years for encephalitis and during infancy
for aseptic meningitis.
The temporal trends of encephalitis and aseptic meningitis in the population of Olmsted County are of interest. Although the incidence of encephalitis showed
little or no variation in the four time intervals considered (Fig 3), the incidence of aseptic meningitis evidenced some wider fluctuations. Figure 4 reveals only
a small number of cases in 1751 through 1953 and two
periods of especially high incidence, 1957 through
1958 and 1779 through 1981. These may indeed
reflect changes in the presence and virulence of the
viruses, particularly for the 1981 period, when the
number of cases was substantial, especially in infants.
The 1950s can be divided into the periods before
and after the development of the polio vaccine. In the
early 1950s there were epidemics of paralytic polio
throughout the United States, and such epidemics occurred in Olmsted County in 1952 and 1953. The
presence of epidemic polio was accompanied by a substantial increase in cases diagnosed as “nonparalytic
polio,” some of which might otherwise have been diagnosed as aseptic meningitis. With a substantial propor-
tion of the childhood population vaccinated after 1955,
nonbacterial meningitis is more likely to have been
regarded as aseptic meningitis, because the polio vaccine became widely regarded as effective as new cases
of paralytic polio virtually disappeared.
The outbreak of aseptic meningitis in 1981, caused
by an epidemic of enterovirus infections, unduly inflated the incidence for the entire period from 1976
through 1981. Thirty-six of the 101 cases of aseptic
meningitis identified in that 6-year period occurred in
1781, and 11 of these were in infants under 1 year of
age. Half of the 36 diagnoses were made in August,
and in 8 cases an enterovirus was established to be the
causative agent. For the 6-year period, only the rate for
those under 1 year of age was significantly increased in
relation to the preceding period (1770 through 1775),
and that increase was largely due to the 1981 outbreak
in infants.
A virus was identified in 15% of the cases of encephalitis and 11% of the cases of aseptic meningitis, a
proportion consistent with that in some series in the
literature {lo, 13-15, 21) but low when compared
with that in other series from laboratory-intensive studies, in which up to 73% of cases were confirmed viral
infections C19, 231.
One possible reason for the small proportion of
cases with a confirmed cause in our series is the different spectrum of severity of the illnesses. In the present
series patients for whom hospitalization was not required generally had milder disease. In many of the
hospitalized patients, detailed microbiological investigations and virus isolations were not regarded as essential to the diagnosis, particularly if the illness began to
Beghi et al: Viral EncephalitidMeningitis
291
improve quickly after admission or if a preceding childhood infection with the potential for encephalogenic
disease suggested a provisional causative agent and
thereby reduced the concern of the physician in making an immediate, intensive search for the responsible
virus. Also, the necessary repetition of the complement fixation or the hemagglutination inhibition tests
following the acute phase of the disease would be most
likely to be done for hospitalized patients with a prolonged and severe course.
The evolution of microbiological techniques over
the period of 32 years also strongly influenced the
frequency of virus detection. The introduction of
new tests (e.g., counterimmunoelectrophoresis) and
the willingness of physicians to make greater use of the
laboratory brought about remarkable progress in the
understanding of the causes of these diseases, even
though the rate of hospitalization has continuously
been decreasing (as discussed). In none of the cases of
encephalitis between 1950 and 1959 did laboratory
tests establish the specific cause. In 10 (14%) of the
cases from 1960 to 1969, there was evidence of a virus,
and there were 19 cases (23%) with specified cause
from 1970 through 1981. Among the cases of aseptic
meningitis, there were 3 (5%) in which a viral cause
was established in the 1950s (all were adults, 2 of
whom had clinical mumps), 6 (9%) in the 1960s, and
24 (15%) in the last period, 1970 through 1981.
Varicella, rubella, measles, or mumps occurred
about one week prior to the onset of the neurological
symptoms in 14% of the patients with encephalitis and
in 11% of those with aseptic meningitis. Respiratory
infections, gastrointestinal illnesses, and otitis were recorded in 28% of the patients with viral encephalitis
and in 24% of those with aseptic meningitis. These
findings constitute presumptive evidence that CNS invasion by virus was often preceded by involvement of
other tissues.
The relevance of antecedent diseases and events
must be evaluated carefully. Often the information was
available only on recall by parents or the patient, and
thus the estimation of frequency is subject to error,
especially for mild disorders. Furthermore, the significance of such an event as a possible cause of the
CNS infection depends on the nature of the suspected
event. Mumps is frequently known to precede or be
concurrent with aseptic meningitis; it is less frequently
associated with encephalitis. Measles, varicella, and
rubella viruses are more likely to induce a postinfectious encephalitis with evidence of lesions in the brain
parenchyma 1241.
After 1972 mumps was not recorded as an antecedent disease in Olmsted County cases, although
mumps virus was detected in a patient with encephalitis
in 1073. Measles was last recorded as an antecedent
event in 1965. Conversely, varicella preceded the on-
292 Annals of Neurology
set of encephalitis as recently as the last year of the
study. The rates for mumps and measles, as reported
by the CDC for the United States, decreased in the
decade 1971 through 1980, but varicella did not decrease in the same period [6}. Although the quantitative limitations of the CDC reporting system have been
noted, qualitatively there is a parallel between their
findings and ours that reflects the efficacy of immunization campaigns (started in the United States in 1963 for
measles and in 1967 for mumps). The different trend
manifested by varicella encephalitis in our population
stresses the need for an effective varicella immunization program.
The occurrence of other disorders or events before
the onset of neurological symptoms does not necessarily indicate a causal mechanism, even if in certain cases
one could be tempted to draw such an inference. For
example, a woman with herpes genitalis bore a child
who developed facial lesions and stomatitis; these conditions were followed by encephalitis. Herpes simplex
virus was isolated from the skin lesions, but culture and
tests of the CSF and serum were negative. A 5-yearold girl with diffuse gingivostomatitis due to herpes
simplex also developed encephalitis, but counterimmunoelectrophoresis was positive for California virus
and results of all other tests were negative. Although
herpes in other tissues suggests a cause if encephalitis
occurs, such a conclusion is not always justified.
An analogous situation occurred in a 6-year-old girl
who had received mumps vaccine five weeks prior to
the onset of encephalitis characterized by seizures,
paralysis, and coma. Complement fixation revealed a
fourfold increase in antibody titer against mumps virus,
as would be expected after vaccination, but the test also
revealed a 16-fold increase in the titer against California virus, consistent with a clinical course characteristic
of encephalitis caused by the California virus 14,111.
This case was not included in the findings reported in
Table 7, because vaccination preceded the onset of
encephalitis by more than four weeks. Similarly, in a 4year-old boy, oral polio and diphtheria-pertussistetanus (DPT) vaccinations were administered two
weeks before the onset of aseptic meningitis, yet the
only microorganism detected was California virus. Another intriguing case, which also emphasizes the issue
of the possible misdiagnosis of nonparalytic polio, was
that a 5-year-old boy who was immunized with the
Sabin vaccine in 1969 and one week later manifested a
clinical and laboratory picture of aseptic meningitis.
The CSF culture did not grow any virus, but polio virus
was isolated in both throat and stool cultures.
Vaccinations, particularly against smallpox and
rabies, have been cited as causes of central and peripheral nervous system disease C3, 18, 291. Other vaccines,
such as those against DPT, polio, and influenza, have
also been mentioned.
Vol 16 No 3 September 1984
In the present series 9 of the 472 patients had a
record of vaccination in the month prior to the illness,
and most of these immunizations were administered in
the previous week. In 5 cases various combinations of
DPT, smallpox, polio, tetanus, and typhoid vaccines
had been administered. Three of the 5 children were
under 1 year of age and had received DFT and polio
vaccine within one week prior to the onset of symptoms. Because the recommended schedule for these
vaccines is three times in the first fifty-two weeks of
life, by chance each child would have at least a 3 in 52,
or 6%, probability of developing an illness within one
week after the administration of the vaccine, assuming a one-week period of risk and that all children received the standard immunizations. In the present study
56 cases of encephalitis and aseptic meningitis were
identified in those under 1 year of age, and on review of
the present history for each case and the available immunization records, 3 of these patients were found to
have been immunized within the week preceding onset
of illness. The resulting proportion, 3 of 56 (5%),is
nearly identical to chance probability. If the identification
of immunization is complete in this age group, the study
suggests that vaccine-related CNS disease occurs no
more often than would be expected on a coincidental
basis. Extension of this type of study to other immunized
populations seems justified.
The potential link between swine influenza immunization and the occurrence of Guillain-BarrC syndrome
has been a matter of interest 1301; the association of the
vaccine and other inflammatory diseases of the peripheral and central nervous systems has been suggested on
an anecdotal basis, void of any sound epidemiological
support 128). In a recent review of the complications of
the vaccinations [9}, isolated reports of both central
and peripheral nervous system disease following swine influenza vaccination were noted, although the frequency
of occurrence was no greater than chance expectation.
Among the patients with aseptic meningitis included
in this study, one adult with a concurrent herpes stomatitis had a history of recent swine influenza vaccination.
In all, nearly 40,000 persons in Olmsted County (68%
of the adult population) received the vaccine during the
last three months of 1976. When we apply the incidence of aseptic meningitis in individuals over the age
of 17 years (7.14per 100,000 person-years) to the
vaccinated population, the number of cases that we
would expect, assuming the vaccination not to be a risk
factor, is 0.3 (95% confidence interval, 0.03 to 5.6) in
the six weeks immediately foilowing the immunization,
an estimate statistically consistent with the 1 case observed. Further, no change in the incidence of CNS
infections was observed during or soon after the vaccination period (see Figs 3 and 4), failing to support any
relationship between the swine influenza vaccine and
the onset of encephalitis or aseptic meningitis.
~
~~~~~
Supported in part by Research Grants NS-l6308A, NS-17750, and
AM-30582 from the National Institutes of Health, Bethesda, MD
20205; and by a Fellowship in Neuroepidemiology awarded to Dr
Beghi by the European Economic Communiry.
The authors acknowledge the assistance of Jim Wentz in developing
case rosters, Mary Beard for residence ascertainment and special
features analysis, Chu-Pin Chu for statistical assistance, Prof Wigbert
C. Wiederholt for his critical review of the manuscript, and Laura B.
Long for manuscript preparation.
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Vol 16 No 3 September 1984
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