Cognitive and Executive Function 12 Years after Childhood Bacterial Meningitis: Effect of Acute Neurologic Complications and Age of Onset

Cognitive and Executive Function 12 Years after Childhood

Bacterial Meningitis: Effect of Acute Neurologic

Complications and Age of Onset

Vicki Anderson,1,2 PHD, Peter Anderson,2 PHD, Keith Grimwood,3 MD, and

Terry Nolan,4 MBBS, PHD1,2Murdoch Children’s Research Institute, Melbourne, Australia, 3Department of Paediatrics and

Child Health, Wellington School of Medicine and Health Sciences, New Zealand, and4School of Population Health Unit, University of Melbourne, Australia

Objectives This study investigated long-term neurobehavioral outcome from childhood

bacterial meningitis, with particular focus on the influence of acute neurologic complications

and age at illness. Methods This prospective, longitudinal study compared survivors of

childhood bacterial meningitis (n 5 109) with grade- and gender-matched controls (n 5 96)

selected from the target children’s schools 12 years post-illness, in order to identify residual

deficits in intellectual, academic, and executive ability. Results Results showed that at 12

years post-illness, children with a history of meningitis were at greater risk of impairment in

each of these domains. However, development was shown to keep pace with that exhibited by

healthy controls, suggesting no deterioration in function with time since illness. While

prediagnosis symptom duration and acute neurologic complications were not predictors of

12-year outcome, meningitis before 12 months of age was significantly related to poorer

performance on tasks requiring language and executive skills. Conclusions These findings

suggest that while the overall impact of meningitis may be relatively general and mild, younger

age at illness is predictive of neurobehavioral outcome. There was no evidence of progressive

deterioration postmeningitis, with comparison of results from 7 to 12 years post-illness

demonstrating significant ‘‘catch-up’’ in aspects of executive function.

Key words childhood meningitis; executive function; cognitive ability.

Bacterial meningitis is a severe and potentially life-

threatening illness most commonly affecting infants and

young children (Davies & Rudd, 1994; Feigin &

Pearlman, 1998). Before antibiotics, survival rates were

less than 10%. Antibiotic treatments, combined with

improved critical care management, have led to a dra-

matic increase in these survival rates. More recently,

Haemophilus influenzae type b (Hib) meningitis immu-

nizations have virtually eliminated this pathogen from

North America, northern Europe, Australia, and New

Zealand (Peltola, Kilpi, & Anttila, 1992; Robbins,

Schneerson, Anderson, & Smith, 1996). The recent

licensing of a conjugated pneumococcal vaccine may

have a similar impact upon the numbers of children with

pneumococcal meningitis (Whitney, 2002). Neverthe-

less, recurring epidemics of meningococcal disease,

antibiotic resistance, and failure of vaccines to reach

many developing countries means that bacterial menin-

gitis remains a serious world health issue (Booy & Kroll,

1998; Schuchat, Robinson, & Wenger, 1997).

All correspondence concerning this article should be addressed to Vicki Anderson, PhD, Department of Psychology,University of Melbourne, Victoria 3010, Australia. E-mail: [email protected].

Journal of Pediatric Psychology 29(2) pp. 67–81, 2004DOI: 10.1093/jpepsy/jsh011

Journal of Pediatric Psychology vol. 29 no. 2 Q Society of Pediatric Psychology 2004; all rights reserved

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Bacterial meningitis results from invasion of the

central nervous system (CNS) by bacteria which over-

come the host defense mechanisms, causing disruption

to cerebrovascular and cerebrospinal fluid dynamics. By

the time of diagnosis, cerebral vasculitis may be

developing, associated with vascular occlusion, cranial

nerve inflammation, and hypoxic injury from regional

alterations of cerebral perfusion. Biochemical changes

also occur, and can result in focal and diffuse cortical

insults (Dodge & Schwartz, 1965). Decreased concen-

tration of glucose in cerebrospinal fluid (in association

with cerebrovascular disruption), cellular electrolyte

imbalance, and inappropriate secretion of antidiuretic

hormone accompany meningitis and have been docu-

mented as risk factors for residual impairments (Feigin&

Pearlman, 1998; Taylor et al., 1990). Morbidity and

mortality result from compression and herniation of

cerebral tissue or focal ischemia, caused by altered

cerebral blood flow (Anderson et al., 1997; Herson &

Todd, 1977; Klein, Feigin, & McCracken, 1986; Snyder,

Stovring, Cushing, Davis, & Hardy, 1981; Stovring &

Snyder, 1980).

Cerebral pathology and clinical symptoms are

mostly transient and subside within weeks for most

children surviving meningitis (Feigin & Pearlman, 1998;

Vienny et al., 1984). However, for some the impact of

these disruptions is fatal or leads to severe residual

impairment, including sensorineural hearing loss and

other cranial nerve dysfunction, seizure disorders,

hemiplegia, ataxia, hydrocephalus, and visual problems

(Claesson, Trollfors, Jodol, & Rosenhall, 1984; Dodge et

al., 1984; Feldman et al., 1982; Jadavji, Biggar, Gold, &

Prober, 1986; Klein et al., 1986; Stovring & Snyder,

1980; Thomas & Hopkins, 1972). In a meta-analysis

involving 19 prospective studies and a total of 1602

children, Baraff, Lee, and Schriger (1993) reported that

4.5% of children died in the acute stages of illness, with

16.4 % of survivors displaying at least one major adverse

outcome (deafness, intellectual disability, epilepsy,

physical impairment).

Neurobehavioral sequelae have been identified in

many survivors; however, the reported frequency and

nature of deficits varies across studies. Some early

researchers documented pervasive impairments in

cognitive functions and academic achievement in post-

meningitis subjects (Kresky, Buchbinder, & Greenberg,

1962; Sell, Merrill, Doyne, & Zimsky, 1972; Sell, Webb,

Pate, & Doyne, 1972; Sproles, Azerrad, Williamson, &

Merrill, 1969). Other, more recent reports document

a favorable disease prognosis, possibly reflecting

improvements in medical care in later studies, or more

representative sampling techniques (Feldman & Mi-

chaels, 1988; Fellick et al., 2001;Taylor et al., 1990).

Subtle deficits in visuomotor coordination, auditory

perception, and language functions are also reported.

Our own study (Anderson et al., 1997) showed that, 7

years post-illness, survivors performed more poorly

than peers with respect to intellectual functions,

particularly verbal ability, motor skills, and educational

progress.

Deficits in executive skills, including attentional

control, planning, and reasoning, have rarely been

assessed, with such skills argued to be immature and

difficult to access in young children (Anderson, 1998).

Recent research suggests that executive impairments

may be common following early brain insult, due to their

developing status and the immature state of associated

brain regions (Dennis, Barnes, Donnelly, Wilkinson, &

Humphreys, 1996; Levin et al., 1991) at time of illness.

Such impairments often escape detection in early child-

hood, becoming apparent only when children are older

and are required to think and reason independently

(Grimwood, Anderson, Anderson, Tan, & Nolan, 2000).

The critical importance of these executive skills for

normal development, and their potential vulnerability

during infancy and early childhood (Anderson & Taylor,

1999; Anderson, Northam, Hendy, & Wrennall, 2001),

suggests that they should be carefully evaluated in

meningitis survivors.

Few studies have addressed specific risk factors or

long-term consequences of childhood bacterial menin-

gitis. Taylor and colleagues (1990) followed 97 Hib

meningitis survivors and found that acute neurologic

complications were predictive of poorer school perfor-

mance and increased behavioral disturbance. Similar

results have been suggested by other researchers (Grim-

wood et al., 1995; Emmett, Jeffery, Chandler, &

Dugdale, 1980), indicating that the more severe the

brain insult, the greater the impact on cognition and

behavior.

Age at illness has also been proposed as a predictor

of outcome. Bacterial meningitis provides a unique

opportunity to study the effects of early neurologic

insults in children who are neurologically normal prior

to disease onset. Follow-up of disease survivors allows

researchers to test hypotheses regarding neural plastic-

ity, to study the relative contributions of biologic and

environmental influences on outcomes, and to explore

the significance of transient neurologic abnormalities for

later development. Recent research has emphasized the

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vulnerability of the immature CNS to generalized insult,

such as cerebral infection, with a number of studies

reporting substantial and permanent deficits in neuro-

behavioral function following such events (Anderson &

Moore, 1995; Ewing-Cobbs, Miner, Fletcher, & Levin,

1989). Further, Bedford et al. (2001) have recently

reported on a questionnaire survey of 1717 children,

aged 5 years, who had suffered meningitis in infancy.

They demonstrated a 10-fold increase in risk for severe

or moderate disabilities at age 5, compared with children

from a healthy control group. Disabilities extended

across health, developmental, and behavioral domains,

but with greatest deficits in neuromotor function,

memory, and learning. They noted that most severe

impairment was observed where illness occurred in the

first month of life.

Previously, our group (Anderson et al., 1997;

Grimwood et al., 1995, 1996) reported a prospective,

7-year follow-up study of 130 school-aged survivors

(mean age 5 8.4 years) and age-matched controls.

Delays in diagnosis, acute neurologic complications, and

illness before age 12 months were identified as risks

contributing to poorer outcome. Results showed that

children with a history of bacterial meningitis, while

generally achieving results within the normal range,

performed more poorly than age-matched controls in

a number of domains including general intelligence,

academic ability, memory, and language. While there

was a suggestion of impaired higher-order cognitive

skills, the age of the cohort at time of assessment

precluded detailed assessment of these skills.

The present study aimed to reevaluate this cohort

12 years postmeningitis, with the assumption that

cognitive and cerebral development would be largely

complete by this age. We were interested in de-

termining the presence and nature of any persisting

deficits which would reflect permanent impairment or,

alternatively, delayed skill acquisition and the role of

acute neurologic complications and age at illness on

outcome. Further, the older age of the cohort enabled

additional testing of executive skills, including atten-

tional control, goal setting, and concept formation/

abstraction. We predicted that children with meningitis

would exhibit deficits in these skills, with impairments

being greater when risk factors of early illness and

neurologic complications were present. Finally, we

hypothesized that since the previous evaluation, exec-

utive functions would have demonstrated slower de-

velopment in meningitis survivors than in healthy

controls.

MethodParticipants

A prospective cohort of all children aged between 3

months and 14 years admitted to the Royal Children’s

Hospital (RCH), Melbourne, with bacterial meningitis

was established during a 3-year period from October

1983 to October 1986. The diagnosis of bacterial

meningitis was determined by lumbar puncture and

identification of bacteria from cerebrospinal fluid. All

children received a standardized treatment protocol,

including penicillin and chloramphenicol until the

pathogen was identified, whereupon a single antibiotic

was administered according to susceptibility testing.

Fluid restriction was enforced for the first 24–48 hours

postadmission. Steroids were not routinely administered.

One hundred and eighty-one children were initially

enrolled in the study. Children with documented

preexisting neurologic and developmental deficits, im-

munodeficiency states, previous CNS surgery, or menin-

gitis secondary to cranial trauma or shunt infections (n5

15) were later excluded. Eight children died during the

course of their illness, leaving a sample of 158 survivors.

The median age at illness was 18 months (range 5 3

months to 14 years), and 60 children (38%) suffered their

illness before 12 months of age.

A 7-year follow-up assessment was conducted

between 1991 and 1993, and 130 (82%) of the original

158 survivors were evaluated. The remaining 28 cases

were unable to be found (n 5 26), refused to participate

(n 5 1), or had died from unrelated causes (n 5 1). A

comparison group (n 5 130) was also introduced into

the study at this time point. Grade- and sex-matched

controls were recruited from the classroom of each child

with meningitis by selecting the next same-sex student

on the class roll. Where parents refused permission to

approach the school (n 5 1), a control was selected in

a similar fashion from a neighboring school to ensure

equivalent socioeconomic background. For meningitis

survivors attending special schools for disabled children

(n 5 7), controls were recruited from another school in

the same region. Children included in the comparison

group had no previous history of meningitis. Results

from this follow-up have been previously reported

(Anderson et al., 1997; Grimwood et al., 1995, 1996).

During 1996 and 1997 children who had partici-

pated in the 7-year follow-up study were again

approached to participate in the present study. At this

12-year review, 109 children postmeningitis (84% of

the 7-year study, 69% of the original cohort) were

Neurobehavioral Outcomes Following Meningitis 69

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reassessed, at a mean of 11.5 (SD 5 0.9) years post-

illness. Of the remainder, 9 had moved out of state, 11

were unable to be contacted, and 1 declined to

participate. For controls, 96 (74%) were reevaluated,

with 5 having moved, 24 unable to be contacted, and 5

declining to participate. The age range of the follow-up

sample was 10–18 years (M 5 12.7, SD 5 1.6). The

demographic and clinical characteristics of the sample

are provided in Tables 1 and 2.

No statistically significant differences were found

between the follow-up sample and the group lost to

follow-up on any of the demographic variables, medical

measures, or full-scale IQ.

Measures

Socioeconomic Status (SES)

SES characteristics at the time of assessment were

measured using two variables: highest level of education

attained by the mother and occupational status. Occu-

pational status was coded using the Daniel Scale of

Occupational Prestige (Daniel, 1983). This scale is

continuous, with a minimum rating of 1 (high prestige)

and a maximum rating of 7 (low prestige). The highest-

ranking parental occupation was used. Ethnicity was

also noted, with language other than English spoken at

home as the marker.

Illness Variables

A prospective questionnaire for presenting history,

examination findings, laboratory and treatment details,

and clinical course was completed during hospitalization

and at the discharge neurologic examination. Several

neurologic variables were investigated as possible risk

factors for long-term outcome. These were based on

findings from previous research (Grimwood et al., 1996;

Herson & Todd, 1977) and included seizures, obtunda-

tion or coma, hydrocephalus, hemiparesis, persistent

hypotonia, visual loss, ataxia, and sensorineural deaf-

ness. Age at illness was dichotomized (� 12, . 12

months of age), in accordance with literature suggesting

a period of brain plasticity within the first 12 months of

life (Dennis, 1980; Kolb, Gibb, & Gorny, 2000; Woods

& Carey, 1979).

Severity Index

A severity rating system (Pentland, Anderson, &

Wrennall, 2000) was developed and a score was derived

for each child in the meningitis sample, following similar

guidelines to those employed by Herson and Todd

(1977). The rating score was determined from the

standardized treatment and recovery protocols em-

ployed during each child’s hospital admission. A

weighted value was assigned to each acute complication,

which Grimwood et al. (1996) had identified as being

associated with adverse outcome, based on the strength

of predictive power. The overall severity rating repre-

sented the sum of these weighted scores. This scoring

procedure is shown in Table 3.

General Performance Variables

Intellectual and academic measures were administered

to provide a detailed description of the cognitive

functioning of the sample.

Wechsler Intelligence Scale for Children–III (WISC-III;

Wechsler, 1992) was administered to all children 16

years and younger. Children aged 17 and 18 years (n 5

7) were administered the Weschler Adult Intelligence

Scale–III. The Full Scale Intellectual Quotient (FSIQ)

was used to measure general intelligence, while three

index scores (verbal comprehension [VC], perceptual

Table I. Demographics of 12-Year Follow-Up Sample

Meningitis

Group

(N = 109)

Controls

(N = 96)

Males, n (%) 60 (55) 51 (53)

Age at testing, years, M (SD) 12.7 (1.6) 13.0 (1.7)

Socioeconomic status,a M (SD) 4.4 (1.3) 4.1 (1.1)

Non-English-speaking households, n (%) 7 (6.4) 2 (2.1)

Maternal education—tertiary, n (%) 32 (29) 34 (35)

No significant differences.a Daniel (1983).

Table II. Clinical Characteristics of Meningitis Sample

Characteristics

Meningitis

(N = 109)

Age at admission (months)

Median (range) 17.0 (3–79)

Age � 12 months, n (%) 40 (37)

Pathogen, n (%)

Haemophilus influenzae type b 85 (78)

Staphylococcus pneumoniae 12 (11)

Neisseria meningitidis 6 (5.5)

Other 6 (5.5)

Complications, n (%)

Prediagnosis symptom duration . 72 hours 18 (17)

Seizures 34 (31)

Focal neurologic signs 7 (6)

Return to normal conscious state . 72 hours 41 (38)

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organization [PO], and freedom from distractibility)

were utilized to assess more specific cognitive domains.

Each score had a mean of 100 and a standard deviation

of 15.

Wide Range Achievement Test–3 (Wilkinson, 1993). This

test provides measures of reading (word decoding),

spelling, and arithmetic ability. Scores are age standard-

ized with a mean of 100 and a standard deviation of 15.

Executive Function Measures

Measures of executive function were chosen based on

the following criteria: (1) adequate normative data for

the age group under investigation, (2) appropriateness of

the measure to the age group, (3) availability of

reliability/validity data, and (4) documentation of the

measure to evaluate aspects of executive function under

examination.

Attentional Control

� Code Transmission Test (Manly, Robertson,

Anderson, & Nimmo-Smith, 1999). This is

a measure of auditory sustained attention normed

for children 6–16 years. Children listen to a tape

recording consisting of a recitation of 360 digits

(40 targets) presented at regular intervals. The

tasks are to identify when two 5s occur together

and to respond with the digit which preceded the

two 5s on the tape. Performance measures include

the total number of correctly identified targets

(Codes–total correct) and number of errors

(Codes–total errors).

� Contingency Naming Test (CNT; Anderson,

Anderson, Northam, & Taylor, 2000; Taylor et

al., 1990). This task taps cognitive flexibility and

is normed for children 6–16 years. It includes four

subtests, each of increasing difficulty. The child is

presented with a card on which are printed three

rows of shapes of different colors (pink, blue, or

green). Within each ‘‘outside’’ shape, a second,

‘‘inside’’ shape is drawn. Above some of the

stimuli, a reverse arrow is drawn. For subtest 1,

the child is required to name the color of each

stimulus, while for the second subtest the aim is

to name the outside shapes. The third and fourth

subtests involve a ‘‘shift’’ in attention. For Trial 3,

the child is provided with two rules to determine

the correct response. If both the inside shape

and the outside shape are the same, the child must

name the color of the stimulus. If the inside and

outside shapes are different, the correct response

is the name of the outside shape. On the fourth

subtest, the child is instructed to follow the same

rules as for Trial 3, except when there is a reverse

arrow above the stimulus. Where an arrow is

present, the child is directed to reverse the rules

from Trial 3 (i.e., where the shapes are the same,

the correct response is the shape of the stimulus).

Completion times in seconds (CNT-time) and

errors (CNT-errors) were recorded.

Goal Setting

� Tower of London (TOL; Shallice, 1982;

Anderson, Anderson, & Lajoie, 1996). This

nonverbal task measures problem-solving ability.

It makes use of three colored balls, which can be

placed onto three pegs of different heights.

Children are required to match a pattern,

presented on a stimulus card, in a prescribed

number of moves while adhering to a number of

specified rules. There are a total of 12 problems. If

a child fails to complete an item correctly, balls

are replaced in their original configurations and

the child has the opportunity to try again, within

a time limit of 60 seconds. Administration and

scoring were according to Anderson et al. (1996)

and generated the following measures: number of

items correct (TOL–trials correct), number of

failed attempts (TOL–extra attempts), and total

time to completion (TOL–time).

� Complex Figure of Rey (CFR; Rey, 1964). This

visually based task assesses planning and

organizational abilities. Children are asked to

copy a complex geometric design using a series of

color pencils, the order of which was noted.

Table III. Severity Rating System

Complication Points

Clinical course

Prediagnosis symptom duration . 24 hours 1

Focal neurologic signs 1

Tertiary referral 2

Failure to return to normal consciousness

within 72 hours 2

Seizures in hospital 3

Seizures .72 hours after admission 3

Deterioration of consciousness in hospital 3

Laboratory parameters

Staphylococcus pneumoniae 2

Cerebro spinal fluid leukocytes , 1000/mm3 2

Serum sodium , 130 mEq/L 2

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Accuracy (CFR-accuracy) was scored according

to Lezak (1993). An organizational strategy score

(CFR-strategy) was derived (Anderson,

Anderson, &Garth, 2001) and provided a strategy

rating between 1 (unrecognizable) and 7

(excellent organization).

Concept Formation/Abstraction

� The Controlled Oral Word Association Test

(COWAT; adapted from Gaddes & Crockett,

1975; Anderson, Lajoie, & Bell, 1995) assesses

verbal fluency/concept formation. Children are

asked to generate words according to a particular

letter category. They are instructed that they have

60 seconds to think of all the words they can

beginning with each letter, are not to use words

beginning with capital letters (e.g., people’s

names), and must say different words every time.

Three trials are administered (F, A, and S).

Number of words generated (COWAT–total

words) and errors/rule breaks (COWAT–total

errors) were recorded.

� Twenty Questions Test (TQT; Mosher &

Hornsby, 1966; Garth, Anderson, & Wrennall,

1997). This task assesses abstract thinking.

Children are presented with a sheet of 42 color

pictures and are told that the examiner is thinking

of one of the pictures. The child must identify the

target by asking up to 20 questions which each

have a yes or no answer. Each child is given five

trials with a different target item for each trial.

Questions are categorized as ‘‘constraint seeking’’

(eliminating two or more alternatives),

‘‘hypothesis seeking’’ (referring to a single picture

only), or ‘‘pseudo-constraint seeking’’ (similar to

a hypothesis-seeking question in that it refers to

only one picture, but it is phrased like

a constraint-seeking question). Measures

included: number of trials solved (TQT–trials

solved), proportion of constraint seeking

(TQT-constraint seeking), and total time for

the five trials (TQT–total time).

� Making Inferences (Wiig & Secord, 1989). This

test assesses higher-order receptive language

skills. Two statements, segments of a short story,

are read aloud by the examiner and printed on

a card placed in front of the child. Four options

are read to the child, who selects the two options

that best explain the story. The test consists of 12

items, for each of which 3 points are awarded

when two plausible inferences are identified, 1

point if only one plausible inference is identified.

The total score is the sum of the points for the 12

items (Making Inferences–total score).

Procedure

Approval for the study was obtained from the RCH ethics

committee, and enrollment in the study was by written

parental consent. Children were evaluated from 1996 to

1997. Examiners were blinded to the medical history of

the children. In addition to neuropsychologic evalua-

tion, all children underwent physical, neurologic, and

audiologic investigation, in fixed order. Assessments

were all performed on the same day, with short breaks

between sessions to avoid fatigue.

Neuropsychologic assessment took place over three

1-hour sessions. The WISC-III was administered in the

first session, with the remainder of the tasks adminis-

tered in set order during the second and third sessions.

Two children in the meningitis group did not

complete testing, due to severe intellectual and physical

disability. These children did not contribute to the

group results for general performance or executive

function measures.

Development of intellectual, educational, and execu-

tive functions was examined by comparing results from

data at the 7-year follow-up (Grimwood et al., 1995) with

the current results of FSIQ scores and the two measures

common to both protocols, COWAT and CFR.

Data Analysis

Data comparisons were performed using SPSS for

Windows, version 11.0.0. (SPSS Inc., Chicago, Illinois).

Gender and SES at testing were treated as covariates for

all univariate analyses of covariance (ANCOVA) and

multivariate analyses of covariance (MANCOVA). Age at

testing was also used as a covariate when age-standard-

ized scores were not available. For MANCOVA analyses,

p , .05 was considered statistically significant; how-

ever, for ANCOVA analyses, p , .01 was reported as

statistically significant to allow formultiple comparisons.

Between-Group Analyses (Meningitis

versus Controls)

ANCOVAs were performed to examine the group

difference for FSIQ. Separate MANCOVAs were used

to assess the group differences for the WISC-III index

scores and academic achievement. MANCOVAs were

also performed to determine group differences for the

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executive domains, namely attentional control, goal

setting, and concept formation.

Medical Predictors

Two-way multivariate and univariate analyses were

undertaken to examine the impact of neurologic

complications. Neurologic complications included sei-

zures, obtundation or coma, hydrocephalus, hemiparesis,

persistent hypotonia, visual loss, ataxia, and sensorineu-

ral deafness. Further examination of the impact of ill-

ness severity was conducting using correlations of the

severity rating and test scores within the meningitis

survivor group.

To assess the impact of age at illness, the meningitis

sample was divided into children experiencing menin-

gitis before 12 months of age (n 5 38) and after 12

months of age (n 5 69). In this study, age at illness is

confounded by age at testing; that is, the early age at

illness group is significantly younger (M 5 11.6, SE 5

0.1) than the later age at illness group (M 5 13.4, SE 5

0.2). Given the relationship between age at testing and

age at illness, it was inappropriate to covary for age at

testing when examining the contribution of this risk

factor. To overcome this problem, we compared the two

age-at-illness groups with age-matched controls and

examined the Group (meningitis vs. control) 3 Age at

Illness (� 12 months, . 12 months) interaction.

Longitudinal Analyses

Finally, repeated-measures ANCOVAs were employed to

investigate changes in performance for cognitive vari-

ables that were available for both the 7- and 12-year

follow-up (FSIQ, COWAT–total words, COWAT–total

errors, and CFR–accuracy).

ResultsMeningitis versus Controls

General Performance

Data for intellectual and academic measures are pre-

sented in Table 4. While mean scores for the meningitis

group were consistently within the average range, the

group tended to perform more poorly than healthy

controls on all measures. Mean FSIQ for the meningitis

group was significantly below that of the control group,

F(1, 199) 5 6.83, p 5 .01. A significant ‘‘group’’ main

effect was identified for the WISC-III index scores

(Pillai’s 5 .041, p , .05), with univariate analyses

revealing that the meningitis group performed signifi-

cantly more poorly than controls on VC, F(1, 194) 5

6.89, p, .01. The meningitis group also tended to score

below controls on perceptual organization, although this

group difference failed to reach statistical significance,

F(1, 194)5 4.86, p5 .03. The MANCOVA for academic

achievement revealed a significant ‘‘group’’ main effect

(Pillai’s 5 .049, p 5 .02), and univariate analyses found

significant group differences in reading, F(1, 198) 5

7.38, p , .01, and spelling, F(1, 199) 5 10.06, p , .01.

Twenty-nine (27%) of the meningitis group required

special educational assistance, while only 12 (12.5%)

controls needed such additional support, x2(1) 5 6.52,

p 5 .011.

Executive Functions

MANCOVAs identified significant ‘‘group’’ main effects

for goal setting (Pillai’s 5 0.076, p , .01) and concept

formation/abstraction (Pillai’s 5 0.091, p , .01), while

no group difference was found for attentional control

(Pillai’s 5 0.016, p . .05). In goal setting, univariate

Table IV. Intellectual and Academic Achievement

Adjusted Meansa

Meningitis (n = 107),b

Mean (SE )

Controls (n = 96),

Mean (SE )

Mean

Difference 95% CI p Value

Intellectual ability

Full Scale IQ 97.2 (1.1) 101.6 (1.2) 4.3 1.1–7.6 .010

Verbal comprehension 95.0 (1.1) 99.4 (1.2) 4.3 1.1–7.6 .009

Perceptual organization 99.4 (1.3) 103.6 (1.4) 4.1 0.4–7.9 .029

Freedom from distractibility 97.7 (1.4) 99.7 (1.5) 2.0 �2.0 to 6.0 .323

Academic ability

Reading 99.0 (1.3) 104.3 (1.4) 5.2 1.4–9.1 .007

Spelling 95.4 (1.3) 101.3 (1.3) 5.9 2.2–9.5 .002

Arithmetic 95.0 (1.2) 97.4 (1.2) 2.5 �0.9 to 5.8 .146

a Group means adjusted for gender, and socioeconomic status.b Two postmeningitis children were unable to complete these tests.

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analyses revealed that the meningitis group was less

accurate than controls when copying, CFR-accuracy:F(1,

198) 5 8.70, p 5 .004, and its organizational strategies

were less efficient, CFR-strategy: F(1, 198) 5 8.46, p 5

.004. Although the group difference failed to reach

significance, the meningitis group tended to be less

planful on theTOLandmademore errors than the control

group, TOL-extra attempts: F(1,198)5 5.40, p, .05). In

concept formation/abstraction, the meningitis group

tended to score lower than controls across all variables,

butMakingInferenceswastheonlyvariable toreachstatis-

tical significance, F(1, 198)5 9.67, p, .01 (see Table 5).

Medical Predictors

Acute Neurologic Complications

Meningitis survivors with complicated (n 5 47) and

uncomplicated (n 5 60) illness histories were compared

on the general performance and executive function

domains. There were no group differences with respect

to age and SES. The complications group did not differ in

terms of FSIQ, F(1, 100) 5 2.31, p . .05), while the

complications main effects for the WISC-III index scores

(Pillai’s 5 0.032, p . .05) and academic achievement

(Pillai’s 5 0.037, p ..05) were not significant. Although

no group differences were observed, the complications

group scored lower than the no-complications group on

all intellectual and academic variables. The complica-

tions main effects for attentional control (Pillai’s 5

0.021, p . .05), goal setting (Pillai’s 5 0.036, p . .05),

and concept formation/abstraction (Pillai’s 5 0.038, p.

.05) failed to reach significance.

Further analysis of the impact of complications was

conducted using the severity rating score, described in

Table 3. In keeping with ANCOVA results, correlations

between the severity rating score and executive function

measures detected no statistically significant relationship

and no consistent trends for the complications group to

perform more poorly than the no-complications group.

Age at Illness

The two meningitis age-at-illness groups (� 12 months,

. 12 months) were similar with respect to presence of

acute neurologic complications, including abnormal

neurologic signs, duration of prediagnostic symptoms,

seizures, or coma. When compared with age-matched

controls, children in the early age at illness group

exhibited significant neuropsychologic deficits, while

children in the late age at illness group performed

Table V. Comparison of Executive Function Performances for Meningitis and Control Groups

Adjusted Meansa

Meningitis (n = 107),b

Mean (SE )

Controls (n = 96),

Mean (SE )

Mean

Difference 95% CI p Value

Attentional control

Codes–total correct 37.1 (0.3) 37.7 (0.3) 0.6 �0.2 to 1.5 .136

Codes–total errors 3.5 (0.4) 2.5 (0.5) �1.0 �2.2 to 0.2 .116

CNT–time 149.1 (2.8) 143.4 (2.9) �5.7 �13.7 to 2.3 .163

CNT–errors 2.6 (0.3) 2.5 (0.3) �0.1 �1.0 to 0.8 .830

Goal setting

TOL–trials correct 11.0 (1.0) 11.2 (1.0) 0.2 �0.1 to 0.5 .189

TOL–extra attempts 6.8 (0.3) 5.9 (0.3) �1.0 �1.8 to �0.1 .021

TOL–time 247.6 (6.4) 229.6 (6.8) �18.0 �36.5 to 0.6 .057

CFR–accuracy 31.7 (0.3) 33.1 (0.3) 1.4 0.5 to 2.3 .004

CFR–strategy 4.7 (0.1) 5.1 (0.1) 0.4 0.1 to 0.7 .004

Concept formation/abstractions

COWAT–total words 25.8 (0.8) 28.1 (0.9) 2.3 �0.1 to 4.6 .060

COWAT–total errors 1.1 (0.1) 0.8 (0.1) �0.3 �0.7 to 0.1 .115

TQT–trials solved 4.4 (0.1) 4.5 (0.1) 0.2 0.0 to 0.4 .130

TQT–constraint-seek Qs 30.3 (0.8) 32.6 (0.8) 2.3 0.0 to 4.6 .046

TQT–total time 534.1 (23.3) 515.2 (24.7) �18.8 �86.2 to 48.5 .582

Making Inferences–total score 26.6 (0.5) 28.8 (0.5) 2.2 0.8 to 3.6 .002

Codes = Code Transmission Test; CNT = Contingency Naming Test; TOL = Tower of London; CFR = Complex Figure of Rey; COWAT = Controlled Oral Word

Association Test; TQT = Twenty Questions Test.a Group means adjusted for age, gender, and socioeconomic status.b Two postmeningitis children were unable to complete these tests.

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similarly to age-matched peers (see Table 6). The Group

3Age at Illness interaction was significant for FSIQ, F(1,

197) 5 5.21, p , .05, with children in the early age at

illness group scoring significantly below age peers. The

MANCOVA for the WISC-III index scores failed to reach

significance (Pillai’s 5 0.028, p . .05), although the

early age at illness group tended to perform below age-

matched controls on VC, F(1, 192)5 5.25, p, .05). The

MANCOVA for academic achievement revealed a signif-

icant Group3Age at Illness interaction (Pillai’s5 0.066,

p, .01). The early age at illness group performed below

age-matched controls in the reading domain (F(1, 196)5

12.47, p 5.001), and tended to score below peers in the

spelling domain, F(1, 197) 5 4.85, p ,.05. For each

executive function domain, the Group 3 Age at Illness

interaction was significant: attentional control (Pillai’s5

0.049, p 5 .05), goal setting (Pillai’s 5 0.060, p , .05),

concept formation/abstraction (Pillai’s 5 0.101, p ,

.01). Children in the early age at illness group made more

errors on the Code Transmission Test, needed more time

on the CNT, required more attempts on the TOL, were

less accurate on the CFR, generated fewer words on the

COWAT, and displayed poorer listening comprehension

(Making Inferences).

Longitudinal Comparison

Repeated-measures ANCOVAs (7- and 12-year follow-

up) were conducted for FSIQ, CFR, and COWAT to

examine developmental trajectories in intellectual and

executive function, respectively, using scores from the

Table VI. Age at Illness and Neuropsychological Functioning Following Bacterial Meningitis

Age at Illnessa

< 12 months (n = 38)

Mean (95% CI)

Matched controls (n = 31)

Mean (95% CI)

> 12 months (n = 69)

Mean (95% CI)

Matched controls (n = 65)

Mean (95% CI)

Intellectual ability

Full Scale IQ 95.3 (91.6, 99.0) 04.9 (100.7, 109.0) 98.3 (95.5, 101.1) 100.0 (97.1, 102.8)

Verbal comprehension 92.4 (88.7, 96.0) 101.8 (97.8, 105.9) 96.5 (93.7, 99.3) 98.1 (95.2, 101.0)

Perceptual organization 99.0 (94.8, 103.2) 106.7 (102.0, 111.3) 99.7 (96.5, 102.9) 102.1 (98.8, 105.3)

Freedom from distractibility 97.7 (93.2, 102.1) 103.5 (98.5, 108.5) 97.8 (94.4, 101.2) 97.9 (94.4, 101.4)

Academic ability

Reading 94.4 (90.1, 98.7) 108.9 (104.2, 113.6) 101.5 (98.4, 104.7) 102.0 (98.8, 105.3)

Spelling 93.9 (89.8, 98.0) 105.4 (100.8, 110.0) 96.3 (93.2, 99.4) 99.4 (96.2, 102.5)

Arithmetic 97.2 (93.5, 100.9) 101.2 (97.0, 105.4) 93.7 (90.9, 96.5) 95.7 (92.8, 98.5)

Attentional control

Codes–total correct 35.4 (34.4, 36.3) 37.7 (36.7, 38.8) 37.9 (37.2, 38.6) 37.8 (37.1, 38.6)

Codes–total errors 5.4 (4.0, 6.8) 2.5 (1.5, 3.6) 2.3 (0.8, 3.9) 2.5 (1.5, 3.6)

CNT–time (seconds) 167.9 (158.3, 177.5) 147.3 (136.7, 157.9) 140.4 (133.4, 147.5) 139.9 (132.6, 147.2)

CNT–errors 3.1 (2.1, 4.1) 2.6 (1.5, 3.7) 2.3 (1.6, 3.0) 2.4 (1.6, 3.1)

Goal setting

TOL–trials correct 10.7 (10.4, 11.0) 11.3 (11.0, 11.7) 11.1 (10.9, 11.4) 11.1 (10.9, 11.4)

TOL–extra attempts 7.8 (6.8, 8.7) 5.6 (4.5, 6.6) 6.4 (5.7, 7.1) 5.9 (5.2, 6.6)

TOL–time 264.4 (243.1, 285.7) 226.1 (202.4, 249.9) 239.8 (223.9, 255.7) 229.6 (213.3, 246.0)

CFR–accuracy 29.4 (28.4, 30.5) 32.7 (31.5, 33.9) 32.8 (32.0, 33.6) 33.4 (32.6, 34.2)

CFR–strategy 4.3 (4.0, 4.7) 4.8 (4.5, 5.2) 4.9 (4.6, 5.1) 5.3 (5.0, 5.5)

Concept formation/abstract

COWAT–total words 22.1 (19.5, 24.8) 29.2 (26.3, 32.1) 27.7 (25.7, 29.7) 27.7 (25.7, 29.8)

COWAT–total errors 1.3 (0.9, 1.7) 0.7 (0.3, 1.2) 1.0 (0.7, 1.3) 0.8 (0.5, 1.1)

TQT–trials solved 6.3 (5.8, 6.8) 5.8 (5.2, 6.4) 5.9 (5.5, 6.3) 5.4 (5.0, 5.8)

TQT–constraint-seeking Qs 29.6 (27.0, 32.2) 32.3 (29.4, 35.2) 30.7 (28.7, 32.6) 32.8 (30.8, 34.8)

TQT–total time 570.1 (491.7, 648.4) 571.9 (485.6, 658.2) 519.9 (462.5, 577.4) 483.0 (423.6, 542.3)

Making Inferences–total 23.7 (22.2, 25.2) 29.2 (27.5, 30.9) 28.1 (27.0, 29.2) 28.7 (27.6, 29.9)

Codes = Code Transmission Test; CNT = Contingency Naming Test; TOL = Tower of London; CFR = Complex Figure of Rey; COWAT = Controlled Oral Word

Association Test; TQT = Twenty Questions Test.a Group means adjusted for age, gender, and socioeconomic status.

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7-year follow-up and current assessment (Table 7). No

Group3Time interaction differences were identified for

IQ, indicating similar developmental trajectories for

meningitis survivors and controls over time. For the

CFR, the analysis identified a significant ‘‘time’’ main

effect, F(1, 198) 5 58.18, p , .001, indicating expected

developmental progress. In addition, a significant in-

teraction was found for Group3Time, F(1, 198)5 5.74,

p 5 .02), with meningitis survivors recording greater

improvements over time (meningitis: 8.17 points;

controls: 6.08 points), suggesting some ‘‘catch-up’’ in

these skills. Significant development over time was also

noted for the COWAT, F(1, 198) 5 38.74, p , .001,

with both groups showing similar rates of improvement

with time. Longitudinal comparisons of meningitis

survivors according to age at illness detected no

significant effects.

DISCUSSION

The aim of the present study was to examine long-term

outcome from childhood bacterial meningitis in a school-

aged population and to investigate the relative contri-

bution of acute neurologic complications as a marker of

brain injury, and age at illness as an indicator of the

vulnerability of the young brain. The study employed

a prospective, longitudinal design and compared post-

meningitis children to age- and grade-matched controls

in the domains of general performance (IQ, educational

skills) and executive functions. Possible confounding

effects of gender and psychosocial factors, such as

geographic region, parental education, and occupation

were controlled by sampling and statistical methods.

Results suggest that even 12 years post-illness,

children with a history of meningitis experience neuro-

behavioral sequelae. However, impairments were not

generally severe in our study. Mean group scores fell

within the average range, with a consistent decrement of

approximately one third of a standard deviation for

meningitis survivors across IQ and educational mea-

sures. Further, there was a greater representation of

children postmeningitis in lower IQ ranges (48–136),

with nine children achieving FSIQs , 80 in comparison

with the three controls (78–135) in this range. Similarly,

children postmeningitis were more than twice as likely

as controls to require special educational assistance

(27.0 vs. 12.5%), suggesting that the impact of

performance differences is of clinical significance.

Across the domains of executive functions, children

with a history of meningitis were consistently less

efficient than their peers. They took longer to complete

tasks, made more errors, were less organized, and

struggled with problem-solving situations within both

verbal and spatial domains. Again, while performances

were not severely impaired, they fell below develop-

mental expectations.

In our previous investigations of this cohort, we

observed a changing pattern of impairments, which led

us to consider whether we were identifying permanent

cognitive deficits or a developmental lag associated with

a transient insult to the developing CNS. At an initial

evaluation, 12 months post-illness, children were noted

to be more likely than expected to have delayed

expressive language development (Anderson, Leaper,

& Judd, 1987). Of note, at that evaluation (mean age at

assessment 5 23 months), language skills could be

argued to be in a state of rapid development (Gardner,

1979; Gleason, 1985), with the possibility that a delay in

language acquisition may explain the poorer per-

formance of children following meningitis. At 7 years

post-illness (mean age at testing 5 8.4 years, SD 5 1.6)

(Anderson et al., 1997; Grimwood et al., 1995),

expressive language skills had developed and no child

required language intervention. However, the cohort

now demonstrated substantial deficits in reading, being

four times more likely than controls to be unable to read

at all, and with almost double the risk of achieving

a reading age of 2 years below chronological age, and

Table VII. Adjusted Group Means and Standard Errors for Measures Used at Both the 7-Year and 12-Year Follow-Up Assessments

Meningitis (n =107)a Controls (n = 96)

7-Year Follow-Up

Adjusted M (SE )

12-Year Follow-Up

Adjusted M (SE )

7-Year Follow-Up

Adjusted M (SE )

12-Year Follow-Up

Adjusted M (SE )

Full-scale IQb 100.3 (1.2) 97.2 (1.1) 105.4 (1.2) 101.6 (1.2)

CFR-accuracyc 23.5 (0.7) 31.7 (0.3) 27.0 (0.7) 33.1 (0.3)

COWAT–total wordsc 17.7 (0.6) 25.8 (0.8) 19.5 (0.7) 28.1 (0.9)

a Two postmeningitis children were unable to complete these tests.b Group means adjusted for gender and socioeconomic status.c Group means adjusted for age, gender, and socioeconomic status.

76 Anderson, Anderson, Grimwood, and Nolan

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thus eligible for a diagnosis of specific reading disability.

Again, it could be argued, given the age of the sample,

that these literacy skills were in a state of development

and may simply be lagging behind rather than perma-

nently impaired. We predicted that identified deficits in

memory and learning may be impeding normal skill

acquisition in areas such as literacy and verbal knowl-

edge, with a hint that potential executive deficits may

further impact on cognitive development.

On this occasion, results may be argued to be

consistent with that expected for a 12-year follow-up

period. Differences, however, continue to exist for

intellectual measures, but there is no apparent de-

terioration in skills, with the gap between meningitis

survivors and controls remaining stable over time. For

literacy skills, a significant group difference was

identified, but overall performance was at expected

levels, implying substantial improvements in this

domain since previous follow-up.

The suggestion of executive deficits identified at the

7-year evaluation was now thoroughly evaluated and

global deficits were identified, encompassing attentional

control, goal setting, and concept formation/abstract

thought. While meningitis survivors continued to

perform more poorly than controls, longitudinal analy-

ses identified some specific gains in goal-setting skills in

the meningitis group over time, with group mean scores

increasing by more than two standard deviations from 7-

to 12-year follow-up. This may reflect that these skills,

which are in an ongoing state of development into

adolescence, continue to show some catch-up with

respect to normal levels of development. In contrast,

more language-based executive abilities showed no such

catch-up. These skills are thought to mature earlier,

around age 10 years, with more gradual improvement

after that time (Anderson, 1998; Levin et al., 1991;

Welsh, Pennington, & Groisser, 1991). If true, it could

be argued that these skills should be mostly developed in

the current cohort, and identified deficits may reflect

a more permanent set of higher-level language deficits.

The presence of such deficits might be consistent with

the mild, but significant, discrepancies across groups

identified at each level. That is, less efficient conceptu-

alization and abstraction skills may subtly reduce

development in a range of cognitive and language

domains through middle childhood. Of note, moving

into adolescence, when the child needs to function

independently, executive difficulties may have increas-

ing impact. This possibility is supported by research

examining survivors of meningitis and other generalized

cerebral insults in adulthood (Anderson et al., 1994;

Dennis, 1989; Gronwall, Wrightson, & McGinn, 1997;

Hugosson et al., 1997), when ongoing deficits are

identified in these higher-level skills.

Acute Neurologic Complications

The present data do not provide evidence for a sustained

adverse effect due to acute neurologic complications. No

differences were identified between children with and

without complications, and no consistent trends for

lower performances were evident, with the two groups

performing similarly across all domains. This is at odds

with results from the longitudinal study of Taylor and

colleagues (1990, 1996), who identify complications as

a major predictive factor in their sample. A number of

explanations may be considered to account for our

findings. It may be that, with time since illness, the

impact of neurologic complications on cognition be-

comes less substantial, with psychosocial factors being

more relevant. Such a pattern has been reported in other

samples of children with early brain injury, where social

disadvantage and limited access to rehabilitation have

been found to be more predictive of outcome with

increasing time since injury (Kinsella et al., 1997; Yeates

et al., 1997). It should be noted that in an earlier report

of this sample (Grimwood et al., 1996), when children

who died as a result of illness were included in

assessment of outcome, the impact of complications,

not surprisingly, became more marked. Finally, the

requirements for task participation increase with older

cohorts, and it has been noted that two children in the

meningitis sample were unable to complete tasks due to

meningitis-related sequelae (e.g., intellectual impair-

ment, blindness, hearing impairments).

These considerations may reflect a tendency for

permanent neurologic complications to be more pre-

dictive of severe functional deficits. In contrast, where

complications are more transient and no obvious

residual physical, sensory, or neurologic deficits are

sustained, ongoing development may be relatively

unaffected by these early symptoms.

Age at Illness

As was the case for our 7-year follow-up, age at illness

continues to be important for long-term outcome. For

intellectual and academic scores, those contracting

meningitis prior to 12 months of age performed more

poorly, with greatest difficulties in VC and reading

ability. For executive functions, younger age at illness

was associated with poorer attentional control and less

Neurobehavioral Outcomes Following Meningitis 77

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efficient higher-level language skills, less accurate

performances, slower generation of verbal responses,

poorer interpretation of complex verbal and visual

materials, and reduced goal-setting abilities. These

results suggest that while the overall impact of

meningitis may be relatively general and mild, age at

illness appears to be particularly relevant for linguistic

and executive functions, which are developing rapidly in

infancy and early childhood. The implication of these

findings is that contrary to neural plasticity theories,

generalized cerebral insult may have a greater impact on

the less mature CNS.

The specific vulnerability of the language system,

consistently identified within this cohort, albeit via

different symptoms at different developmental stages,

would support an interpretation that language skills,

which are emerging but not functional and are in a very

rapid stage of development at the time of illness, are

differentially impaired, with a delay in onset and mastery

of skills and a possible shortfall in eventual level of skill

(Dennis, 1989). The observation of more intact non-

verbal skills, and our understanding that these skills are

more stable during this period, is supportive of such an

explanation. Further research is required to follow

children with early brain injury, such as bacterial

meningitis, into adulthood to establish persisting versus

transient deficits in neurobehavioral function.

Acknowledgment

This research was supported by the Government

Employee’s Medical Research Fund and the Murdoch

Childrens Research Institute

Received July 22, 2002; revisions received December 23,

2002 and May 15, 2003; accepted May 16, 2003

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