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Infectious Disease and Neurocognition
RCT studies for these interventions is strong enough to warrant the evaluation of
CCRT for at- risk African children (Bangirana et al., 2006; Boivin & Giordani, 2009).
CCRT could also then be extended to a variety of other infectious diseases causing
brain injury and persisting neurocognitive decits to children in this setting (e.g.,
human immunodeciency virus, schistosomiasis, meningitis, encephalitis, and
neurocysticercosis).
Participants in their subsequent RCT study with Ugandan complicated malaria survivors as preschoolers were well characterized from a prior prospective
case– control cohort observational study (Bangirana et al., 2014, 2016). Following
acute illness and hospitalization from either SMA or CM, they were longitudinally
evaluated for at least a 2- year period for persisting short- and long- term cognitive
and psychiatric sequelae, until reaching school age. is allowed the researchers to
document the cognitive and psychiatric areas in which most improvement could
potentially occur following CCRT intervention. e initial immunopathogenic assessment of the children during and following acute illness from either SMA or CM
also allowed identication of the immunologic responses that are associated with
cognitive or psychiatric therapeutic need and potential benet from CCRT years
later at school age (John et al., 2006, 2008b, 2008c). A better understanding of the
immunopathogenic processes during and following acute illness in SMA and CM
survivors could lay the groundwork for complementary pharmacologic and behavioral/ rehabilitation (e.g., CCRT) interventions to prevent or decrease cognitive and
psychiatric impairment following malaria (Figure 1 in Boivin et al., 2019a). is is
because CCRT provides a method for focused rehabilitation of specic decit areas
(e.g., attention, working memory) that we and others have already identied in severe malaria (Holding & Boivin, 2013; Idro et al., 2010b).
In an RCT of the benets of CCRT for Ugandan children surviving SMA or CM
in early childhood, 150 school- age SMA/ CM survivors (cases) and 150 non- malaria
children (controls) from the same households were randomized to three treatment
arms: 24 sessions of CCRT customized to improve attention, working memory,
and nonverbal reasoning in which the diculty of the training increased with improved prociency (adaptive training); a limited CCRT arm that did not titrate to
prociency but randomly cycled across the simplest to moderate level of training
(non- adaptive training); or an arm for the cases and controls that consisted of a passive control arm with no computerized training. Malaria children assigned to the
limited- CCRT intervention arm were signicantly better than passive controls on
overall cognitive performance on the Kaufman Assessment Battery for Children
(KABC), as well as on other neurocognitive tests of computerized attention (Tests
of Variables of Attention (TOVA); https:// www.tovat est.com/ ) and neuropsychological performance screening (Cogstate; https:// www.cogst ate.com/ ) (Figure 13.1).
ese improvements were largely driven by working memory gains and gains in
reasoning and planning. Follow- up assessment with the Cogstate computerized
screening test for neuropsychological performance also documented improvements
in attention and on a maze learning task. ese neurocognitive improvements were
Cerebral Malaria 189
more dramatic for the malaria survivors (both SMA and CM) than for their control counterparts, and the neurocognitive training gains tended to persist better at
1- year post- training follow- up for the CCRT non- titration arm, especially for the
more adversely aected malaria survivors (the CM group) (Boivin et al., 2019a;
Veretennikova et al., 2018).
In a subsequent secondary analysis of their CCRT RCT ndings, the study team
did document that titrated CCRT training resulted in more ecient and steeper gains
in neurocognitive performance, as measured internally by the computer training
games themselves (Larrivey et al., 2022). However, both intervention arms (adaptive and non- adaptive CCRT) did show signicant benet, as did both the severe
malaria and non- malaria cohorts. Furthermore, contrary to what was hypothesized,
study children benetted from the CCRT intervention irrespective of the severity of
neurocognitive impairment in the aermath of the acute illness. eir study participants’ socioeconomic status (urban versus rural) or degree of prior experience with
computers in school or home also did not seem to mitigate CCRT neurocognitive
benet. ese ndings are important because they support the application of this
sort of rehabilitative intervention across a broad spectrum of brain- injured children
in the aermath of infectious disease or trauma, even in resource- constrained or impoverished settings.
Neurological sequalae from cerebral malaria and
neurocognitive function
Children are at risk for signicant cognitive sequelae from severe malaria, especially
if complex seizures are poorly managed during the acute illness phase and give rise
to recurring seizures and status epilepticus in the months and years following recovery (Birbeck et al., 2010; Opoka et al., 2009). e relationship between seizures
from CM and impaired working memory sequelae was established early in the evaluation of CM surviving school- age children in Kili, Kenya (Abubakar et al., 2007;
Kihara et al., 2009). In examining the degree of impairment of executive function
in Kenyan children exposed to SMA and CM, Kariuki et al. (2014) observed that
persisting complex seizures especially in CM survivors were related to reasoning/
planning problems (executive functioning decits). ey concluded that eective
prophylaxis and management of malaria- associated acute seizures may improve executive functioning performance scores of children (Kariuki et al., 2012, 2014).
Unfortunately, early attempts to prophylactically diminish seizures during the
acute phase of CM in Kenyan children with phenobarbital increased mortality and
did not result in long- term neurocognitive benet (Abubakar et al., 2007). is is
likely because of the role of brain inammation and accompanying brainstem herniation in acute CM that may disrupt cranial nerve pathways important for respiratory
and other vital functions. is has been documented in magnetic resonance imaging
studies with Malawian children during the acute phase of CM (Kampondeni et al.,
Infectious Disease and Neurocognition
2018, 2020; Seydel et al., 2015). is same study team went on to document that the
degree of brain inammation and brainstem herniation might be predictive of the
degree of long- term neurocognitive impairment in surviving Malawian CM children (Brim et al., 2017). is is perhaps due to the role that proinammatory mediators, coupled with localized oxidative stress factors induced by free heme derived
from hemolysis of infected erythrocytes, have on consequent axonal damage and
demyelination, particularly in the white matter pathways of the brain (Monteiro
et al., 2014). Remarkably these factors cross the blood– brain barrier to reach brain
parenchyma and other brain neurons— observed as petechial hemorrhaging at
postmortem. Given the lack of proven adjuvant therapies during the acute phase
of CM illness in reducing mortality and morbidity (Schiess et al., 2020), the role of
neurocognitive and behavioral rehabilitation in the aermath of CM and SMA becomes all the more critical in enabling surviving children to achieve a better quality
of life and functionality. e evidence provided by the application of CCRT training
by our group provides a hopeful avenue for improving working memory, behavior,
executive functioning, and other cognitive domains most at risk following severe
malaria (Bangirana et al., 2009a, 2011, 2013a; Boivin & Giordani, 2009; Boivin et al.,
2019a).
In prospective longitudinal studies, our Ugandan study team has demonstrated an
association between cognition and academic performance in children surviving malaria with neurological involvement (Bangirana et al., 2013b). ese outcomes from
complicated malaria exposure in early childhood seem to be modied in part by the
severity of anemia that accompanies the acute illness phase (Boivin et al., 2016) and
can persist aerwards in the form of early developmental delays unless the risk factors for chronic anemia are eectively treated (Boivin & Giordani, 1993; Boivin et al.,
1993; Mireku et al., 2016). Furthermore, these neurodevelopmental delays from
anemia and neurocognitive decits in the aermath of CM are correlated with academic abilities as the child reaches school age (Bangirana et al., 2013b). Given that
processing speed, perceptual organizational ability, vigilance attention, planning
and reasoning, working memory, and behavioral processes such as emotional regulation and behavioral inhibition are signicantly correlated with academic performance (Nesayan et al., 2019), CCRT should benet academic performance in severe
malaria survivors if the intervention improves these neurocognitive abilities.
Neuropsychological rehabilitation and school
performance in cerebral malaria survivors
Our Ugandan CCRT research team did a follow- up study of our SMA/ CM case–
control study cohorts to evaluate the academic skills benets of cognitive training
intervention for children participating in our RCT study (Boivin et al., 2019a). In
evaluating the cognitive burden of severe malaria in the Ugandan classroom and the
eects of a computerized intervention, Miller and colleagues evaluated 216 school
Cerebral Malaria 191
reports from 300 Ugandan school- age children participating in our RCT study. At
baseline, malaria had no eect on academic performance, but age and socioeconomic status had some eect. At 1 year following completion of CCRT, there was no
eect of the intervention on academic change from study baseline to 1- year followup (Miller et al., 2022). However, factors such as sex and home environment did
demonstrate some eect on school performance, as would be expected (Bangirana
et al., 2009b).
Contrary to early ndings by Bangirana and colleagues using the Wide Range
Achievement Test (WRAT) to gauge academic skills including spelling, reading, and
arithmetic (Bangirana et al., 2011), Miller et al. (2022) did not observe that survivors
of SMA/ CM would demonstrate lower school performance than healthy comparisons. ey also did not observe that CCRT intervention would improve the academic
performance of survivors in classroom, as opposed to performance on achievement
tests such as the WRAT. is suggests that future interventions ought to consider the
inuence of age, sex, and socioeconomic status when caring for the cognitive needs
of children in the aermath of CM/ SMA if we hope to signicantly enhance their
ability to achieve academic success and, thus, improve quality of life in the long term.
Psychiatric eects of cerebral malaria
Boivin and colleagues documented neurocognitive decits in retinopathy- positive
CM school- age survivors in Malawi (Boivin et al., 2011, 2014) using the same neuropsychological tests as were used in their prospective studies in Uganda (Boivin et al.,
2007; John et al., 2008a) and in a retrospective study with Senegalese CM survivors
(Boivin, 2002). In fact, severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of Malawian children with fatal CM (Barrera et al.,
2015, 2018; MacCormick et al., 2014). Because of numerous reports by parents of
these children of serious persisting psychosocial and behavioral problems occurring
following recovery from the CM illness in this cohort of Malawian acute phase
retinopathy- positive children, Boivin and colleagues performed a follow- up psychiatric evaluation of a subgroup of those children. ey focused on children from their
retinopathy- positive CM cohort who were referred to their study center for followup evaluation because of persisting and signicant behavioral problems.
Birbeck and colleagues had reported from a comprehensive neurological evaluation of our cohort of retinopathy- positive CM survivors that 11 percent of children presented with signicant persisting behavioral problems aer the acute illness
(Birbeck et al., 2010). However, no psychiatric screening tool for children has been
validated in Malawi. In our follow- up study, we were able to evaluate the predictive
sensitivity of the Achenbach Child Behavior Checklist (CBCL) (Boivin et al., 2011,
2014) to a Diagnostic and Statistical Manual Mental Disorders, fourth edition (DSM-
IV) (American Psychiatric Association, 1994) clinical diagnosis in children referred
for psychiatric evaluation because of persisting behavior problems (Magen et al.,
Infectious Disease and Neurocognition
2011). Children referred for psychiatric clinical evaluation had already been assessed with the CBCL (given to their caregivers) as part of a larger study of exposure–
control cohorts documenting the neurodisabilities associated with CM. Twenty- one
CM survivors and ten control children (20 boys, 11 girls) ranging in age from 5 to
18 years (average 10 years) were referred for DSM- IV clinical evaluation because
of persisting behavior problems following CM illness or study enrollment. Fieen
of the 31 children (48 percent) had a DSM- IV axis 1 diagnosis of ADHD, and 15 of
the 31 had a diagnosis of oppositional deant disorder (ODD). Nine of the 15 were
diagnosed with both. Most of the ADHD children (12/ 15 or 80 percent) were referrals from the CM group. Nine of the 15 (60 percent) ADHD children were boys, as
were 11 of 15 (73 percent) of children with ODD (73 percent). e CBCL Attention
Problems scale was signicantly predictive of DSM diagnosis for ADHD (p = 0.02,
odds ratio: 1.57, 95 percent condence interval: 1.07– 2.28) in a logistic regression
model adjusted for the CBCL ODD scale, age, sex, quality of home environment,
and nutritional well- being (proportion of mid- upper- arm circumference to height).
In a similar analysis with DSM- IV ODD as the outcome, the CBCL Rule Breaking
scale (but not the CBCL ODD measures) was signicantly predictive of ODD clinical diagnosis (p = 0.033). We concluded from these ndings that children referred
for behavioral problems in a study of developmental neurodisabilities from CM were
most oen diagnosed with ADHD or ODD, or both. Even when given 1– 2 years
before the DSM- IV clinical evaluation, the CBCL had good predictive validity as a
screening measure for ADHD. e Rule Breaking CBCL scale was sensitive to ODD.
Magen and colleagues concluded that the Achenbach CBCL was eective as a pediatric psychiatric screening measure in our Malawian study setting for CM survivors
(Magen et al., 2011).
Idro and colleagues also documented psychiatric diculties for Ugandan children
surviving CM (Idro et al., 2010a). Subsequent evaluations with other Ugandan cohorts of CM and SMA survivors revealed persisting behavioral problems like those
we documented in our Malawian cohorts, namely ODD and ADHD (Idro et al.,
2016), as well as problems related to poor psychosocial adjustment, aggression, selfinjurious behavior, impulsivity, and rule- breaking tendencies (Ssenkusu et al., 2016).
Akpalu et al. (2012) provided further evidence in support of an association between
severe malaria and mental disorders in school- age sub- Saharan African children in
the form of a systematic review (Akpalu et al., 2012). In their review, eight studies
met criteria for inclusion, including four (50 percent) from Kenya, three (37.5 percent) from Uganda, and one (12.5 percent) from Senegal. e authors concluded
that Plasmodium falciparum malaria is associated with mental disorders and that
follow- up evaluation and care should be made available for these vulnerabilities in
survivors of severe malaria.
Given the relationship between severe malaria and mental health needs for schoolage CM survivors, might CCRT be of benet for psychosocial problems? In our pilot
studies of CCRT with CM survivors, we reported that CBCL internalizing symptoms (e.g., anxiety, depression, and somatic complaints) were signicantly reduced
Cerebral Malaria 193
following training (Bangirana et al., 2009a). We therefore evaluated internalizing
and externalizing symptoms using the CBCL in our CCRT RCT study (Bangirana
et al., 2009c). In addition to the CBCL, we also used the Behavior Rating Inventory
for Executive Function (BRIEF) (Gioia et al., 2003). In earlier assessments with CM
school survivors, we documented that the CBCL externalizing symptoms corresponded to the BRIEF Behavior Regulation Index for measuring behavior problems
(Familiar et al., 2015). We believed that both the CBCL and the BRIEF could provide complementary screening assessments from caregiver reports for their child
to better understand the potential behavioral benets of CCRT in addition to the
neurocognitive rehabilitative benets (Boivin et al., 2019a). At 1 year aer training,
the limited CCRT malaria children had more rapid Cogstate card detection (attention) (p = 0.02) and improved BRIEF Global Executive Index, representing all BRIEF
clinical scales (p = 0.01) as compared to passive controls. For the CBCL, there were
no signicant dierences in psychiatric symptoms as reported by the child’s primary
caregiver between the CCRT and passive control intervention arms either for the severe malaria or non- malaria cohorts.
Caregiver training to prevent mental health
problems in children surviving cerebral malaria
Bangirana et al. (2021) published the rst caregiver training intervention to address psychiatric problems in CM survivors. e Creating Opportunities for Parent
Empowerment (COPE) program was adapted to this group to provide educational
and behavioral caregiver training intervention to equip parents with psychiatric
problems for their preschool- age children following recovery from acute CM illness. Phase I was delivered within 6– 16 hours of hospital admission and consisted
of information pertaining to their child’s possible emotional reactions from hospital
admission. e emphasis was on information for the parents that could facilitate
their child’s coping responses to hospitalization. Phase II was implemented following transfer from acute care to the general ward and consisted of parent– child
skills- building activities that included using dolls in role playing to better express
and manage emotions, along with stories and games. Phase III involved a telephone
call with the parents several days aer discharge when a 5- minute script was read
that reinforced parenting behaviors to facilitate more positive emotional outcomes
for post- discharge emotional and behavioral problems on the part of the child.
Compared to parent– child dyads randomized to the control arm of this RCT at
6- month post- discharge follow- up, the COPE behavioral intervention arm did not
show any signicant benet on CBCL or Strengths and Diculties Questionnaire
(SDQ) caregiver report outcomes. Likewise, caregiver anxiety and depression were
similar for the two groups. However, caregiver depression and anxiety at hospital admission (enrollment) prior to treatment- arm randomization were signicantly related to presence of diarrhea and behavior problems reported for the child. In their
Infectious Disease and Neurocognition
nal analysis, the authors concluded that only caregiver depression, education level,
and the child’s sex (more CBCL internalizing problems for the girls) were associated
with reported mental health problems at hospital admission. For future work in this
area, the authors suggested a longer period of follow- up for the CM survivors and
their caregivers, along with a more in- depth caregiver training intervention. We also
recommend the importance of gauging the delity of intervention for such caregiver
training studies, as illustrated by Boivin and colleagues’ previous early childhood development work with Ugandan children living with HIV (Boivin et al., 2013a, 2013b).
Electroencephalographic clinical biomarkers
of pathogenesis and cerebral malaria
neurocognitive deficits
Ugandan children enrolled in the CCRT RCT study reported by Boivin and colleagues (Boivin et al., 2019a) had been previously enrolled in a prospective study
of the neurodevelopmental eects of CM and SMA during the acute phase of their
illness (Bangirana et al., 2014, 2016). ese children were evaluated with electroencephalography (EEG) roughly 72 hours post admission, typically just aer
emerging from coma, to characterize whether brain activity appeared normal or not
(e.g., epileptiform activity such as temporal lobe seizures, diuse slow- wave form
abnormality). Postels et al. (2018) report on these study ndings, in combination
with a cohort of CM survivors who underwent EEG evaluation during CM illness in
Blantyre, Malawi (Postels et al., 2018). Despite the demographic and clinical heterogeneity among CM hospital admissions in Malawi and Uganda, Postels et al. (2018)
found that EEG ndings during the acute phase of illness did predict mortality and
neurological morbidity for these children. Because of this, the authors concluded
that an EEG study of CM children early in their acute illness could have prognostic
value and be used to identify children especially at risk for adverse mortality and
morbidity outcomes and in need of additional supportive treatment and supportive
care following recovery.
Stimulus- dependent EEG studies (e.g., evoked potential studies for novel visual
and auditory stimuli) have been used by other investigators to evaluate brain and behavior integrity and subsequent neurocognitive function in surviving CM children
in sub- Saharan Africa (Kihara, 2013; Kihara et al., 2010). Because of this, Boivin and
colleagues explored whether EEG abnormality at 72 hours post admission for CM
might be predictive of subsequent CCRT performance benet to address attention
and learning decits at school age for Ugandan survivors. Diuse slow- wave abnormality, consistent with encephalopathy, was the most prevalent EEG abnormality
during the acute phase following hospital admission (Postels et al., 2018). is was
evident in about half of the preschool- age children whom we were eventually able to
enroll in our CCRT RCT at school age (Boivin et al., 2019a). Using the Cogstate computerized screening test for neurocognitive performance, we observed that children
Cerebral Malaria 195
EEG diffuse slow wave abnormality at 72hrs post
admission for CM
CogState card color
CogState card turning
CM group
with a normal EEG during the acute phase of CM illness demonstrated signicantly
greater gains on vigilance attention as measured from before to aer CCRT training
compared to those with abnormal EEG (Boivin, unpublished data; Figure 13.2, top
graph). e CCRT training occurred for these children from 2 to 3 years aer CM
admission for CM CCRT treatment group on cogstate card
color identification task (choice reaction time)
3.40
3.20
3.00
mean msec)
2.80
identification task (log10
2.60
EEG normal
EEG diffuse slow wave abnormality at 72hrs post
admission for CM CCRT treatment group on groton maze
learning test moves-per-second (task efficiency)
.40
.30
4
.20
77
.10
Groton maze learning test
.00
EEG normal EEG abnormal
EEG diffuse slow wave abnormality at 72hrs post
CCRT treatment group on groton on cogstate card
turning detection task (choice rection time)
3.40
3.20
3.00
mean msec)
2.80
attention task (log10
2.60
EEG normal
EEG abnormal
CM group
104
74
CM group
4
EEG abnormal
Test
Pre-CCRT
Post-CCRT
101
Pre-CCRT
Post-CCRT
Pre-CCRT
Post-CCRT
Test
Test
Figure 13.2 Box plots from before (pre- CCRT; blue box) to aer (post- CCRT; green box)
depicting the performance for cerebral malaria (CM) children on the Cogstate test of attention
(identification task) speed (faster is better) and Groton Maze learning task (higher score is better
in terms of correct moves per second on the maze learning). The box plots are for those children
with a normal EEG (le boxes) or an abnormal EEG (right boxes) within 72 hours of hospital
admission during acute illness. The box plots show the first quartile (top) and third quartile
(bottom) with the median bisecting the box, along with the range of outliers and individual
extreme outliers in terms of Cogstate performance.
Infectious Disease and Neurocognition
Cerebral Malaria CCRT Group
Detection speed improvement:
07
vWF (% of Normal)
Detection speed improvement:
illness and their initial EEG ndings. e same was true for the Cogstate task of
Groton Maze Learning Test (Figure 13.3, bottom graph).
Veretennikova and colleagues then used EEG and neuropsychological assessment ndings at 6 months aer hospital discharge to explore their utility as biomarkers for neurodevelopmental outcomes in CM survivors using stochastic
1.50
2
Linear = 0.184
R
1.00
0.50
8-week period
0.00
before and after CCRT
–0.50
1.50
100
200 300
Cerebral Malaria Control Group
400 500 60
vWF (% of Normal)
2
R
Linear = 0.005
00
1.00
0.50
8-week period
0.00
before and after CCRT
–0.50
0
200
400 600 800
Figure 13.3 Scatterplots with the Least- Squares fit and R2 linear regression coeicient are
presented depicting the relationship between von Willebrand factor (vWF) immunology
biomarker levels (horizontal axis) during the acute phase for cerebral malaria when initially
hospitalized. Higher levels means that vWF levels were higher compared to normative reference
points for this chemokine biomarker. The vertical axis depicts Cogstate test attention speed
(detection speed) performance improvement (higher is more improvement) from before to
aer the 24 computerized cognitive rehabilitation training (CCRT) sessions (over 2 months).
The two intervention arms depicted from Figure 13.1 are either CCRT intervention arm (top
graph), or no CCRT training (passive control arm) (bottom graph) intervention arms for the
cerebral malaria cohort of children. Faster speeds (greater values) on the vertical axis indicates
better attention performance improvement on this Cogstate task. The higher the vWF level
during acute illness for cerebral malaria, the slower the attention reaction time following the
CCRT training period. This relationship is only apparent for the CCRT intervention group (upper
graph), and not for the control group (no CCRT intervention, lower graph).
Cerebral Malaria 197
modeling techniques (Veretennikova et al., 2018). e objective of this study was
to test statistical features from the EEG recordings shortly aer hospital admission
and during coma as predictors of neurodevelopment and cognition of Ugandan
children aer coma due to CM. ey modeled the increments of the frequency
bands of EEG time series as student processes, using these parameters along with
clinical and demographic data in a machine- learning algorithm for the prediction
of children’s neurodevelopmental and cognitive scores at 6- month follow- up. e
key innovation of this work is in the identication of stochastic EEG features that
can serve as language- independent markers of the impact of CM on the developing brain.
Subsequent work by Patel and colleagues with Malawian CM survivors compared an automated spectral analysis for ten CM survivors who went on to develop seizures and ten age- and sex- matched controls undergoing conventional
visual analysis (Patel et al., 2020). The spectral analysis proved very specific
and accurate in identifying CM survivors who went on to develop epilepsy,
whereas the conventional visual analysis did not. Combined with our Ugandan
stochastic modeling EEG findings, these results suggest that automated EEG
analysis during acute illness for CM children upon hospital admission can enhance prognostic determination of which children are in most need of rehabilitative interventions. This is especially important in resource- constrained
settings such as sub- Saharan Africa, where trained clinicians may not always be
readily available to read an EEG study conventionally or accurately in a timely
manner. Since that time, Leonenko and colleagues have published the outcomes
of using a multimodal diffusion model (mixed generalized Gaussian distributions) to improve prognostic prediction of outcomes for EEG evaluations of
CM Ugandan patients in our previous studies (Leonenko et al., 2023). The EEG
data were the same used in our previous CCRT studies of Ugandan CM survivors (Boivin et al., 2019a).
Severe malaria biomarkers of pathogenesis and
neurodevelopmental and neuropsychological deficits
John et al. (2008b) documented in previous studies with Ugandan school- age
CM survivors that proinammatory cytokine levels such as systemic tumor necrosis factor alpha (TNF- α) were predictive of severity of persisting attention and
working memory decits at follow- up. is group later conrmed these ndings
in a subsequent cohort of CM survivors in terms of both persisting neurologic,
neurodevelopmental, and neuropsychological decits (Shabani et al., 2017). Based
on previous ndings (Shabani et al., 2015), they hypothesized that TNF- α may contribute to the pathogenesis of CM by promoting endothelial activation and parasite
sequestration. ey compared plasma and cerebrospinal uid (CSF) TNF- α levels in
children with CM to mortality, acute and chronic neurologic decits, and long- term