Brain magnetic resonance imaging in imported malaria

Abstract

Background
Previous studies have documented a spectrum of brain magnetic resonance imaging (MRI) abnormalities in patients with cerebral malaria, but little is known about the prevalence of such abnormalities in patients with non-cerebral malaria. The aim of this study was to assess the frequency of brain MRI findings in returning travellers with non-cerebral malaria.

Methods
A total of 17 inpatients with microscopically confirmed Plasmodium falciparum non-cerebral malaria underwent structural brain MRI at 3.0 Tesla, including susceptibility-weighted imaging (SWI). Presence of imaging findings was recorded and correlated with clinical findings and parasitaemia.

Results
Structural brain abnormalities included a hyperintense lesion of the splenium on T2-weighted imaging (n = 3) accompanied by visible diffusion restriction (n = 2). Isolated brain microhaemorrhage was detected in 3 patients. T2-hyperintense signal abnormalities of the white matter ranged from absent to diffuse (n = 10 had 0–5 lesions, n = 5 had 5–20 lesions and 2 patients had more than 50 lesions). Imaging findings were not associated with parasitaemia or HRP2 levels.

Conclusion
Brain MRI reveals a considerable frequency of T2-hyperintense splenial lesions in returning travellers with non-cerebral malaria, which appears to be independent of parasitaemia.

Full text

Frölichetal. Malar J (2019) 18:74
https://doi.org/10.1186/s12936-019-2713-2
RESEARCH
Brain magnetic resonance imaging
inimported malaria
Andreas M. Frölich1, Pinkus Tober‑Lau2, Michael Schönfeld1, Thomas T. Brehm3, Florian Kurth2,
Christof D. Vinnemeier3,4, Marylyn M. Addo3,5, Jens Fiehler1 and Thierry Rolling3,4*
Abstract
Background: Previous studies have documented a spectrum of brain magnetic resonance imaging (MRI) abnormali‑
ties in patients with cerebral malaria, but little is known about the prevalence of such abnormalities in patients with
non‑cerebral malaria. The aim of this study was to assess the frequency of brain MRI findings in returning travellers
with non‑cerebral malaria.
Methods: A total of 17 inpatients with microscopically confirmed Plasmodium falciparum non‑cerebral malaria
underwent structural brain MRI at 3.0 Tesla, including susceptibility‑weighted imaging (SWI). Presence of imaging
findings was recorded and correlated with clinical findings and parasitaemia.
Results: Structural brain abnormalities included a hyperintense lesion of the splenium on T2‑weighted imaging
(n = 3) accompanied by visible diffusion restriction (n = 2). Isolated brain microhaemorrhage was detected in 3
patients. T2‑hyperintense signal abnormalities of the white matter ranged from absent to diffuse (n = 10 had 0–5
lesions, n = 5 had 5–20 lesions and 2 patients had more than 50 lesions). Imaging findings were not associated with
parasitaemia or HRP2 levels.
Conclusion: Brain MRI reveals a considerable frequency of T2‑hyperintense splenial lesions in returning travellers
with non‑cerebral malaria, which appears to be independent of parasitaemia.
Keywords: Malaria, Imported malaria, Cerebral malaria, MRI, P. falciparum, Complicated malaria, Uncomplicated
malaria, Splenium, Splenial lesion
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/
publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Background
Malaria is a systemic parasitic disease involving multi-
ple organ systems in severe cases. Patients present with
a spectrum of clinical syndromes ranging from the mild
to the life-threatening. Cerebral malaria, defined as
impaired consciousness (Glasgow Coma Scale score < 11)
in the absence of another cause than malaria, accounts
for a large part of morbidity and mortality in the acute
phase of severe malaria. Pathophysiologically, it is
thought to be at least partially related to the sequestra-
tion of infected erythrocytes in the microvasculature of
the brain with ensuing obstruction and hypoperfusion
[1, 2]. However, it is unlikely that parasite sequestration
and involvement of the brain is present only in patients
with strictly defined cerebral malaria. It seems that
sequestration in the cerebral and other microvasculature
also occurs in other forms of severe and even uncompli-
cated malaria along a continuum with only the highest
sequestered biomass being seen in cerebral malaria [3,
4]. So far, most investigations describing brain MRI have
focused on patients with cerebral malaria. In adults, rela-
tively few case reports have described the occurrence of
a splenial lesion in patients with cerebral malaria [5–8].
Only one manuscript has assessed cerebral involvement
in uncomplicated malaria and also described transient
lesions in the splenium as distinct findings [9]. In addi-
tion, few reports suggest that susceptibility-weighted
imaging (SWI), an imaging technique highly sensitive
Open Access
Malaria Journal
*Correspondence: t.rolling@uke.de
3 Divisions of Infectious Diseases and Tropical Medicine, I. Department
of Internal Medicine, University Medical Centre Hamburg‑Eppendorf,
Hamburg, Germany
Full list of author information is available at the end of the article
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 2 of 6
Frölichetal. Malar J (2019) 18:74
to microhaemorrhages, may reveal brain microhaem-
orrhages in patients with cerebral malaria [10, 11].
Imported malaria differs from malaria cases in endemic
regions regarding several aspects. Affected patients
are mainly adults with no or waning prior anti-malarial
immunity [12]. Asymptomatic chronic parasitaemia is
rare, as are coinfections such as bacteraemia and nutri-
ent deficiencies [13]. Due to the absence of these factors,
returning travellers with malaria form a more homogene-
ous population in which to investigate cerebral involve-
ment by magnetic resonance imagin (MRI) without a
confounding effect.
e aim of this study was to assess the frequency of
cerebral microhaemorrhages and other brain MRI find-
ings in returning travellers with malaria and to assess
whether these findings are associated with parasitaemia
and of clinical disease along the spectrum of mild to
complicated malaria.
Methods
Patients
Recruitment took place between December 2014 and
October 2016 at the University Medical Centre Ham-
burg–Eppendorf. Inpatients with microscopically-con-
firmed Plasmodium falciparum malaria were asked
to participate in the study. Patients had to be fluent in
German or English and be residents of Germany to be
included in the study. is would provide the basis for
informed consent and give the possibility to follow-
up patients if any incidental finding would have been
detected on cerebral MRI. Unconscious patients could
not be included in the study. Obese patients as well as
those with claustrophobia were excluded due to the
constraints of the available MRI. Patients were treated
according to the discretion of the responsible physi-
cian, and this decision was independent of any study
participation.
Parasitaemia andHRP2 measurements
Peripheral parasitaemia was determined on drawn
venous blood by standard World Health Organization
(WHO) microscopy techniques at the Bernhard-Nocht-
Institute for Tropical Medicine. PfHRP2 was measured
by double site sandwich ELISA. ELISA plates (F96 CERT.
Maxisorp Nunc-Immuno plate, ermo Fisher Scientific
Inc., Waltham, MA, USA) were incubated at 4°C over
night with primary IgM antibody (MBS563506, MyBio-
Source, Inc., San Diego, CA, USA) diluted to 1µg/ml in
2% BSA and 98% PBS and then washed with 0.1% PBS/
Tween20 (PBST). Samples were pre-diluted in PBST
(depending on parasitaemia 1:2, 1:10 or 1:100) and then
3 more times in dilution series (1:2) along with a PfHRP2
standard dilution series starting at 10 ng/ml (kindly
provided by DJ Sullivan, Johns Hopkins Bloomberg
School of Public Health, Baltimore, MD), transferred in
doubles to the pre-coated plate (100µl/well) and incu-
bated for 1h at room temperature. After washing 100µl
of secondary IgG antibody (MBS563505, MyBioSource,
Inc., San Diego, CA, USA) diluted to 0.2 µg/ml were
transferred to each well, incubated for 1h at room tem-
perature and washed. Finally, 100µl of TMB chromogen
(TMB ELISA Substrate Solution, eBiosciences, Inc., San
Diego, CA, USA) were transferred to each well, incu-
bated for 5min and the reaction stopped with 50µl 1M
sulfuric acid. Extinction measurement was performed
at 450nm with FilterMax F5 (Molecular Devices, LLC,
San Jose, CA, USA) and analysed with SoftMax Pro
6.3 (Molecular Devices, LLC, San Jose, CA, USA) and
Microsoft Excel. Samples lying outside the linear stand-
ard range were re-analysed at higher dilution.
Brain MRI acquisition
e goal was to perform the MRI within 24h after anti-
malarial treatment was initiated. If this was not feasible,
patients were still included in the study if the MRI could
be performed within 48h after treatment was initiated.
Brain MRI was acquired using a 3 Tesla Magnetom
Skyra (Siemens, Erlangen, Germany). e proto-
col (Table 1) included 3D fluid-attenuated inversion
recovery (FLAIR), 3D T2 turbo spin echo (T2w), 3D
gradient-recalled T1 weighted imaging (T1w), axial sus-
ceptibility-weighted imaging (SWI) and axial intravoxel
incoherent motion diffusion weighted imaging (DWI)
with calculation of maps of the apparent diffusion coef-
ficient (ADC). No contrast medium was administered.
Image analysis
Brain MRI was independently assessed for structural
lesions by two radiologists (AF, MS) blinded to clini-
cal information. Disagreements were settled by consen-
sus. One radiologist (AF) counted the total number of
hyperintense white matter lesions on 3D FLAIR imag-
ing as well as the total number of punctate intracerebral
hypointense lesions corresponding to microhaemor-
rhages on SWI.
Table 1 MR sequence characteristics
Sequence Repetition
time inms Echo
time
inms
Inversion
time
inms
Flip
angle Slice
thickness
inmm
3D flair 4700 392 1800 120 0.9
SWI 37 25 – 15 1.5
DWI 4700 85 – 90 3.0
MPRAGE 1900 2.5 900 9 0.9
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Frölichetal. Malar J (2019) 18:74
To measure the ADC in different brain regions, circular
ROIs were manually placed by a radiologist (AF) on ADC
maps in the following locations: Bilateral posterior limb
of the internal capsule and corona radiata as well as the
central genu and splenium of the corpus callosum.
Statistical analysis
Variables are reported using standard descriptive sta-
tistics. ADC values were compared to normative values
using an independent t test. Pearson correlation was used
to assess for associations between ADC values and labo-
ratory findings. e association between the occurrence
of a splenial lesion or of microhaemorrhages with para-
sitaemia and HRP2 levels was assessed by Wilcoxon rank
sum test.
Results
A total of 17 patients underwent MRI and were included
in the analysis (Table 2). Half (n = 8) were immigrants
from malaria-endemic countries who were visiting
friends and relatives (VFR), while the other half were
travellers not originating from malaria-endemic coun-
tries. Only three patients were women. Patients’ age
ranged between 20 and 64years. One patient additionally
had type II diabetes, one had known hypertension, and
one had been treated for non-Hodgkin lymphoma 5years
prior to the malaria diagnosis. None of the others had
any relevant comorbidities.
Severity of malaria ranged from very mild (with few
clinical symptoms and less than 0.1% of infected erythro-
cytes) to severe (with neurological involvement and very
high parasitaemia of 40% of infected erythrocytes). For-
mally, five patients were classified as complicated malaria
according to WHO criteria [14]. ree of these patients
with complicated malaria and one patient with formally
uncomplicated malaria had reduced vigilance and/or
confusion (Glasgow Coma Scale scores between 12 and
14), but did not meet the criteria of cerebral malaria, as
defined by the WHO [14, 15]. No focal neurological defi-
cits were noted on neurological examination of any of the
included patients.
Brain MRI ndings
Structural brain abnormalities detected included a hyper-
intense lesion of the splenium on T2-weighted imaging
(n = 3), accompanied by visible diffusion restriction in
two cases (Fig.1). An isolated single brain microhaemor-
rhage was detected in 3 patients. Small focal T2-hyperin-
tense signal abnormalities of the deep and periventricular
white matter were frequent findings, ranging from absent
to diffuse (n = 10 had 0–5 lesions, n = 5 had 5–20 lesions
and 2 patients had more than 50 lesions).
Mean ADC values for the different locations are dis-
played in Table3. Neither parasitaemia nor HRP2 levels
correlated with the ADC in any of the locations (p > 0.05
Table 2 Baseline characteristics ofincluded participants
Values represent median and range, unless otherwise specied
N 17
Male sex, n (%) 14 (82%)
Age, years 49 (20–64)
Visiting friends and relatives, n(%) 8 (47%)
Percentage of infected erythrocytes 1% (0.1–40%)
Patients with complicated malaria, n (%) 5 (31%)
Hyperparasitaemia (> 10%) 4
Shock, needing vasopressor support 1
Spontaneous bleeding 1
Haemoglobinuria 1
Acute kidney injury 1
GCS at presentation (median, range) 15 (12–15)
Neurological symptoms at presentation, n(%)
Headaches 7 (41%)
Aphasia 2 (12%)
Disorientation 2 (12%)
Somnolence 1 (6%)
Haemoglobin at presentation, g/dl 13.1 (10.3–15.7)
White blood count at presentation, /µl 4.8 (3.7–10.3)
Thrombocyte count at presentation, /µl 61 (11–209)
Treatment regimens, n (%)
Artesunate, followed by Atovaquone/proguanil 5 (29%)
Dihydroartemisinin/piperaquine 6 (35%)
Atovaquone/proguanil 5 (29%)
Mefloquine 1 (6%)
Fig. 1 Splenial lesion. In a 39‑year old male patent, axial apparent
diffusion coefficient map from diffusion weighted imaging A
shows a focal lesion in the splenium of the corpus callosum with
strong diffusion restriction (arrow). There is slight accompanying
signal hyperintensity on the corresponding Flair image (B). Slight
hyperintensity of the bilateral thalami was uniformly seen on our
scanner with this sequence and considered artefactual
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Frölichetal. Malar J (2019) 18:74
for all). In patients with a splenial lesion (n = 3), the ADC
measured in the splenium was significantly lower than
in those without a splenial lesion (0.351 ± 0.147 * 10−3
mm2/s vs. 0.682 ± 0.074 * 10−3 mm2/s; p < 0.001), while
the ADC in all other measured locations was not sig-
nificantly different between these groups (p > 0.05 for all,
Table3). e occurrence of a splenial lesion was not asso-
ciated with parasitaemia (median parasitaemia of 1.5%
infected erythrocytes in patients without a splenial lesion
vs. 1.0% in those with a splenial lesion, p = 0.231) or
HRP2 levels (median HRP2 levels of 27ng/ml in patients
without a splenial lesion vs. 1ng/ml in those with a sple-
nial lesion, p = 0.142).
None of the patients with a splenial lesion had hyper-
parasitaemia, acute kidney injury, severe anaemia,
decreased vigilance or confusion. Timing of MRI was
similar for patients with a splenial lesion and those with-
out a splenial lesion (median time of 18h for those with-
out a lesion and 23h for those with a lesion, p = 0.1306).
Furthermore parasitaemia did not correlate with the
number of white matter lesions (r = − 0.22; p = 0.41).
ere was no association between the occurrence of a
microhaemorrhage and parasitaemia (median parasi-
taemia of 1% in both groups, p = 0.719). or HRP2 levels
(median HRP2 levels of 26 ng/ml in patients without a
microhaemorrhage vs. 1 ng/nl in patients with a single
microhaemorrhages, p = 0.051).
Discussion
e present study describes the frequency of brain MRI
abnormalities in a cohort of returning travellers with
non-cerebral malaria. Over 80% of study participants
were male, which is in line with national notification
reports for malaria, which show a three-time higher
malaria incidence in male returning travellers to Ger-
many [16]. Clinically silent splenial lesions were seen
in moderate frequency and were in part accompanied
by diffusion restriction. Similar splenial lesions were
detected at an even higher frequency in a cohort of chil-
dren with a clinical definition of cerebral malaria in an
endemic area [17] as well as in smaller series of uncom-
plicated endemic malaria [9]. In the present cohort,
splenial lesions also occur in returning travellers with
non-cerebral malaria with a potentially lower frequency
in this specific population. Possibly, this lower frequency
may be related to the lower rate of comorbidities, such
as bacteraemia, in the target population compared to
endemic malaria. Additionally, MRI was not performed
concurrently to treatment start. While there was no asso-
ciation between MRI timing and occurrence of splenial
lesions, some less pronounced lesions may have been
missed due to late MRI.
In the absence of a correlation between parasitaemia
or HRP2 levels and the presence of splenial lesions, the
occurrence of such lesions may not be directly linked
to parasitaemia of infected erythrocytes but may rather
be an epi-phenomenon. On the other hand, the higher
prevalence of splenial involvement observed in more
severely affected children with cerebral malaria [17]
would suggest a link to disease severity. Possible explana-
tions include the modest sample size in the current study
as well as the restriction to patients with non-cerebral
malaria due to ethical.
Given the sample of patients with splenial lesions
and ensuing low power, more data are needed to assess
whether this imaging finding may carry prognostic impli-
cations. In the setting of acute malarial infection, it might
be theoretically conceivable that the presence of early
brain imaging findings could help better predict patients
at risk of developing complicated or cerebral malaria.
However, due to the small sample and lack of follow-up,
this was beyond the scope of the present study.
Few previous studies have reported the use of SWI in
the context of malaria, describing brain microhaemor-
rhages in one adult and in sixteen children with cerebral
malaria [10, 11]. Using this highly sensitive technique, the
frequency of such microhaemorrhages in returning trav-
ellers with non-cerebral malaria is low and may overlap
with the range expected in the normal population. For
comparison, one of the largest population-based studies
(the Rotterdam scan study) showed cerebral microbleeds
in 17.8% of the general population aged 60–69years and
38.3% in those over 80years compared to 17.6% in the
study population (median age 49 years). Comparison
of these results is complicated by differences in MRI
technique, age and comorbidities. While study patients
were younger (which should decrease the number of
microbleeds observed), SWI was used, which increases
sensitivity for cerebral microbleeds compared to the
Table 3 Apparent diusion coecient values in patients
withandwithout T2-hyperintense splenial lesions
Values represent mean and standard deviation
Location Mean apparent diusion
coecient (10−3mm2/s)
Splenial
lesion
absent
Splenial
lesion
present
Corpus callosum: Splenium 682 ± 74 351 ± 147 p < 0.001
Corpus callosum: Genu 691 ± 56 682 ± 30 p = 0.84
Corona radiata: left 646 ± 39 632 ± 26 p = 0.64
Corona radiata: right 627 ± 45 627 ± 9 p = 0.98
Internal capsule: left 660 ± 67 684 ± 14 p = 0.64
Internal capsule: right 604 ± 51 641 ± 38 p = 0.35
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Frölichetal. Malar J (2019) 18:74
T2*-weighted gradient-recalled echo sequences [18] that
have been utilized in population-based studies including
the Rotterdam study [19]. e few microhaemorrhages
that were detected did not show a correlation with para-
sitaemia or clinical symptoms. Furthermore, no patient
demonstrated more than a single microbleed, and the
diagnostic utility of a single isolated microhaemorrhage
has previously been questioned [20]. ese findings
argue against the hypothesis that clinically silent cerebral
microbleeds occur at an increased frequency in returning
travellers with malaria and in low parasitaemia. However,
these results cannot be readily translated to sequestered
infected erythrocytes. As these would be expected to
remain intravascularly (in contrast to cerebral micro-
bleeds, which require extravasation of erythrocytes), any
sequestered infected erythrocytes were likely too small
or too mobile to be detected by the imaging protocol. On
the other hand, it cannot be excluded that sequestered
erythrocytes may in fact be detected by SWI but were
simply not present in the study patient’s cerebral circula-
tion, although this seems unlikely. Further optimization
of the SWI imaging protocol or imaging at even higher
field strengths may increase the sensitivity for detection
of sequestered parasitized erythrocytes.
T2-hyperintense foci of white matter signal abnor-
mality were detected in most patients and ranged from
absent to extensive, with most patients displaying no or
very limited white matter changes. Large population-
based studies have found a considerable frequency of
such lesions and have correlated the number and extent
of such lesions with age and vascular risk factors, com-
monly suggesting a microvascular origin of these signal
changes [21]. e number of such lesions did not corre-
late with parasitaemia. Although the study design does
not allow to rule out a connection of these white mat-
ter changes with malarial infection, it is most likely that
these changes are of microvascular aetiology and con-
sider them incidental lesions.
Limitations
Since the primary study hypothesis concerned the detec-
tion of clinically silent cerebral microhaemorrhages, a
routine follow-up MRI examination was not included in
the study design. Follow-up MRI was recommended to all
participants with a splenial lesion to check for resolution,
but results were not available due to loss of these patients
to follow-up. Previous studies have shown reversibility of
splenial lesions observed in malaria patients [5, 6, 9].
Conclusions
Brain MRI reveals a moderate frequency of T2-hyper-
intense splenial lesions in returning travellers with non-
cerebral malaria, which appears to be independent of
parasitaemia. More data are needed to assess whether
this imaging finding may have clinical or prognostic
implications.
Authors’ contributions
AMF conceived and designed the study, recruited patients, handled data
processing, analysed the imaging data, drafted and edited the manuscript. TR
conceived and designed the study, recruited patients, handled data process‑
ing, analysed clinical and laboratory data, drafted and edited the manuscript.
MS performed image data analysis and edited the manuscript. MA recruited
patients, analysed clinical data and edited the manuscript. TB recruited
patients, analysed clinical data and edited the manuscript. PTL and FK per‑
former HRP2‑ELISA and data analysis and edited the manuscript. CV recruited
patients, analysed clinical data and edited the manuscript. JF assisted in image
data analysis, handled data processing and edited the manuscript. All authors
read and approved the final manuscript.
Author details
1 Department of Diagnostic and Interventional Neuroradiology, University
Medical Centre Hamburg‑Eppendorf, Hamburg, Germany. 2 Department
of Infectious Diseases and Pulmonary Medicine, Charité‑Universitätsmedizin
Berlin, Corporate Member of Freie Universität Berlin, Humboldt‑Universität
zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.
3 Divisions of Infectious Diseases and Tropical Medicine, I. Department
of Internal Medicine, University Medical Centre Hamburg‑Eppendorf, Ham‑
burg, Germany. 4 Clinical Research Department, Bernhard‑Nocht‑Institute
for Tropical Medicine, Hamburg, Germany. 5 Department for Clinical Immunol‑
ogy of Infectious Diseases, Bernhard‑Nocht‑Institute for Tropical Medicine,
Hamburg, Germany.
Acknowledgements
We thank the patients for participation in our study. We thank Drs. Benno
Kreuels, Dominic Wichmann, Stefan Schmiedel, Sabine Jordan, and Camilla
Rothe for recruitment of patients.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
The datasets used and analysed during the current study are available from
the corresponding author for research purposes on reasonable request.
Consent for publication
Within the informed consent process, participants agreed that aggregated,
anonymized data can be shared and used for publication.
Ethics approval and consent to participate
The study has been granted an approval by the Medical Council in Hamburg
(PV4757). Participants were solely included if they understood and signed the
informed consent form.
Funding
The study was supported by intramural funding of the Department of Neuro‑
radiology and the I. Department of Internal Medicine at the University Medical
Centre Hamburg‑Eppendorf. There was no external funding.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Received: 24 October 2018 Accepted: 8 March 2019
References
1. Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, et al. Dif‑
ferentiating the pathologies of cerebral malaria by postmortem parasite
counts. Nat Med. 2004;10:143–5.
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Page 6 of 6
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2. Pongponratn E, Turner GD, Day NP, Phu NH, Simpson JA, Stepniewska K,
et al. An ultrastructural study of the brain in fatal Plasmodium falciparum
malaria. Am J Trop Med Hyg. 2003;69:345–59.
3. Cunnington AJ, Bretscher MT, Nogaro SI, Riley EM, Walther M. Compari‑
son of parasite sequestration in uncomplicated and severe childhood
Plasmodium falciparum malaria. J Infect. 2013;67:220–30.
4. Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut
K, Chotivanich K, et al. Estimation of the total parasite biomass in acute
falciparum malaria from plasma PfHRP2. PLoS Med. 2005;2:e204.
5. Hantson P, Hernalsteen D, Cosnard G. Reversible splenial lesion syndrome
in cerebral malaria. J Neuroradiol. 2010;37:243–6.
6. Vyas S, Gupta V, Hondappanavar A, Sakhuja V, Bhardwaj N, Singh P,
et al. Magnetic resonance imaging of cerebral malaria. J Emerg Med.
2012;42:e117–9.
7. Yadav P, Sharma R, Kumar S, Kumar U. Magnetic resonance features of
cerebral malaria. Acta Radiol. 2008;49:566–9.
8. Maude RJ, Barkhof F, Hassan MU, Ghose A, Hossain A, Abul Faiz M, et al.
Magnetic resonance imaging of the brain in adults with severe falcipa‑
rum malaria. Malar J. 2014;13:177.
9. Laothamatas J, Sammet CL, Golay X, Van Cauteren M, Lekprasert V,
Tangpukdee N, et al. Transient lesion in the splenium of the corpus cal‑
losum in acute uncomplicated falciparum malaria. Am J Trop Med Hyg.
2014;90:1117–23.
10. Nickerson JP, Tong KA, Raghavan R. Imaging cerebral malaria with a
susceptibility‑weighted MR sequence. Am J Neuroradiol. 2009;30:e85–6.
11. Potchen MJ, Kampondeni SD, Seydel KB, Haacke EM, Sinyangwe SS,
Mwenechanya M, et al. 1.5 Tesla magnetic resonance imaging to inves‑
tigate potential etiologies of brain swelling in pediatric cerebral malaria.
Am J Trop Med Hyg. 2018;98:487–504.
12. Kurth F, Develoux M, Mechain M, Malvy D, Clerinx J, Antinori S, et al.
Severe malaria in Europe: an 8‑year multi‑centre observational study.
Malar J. 2017;16:57.
13. Marks ME, Armstrong M, Suvari MM, Batson S, Whitty JMC, Chiodini
PL, et al. Severe imported falciparum malaria among adults requiring
intensive care: a retrospective study at the hospital for tropical diseases,
London. BMC Infect Dis. 2013;13:118.
14. WHO. Guidelines for the treatment of malaria. 3rd ed. Geneva: World
Health Organization; 2015.
15. WHO. Communicable Diseases Cluster Severe falciparum malaria. Trans R
Soc Trop Med Hyg. 2000;94(Suppl 1):S1–90.
16. Robert Koch Institut. Infektionsepidemiologisches Jahrbuch meldepfli‑
chtiger Krankheiten für 2016. Berlin, 2017.
17. Potchen MJ, Kampondeni SD, Seydel KB, Birbeck GL, Hammond CA,
Bradley WG, et al. Acute brain MRI findings in 120 Malawian children with
cerebral malaria: new insights into an ancient disease. Am J Neuroradiol.
2012;33:1740–6.
18. Nandigam RN, Viswanathan A, Delgado P, Skehan ME, Smith EE, Rosand J,
et al. MR imaging detection of cerebral microbleeds: effect of suscep‑
tibility‑weighted imaging, section thickness, and field strength. Am J
Neuroradiol. 2009;30:338–43.
19. Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ,
Hofman A, et al. Prevalence and risk factors of cerebral microbleeds: the
Rotterdam Scan Study. Neurology. 2008;70:1208–14.
20. Schrag M, Greer DM. Clinical associations of cerebral microbleeds
on magnetic resonance neuroimaging. J Stroke Cerebrovasc Dis.
2014;23:2489–97.
21. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R,
et al. Neuroimaging standards for research into small vessel disease
and its contribution to ageing and neurodegeneration. Lancet Neurol.
2013;12:822–38.
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