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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.
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Frölichetal. Malar J (2019) 18:74
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*
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
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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 [58].
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
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
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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.
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
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
angle Slice
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.
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 * 103
mm2/s vs. 0.682 ± 0.074 * 103 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).
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 (103mm2/s)
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.
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].
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
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.
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.
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
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... Notably, there was no MRI evidence of microvascular dysfunction or restricted diffusion in either group in this study. Similar imaging protocols have previously demonstrated restricted diffusion in the splenium of the corpus callosum in a moderate proportion of patients presenting with uncomplicated P. falciparum infection 10,11 ; however, our observations suggest that these changes are not present or not detectable in the earliest stages of infection. ...
... SUV is the most commonly used measurement of radiotracer activity, and represents the ratio of tissue radioactivity related to FDG at a given time and the injected dose of radioactivity per kilogram of participant weight. The apparent diffusion co-efficient (ADC) was estimated for a manually defined region of interest in the corpus callosum representing the splenium, as restricted diffusion has been reported in this region in cases of uncomplicated P. falciparum infection 10,11 . ADC represents the relative mobility of water in the tissue, and changes may reflect pathology including relative ischemia 13 . ...
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Cerebral malaria is the most serious manifestation of severe falciparum malaria. Sequestration of infected red blood cells and microvascular dysfunction are key contributing processes. Whether these processes occur in early stage disease prior to clinical manifestations is unknown. To help localize and understand these processes during the early stages of infection, we performed 18-F fluorodeoxyglucose positron emission tomography/magnetic resonance imaging in volunteers with Plasmodium falciparum induced blood stage malaria (IBSM) infection, and compared results to individuals with P. vivax infection, in whom coma is rare. Seven healthy, malaria-naïve participants underwent imaging at baseline, and at early symptom onset a median 9 days following inoculation (n = 4 P. falciparum, n = 3 P. vivax). Participants with P. falciparum infection demonstrated marked lability in radiotracer uptake across all regions of the brain, exceeding expected normal variation (within subject coefficient of variation (wCV): 14.4%) compared to the relatively stable uptake in participants with P. vivax infection (wCV: 3.5%). No consistent imaging changes suggestive of microvascular dysfunction were observed in either group. Neuroimaging in early IBSM studies is safe and technically feasible, with preliminary results suggesting that differences in brain tropism between P. falciparum and P. vivax may occur very early in infection.
... Quantitative measurement of P. falciparum histidine rich protein 2 (PfHRP2) was performed on serum samples from d0 by double sandwich ELISA as described before [26][27][28]. In short, ...
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Background: Artemisinin combination therapy (ACT) for the treatment of malaria is highly effective, well tolerated and safe. Episodes of delayed hemolysis occur in up to 57.9% of patients with severe malaria treated with intravenous artesunate, mainly caused by 'pitting' of infected red blood cells (RBCs) in the spleen and delayed loss of these once-infected RBCs (oiRBCs). Several reports indicate that post-treatment hemolysis (PTH) also occurs in uncomplicated malaria treated with oral ACT, calling for systematic investigation. Methods: Prospective observational study to identify the proportion of patients with PTH after oral ACT, defined as increased lactate dehydrogenase activity and low haptoglobin level on day 14 after treatment. Patients were enrolled at two study centres in Germany and Italy. Study visits took place on days 1, 3, 7, 14, 28. Laboratory investigations included extended clinical routine laboratory tests, quantitative P.f.-HRP2, anti-RBC antibodies, and oiRBCs. State of semi-immunity to malaria was assessed from childhood and ongoing exposure to Plasmodium spp. as per patient history. Results: A total of 134 patients with uncomplicated malaria and 3-day ACT treatment were recruited. Thirty-seven (37.4%) of 99 evaluable patients with P.f. and none of nine patients with non-P.f. malaria exhibited PTH on d14. Patients with PTH had higher initial parasitaemia, higher oiRBC counts on d3, and a 10-fold decrease in oiRBCs between d7 and d14 compared to patients without PTH. In patients with PTH, loss of haemoglobin (Hb) was 4-fold greater in non-Africans than in Africans (-1.3 vs -0.3 g/dl). Semi-immune African patients with PTH showed markedly increased erythropoiesis on d14 compared to not semi-immune African and non-African patients with PTH. Conclusions: PTH is common in patients with uncomplicated malaria and oral ACT. While the observed loss of Hb will not be clinically relevant in most cases, it could aggravate pre-existing anaemia and warrants follow-up examinations in populations at risk.
... However, it is impossible to identify neuronal cell loss after cytotoxic swelling in the follow-up images, and more permanent neurological damage cannot be excluded in these patients. In 1 patient with SNCM with a GCS score of 15, we noted a small cytotoxic lesion of the corpus callosum with diffusion-weighted imaging, a finding previously reported in both SNCM [36] and CM [37]. Another patient with SNCM with a slight reduction in GCS score had cytotoxic edema at MR imaging, a common feature of CM not observed in UM. ...
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Background: Cerebral malaria in adults is associated with brain hypoxic changes on magnetic resonance (MR) images and has a high fatality rate. Findings of neuroimaging studies suggest that brain involvement also occurs in patients with uncomplicated malaria (UM) or severe noncerebral malaria (SNCM) without coma, but such features were never rigorously characterized. Methods: Twenty patients with UM and 21 with SNCM underwent MR imaging on admission and 44-72 hours later, as well as plasma analysis. Apparent diffusion coefficient (ADC) maps were generated, with values from 5 healthy individuals serving as controls. Results: Patients with SNCM had a wide spectrum of cerebral ADC values, including both decreased and increased values compared with controls. Patients with low ADC values, indicating cytotoxic edema, showed hypoxic patterns similar to cerebral malaria despite the absence of deep coma. Conversely, high ADC values, indicative of mild vasogenic edema, were observed in both patients with SNCM and patients with UM. Brain involvement was confirmed by elevated circulating levels of S100B. Creatinine was negatively correlated with ADC in SNCM, suggesting an association between acute kidney injury and cytotoxic brain changes. Conclusions: Brain involvement is common in adults with SNCM and a subgroup of hospitalized patients with UM, which warrants closer neurological follow-up. Increased creatinine in SNCM may render the brain more susceptible to cytotoxic edema.
... 5 In a series of children with cerebral malaria from Malawi CLOCC was the second most common finding of white matter diffusion restriction in MRI, however, similar lesions were shown to be present also in uncomplicated cases of imported malaria. 6 Thus, whether CLOCC clearly represents cerebral involvement or even precedes clinical deterioration in malaria remains to be elucidated. In all, this case demonstrates that access and provision of pre-travel healthcare for travelers VFR still has to be improved and that awareness of classic tropical diseases remains essential in times of a pandemic. ...
We report the case of a 29-year-old male in whom COVID-19 concerns led to a delayed diagnosis of falciparum malaria. The patient developed symptoms of cerebral malaria with cytotoxic lesions of the corpus callosum (CLOCC) in magnetic resonance imaging (MRI).
... MRI in CM has revealed: (1) lesions mainly in the frontoparietal lobe, corpus callosum, and internal capsule [106], (2) vasogenic and cytotoxic edema mainly in posterior areas of the brain [107], and (3) focal or diffuse lesions in the centrum semiovale, corpus callosum, thalamus, and cortex [106,107]. Notably, cases of noncerebral malaria also show brain changes on MRI [108]. ...
Full-text available
Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract
... As access to clinical imaging infrastructure in malaria endemic areas continues to improve, an increasing number of studies have demonstrated the utility of MRI to evaluate the brain in cerebral [12] and uncomplicated falciparum malaria [13,14]. In contrast, PET imaging in malaria is limited to a small number of nonhuman primate studies [15,16] and a single case report of serendipitous imaging in suspected lymphoma [17]. ...
Full-text available
Background Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum , which is known to undergo microvascular tissue sequestration, little is known about the behavior of P . vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life. Methods and findings To identify organ-specific changes during the early stages of P . vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P . vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P . falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species ( n = 3 P . vivax ; n = 4 P . falciparum ). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume ( P . vivax : +28.8% [confidence interval (CI) +10.3% to +57.3%], P . falciparum : +22.9 [CI −15.3% to +61.1%]) and radiotracer uptake ( P . vivax : +15.5% [CI −0.7% to +31.7%], P . falciparum : +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P . vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow ( P . vivax : +4.6% [CI −15.9% to +25.0%], P . falciparum : +3.2% [CI −3.2% to +9.6%]) or liver ( P . vivax : +6.2% [CI −8.7% to +21.1%], P . falciparum : −1.4% [CI −4.6% to +1.8%]) following infection with either species. In participants with P . vivax , hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P . vivax infection compared to P . falciparum . The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity. Conclusions PET/MRI indicated greater splenic tropism and metabolic activity in early P . vivax infection compared to P . falciparum , supporting the hypothesis of splenic accumulation of P . vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism.
... Several gaps remain in our understanding of the relationship between epilepsy and malaria. Only a few reports of MRI and neuropathological evaluations in acute cerebral malaria episodes are available and none has focused on long-term sequelae such as epilepsy [65][66][67][68] . The epileptogenic substrates associated with cerebral malaria are also yet to be fully clarified. ...
Purpose of the review: Malaria, Chagas Disease and Human African Trypanosomiasis are vector-borne protozoan illnesses, frequently associated with neurological manifestations. Intriguing but ignored, limited mainly to resource-limited, tropical settings, these disorders are now coming to light because of globalisation and improved diagnosis and treatment. Enhanced understanding of these illnesses has prompted this review. Recent findings: Methods of diagnosis have currently transitioned from blood smear examinations to immunological assays and molecular methods. Tools to assess neurological involvement, such as magnetic resonance imaging, are now increasingly available in regions and countries with high infection loads. Sleep and other electrophysiological technologies (electroencephalography, actigraphy) are also promising diagnostic tools but requiring field-validation. Access to treatments was formerly limited, even as limitations of agents used in the treatment are increasingly recognised. Newer agents are now being developed and trialled, encouraged by improved understanding of the disorders' molecular underpinnings. Summary: Prompt diagnosis and treatment are crucial in ensuring cure from the infections. Attention should also be due to the development of globally applicable treatment guidelines, the burden of neurological sequelae and elimination of the zoonoses from currently endemic regions.
... Several gaps remain in our understanding of the relationship between epilepsy and malaria. Only a few reports of MRI and neuropathological evaluations in acute cerebral malaria episodes are available and none has focused on long-term sequelae such as epilepsy [65][66][67][68] . The epileptogenic substrates associated with cerebral malaria are also yet to be fully clarified. ...
Full-text available
Zoonotic and vector-borne parasites are important preventable risk factors for epilepsy. Three parasitic infections — cerebral malaria, Taenia solium cysticercosis and onchocerciasis — have an established association with epilepsy. Parasitoses are widely prevalent in low-income and middle-income countries, which are home to 80% of the people with epilepsy in the world. Once a parasitic infection has taken hold in the brain, therapeutic measures do not seem to influence the development of epilepsy in the long term. Consequently, strategies to control, eliminate and eradicate parasites represent the most feasible way to reduce the epilepsy burden at present. The elucidation of immune mechanisms underpinning the parasitic infections, some of which are parasite-specific, opens up new therapeutic possibilities. In this Review, we explore the pathophysiological basis of the link between parasitic infections and epilepsy, and we consider preventive and therapeutic approaches to reduce the burden of epilepsy attributable to parasitic disorders. We conclude that a concerted approach involving medical, veterinary, parasitological and ecological experts, backed by robust political support and sustainable funding, is the key to reducing this burden.
Purpose of review: The present review focuses on parasitic infections of the central nervous system (CNS) that can affect the international traveler. Recent findings: The epidemiology of imported parasitic infections is changing and clinicians are treating increasing numbers of returned travelers with parasitic infections in the CNS with which they are not familiar. Summary: The epidemiology, life cycle, clinical manifestations, diagnosis, and treatment of parasites that affect the CNS will be discussed.
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Background Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria. Methods The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria. ResultsFrom 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate. Conclusion The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.
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Background Magnetic resonance imaging (MRI) allows detailed study of structural and functional changes in the brain in patients with cerebral malaria. Methods In a prospective observational study in adult Bangladeshi patients with severe falciparum malaria, MRI findings in the brain were correlated with clinical and laboratory parameters, retinal photography and optic nerve sheath diameter (ONSD) ultrasound (a marker of intracranial pressure). Results Of 43 enrolled patients, 31 (72%) had coma and 12 (28%) died. MRI abnormalities were present in 79% overall with mostly mild changes in a wide range of anatomical sites. There were no differences in MRI findings between patients with cerebral and non-cerebral or fatal and non-fatal disease. Subtle diffuse cerebral swelling was common (n = 22/43), but mostly without vasogenic oedema or raised intracranial pressure (ONSD). Also seen were focal extracellular oedema (n = 11/43), cytotoxic oedema (n = 8/23) and mildly raised brain lactate on magnetic resonance spectroscopy (n = 5/14). Abnormalities were much less prominent than previously described in Malawian children. Retinal whitening was present in 36/43 (84%) patients and was more common and severe in patients with coma. Conclusion Cerebral swelling is mild and not specific to coma or death in adult severe falciparum malaria. This differs markedly from African children. Retinal whitening, reflecting heterogeneous obstruction of the central nervous system microcirculation by sequestered parasites resulting in small patches of ischemia, is associated with coma and this process is likely important in the pathogenesis.
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Patients with acute uncomplicated Plasmodium falciparum malaria have no evident neurologic disorder, vital organ dysfunction, or other severe manifestations of infection. Nonetheless, parasitized erythrocytes cytoadhere to the endothelium throughout their microvasculature, especially within the brain. We aimed to determine if 3 Tesla magnetic resonance imaging studies could detect evidence of cerebral abnormalities in these patients. Within 24 hours of admission, initial magnetic resonance imaging examinations found a lesion with restricted water diffusion in the mid-portion of the splenium of the corpus callosum of 4 (40%) of 10 male patients. The four patients who had a splenial lesion initially had evidence of more severe hemolysis and thrombocytopenia than the six patients who had no apparent abnormality. Repeat studies four weeks later found no residua of the lesions and resolution of the hematologic differences. These observations provide evidence for acute cerebral injury in the absence of severe or cerebral malaria.
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Objectives To determine whether sequestration of parasitized red blood cells differs between children with uncomplicated and severe Plasmodium falciparum malaria. Methods We quantified circulating-, total- and sequestered-parasite biomass, using a mathematical model based on plasma concentration of P. falciparum histidine rich protein 2, in Gambian children with severe (n = 127) and uncomplicated (n = 169) malaria. Results Circulating- and total-, but not sequestered-, parasite biomass estimates were significantly greater in children with severe malaria than in those with uncomplicated malaria. Sequestered biomass estimates in children with hyperlactataemia or prostration were similar to those in uncomplicated malaria, whereas sequestered biomass was higher in patients with severe anaemia, and showed a trend to higher values in cerebral malaria and fatal cases. Blood lactate concentration correlated with circulating- and total-, but not sequestered parasite biomass. These findings were robust after controlling for age, prior antimalarial treatment and clonality of infection, and over a realistic range of variation in model parameters. Conclusion Extensive sequestration is not a uniform requirement for severe paediatric malaria. The pathophysiology of hyperlactataemia and prostration appears to be unrelated to sequestered parasite biomass. Different mechanisms may underlie different severe malaria syndromes, and different therapeutic strategies may be required to improve survival.
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Malaria is the commonest imported infection in the UK. Malaria requiring ICU admission has a reported mortality of up to 25%. The relationship between ethnicity, immunity, and risk of malaria is complex. The Malaria Score for Adults (MSA) and Coma Acidosis Malaria (CAM) score have recently been proposed to risk stratify patients with malaria. Retrospective study of patients with WHO severe falciparum malaria admitted to ICU at the Hospital for Tropical Diseases, London, UK. The relationship between clinical variables and risk of death or a prolonged ICU stay were examined with logistic regression. The predictive value of the MSA and CAM score were calculated. 124 patients were included. Cerebral malaria and acute kidney injury occurred earlier (median day 1) than acute respiratory distress syndrome (median day 3). Six patients had community acquired bacterial co-infection. Eight patients were co-infected with HIV, five of whom were newly diagnosed. The positive predictive value of a CAM score ≥2 or an MSA ≥5 for death were 12% and 22% respectively. Five patients died. No variable was significantly associated with risk of death. There were no significant differences between individuals raised in endemic countries compared to non-endemic countries. Mortality in patients managed in a specialist centre was low. Patients who died succumbed to complications associated with a prolonged stay on ICU rather than malaria per se. The clinical usefulness of the MSA and CAM score was limited. Co-infection with HIV was relatively common but compared to studies in children, bacteraemia was uncommon. The relationship between ethnicity and immunity to severe disease is complex.
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There have been few neuroimaging studies of pediatric CM, a common often fatal tropical condition. We undertook a prospective study of pediatric CM to better characterize the MRI features of this syndrome, comparing findings in children meeting a stringent definition of CM with those in a control group who were infected with malaria but who were likely to have a nonmalarial cause of coma. Consecutive children admitted with traditionally defined CM (parasitemia, coma, and no other coma etiology evident) were eligible for this study. The presence or absence of malaria retinopathy was determined. MRI findings in children with ret+ CM (patients) were compared with those with ret- CM (controls). Two radiologists blinded to retinopathy status jointly developed a scoring procedure for image interpretation and provided independent reviews. MRI findings were compared between patients with and without retinopathy, to assess the specificity of changes for patients with very strictly defined CM. Of 152 children with clinically defined CM, 120 were ret+, and 32 were ret-. Abnormalities much more common in the patients with ret+ CM were markedly increased brain volume; abnormal T2 signal intensity; and DWI abnormalities in the cortical, deep gray, and white matter structures. Focal abnormalities rarely respected arterial vascular distributions. Most of the findings in the more clinically heterogeneous ret- group were normal, and none of the abnormalities noted were more prevalent in controls. Distinctive MRI findings present in patients meeting a stringent definition of CM may offer insights into disease pathogenesis and treatment.
The hallmark of pediatric cerebral malaria (CM) is sequestration of parasitized red blood cells in the cerebral microvasculature. Malawi-based research using 0.35 Tesla (T) magnetic resonance imaging (MRI) established that severe brain swelling is associated with fatal CM, but swelling etiology remains unclear. Autopsy and clinical studies suggest several potential etiologies, but limitations of 0.35 T MRI precluded optimal investigations into swelling pathophysiology. A 1.5 T MRI in Zambia allowed for further investigations including susceptibility-weighted imaging (SWI). SWI is an ideal sequence for identifying regions of sequestration and microhemorrhages given the ferromagnetic properties of hemozoin and blood. Using 1.5 T MRI, Zambian children with retinopathy-confirmed CM underwent imaging with SWI, T2, T1 pre- and post-gadolinium, diffusion-weighted imaging (DWI) with apparent diffusion coefficients and T2/fluid attenuated inversion recovery sequences. Sixteen children including two with moderate/severe edema were imaged; all survived. Gadolinium extravasation was not seen. DWI abnormalities spared the gray matter suggesting vasogenic edema with viable tissue rather than cytotoxic edema. SWI findings consistent with microhemorrhages and parasite sequestration co-occurred in white matter regions where DWI changes consistent with vascular congestion were seen. Imaging findings consistent with posterior reversible encephalopathy syndrome were seen in children who subsequently had a rapid clinical recovery. High field MRI indicates that vascular congestion associated with parasite sequestration, local inflammation from microhemorrhages and autoregulatory dysfunction likely contribute to brain swelling in CM. No gross radiological blood brain barrier breakdown or focal cortical DWI abnormalities were evident in these children with nonfatal CM.
Susceptibility-weighted and gradient-recalled echo T2* magnetic resonance imaging have enabled the detection of very small foci of blood within the brain, which have been termed "cerebral microbleeds." These petechial intraparenchymal hemorrhages have begun to emerge as diagnostically and prognostically useful markers in a variety of disease states. Severe hypertension and cerebral amyloid angiopathy are perhaps the best established microhemorrhagic conditions from neuroimaging literature; however, many others are also recognized including cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL), moyamoya disease, fat embolism, cerebral malaria, and infective endocarditis. Microbleeds are also a common finding in the setting of trauma and stroke. The purpose of this review is to broadly describe the neuroimaging of cerebral microbleeds in a wide variety of conditions, including the differences in their appearance and distribution in different disease states. In a few situations, the presence of microbleeds may influence clinical management, and we discuss these situations in detail. The major importance of this emerging field in neuroimaging is the potential to identify microvascular pathology at an asymptomatic or minimally symptomatic stage and create a window of therapeutic opportunity.
Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).