Cerebral Venous Thrombosis in Sub-Saharan Africa: A

Systematic Review

Yanina Baduro, MD,* and Jos
e M Ferro, MD, PhD†,‡

Background: The clinical epidemiology of cerebral venous thrombosis (CVT) in Sub-

Saharan Africa is unknown. Such information may be relevant for service planning,
prevention and for adapting existing CVT management guidelines to that zone of
the World. Aims: Systematic review to describe the demography, associated condi-
tions, clinical and neuroimaging features, treatment and outcome of CVT in Sub-
Saharan Africa. Summary of review: We searched MEDLINE, Cochrane Database of
Systematic Reviews, clinicaltrials.gov and reference lists of included studies for
studies reporting original data on CVT in sub-Saharan Africa. We included 20
observational studies describing 287 CVT patients, 11 case reports (13 patients) and
9 case series (274 patients). All studies had a high risk of bias. In case series 58.6 %
of the patients were female, the most common associated condition was infection
(63.1%), followed by oral contraceptives (7.3%), pregnancy/puerperium (6.2 %),
and prothrombotic conditions (2.2%). CT was the most common method to diag-
nose CVT (85%). Ninety-nine percent (101/102) of patients reported in case series
after the year 2000 were anticoagulated. In case series, 21/210 with information (10
%) patients died in the acute phase, while 60/129 with information (46.5%) recov-
ered without sequels. Conclusions: The low number of reported CVT cases from
Sub-Saharan Africa suggests that CVT is either infrequent, not diagnosed or not
reported. Infection is the most common risk factor. Most CVT cases were confirmed
by CT alone. Almost all patients reported after year 2000 received anticoagulation.
Death rate was higher than in high income countries.
Key Words: Cerebral venous thrombosis—Sub-Saharan Africa—CT—
Anticoagulation—Pregnancy—Infection
© 2021 Elsevier Inc. All rights reserved.

Background composed predominantly by low-income countries, such

as Sub-Saharan Africa, is almost unknown.
The global clinical epidemiology of cerebral venous
There are several reasons to consider that the frequency
thrombosis (CVT) is well described in high-income coun-
of CVT may be higher in Sub-Saharan Africa and that
tries1,2 and in some middle-income countries, where hos-
their clinical features may be different from those seen in
pital-based case series,3,4 suggest that the frequency of
high-income countries. CVT is more frequent in young
CVT is probably higher than in high-income countries.
and middle-aged adults,5 who are the predominant age
The clinical epidemiology of CVT in World zones
groups in Sub-Saharan Africa. Iron and folate nutritional
deficiencies may lead to severe anemia and to hyperho-
From the *Serviço de Neurologia, Hospital Central de Maputo,
mocysteinemia, which are known risk factors for CVT.5
Maputo, Mozambique; †Serviço de Neurologia, Departamento de
Neuroci^encias e Sa
ude Mental, Hospital Santa Maria- CHULN, Lis-
Limited access to Public Health and comprehensive
boa, Portugal; and ‡Faculdade de Medicina, Universidade de Lisboa. Health Care may contribute to higher numbers of CVT
Received September 10, 2020; revision received February 16, 2021; complicating pregnancy and puerperium, ear, nose, sinus,
accepted February 19, 2021. throat and facial infections. Highly prevalent infections
Address correspondence to Jos
e M Ferro, MD, PhD, Serviço de
such as HIV and malaria are other potential contributing
Neurologia, Serviço de Neurologia. Departamento de Neuroci^en-
cias e Sa

ude Mental, Hospital Santa Maria- CHULN, Lisboa, Portu-
factors.5
gal. E-mail: [email protected]. On the other hand, CVT may be underdiagnosed in
1052-3057/$ - see front matter Sub-Saharan Africa. Missed diagnosis of CVT may be
© 2021 Elsevier Inc. All rights reserved. related to low awareness of this condition, in comparison
https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.105712

Journal of Stroke and Cerebrovascular Diseases, Vol. 30, No. 6 (June), 2021: 105712 1
2 Y. BADURO AND J.M. FERRO

to other more prevalent diseases and to very limited included papers was performed independently by the
access to CT and specially MR. Such limited access to CT/ two authors, disagreements being solved by consensus.
CTV and MR/MRV may preclude early diagnosis and
recognition of mild and initial presentations of CVT.5 Data collection process and data items
The aim of this systematic review is to describe the
For the selected studies we extracted the following data:
demographics, etiology, clinical and neuroimaging fea-
tures, treatments, outcome and mortality and to explore country, study design, year of publication, participants
time-trends of CVT in Sub-Saharan Africa. Such informa- age, sex, associated conditions, clinical features, neuroim-
tion may be relevant for raising awareness for the possible aging (method to confirm the diagnosis and sinus/veins
diagnosis of CVT in some clinical scenarios, for service occluded), treatment (anticoagulation, surgery), func-
planning (e.g., access to imagery, treating infections, tional outcome and mortality. We accepted the definitions
improving peri-natal health care) and for adapting exist- of all variables as reported by the authors. Data were
ing CVT management guidelines6,7 to that zone of the extracted from reports to predesigned tables, indepen-
dently by the two authors, disagreements being solved by
World
consensus.
Methods
Risk of bias in individual studies
For the purpose of this systematic review, we fol-
lowed Meta-Analysis of Observational Studies in Epi- The risk of bias of individual studies was evaluated in
demiology (MOOSE)8 and Preferred Reporting Items accordance with the Newcastle Ottawa Quality Assess-
for Systematic Reviews and Meta-Analyses (PRISMA)9 ment Scale for cohort studies10 and the tool for evaluating
guidelines. the methodological quality of case reports and case series
proposed by Murad and colleagues.11 Quality of report-
Eligibility Criteria ing was independently analyzed by the two authors, dis-
agreements being solved by consensus
We considered published observational studies report-
ing original data on any of demographics, etiology, clini- Data presentation and statistical analysis
cal and neuroimaging features, associated conditions,
treatment, functional outcome and mortality on patients For each study we counted total number of patients,
with cerebral venous thrombosis in Sub-Saharan Africa. number with information on each variable and number
Cerebral venous thrombosis had to be confirmed by imag- with condition of interest for that variable and the corre-
ing (CT, CT-Venography, MR, MR-Venography or IA sponding percent. We planned to perform a simple
arteriography), surgery or autopsy. Any observational pooled analysis of grouped data, for case series with more
study design was accepted, including case reports and than 5 patients.
small (n<10) case series. We excluded studies where only To explore temporal trends, we planned a priori to com-
the tittle was available. Articles in English, French, Span- pare (Chi square test with continuity correction and Fish-
ish, and Portuguese were accepted. er’s Exact Test, when appropriate), associated conditions,
neuroimaging method, treatment with anticoagulation,
Information sources and search strategy death and functional outcome reported in more recent
case series (2000. 2020) with the same information from
A systematic search using combinations of keywords less recent ones (before 2000).
was performed in the following databases: Pubmed,
Cochrane Database of Systematic Reviews and clinical-
Results
trials.gov., from inception to January 2021, with no lan-
guage limitations. We adopted the search strategy for Study selection, data items and risk of bias
cerebral venous thrombosis used by ESO-EAN CVT
We identified 101 potentially eligible studies for
Guidelines7 in combination with Africa, Sub-Saharan
detailed evaluation and verification of overlaps in study
Africa, and each individual country of Sub-Saharan
populations (Fig. 1). We finally included 20 studies from
Africa. The reference lists of potential eligible studies/
Sub-Saharan Africa, consisting of 11 case reports describ-
selected studies reference lists were crosschecked for addi-
ing 13 patients12 22 (Supplemental tables 1 and 2), and
tional studies
nine hospital case-series23 31 (Table 1, supplemental table
3) from Burkina Faso, Kenya, Senegal, South Africa,3
Study Selection
Sudan and Zimbabwe2, reporting 274 CVT patients. There
Tittles were retrieved through electronic identification were no population-based studies, and also no multina-
were screened for potential eligibility by title and abstract tional or multicenter studies. Five cases series included
analysis by the two authors. Whenever possible full texts only patients with cavernous sinus thrombosis26, 27,29,30 or
were obtained of those potentially eligible. Selection of lateral sinus thrombosis.28,29,30 All studies had a high risk
CEREBRAL VENOUS THROMBOSIS IN SUB-SAHARAN AFRICA 3

Fig. 1. PRISMA 2009 Flow Diagram

of bias. Four case series23,26,27,30 had missing data for sev- the cavernous sinus was frequent (30.8% and 16.6%,
eral variables: gender and age (1 study), neuroimaging (3 respectively).
studies), treatment (1 study), death (2 studies), functional The most common associated condition was infection
outcome (4 studies) (supplemental table 3). The studies of (61.5% in case reports and 63.1% in case series). Most of
higher quality (case series from Burkina Fasso24 and Sene- the infections were sinusitis, otitis and mastoiditis. HIV
gal31 were scored two stars.10 was diagnosed in four patients in case reports (30.8%) and
in 10 (3.6%) of the patients in case series. Other frequent
associated conditions were oral contraceptives (38.4% and
Demography, symptoms and signs, associated conditions 7.3% in case reports and case series, respectively) and
and neuroimaging pregnancy/ puerperium (7.7% and 6.2%, respectively).
Thrombophilia could be diagnosed in 30.8% of case
In both case reports and case series (Supplemental table reports and 2.2% of patients in case series). Malignancy
2 and Table 1) headache was the most common presenting was only detected in three patients. Trauma and health
symptom (92.3% and 71.6% in case reports and case care-related CVT (epidural anesthesia) were reported
series, respectively), followed by focal neurological defi- only once each.
cits (38.5% and 23.8%). Papilledema was seen in 15.4% of CT (92.3% and 85%, in case reports and case series
patients in case reports and 8.4% in case series. In case respectively) was the most commonly used method, fol-
reports, the superior sagittal sinus was the most frequent lowed by MR and MR venography (46.2% and 24.4%).
site of occlusion (61.5%), followed by the lateral sinus
(transverse and/or sigmoid sinuses) (38.4%), while in
Treatment, mortality and functional outcome
case series there were more patients with thrombosis of
the lateral sinus (58.6%) than of the superior sagittal sinus Anticoagulation was used in 76.9% of the patients
(25%). In both case reports and case series, thrombosis of described in case reports, and in 54.3% of those in cases
4 Y. BADURO AND J.M. FERRO

Table 1. Summary of 9 case series reporting 274 patients with cerebral vein thrombosis from Sub-Saharan countries

Minimum-maximum Number % Valid %*

Age 8 months-78 years
Females 153 55.8 58.6
Associated conditions
Infection 173 63.1
Contraceptives 20 7.3
Pregnancy & puerperium 17 6.2
Thrombophilia 6 2.2
Antiphospholipid syndrome 4 1.5
Protein S deficiency 2 0.7
Cancer 4 1.5
Behçet
s disease 6 2.2
Other systemic disease 4 1.5
Trauma 1 0.4
Epidural anaesthesia 1 0.4
Symptoms and signs
Counts not stated 13 4.76
Headache 187 68.2 71.6
Neck pain/stiffness 36 13.1 13.8
Papilloedema 22 8.0 8.4
Visual disturbances 11 4.0 4.2
Focal deficits 62 22.6 23.8
Seizures 44 16.0 16.9
Decreased alertness 13 4.7 4.9
Cavernous sinus syndrome 38 13.8 14.6
Other cranial nerve palsies 21 7.7 8.0
Neuroimaging diagnostic method
No information 40 14.6
CT 199 72.6 85.0
MR/MR venography 57 20.8 24.4
Thrombosed sinus/veins
No information/no counts 30 10.9
Superior sagittal 61 22.2 25.0
Transverse/sigmoid 143 52.2 58.6
Straight 9 3.3 3.7
Deep venous system 7 2.6 2.9
Cavernous 38 13.9 15.6
Cortical vein 12 4.4 4.9
Anticoagulation
No information 51 18.6
Any anticoagulant 121 44.2 54.3
UF heparin 35 12.8 15.7
LMWH 86 31.4 38.6
VKA 86 31.4 38.6
Death
No information 64 23.4
Death 21 7.7 10.0
Sequels
No information 145 52.9
Complete recovery 60 21.9 46.5
Partial recovery 48 17.5 37.2
*Only shown if there was missing data.
UF unfractionated LMWH low molecular weight heparin VKA vitamin k antagonist.

series. Anticoagulation was used in only 20 out of 121 treatment, shunting were not reported. Hemicraniectomy
patients (16.5%) from case series reporting only cavernous was successfully applied in one patient. In case series, 21
or lateral sinus thrombosis, almost all (113 of 121, 93.4%) out of 210 (10 %) of the patients with information on vital
associated with infections. Thrombolysis, endovascular outcome died, while 60 out of 129 (46.5%) with
CEREBRAL VENOUS THROMBOSIS IN SUB-SAHARAN AFRICA 5

information on functional outcome recovered without and patterns of CVT was published in 2018,36 but the
sequels (supplemental tables 1 and 2). results are not yet available. Maali and co-workers (37) on
a review publication on continental disparities of CVT,
Comparison of cases series published before and after year mention 122 reported cases from Africa, but their review
2000 also included North Africa.
This review has several major limitations. There were
Statistical comparison between case series published
only 20 publications and 11 were case reports. All but two
before and after the year 2000 (supplemental table 3),
studies had low quality. Several studies had missing
showed a significant decrease in CVT associated with
information on some important variables, namely post-
infections (112 patients out of 121 with information vs.
discharge outcome. The retrieved studies had a high risk
61/153, x2 = 80.3, p < 0.0001), a much more frequent use
of bias, namely on selection of subjects, confirmation of
of anticoagulation in recent years (20/121 vs. 101/102,
diagnosis, evaluation of outcome and also publication
x2 = 151.1, p < 0.0001), but no significant difference in
bias. Some case series were from ear-nose-throat services,
mortality (10/108 vs. 11/102, x2 = 0.017, p = 0.89). CVT
causing publication bias towards infectious causes and to
diagnosis by MR was only reported in 3 case series pub-
cavernous and lateral sinus thrombosis. Because of miss-
lished after 2000.
ing data on some variables, the pooled frequencies,
despite being presented separately for case reports and
Discussion
case series, should be read with caution. Some studies
We found published information on 287 CVT patients were published before the year 2000. These older studies
in Sub-Saharan Africa, published in 11 cases report and were biased towards cases detected in association with
nine case series. The low number of reported cases sug- nose-sinus-ear and mastoid infections. Strong points of
gests that CVT is either infrequent, not diagnosed or not the systematic review include the use of standard meta-
reported. It is also possible that mild cases do not seek analysis methods, of an already used search strategy and
medical services. The diagnosis of CVT is difficult, in par- inclusive eligibility criteria, the large number as cases
ticular if there is no easy access to MR.5 Non contrast CT included and the possibility to explore time trends.
fails the diagnosis of CVT in one out of four cases.32 With- Despite the limitations, our review points that detection
out access to MR, misdiagnosis of severe presentations and early treatment of infections may contribute to pre-
forms of CVT may also easily occur, in particular in the vent CVT associated with infections and CVT fatality in
differential diagnosis with more prevalent conditions Sub-Saharan Africa. Due to very limited access to MRI,
such as meningitis, cerebral complications of HIV, cere- revised CVT guidelines may consider to recommend non-
bral malaria and arterial stroke. contrast CT to confirm the diagnosis of CVT, when MR,
In comparison to descriptive epidemiological informa- MRV or CTV are not available. We hope the results of this
tion from high- and middle-income countries3,33,34,35 systematic review help to increase the awareness for the
(Supplemental Table 4), the sex distribution and clinical diagnosis of CVT among physicians practicing in Sub-
manifestations of CVT in Sub-Saharan Africa appear to be Saharan Africa
similar. Many CVT cases were confirmed by CT alone.
Infection was the most common risk factor. CVT associ-
ated with pregnancy and puerperium were less frequent Authors contributions
than expected. Contraceptives were less often mentioned
Both authors contributed to the conception and design
than in high-income countries. The majority of patients
of the project, the acquisition, analysis, and interpretation
with CVT not associated with infection received anticoa-
of data for the work; Yanina Baduro drafted the 1st ver-
gulation. Death rate was higher than in high- and middle-
sion of the work, which was reviewed critically for impor-
income countries. Some of these differences may be real,
tant scientific and intellectual content by Jos
e Ferro. Jos
e
notably the high frequency of infection, the lower fre-
Ferro wrote the revised version of the manuscript.
quency of contraceptives as the “cause” of CVT and the
Both authors read and approved the final version of the
higher mortality. Some may be due to referral/selection
manuscript.
bias, to much less use of MRI and thrombophilia testing
This work is not intended to be submitted elsewhere,
and to less access/use of health care services by women
while being considered for publication in the Journal of
in Sub-Saharan Africa.
Stroke & Cerebrovascular Diseases
We found a time trend indicating a decrease in CVT
associated with infection, use of MR to confirm the diag-
nosis and more frequent use of anticoagulation in the last
Supplementary materials
two decades.
No previous reviews of CVT in Sub-Saharan Africa Supplementary material associated with this article can
have been previously published. A protocol for a system- be found in the online version at doi:10.1016/j.jstrokecere
atic review and meta-analysis of the global epidemiology brovasdis.2021.105712.
6 Y. BADURO AND J.M. FERRO

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