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Overview of the Effect and Epidemiology of Parasitic
Central Nervous System Infections in African
Children
Macpherson Mallewa, PhD,*,† and Jo M. Wilmshurst, MD‡
Infections of the central nervous system are a significant cause of neurologic dysfunction in
resource-limited countries, especially in Africa. The prevalence is not known and is most
likely underestimated because of the lack of access to accurate diagnostic screens. For
children, the legacy of subsequent neurodisability, which affects those who survive, is a
major cause of the burden of disease in Africa. Of the parasitic infections with unique effect
in Africa, cerebral malaria, neurocysticercosis, human African trypanosomiasis, toxoplasmosis, and schistosomiasis are largely preventable conditions, which are rarely seen in
resource-equipped settings. This article reviews the current understandings of these
parasitic and other rarer infections, highlighting the specific challenges in relation to
prevention, diagnosis, treatment, and the complications of coinfection.
Semin Pediatr Neurol 21:19-25 C 2014 Published by Elsevier Inc.
Introduction
Infections of the central nervous system (CNS) are among the
most devastating diseases with high mortality and morbidity.
These are infections caused by various pathogens including
bacteria, mycobacteria, virus, fungus, and parasites. Although
these infections occur worldwide, Africa particularly bears a
huge burden of these infections. The burden of these diseases
is made worse because survivors are often left with neurologic
sequelae affecting mobility, sensory organs, and cognitive
functions, as well as epilepsy. They inflict suffering by causing
lifelong disabilities, disfigurement, reduced economic productivity, and social stigma.1
CNS infections are underestimated as a cause of neurologic dysfunction in resource-limited countries, especially in
Africa. According to World Health Organization (WHO)
estimates, there are approximately 1 billion people who are
affected by 1 or more neglected tropical diseases. These
diseases are considered “neglected” because they occur
*Department of Paediatrics and Child Health, College of Medicine, Queen
Elizabeth Central Hospital, Blantyre, Malawi.
†Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre,
Malawi.
‡Department of Pediatric Neurology, Red Cross War Memorial Children’s
Hospital, School of Child and Adolescent Health, University of Cape
Town, Cape Town, South Africa.
Address reprint requests to Macpherson Mallewa, PhD, Department of
Paediatrics and Child Health, College of Medicine, P/B 360, Blantyre 3,
Malawi. E-mail: [email protected]
1071-9091/14/$-see front matter & 2014 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.spen.2014.02.003
mostly in the poorest of populations. Among these
neglected tropical diseases are several infections that affect
the CNS such as human African trypanosomiasis (HAT),
Chagas disease, leprosy, malaria, and neurocysticercosis
(NCC).2 Human immunodeficiency virus (HIV) and tuberculosis also create a heavy disease burden and are addressed
in other articles of this edition.
In this review, we highlight the understandings from
some of the parasitic infections that significantly affect the
CNS in African children. In a parallel article, the key viral
infections of significance in Africa are reviewed.
Cerebral Malaria
Pediatric cerebral malaria (CM) affects 3 million children
each year resulting in approximately 1 million deaths, with
90% of CM-related deaths occurring in Africa.3 Recent
reports suggest that cases of pediatric CM are falling
significantly throughout areas where malaria is endemic.4
There has been a reduction in the numbers of malaria
cases and malaria-related deaths by up to 50% over the past
decade in several African countries including Tanzania,
Kenya, and Zambia.5–7 Possible reasons for the reductions
are multifactorial, which include not only improvement in
quality of health systems, for example, better diagnostics
and implementation of highly effective antimalarial drugs,
but also scale investments in intervention strategies that
result in achieving high coverage of bed nets and
19
M. Mallewa and J.M. Wilmshurst
20
Table The Blantyre Coma Scale92
Verbal
0: No cry
1: Inappropriate cry or moan
2: Appropriate cry
Motor
0: Nonspecific or no response
1: Withdrawal from pain
2: Localizes pain
Eye
0: Not directed
1: Directed eye movements
intensification of indoor residual spraying of insecticides.
Moreover, there has been implementation of intermittent
presumptive treatment in vulnerable groups.3 Climatic
changes globally and changes in rainfall and humidity may
also have affected malaria vectors.8 However, whether these
trends persist remains to be seen.
The main pathologic process that leads to coma in
pediatric CM is sequestration of parasitized red blood cells
in the cerebral microcirculation leading to obstruction.9
The Blantyre Coma Scale (Table) is used in patient
assessments where CM is highly suspected based on
(1) coma with no localizing response to pain that persists
for more than 1 hour if the patient has experienced a
generalized seizure, (2) asexual forms of Plasmodium falciparum found in the blood, and (3) exclusion of other causes
of encephalopathy.10 Newer antimalarial agents that rapidly
clear peripheral parasitemia improve survival, but mortality
rates remain at 12%-25%.11 In high-transmission areas,
asymptomatic parasitemia is common, and as such in a child
with febrile illness and parasitemia, it represents a diagnostic
dilemma as to whether the illness is owing to the parasitemia or another pathology. A postmortem study in
Malawi of children meeting WHO case definition of CM
found that 23% had a nonmalarial cause of their coma.9
Retinal examination is now recommended, as retinopathy
has a high specificity and sensitivity to features diagnostic of
CM (Fig. 1).12,13 Malaria and HIV coinfection cases are
likely to occur in sub-Saharan Africa, where both diseases
are endemic. There are few reports on the effect of HIV on
the presentation and outcome of CM.14,15 Other viral
infections can masquerade as CM, and such dual infections
result in poorer outcome.16,17
Artemisinin-based combination therapies are now recommended by the WHO as first-line treatment of uncomplicated falciparum malaria in all areas where malaria is
endemic.18 Parenteral artesunate is replacing quinine for
the treatment of severe malaria.3 Unlike other parts of the
world, resistance trends are yet to be seen in Africa.19
Latin America, Asia, and sub-Saharan Africa.20,21 NCC
represents an important cause of seizures in children in
endemic countries21 as well as a major cause of epilepsy in
Africa.22,23 Lesions in NCC can be “active” when they are
associated with parenchymal cysts on magnetic resonance
imaging, or computed tomographic scans, or “inactive”
when scans show calcifications, which are better appreciated
on computed tomographic imaging (Fig. 2).24,25
Clinical manifestations of NCC are influenced by the
number, size, location, and stage of the parasites as well as
the immune response of the host with the associated
inflammation. Seizure disorders are typically seen in relation
with degenerating cysts and the associated brain inflammation. However, NCC may present with almost any neurologic
manifestation including encephalopathy and psychiatric disorders.26,27 Extraparenchymal NCC can present with signs of
raised intracranial pressure.28 The overall prognosis is good,
and clinical manifestations tend to decrease with time.29
A suspected diagnosis of NCC is confirmed with a
combination of neuroimaging and serology.30,31 In most
parts of Africa, neither resource is available, and management is based on clinical suspicion.
The effect of HIV coinfection on the natural history of
NCC has not been fully studied. Small case series in HIVcoinfected individuals report the occurrence of basilar
meningitis (racemose cysticercosis), also giant cysts that
are uncommon in immunocompetent hosts.32–34
Praziquantel and albendazole are the recommended antiparasitic drugs for the treatment of NCC.35 The use of
concomitant steroids is mandatory to decrease the risk of
neurologic symptoms that may appear during treatment.
However, no standard dose or duration is determined.36
NCC is a potentially eradicable disease. With successful
implementation of treatment in humans and pigs as well as
Neurocysticercosis
Cysticercosis is probably the most common parasitic infection of the CNS globally. It is due to the brain infiltration by
the larval stage of the cestode Taenia solium (cysticerci). This
parasite is commonly found in resource-poor countries of
Figure 1 The typical findings of malaria retinopathy. With permission from Dr Ian J C MacCormick. (Color version of figure is
available online.)
Overview of the effect and epidemiology of parasitic CNS infections in African children
Figure 2 CT brain imaging of a 7-year-old girl from the Eastern
Cape of South Africa with a severe seizure disorder, and associated
neuroregression, secondary to neurocysticercosis. All stages of the
disease are seen from the vesicular (cyst and scolex), colloidal (ring
enhancement with edema), granular nodular degeneration
(decreased enhancement and edema with early calcification)
through to involution (calcification). CT, computed tomographic.
enforcement of hygienic measures, for example, enforcing
pig pens, building of latrines, and hand washing after toilet
use, cases of T. solium infestation may be prevented and
therefore cases of epileptic seizures, reducing the burden of
suffering. Consequently, this would reduce socioeconomic
losses to African societies.37
Human African Trypanosomiasis
Infection with Trypanosoma brucei gambiense, which causes
the West African trypanosomiasis, or Trypanosoma brucei
rhodesiense, which causes the East African disease, is transmitted by the bite of an infected tsetse fly.
Over the last decade, stepped-up public health control
efforts in the major endemic countries in sub-Saharan Africa
have resulted in the reduction of cases of HAT from
300,000-500,000 cases to approximately 50,000-70,000
cases. However, 17,000 new cases still occur annually.38
These new cases of the Gambian sleeping sickness
occurred in the Democratic Republic of the Congo
(10,369 new cases in 2004), Angola, Sudan, Republic of
Congo, and Central African Republic.38 T. b. rhodesiense was
the cause for the remaining HAT cases found in sub-Saharan
Africa, mostly in Malawi, Uganda, and the United Republic
of Tanzania.38 Currently, Uganda is the only country with
both Gambian and Rhodesian HAT, but to date, each focus
of infection is geographically separated.39 Populations in the
age group between 15 and 45 years and living in remote
rural areas are considered especially vulnerable to both
21
forms of HAT.38 Young children are also at risk of HAT,
with cases in Gabon reported.40 Two 10-month-old infants
with HAT have been reported, which implies that transplacental infection can occur.41
Following multiplication of the parasites at the infection
site, a hemolymphatic stage occurs with waves of parasitemia (stage 1), which is followed by trypanosomes
invading the nervous system and causing leukoencephalitis
(the meningoencephalitic stage 2).42
Initially the trypanosomes are restricted to cerebral
periventricular organs and the choroid plexus, outside the
blood-brain barrier (BBB), as well as the dorsal root ganglia
in the spinal cord. Later, parasites cross the BBB at
postcapillary venules.43 Figure 2 illustrates the diffuse white
matter involvement seen on neuroimaging.
The clinical course is different for the 2 forms of African
trypanosomiasis; the West African disease is more indolent
compared with the East African disease, which follows a
more acute progression (Fig. 3). Both have 2 distinct phases
after a chancre stage at the site of inoculation. The early, or
hemolymphatic, stage consists of fever and lymphadenopathy. West African disease can be asymptomatic for several
years before progressing to the second, or encephalitic,
stage. East African disease is typically more rapid, progressing over several weeks to a spectrum of neurologic
symptoms including headache, personality changes, daytime
somnolence, and sensory, motor, and psychiatric disorders.
This also includes the characteristic sleep disturbances that
the disease is known for and progressive stupor.44
Diagnosis is confirmed by direct observation of intracellular trypomastigotes in serum or cerebrospinal fluid
(CSF). Serum antibody detection tests are sensitive and
specific for both acute and chronic forms of Trypanosoma
brucei infections.45 It is not clear whether HIV infection
alters the epidemiology or clinical course of either type of
HAT. Reports are conflicting. In a rural Congolese hospital,
among 18 patients treated with melarsoprol, 3 of the 4 HIVpositive individuals developed encephalopathy and died,
whereas all the 14 HIV-negative patients recovered.46
However, another study in Côte d’Ivoire found no difference
Figure 3 A 27-year-old patient with HAT demonstrating extensive
white matter involvement.49
22
in clinical presentation and response to treatment in HAT
patients with and without HIV.47
HAT is invariably lethal if left untreated. Suramin and
pentamidine, although effective for stage 1 disease, penetrate
the BBB poorly and are therefore ineffective at stage
2 disease. For the late encephalitic stage of HAT, the
treatment of choice is arsenic compounds, such as melarsoprol, which are associated with severe and even lethal side
effects. These agents are still widely used in Africa. There is
also an increase in melarsoprol-refractory HAT cases.42 The
alternative treatment is DL-α-difluoromethylornithine, which
is only effective against the West African form of HAT,
requires daily intravenous injection, has adverse effects, is
expensive, and is not readily available.
There is no vaccine, or drug, for a prophylaxis against
HAT. Control of African trypanosomiasis requires 2 strategic
approaches: reducing the disease reservoir and controlling
the tsetse fly vector. Humans are the main disease reservoir
for T. b. gambiense, therefore the main control strategy for this
subspecies is active case finding through population screening, followed by treatment of the infected persons when
identified. Tsetse fly traps are sometimes used as an adjunct.
Reducing the reservoir of infection for T. b. Rhodesiense on
the contrary is more difficult, as there are a variety of animal
hosts. Vector control is the primary strategy in use. This is
usually done with traps or screens, in combination with
insecticides and odors that attract the flies.48
Toxoplasmosis
Toxoplasmosis is a parasitic infection caused by the protozoan Toxoplasma gondii. It is widely distributed throughout
the world, and it is known to cause infection in all warmblooded animals, including humans. It is estimated that
globally one-third of the human population is chronically
infected with T. Gondii. In Africa, childhood toxoplasmosis is
usually through congenital infections. The prevalence of
toxoplasmosis varies by geographic location based on several
factors including climate, agricultural practices, eating habits,
feline population density, and socioeconomic status.49 There
are few studies on the prevalence of toxoplasmosis in Africa.
However, 1 study showed that To. gondii is widespread in
Mali, and elsewhere in West Africa, in both urban and rural
areas, and that rising seroprevalence in women of childbearing age indicates a significant risk of congenital disease.50
In children with HIV infection, toxoplasmosis is most
often due to the reactivation of latent infection. One-third of
HIV-infected people with serum antitoxoplasma IgG antibodies develop toxoplasma encephalitis.51,52 The incidence of
toxoplasma encephalitis is reduced among HIV-infected
people receiving trimethoprim-sulfamethoxazole or dapsonepyrimethamine therapy as a prophylaxis against Pneumocystis
carinii pneumonia.53
The severity of congenital toxoplasmosis is influenced
largely by the timing of maternal infection, especially later in
the pregnancy.54,55 Ocular disease, mainly chorioretinitis,
mild or severe congenital neurologic defects, learning
M. Mallewa and J.M. Wilmshurst
disabilities, or a combination occur.50,54,55 Learning difficulties develop with advancing age owing to recrudescence
of bradyzoite cysts.56,57 In older children, toxoplasmosis
typically presents as a subclinical infection. In the immunocompromised individuals, clinical manifestations of CNS
toxoplasmosis typically include headache, altered mental
status, seizures, focal neurologic deficits, hemiparesis, ataxia,
and cranial nerve palsies.58,59
Although uncommon, toxoplasmosis of the spinal cord is
reported in HIV-infected patients although very rare in HIVnegative individuals.60,61
Definitive diagnosis is made when tachyzoites are identified in biopsy samples. However, identification of anti–To.
gondii antibodies by enzyme-linked immunosorbent assay is
both sensitive and specific for the diagnosis. Polymerase
chain reaction assay of CSF is highly specific and sensitive in
some laboratories. Analysis is challenging even in resourceequipped settings and very limited in most parts of Africa.62
On neuroimaging, the existence of multiple ring-enhancing
lesions in the basal ganglia or cerebrum, especially in the
presence of antitoxoplasma IgG antibodies, suggests the
presence of CNS toxoplasmosis and is sufficient to start
presumptive treatment for CNS toxoplasmosis.
In resource-limited countries, such as sub-Saharan Africa,
at present, the treatment of toxoplasmosis is usually initiated
on presumptive diagnosis in at-risk groups such as HIVpositive individuals, and the clinical diagnosis is made
because of clinical (and where possible, radiologic) response
to specific therapy. This is owing to the unavailability of
resources to make the radiologic and serologic confirmation
of the infection.63
There is treatment available for acute infection. However,
no drugs are known to be effective against these latent forms
of toxoplasmosis.
Immunocompromised individuals are particularly at risk
of death from primary or recrudescent infection. Drugs for
the treatment of CNS toxoplasmosis should include pyrimethamine, sulfadiazine, and folinic acid.64
Schistosomiasis (Bilharzia)
The worldwide prevalence of CNS schistosomiasis has a
marked variability (0.3%-30%).65,66 In endemic areas such
as Malawi, schistosomiasis is a frequent cause of nontraumatic myelopathies (6%).67 Neuroschistosomiasis is
probably the most severe clinical form of the schistosome
infection.68–71
From case studies, there is a suggestion that neurologic
complications early in the course of infection are due to egg
deposition, and this follows the migration of adult worms to
the brain or spinal cord. Granuloma formation follows with
thousands of eggs deposited. This is the hallmark of
neuroschistosomiasis.70,71
Schistosomiasis infection of the CNS includes signs and
symptoms of increased intracranial pressure, myelopathy, and
radiculopathy.68–71 Complications of intracerebral disease
may include headache, visual disturbances, delirium, seizures,
Overview of the effect and epidemiology of parasitic CNS infections in African children
motor deficit, ataxia, and encephalopathy. Features of acute
transverse myelitis and subacute myeloradiculopathy of the
lumbosacral region are probably the most commonly
reported neurologic manifestations of both Schistosoma mansoni and Schistosoma haematobium infection. However, acute
encephalitis following involvement of the cortex, subcortical
white matter, basal ganglia, or internal capsule is the usual
presentation in infection by Schistosoma japonicum.70,71
In HIV-infected individuals, schistosomiasis induces less
granuloma formation around the egg. The few cases of CNS
schistosomiasis in HIV-infected people suggest that this may
predispose to a disseminated, or miliary, form of the
infection.72,73
The finding of eggs in the stool, or positive serology result,
is supportive but not direct evidence of schistosomiasis of the
CNS. A positive diagnostic finding coupled with neuroimaging, and in the context of neurologic symptoms, makes
neuroschistosomiasis a likely diagnosis. Definitive diagnosis
requires histopathologic study at biopsy when there is
schistosome eggs and granulomas.64 Radiologic and histopathologic diagnoses are unavailable in most African settings
making the management of neuroschistosomiasis a challenge.
Praziquantel is the effective treatment for all Schistosoma
species, and is curative in 60%-90% of cases.74 Artemether,
unlike praziquantel, is more effective against immature
migrating larvae (schistosomula), and in combination with
praziquantel has synergistic properties.75 When praziquantel
is ineffective, oxamniquine may be used for treatment.76
The control of schistosomiasis is mostly based on largescale treatment of at-risk population groups, access to safe
water, improved sanitation, hygiene education, and snail
control.
To reduce disease burden, periodic treatment of at-risk
populations is recommended, as this cures mild symptoms,
prevents infected people from developing severe, late-stage
chronic disease, and also stops the infection spreading to
others. A major limitation to schistosomiasis control is
access to praziquantel, with only 10% of affected people
receiving treatment in 2011.77
Miscellaneous Parasitic
Infections of the CNS
Naegleria fowleri (Primary Amebic
Meningoencephalitis)
Primary amebic meningoencephalitis (PAM) is caused by
N. fowleri. It is commonly referred to as “brain-eating
ameba.” This is a free-living single-celled organism which
is present throughout the world.78 Most infections occur in
children and young adults who play or dive in bodies of
stagnant freshwater.79 Less than 100 cases are reported
worldwide. Most likely this reflects underreporting.
The infection is almost invariably fatal, with mortality
approaching 95%, which usually occurs within 72 hours of
onset of symptoms.80 Early recognition of infection can
result in effective treatment for a few patients.81
23
Signs of meningitis are common, and some patients
present with seizures or coma. Differentiation between PAM
and bacterial meningitis can be difficult, particularly in subSaharan African, hence the underreporting. Diagnosis is by
polymerase chain reaction analysis, but this is unavailable in
most African settings where the disease occurs.82
Neuroimaging is usually normal at onset; however, severe
edema may be present in some patients.83 Autopsy findings
are usually localized to the posterior fossa and brain
stem.64,84 Treatment is with intrathecal amphotericin B.85
Neurologic Complications of
Paragonimus Infections
This is the only lung fluke that is capable of infecting
humans. An estimated 20 million people are infected
worldwide, with 10 million in China alone.86 The “oriental
lung fluke,” Paragonimiasis westermani, is endemic throughout Asia and Western Africa. Meningoencephalitis is the
most common CNS complication and may persist for 6-8
weeks. Symptoms during chronic CNS infection are often
vague and may include headache, weakness, or nausea.
Other CNS complications include transverse myelitis and
myelopathy.87 Seizures are usually present in patients with
more extensive CNS involvement. Untreated CNS disease
carries a mortality rate of almost 5%.88 Definitive diagnosis
of CNS involvement requires demonstration of eggs in CSF
or brain biopsy material, and this causes diagnostic challenges in African settings.89 Plain skull radiographs can be
used, and they are often dramatic, demonstrating a characteristic “soap-bubble” appearance.90 The treatment of choice
for paragonimiasis is Praziquantel.91
Conclusion and Future
Directions
Although parasitic infections of the CNS seem to be
infections of resource-limited countries, with the increasing
amount of international travel, all travelers to endemic
regions are potentially at risk, with such infections becoming
increasingly prevalent throughout the world. With the
advent of increasing global travel, more potent immunosuppression, and HIV infection, parasitic and viral CNS
infections will likely become even more commonplace. Basic
familiarity with common pathogens can make diagnosis
more expeditious and efficient. For the clinician confronted
with a patient with suspected parasitic infection, additional
assistance with diagnostic evaluation and therapy can be
obtained at the following Web sites www.cdp.cdc.gov/dpdx/
and www.who.int/inffs/en/index.html.
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