Cerebral Malaria

Malaria is the most important parasitic infection worldwide. Nearly 3.3 billion people were at risk of malaria in 2010, and an estimated 149 million to 274 million cases were reported. About 655,000 deaths were due to malaria, more than 85 percent of which were in children younger than 5 years of age. Despite a decrease in the prevalence by 17 percent in the last decade, much of this decline was in the European, American, and Western Pacific regions. Currently, 81 percent of cases are from Africa. Prior to intensive worldwide efforts toward malaria control by the United Nations and the Global Fund to Fight AIDS, Tuberculosis, and Malaria, malaria was estimated to cost Africa about 12 billion dollars annually.

Malaria infection is widely distributed ( Fig. 47-1 ), with Plasmodium falciparum predominating in sub-Saharan Africa, Haiti, New Guinea, Southeast Asia, South America, and Oceania. The majority of cases of malaria in the United States are imported by travelers to and immigrants from malarial areas, with more than 8,000 cases reported from 1999 through 2008.

Global map of malaria transmission.

(From the US Centers for Disease Control and Prevention.)

Five species of malaria infect humans: P. falciparum , Plasmodium vivax , Plasmodium ovale , Plasmodium malariae , and Plasmodium knowlesi. The life cycle of Plasmodium is similar across species. The infective sporozoites are injected by female Anopheles mosquitoes into subcutaneous tissue or directly into the blood stream, and thereafter circulate to the liver to invade hepatocytes. Parasites multiply, and after 1 to 2 weeks, schizonts rupture and release thousands of merozoites, which then enter the bloodstream to infect erythrocytes. All exoerythrocytic forms of P. falciparum rupture at about the same time, and none persists chronically in the liver.

Invasion of erythrocytes by merozoites requires specific surface receptors on the parasite and erythrocyte. In contrast with other Plasmodium species, P. falciparum uses multiple redundant pathways to invade, including sialic acid–dependent glycophorin pathways, and non-sialic acid–dependent ones. In addition, P. falciparum can invade erythrocytes of all ages, and parasitemia can reach high levels. The magnitude of parasitemia was previously thought to relate to the degree of morbidity and mortality, but other factors such as the degree of metabolic stress in nutritionally deficient children, presence of parasitic coinfections, and other less-understood mechanisms may play significant roles in adverse outcomes.

Within the erythrocyte, merozoites eventually develop into schizonts, which rupture to release merozoites capable of infecting new erythrocytes. Only the asexual erythrocytic stages are directly deleterious to the host, and the mechanisms involved in the development of clinical manifestations are related to fever, anemia, and tissue hypoxia, as well as host factors including immunopathologic events.

P. falciparum causes the most significant morbidity and mortality. A number of serious complications can occur in P. falciparum malaria, including acute renal failure, pulmonary edema, acidosis, hypoglycemia, and cerebral malaria.

Cerebral malaria occurs in 0.5 to 1 percent of P. falciparum cases, and is associated with a 15 to 20 percent mortality. Significant neurologic sequelae develop in 11 percent of cases. Sequestration of parasitized erythrocytes within the capillaries of the cerebral cortex is typically observed, but is likely not the only pathogenic mechanism. While the pathogenesis of cerebral malaria is incompletely understood and remains highly speculative, it is postulated that parasitized red blood cells express parasite-derived variant surface antigens, causing the erythrocytes to adhere to endothelial cells of venules, resulting in microvascular obstruction. Cerebral malaria is associated with specific var genes, the gene family that encodes the malarial cytoadherence protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Specifically, a subset of group A var genes containing domain cassettes 8 and 13 of the PfEMP1 were shown to be associated with severe cerebral malaria in children, and encoded the ligand that mediated adhesion to brain endothelium.

Endothelial cells are a major site of pathology, particularly in cerebral malaria, as these show signs of activation, including characteristic morphologic changes, upregulation of surface adhesion molecules and antigens, and production of numerous cytokines and other mediators. Proinflammatory cytokines such as tumor necrosis factor α (TNF-α), lymphotoxin, interferon-γ (IFN-γ), and interleukin-1β (IL-1β) may play a role in pathogenesis, as these are increased in cerebral malaria. Nitrous oxide was initially thought to contribute to the development of cerebral malaria, but recent studies have suggested that it plays a critical role in improving survival by modulating the immune response. Two randomized control trials are under way using inhaled nitrous oxide as adjuvant therapy in children with severe malaria to test this hypothesis. Increased intracranial pressure does contribute to morbidity and mortality, and is a marker for poor outcomes. However, opening pressures have not correlated with mortality, and are probably not a critical factor in determining survival.

High fever and rigors are the hallmarks of acute malaria. A prodrome may occur with malaise, headache, myalgias, and fatigue that can mimic viral illness. Other manifestations include backache, arthralgias, abdominal pain, nausea, vomiting, cough, tachypnea, lethargy, and delirium. Fever commonly rises to 105°F and may remain elevated between paroxysms of P. falciparum infection. On examination, patients frequently have splenomegaly and tender hepatomegaly. Lymphadenopathy is not a feature, and its presence should prompt investigation of an alternative etiology.

The World Health Organization (WHO) defines cerebral malaria as unarousable coma in a person with P. falciparum asexual parasitemia, in whom other causes of encephalopathy have been excluded. While this definition is very specific, patients typically manifest a spectrum of disease, and many will need to be treated as cerebral malaria. Presenting features may include seizures (15 to 20% in adults, 80% in children), disturbances of consciousness, acute delirium, meningismus, and, infrequently, focal neurologic abnormalities, including pyramidal signs, cranial nerve abnormalities, or movement disorders. Decorticate posturing or decerebrate posturing is more common in children and may indicate hypoglycemia or increased intracranial pressure. Adults are more likely than children to present with diffuse encephalopathy and no focal neurologic signs. Other causes of CNS infection and encephalopathy must be excluded, and biochemical screening of blood and examination of cerebrospinal fluid (CSF) are mandatory. Hypoglycemia may occur as a complication of severe P. falciparum malaria or its treatment, especially in pregnant patients or in association with severe disease, and may be responsible for deteriorating neurologic status.

Cerebral malaria should be suspected in any person with impaired consciousness, fever, and recent travel to or residence in a P. falciparum –endemic country. Demonstration of malaria parasites (specifically P. falciparum ) in thick and thin blood smears establishes the diagnosis. However, sensitivity and specificity of microscopy are operator dependent, and can be problematic in nonendemic countries, where laboratory technicians are not experienced in microscopic evaluation, or in resource-limited settings where diagnostic equipment is substandard or unavailable. Methods with similar or greater sensitivity than blood smears are available. These techniques include an enzyme-linked immunosorbent assay (ELISA) for a histidine-rich P. falciparum antigen, an immunoassay for species-specific parasite lactate dehydrogenase isoenzymes, and DNA hybridization and amplification of parasite DNA or mRNA using polymerase chain reaction (PCR).

Several point-of-care diagnostics based on these immunoassays have been developed and field-tested. However, these tests are considered complementary to microscopy since thick smears remain more sensitive in expert hands, speciation with antigen tests only distinguishes between falciparum and non-falciparum species, and the test can be persistently positive for a time after clearance of parasitemia. Moreover, point-of-care assay results are qualitative and cannot be used to measure parasite burden.

A variety of abnormalities in laboratory tests may be observed in cases of falciparum malaria, including a normocytic, normochromic hemolytic anemia, leukopenia, monocytosis, thrombocytopenia, proteinuria, azotemia, elevated liver enzymes, and disseminated intravascular coagulation. With severe P. falciparum malaria, lactic acidosis, elevated blood creatinine, and hypoglycemia may be observed.

When cerebral malaria is a consideration, lumbar puncture should be performed to exclude other causes of encephalopathy. In cerebral malaria, CSF examination occasionally reveals elevated protein concentration or mild pleocytosis, especially if seizures have occurred. Hypoglycorrhachia is not a feature and would indicate other causes. Imaging with computed tomography (CT) may show some brain edema in advanced stages. Magnetic resonance imaging (MRI) often shows brain enlargement without edema. Funduscopy should be performed since the presence of malaria retinopathy is the only reliable clinical feature that distinguishes cerebral malaria from other CNS pathologies.

Delay in the diagnosis of P. falciparum infection can prove to be fatal because patients, especially children, who appear clinically stable may deteriorate rapidly if not treated. If P. falciparum infection is suspected, patients should be hospitalized. Travel history to P. falciparum –endemic areas should be elicited, and it should be determined whether the patient took adequate antimalarial prophylaxis. Adults with uncomplicated P. falciparum malaria suspected to be chloroquine-resistant, and who are not desperately ill and are capable of taking oral medication, can be treated with oral atovaquone plus proguanil (four 250 mg/100 mg tablets daily for 3 days), with artemether-lumefantrine (four tablets twice a day for 3 days), or with oral quinine (650 mg salt three times daily) plus doxycycline (100 mg twice daily) or clindamycin (20 mg/kg daily in three divided doses) for 7 days. Alternative agents for oral treatment include mefloquine (unless there is concern for resistance if acquired in the regions of Southeast Asia), chloroquine, and hydrochloroquine (if acquired in chloroquine-sensitive areas). Oral quinine may cause cinchonism, characterized by tinnitus, headache, nausea, and visual disturbances.

Severe malaria, including cerebral malaria, should be treated parenterally. Quinidine gluconate is given by continuous intravenous infusion (10 mg/kg loading dose, then 0.02 mg/kg per minute). This is usually continued for 72 hours and stopped sooner if parasitemia decreases to 1 percent or less. Quinidine can be cardiotoxic, and appropriate monitoring must be performed. Once the patient improves and can take oral medication, quinidine can be discontinued and a 7-day course of treatment can be completed with a combination of oral quinine and tetracycline. Intravenous artesunate is available as an investigational new drug from the Centers for Disease Control, and should be administered with either atovaquone–proguanil, doxycycline, clindamycin (in pregnant women), or mefloquine.

After initiation of antimalarial therapy, patients with P. falciparum infection must be closely monitored for complications and response to treatment. Seizures should be treated with anticonvulsants, and frequent glucose monitoring is essential to manage hypoglycemia, especially in those treated with quinidine or quinine. Maintaining adequate fluid balance is critical in preventing further morbidity, especially in those with renal failure or pulmonary edema. Blood transfusions can be used to correct anemia, but can lead to significant fluid overload. Despite a lack of clear evidence, the CDC strongly recommends exchange transfusions for severe malaria, including those patients with cerebral malaria, acute respiratory distress syndrome, renal failure, or parasitemia exceeding 10 percent.

Hyperosmolar agents such as mannitol are helpful in patients with increased intracranial pressure. Other adjunctive therapies such as corticosteroids and chelating agents provide little benefit and should be avoided because of deleterious effects. Trials looking at the effect of inhaled nitrous oxide or erythropoetin on cerebral malaria are under way.

Cerebral Toxoplasmosis

Toxoplasma gondii is an apicomplexan protozoan that causes a zoonosis which manifests as an encephalitis or a chorioretinitis in humans. Infection may be acute or chronic, symptomatic or asymptomatic, and may affect both normal and immunocompromised hosts. The prevalence of Toxoplasma infection worldwide is 25 to 30 percent, but varies greatly between 10 and 80 percent depending on location. Infection is typically acquired when oocysts (containing sporozoites) or cysts (containing bradyzoites) are ingested from contaminated soil, water, fruits, vegetables, animal litter, or undercooked meat. Other known routes of transmission include congenital infection, accidental inoculation of organisms in laboratory workers, and organ transplantation.

Cats are the definitive hosts of Toxoplasma , and are a major zoonotic reservoir. Oocysts or cysts can infect virtually any mammalian host. After these are ingested by cats, T. gondii invades the intestinal epithelial cells and begins the definitive life cycle, eventually producing millions of oocysts.

Upon entry into humans, the sporozoite or bradyzoite, depending on the infective stage ingested, transforms into a tachyzoite that disrupts host cells and disseminates via the lymph and blood. The tachyzoite invades host cells and forms a protective parasitophorous vacuole within the cytoplasm. Interestingly, the parasite is able to modify the host cell behavior by commandeering the cell’s signaling cascades and other metabolic processes. T. gondii enters protected sites such as the brain and cornea, presumably through infected leukocytes, which exhibit increased migration and adhesion. Tachyzoite invasion is associated with a robust Th-1 response mediated by IL-12 and IFN-γ secretion by macrophages, neutrophils and dendritic cells, causing the proliferation of CD4 ⁺ and CD8 ⁺ T-cells. T. gondii modulates the host immune response as it shifts from active to latent infection by tightly regulating IL-12 production in order to prevent host death. This ensures that the parasite is able to infect the host chronically and increases the chances of replication and transmission. The tachyzoites eventually transform into bradyzoites, forming cysts that are established in numerous tissues and organs. These elicit little or no inflammatory response but persist as reservoirs for reactivation or transmission ( Fig. 47-2 ).

Toxoplasma gondii cyst in brain tissue stained with hematoxylin and eosin.

(From the US Centers for Disease Control and Prevention.)

Approximately 80 percent of primary toxoplasmosis infection is asymptomatic in immunocompetent adults. Nontender cervical adenopathy is most frequently seen among symptomatic individuals, but generalized adenopathy may be present. In some cases, adenopathy is accompanied by fever, night sweats, malaise, sore throat, rash, hepatosplenomegaly, and atypical lymphocytosis. The course of toxoplasmosis is usually benign and self-limited. A minority of patients can develop persistent lymphadenopathy. Rarely, immmunocompetent individuals have progressive disseminated disease with CNS infection.

Chorioretinitis from T. gondii occurs mostly in congenital infection, but may occasionally present in acute or reactivation disease. The lesion is a focal, necrotizing retinitis with intense vitreal inflammation, showing a characteristic “headlight in fog” appearance. Relapses of chorioretinitis are frequent, and are evident in the areas around the chorioretinal scars ( Fig. 47-3 ).

Toxoplasma chorioretinitis: a pale, atrophied lesion containing black pigment.

(From the US Centers for Disease Control and Prevention.)

Congenital infection is a result of primary infection of the mother during gestation. Chronic infection in the immunocompetent mother prior to conception is not transmitted to the fetus, but transmission has been documented with reactivation disease in HIV-infected pregnant women. Infection acquired in the first trimester is severe and can be associated with spontaneous abortion. Infection later in pregnancy can be symptomatic and be of variable severity depending on individual factors. In the newborn, the presence of hydrocephalus, retinochoroiditis, or intracranial calcifications is suggestive of congenital toxoplasmosis and should be evaluated accordingly. Most infants are asymptomatic at birth, but may present with overt symptoms, including severe developmental delay later in life.

Severe and often fatal toxoplasmosis has occurred in patients immunocompromised by treatment with corticosteroids or cytotoxic agents, and in those with lymphoreticular malignancies, organ transplantation, or acquired immunodeficiency syndrome (AIDS). In HIV infection, the rate of reactivation toxoplasmosis is highest in those with full-blown AIDS. While most disease in these patients is from reactivation, primary infection may occur. Immunodeficient individuals with toxoplasmosis usually manifest with encephalitis, meningoencephalitis, or mass lesions ( Fig. 47-4 ). Pneumonitis or myocarditis may also develop.

Magnetic resonance imaging (MRI) with toxoplasmosis in a patient with AIDS. Left image is a T2-weighted MRI showing the lesion with extensive perilesional edema; right image shows T1 contrast-enhancement of toxoplasmosis lesion.

(Courtesy of Dr. Nicolette Mariano.)

Early in the HIV epidemic, one-third or more of AIDS patients with antibodies to T. gondii developed reactivation CNS disease. However, the widespread use of antimicrobial drugs to prevent Pneumocystis jiroveci and the advent of potent combination antiretroviral therapy has resulted in decreased toxoplasmosis-associated deaths. In HIV-infected persons, Toxoplasma encephalitis usually develops when the CD4 count falls below 100/mm ³ . These patients most frequently have multifocal abscesses scattered throughout the cerebral hemispheres and present subacutely with focal neurologic deficits. The occurrence of fever, headache, seizures, and alterations in mental state is variable.

The diagnosis of primary toxoplasmosis in immunocompetent hosts, transplant patients, and pregnant women is typically established through serology: with a positive IgM, IgG seroconversion in paired sera, or a twofold increase in IgG titers. Prenatal diagnosis can be confirmed by PCR or mouse assays of amniotic fluid or serology from newborn serum or cord blood. Most disease in immunocompromised hosts is reactivation disease, and so the presence of IgG antibodies is suggestive of the diagnosis. Histology of brain biopsy specimens confirms the diagnosis, but is impractical in most cases. PCR of serum, CSF, and biopsy tissue has been done with varying degrees of success. CSF PCR is very specific, but sensitivity is low (50%) and it may become negative after treatment is started. Mouse assays of these specimens are usually performed only in reference laboratories. For retinochoroiditis, serology of aqueous humor in parallel with serum can help establish the diagnosis, and PCR of these samples can detect the parasite as well.

Cranial imaging should be performed in patients with suspected CNS toxoplasmosis. MRI usually reveals multiple ring-enhancing or solid lesions typically located in the basal ganglia ( Fig. 47-4 ). In severe immunosuppression, atypical presentations with either a solitary lesion or lack of enhancement may occur. In infants, CT is the method of choice, although ultrasound can be used. Mononuclear pleocytosis, elevated protein, and normal glucose are often reported in the CSF; these are nonspecific, and lumbar puncture may be hazardous in those with large mass lesions.

Definitive diagnosis of toxoplasmosis is made in the presence of a compatible clinical syndrome, consistent findings on MRI, CT, or other imaging modalities, and detection of the protozoan in a clinical sample. Patients with suspected Toxoplasma encephalitis, in the context of a positive IgG antibody, are typically started on empiric therapy and monitored for clinical and imaging response for about 3 weeks. Biopsy is reserved for refractory cases, or when alternative diagnoses such as CNS lymphoma cannot be excluded.

Immunocompetent patients with lymphadenopathy are usually not treated unless they have severe or persistent disease. Individuals exposed through laboratory accidents or via transfusions can develop severe disease and should receive treatment. These patients should be treated for 2 to 4 weeks with a combination of pyrimethamine, sulfadiazine, and folinic acid and then reassessed.

Suspected cases of ocular toxoplasmosis with documented inflammatory changes on fundoscopy should be started on treatment to prevent progression to blindness. Pyrimethamine, sulfadiazine, and leucovorin are used as therapy, using weight-based dosing for neonates and infants. Clindamycin can be substituted for sulfadiazine in cases of sulfonamide hypersensitivity. Corticosteroids are used adjunctively to decrease inflammation and the risk of complications especially if cerebral edema is present on neuroimaging.

Management of infected pregnant women varies between countries and within countries. Confirming a diagnosis of acute infection is essential due to the potential toxicity of the drugs used for treatment and in guiding any decision to terminate the pregnancy. Specific treatment indications and regimens for pregnant women have been reviewed elsewhere.

Acute disseminated infection in immunocompromised patients should always be treated. Treatment is continued for 4 to 6 weeks beyond the resolution of all signs and symptoms. Acute toxoplasmosis is most likely to occur in seronegative transplant patients receiving organs from seropositive donors. Secondary prophylaxis to prevent recurrences is of benefit, and should be continued for life unless the original immunocompromising condition has significantly improved or resolved.

AIDS patients with CD4 counts less than 100 cells/mm ³ are already on primary toxoplasmosis prophylaxis if they are on trimethoprim-sulfamethoxazole for Pneumocystis pneumonia (PCP). Patients who usually develop reactivation toxoplasmosis encephalitis are those with a late HIV diagnosis, or who are on alternative PCP prophylaxis without anti- Toxoplasma activity. The treatment of Toxoplasma encephalitis in HIV patients should always utilize at least two agents. There is evidence that trimethoprim- sulfamethoxazole (15 to 20 mg/kg daily of the trimethoprim component in three divided doses) is better tolerated and may be as effective as the standard pyrimethamine-sulfadiazine combination. This regimen can be utilized as intravenous therapy for severely ill patients. Induction treatment should be continued for at least 6 weeks, followed by maintenance therapy until CD4 counts are above 200 cells/mm ³ for at least 3 months.

First-line treatment for toxoplasmosis is usually a combination of pyrimethamine and a sulfonamide. These antifolates are active against tachyzoites and are synergistic in combination. Pyrimethamine is lipid-soluble and readily penetrates the brain parenchyma even in the absence of inflammation. In severe infection in adults, a loading dose of 200 mg is given orally followed by 50 to 75 mg daily for 3 to 6 weeks. Folinic acid (10 to 25 mg/day), during and for 1 week after pyrimethamine treatment has ceased, is added to decrease bone marrow suppression. For adults, sulfadiazine is also given at a dose to 1 to 1.5 g orally every 6 hours. Clindamycin 600 mg orally or intravenously every 6 hours can be substituted for sulfa drugs in case of hypersensitivity. Other agents that have been used include trimethoprim-sulfamethoxazole (see earlier), dapsone, clarithromycin, azithromycin, and atovaquone. There are different dosing regimens for children.

African Trypanosomiasis

Human African trypanosomiasis, more commonly known as sleeping sickness, affects 300,000 people in sub-Saharan Africa, with 32,000 new cases occurring every year. Approximately 60 million people living in endemic areas are at risk. The vector, Glossina , is also known as the tsetse fly. Two distinct forms exist: western (chronic) sleeping sickness, due to infection by Trypanosoma brucei gambiense , and eastern and southern (acute) sleeping sickness, caused by Trypanosoma brucei rhodesiense.

Trypanosoma brucei gambiense occurs mainly in the northern and western areas of sub-Saharan Africa, and is responsible for the majority of cases. The disorder has a subacute course and is perpetuated mainly through local reservoirs of chronically infected humans. East African trypanosomiasis occurs in the eastern and southern parts of equatorial Africa and is typically acquired from zoonotic sources. It has a more fulminant course, with death occurring within a few weeks after infection, thereby decreasing the possibility of human reservoirs for infection. Most cases in travelers have been due to T. b. rhodesiense.

Trypanosoma brucei undergoes several developmental stages in the tsetse fly over a life cycle of about 3 weeks. Upon ingestion with a blood meal, bloodstream trypomastigotes become procyclic trypomastigotes in the insect midgut and divide rapidly. These then leave the midgut and transform into epimastigotes, eventually making their way into the fly’s salivary glands. They change into metacyclic trypomastigotes, which are injected into the human or mammalian host with the blood meal. The metacyclic trypanosomes transform into the bloodstream form and invade extracellular spaces, including the blood, lymphatics, tissue fluids, and, eventually, the CNS via the CSF ( Fig. 47-5 ).

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