CHAPTER 46 Parasitic Infections
Parasitic diseases of the central nervous system (CNS) affect millions of people in the developing world, where most infections are linked to poverty and related conditions. In addition, increased tourism and immigration have turned some formerly geographically restricted parasitic infections into widespread conditions.1 Parasites are divided primarily into protozoa and helminths. Protozoa are simpler unicellular microorganisms, whereas helminths are multicellular organisms with functional structures and complex life cycles that usually involve two or more hosts. Helminth parasites include nematodes (roundworms), trematodes (flukes), and cestodes (tapeworms). Infection of the CNS by parasites causes pleomorphic and nonspecific clinical syndromes, including seizure disorders, subacute or chronic meningitis, acute or subacute encephalitis, space-occupying brain lesions, stroke, and myelopathy.2 In this chapter we review the most common parasitic infections of the CNS.
Protozoal Infections
Malaria
Plasmodium infections have a complex biologic cycle. Humans are infected when the sporozoite forms of the parasite are inoculated through the skin during a blood meal by a female Anopheles mosquito. Sporozoites are carried to the liver of the host, where they hide and mature into tissue schizonts that liberate many merozoites, or products of asexual division. Merozoites enter the bloodstream, parasitize red blood cells, mature into trophozoites, and again divide to produce schizonts, which will rupture and simultaneously release many merozoites into the circulation. These merozoites invade a new group of red cells and the cycle continues. A proportion of trophozoites transform into male or female gametocytes. The life cycle is completed when the mosquito ingests gametocytes in infected human red blood cells and they reproduce sexually in the mosquito to form sporozoites.3 Of the four species of malaria parasites that can infect humans, only Plasmodium falciparum causes cerebral malaria.
Clinical Manifestations
Cerebral malaria is a major cause of mortality in the world, mostly in Africa. The current definition of cerebral malaria requires all of the following: (1) unarousable coma, (2) evidence of acute infection with P. falciparum, and (3) no other identifiable cause of coma.3 Fever is the initial complaint. This is followed by progressive somnolence associated with seizures, extensor posturing, and disconjugate gaze. Retinal hemorrhages suggest a poor prognosis. Some patients, particularly children, have focal signs related to cerebral infarcts or hemorrhage. Hypoglycemia, pulmonary edema, renal failure, bleeding diathesis, and hepatic dysfunction may complicate the course of the disease.4 Up to 25% of patients die despite medical care. Permanent sequelae, more common in children, include mental retardation, epilepsy, blindness, and motor deficits.5
Diagnosis
P. falciparum may be seen by examining thin and thick blood smears with Giemsa stain; repeated examinations may be needed because the parasitemia is cyclic. Although cerebrospinal fluid (CSF) is usually normal, routine CSF examination is mandatory to exclude other causes of encephalopathy. Neuroimaging studies may show brain swelling or small hemorrhages in severe cases.6
Pathology
Brain edema and small ring hemorrhages in the subcortical white matter are found in almost 80% of fatal cases. The hemorrhaging is caused by extravasation of erythrocytes as a result of endothelial damage. The erythrocytes that form the ring hemorrhages are not parasitized, thus suggesting that the damage to blood vessels is related to the liberation of cytokines and vasoactive substances (humoral hypothesis). Capillaries and venules are plugged by clumped, parasitized erythrocytes, which causes brain damage because of obstruction of the cerebral microvasculature, reduced cerebral blood flow, increased concentrations of lactic acid, and ischemic hypoxia (mechanical hypothesis).7 The brains of patients who survive the acute phase of the disease have granulomatous lesions (Dürck’s nodules) at the site of the ring hemorrhages.
Treatment
Because of chloroquine-resistant strains of P. falciparum, quinine is the drug of choice for cerebral malaria. After an initial loading dose (20 mg/kg), the maintenance dose of quinine should be adjusted according to plasma concentrations to prevent accumulation. Quinidine may be used when quinine is not available. More recent clinical trials have shown that artemether, an artemisinin derivative, is equally as effective as but less toxic than quinine for the treatment of cerebral malaria.8 Artesunate, another artemisinin derivative, can reduce mortality by more than a third in comparison to quinine.9 Systemic complications must be recognized and treated. Symptomatic measures include anticonvulsants, sedatives, and osmotic diuretics. Corticosteroids are harmful to comatose patients with cerebral malaria.10
Toxoplasmosis
After the acquired immunodeficiency syndrome (AIDS) epidemic, toxoplasmosis has become a highly common parasitic disease of the CNS.11 Toxoplasma gondii is a protozoan acquired by the ingestion of contaminated cat feces or by eating undercooked meat. In AIDS patients, CNS toxoplasmosis most often results from reactivation of a dormant infection with T. gondii. CNS toxoplasmosis may also develop in immunocompetent hosts during acute infections, and fetuses may be involved as a result of placental transmission of tachyzoites from women who acquire the disease during pregnancy.
Clinical Manifestations
Neurological symptoms rarely develop in immunocompetent hosts, although an acute encephalitis with fever, irritability, seizures, and drowsiness progressing to coma occurs in some cases. Immunocompromised hosts are also susceptible to an acute encephalitic syndrome or, more frequently, a subacute disease characterized by focal signs associated with seizures and signs of intracranial hypertension.12,13 Apparently, this focal form predominates in AIDS patients who contracted latent infection before the depletion of CD4+ cells, whereas the diffuse encephalitic form, in which multiple parasite-containing microglial nodules are disseminated through the brain, is more common in those who became infected after they were immunosuppressed.14 Meningeal signs rarely occur in patients with cerebral toxoplasmosis because the pathologic lesions are usually confined to the brain parenchyma and do not disseminate through the subarachnoid space.14 In AIDS patients, the clinical picture is usually complicated because of concurrent infections.
Diagnosis
In normal hosts, a fourfold rise in serum antibody titer is a sensitive indicator of acute infection. The sustained persistence of specific IgM antibodies and high IgG titers in a significant proportion of individuals in the general population complicates the serologic interpretation for discrimination between latent infection and active infection, regardless of their human immunodeficiency virus serologic status.15–17 There is controversy regarding the positive predictive value of high IgG titers for presumed CNS toxoplasmosis in AIDS patients.18,19 The role of serology in AIDS patients is to establish at-risk status for active disease. Absence of antibodies in AIDS patients with CNS toxoplasmosis is rarely seen and should raise the possibility of an alternative diagnosis.15,20 Neuroimaging studies show ring-enhancing lesions surrounded by edema; the lesions are usually multiple and may be located in the subcortical white matter, the basal ganglia, or the brainstem.21 However, ring-enhancing lesions are not pathognomonic for cerebral toxoplasmosis because they may be observed in other diseases affecting AIDS patients, so definitive diagnosis requires histologic demonstration of the parasite. Empirical therapy followed by repeated neuroimaging studies at 3 weeks has been proposed as an alternative to biopsy in AIDS patients. Polymerase chain reaction (PCR) techniques have been introduced with promising results for the detection of T. gondii DNA from the CSF of patients with cerebral toxoplasmosis.22
Pathology
T. gondii may produce a focal or diffuse necrotizing encephalitis associated with perivascular inflammation. Cerebral abscesses may also occur and are most often located at the corticosubcortical junction, basal ganglia, and upper brainstem.23 They consist of a necrotic center and a periphery in which multiple tachyzoites and cysts are seen together with patchy areas of necrosis and perivascular cuffing of lymphocytes. Glial nodules composed of astrocytes and microglial cells are common in the surrounding brain tissue.
Treatment
The combination of pyrimethamine (100 to 200 mg the first day, followed by 50 to 75 mg/day for 6 weeks) and sulfadiazine (4 to 6 g/day for 6 weeks) is the therapy of choice for CNS toxoplasmosis.24 Clindamycin, clarithromycin, trimetrexate, piritrexim, and atovaquone are alternative drugs in patients in whom skin reactions to sulfadiazine develop.25 In AIDS patients, permanent maintenance therapy with pyrimethamine and sulfadiazine is usually advised to decrease the risk for relapse.
African Trypanosomiasis
Clinical Manifestations
T. brucei invades the CNS very shortly after inoculation and remains latent for a long time.26,27 Thereafter, the disease enters into a stage in which the symptoms—fever, hepatosplenomegaly, and cervical lymphadenopathy (Winterbottom’s sign)—suggest activation of the reticuloendothelial system. Somnolence, apathy, involuntary movements, and rigidity then appear. The neurological manifestations progress to dementia, stupor, coma, and death.
Diagnosis
T. brucei may be isolated from blood smears and from CSF, lymph node, and bone marrow aspirates. Repeated examinations and concentration techniques may be necessary. CSF examination may reveal lymphocytic pleocytosis, increased protein, and the typical Mott cells (plasma cells filled with eosinophilic inclusions of IgM). Demonstration of motile trypanosomes in CSF confirms CNS involvement. Chronic disease may be diagnosed by immune tests performed with serum or CSF. Neuroimaging findings are nonspecific and include diffuse changes in white matter, hyperintensity in the basal ganglia, and ventricular enlargement.28,29
Treatment
When CNS symptoms and signs of CSF inflammation have appeared, therapy requires the use of melarsoprol. This arsenic drug produces a severe reactive encephalopathy in about 10% of patients, half of whom die of it. The role of pretreatment with corticosteroids to prevent this reaction is unclear.30
American Trypanosomiasis
Triatomine bugs (“kissing bugs”), found mostly in the genus Triatoma, are the vector for T. cruzi. These insects infect humans by biting them to feed on their blood and defecating in the area. T. cruzi parasites in the insect’s feces are then exposed to the bite wound or facial mucosae (eyes, mouth), usually by the bitten person when scratching. More rarely, infection can be acquired through uncooked food contaminated with infected bug feces, from blood/organ donation, or congenitally from an infected mother. An estimated 10 to 12 million people are currently infected with T. cruzi in Latin America, approximately 30% of whom, or 3 to 4 million, have or will eventually have consequent life-threatening cardiac or gastrointestinal disease, or both.31–33 CNS disease is rare and occurs mostly in immunocompromised individuals.
Clinical Manifestations
Unilateral orbital edema (Romaña’s sign) is considered the typical sign of acute Chagas’ disease and reflects the site of a bite. The edema is associated with mild constitutional symptoms, although early invasion of the CNS by trypanosomes may cause a diffuse encephalopathy, particularly in infants and patients with AIDS.34 Chronic disease is not usually associated with primary neurological complications; however, cardioembolic brain infarcts develop in some patients as a result of chagasic dilated cardiomyopathy. In addition, immunocompromised patients can experience reactivation of chronic infections, which results in a rapidly fatal meningoencephalitic syndrome similar to that observed in acute infections.35
Pathology
The brains of patients with Chagas’ disease involving the brain show multiple areas of hemorrhagic necrosis, glial proliferation, and perivascular infiltrates of inflammatory cells.36
Treatment
Antitrypanosomal drug therapy with either nifurtimox or benznidazole can cure most, if not all, congenitally infected infants when treated early in life, as well as 60% or more of infected children. The earlier the treatment in the course of infection, the higher the probability of cure. Chronic Chagas’ disease has no specific treatment. Nevertheless, recent studies suggest that adults with clinical signs of early chronic Chagas’ disease may also benefit from specific drug therapy.37 However, antitrypanosomal drug therapy requires prolonged administration of one of the only two available drugs, both with significant side effects and elevated cost.
Free-Living Amebae
Free-living amebae of the genera Acanthamoeba, Balamuthia, and Naegleria may invade the CNS.38 Acanthamoeba spp. and Balamuthia mandrillaris are opportunistic pathogens that affect mainly immunocompromised patients, and they invade the CNS by the hematogenous route from a primary infection of the skin or the respiratory tract. In contrast, Naegleria fowleri infection occurs in normal hosts and is acquired during swimming in warm fresh water; the parasites enter through the nasal cavity and migrate through olfactory nerves to the CNS.
Clinical Manifestations
Acanthamoeba spp. and B. mandrillaris produce a subacute disease called granulomatous amebic encephalitis characterized by low-grade fever, focal signs, seizures, intracranial hypertension, and behavioral changes; the disease runs a progressive course over a 2- to 8-week period.38–40 Balamuthia infection is usually manifested initially by a centrofacial skin lesion, which allows the diagnosis. N. fowleri causes primary amebic meningoencephalitis, a fulminant disease carrying a grim prognosis that resembles acute bacterial meningitis.38,41
Diagnosis
Neuroimaging studies usually show multiple ring-enhancing lesions in patients infected with Acanthamoeba spp. and B. mandrillaris and diffuse edema in those infected with N. fowleri.42 Examination of fresh CSF may reveal mobile trophozoites in patients with N. fowleri encephalitis. In contrast, the diagnosis of infection with Acanthamoeba spp. and B. mandrillaris usually rests on the demonstration of parasites in biopsy specimens.
Pathology
CNS infection by Acanthamoeba spp. and B. mandrillaris results in the formation of hemorrhagic brain abscesses surrounded by a granulomatous inflammatory infiltrate. Invasion of arterial walls by trophozoites causes a necrotizing angiitis that may lead to cerebral infarcts.39,40 N. fowleri induces purulent meningitis associated with diffuse hemorrhagic necrosis of the brain parenchyma; involvement is more prominent in the frontal lobes and the olfactory bulbs, around the portal of entry of the microorganisms.41
Amebiasis by Entamoeba histolytica
The intestinal parasite E. histolytica normally causes dysenteric diarrhea or liver abscesses. It may invade the CNS from the colon or liver in patients with severe infections (usually in the setting of advanced systemic amebiasis) and produce a multifocal encephalopathy.43 Neuroimaging studies generally show multiple ring-enhancing lesions. The diagnosis of E. histolytica amebiasis is made by demonstration of parasites in biopsy specimens. Pathologic examination of tissue infected with E. histolytica shows multiple ill-defined brain abscesses formed by a central hemorrhagic area and a rim of necrotic tissue.43 Surgery and metronidazole are advised for E. histolytica brain abscesses.43
Helminthic Infections
Cysticercosis
Cysticercosis occurs when humans become intermediate hosts of Taenia solium by ingesting its eggs from contaminated food or through contact with the feces of T. solium carriers. After ingestion, the eggs mature into oncospheres, which are then carried into the tissues of the host, where cysticerci develop. Invasion of the parasites into the CNS causes neurocysticercosis (NCC).44
Clinical Manifestations
Epilepsy is the most common manifestation of NCC,45 but a variety of focal neurological signs have also been described in patients with NCC. These manifestations usually follow a subacute course, thus making it difficult to differentiate NCC from neoplasia or other infections of the CNS. Hydrocephalus, mass effect, and cysticercotic encephalitis are the most common causes of intracranial hypertension in patients with NCC.46,47 As a result of intense inflammation around cysticerci and diffuse cerebral edema, cysticercotic encephalitis is a particularly severe form of NCC characterized by headache, vomiting, generalized seizures, decreased visual acuity, and clouding of consciousness.47 Manifestations of spinal cysticercosis include motor and sensory deficits, which vary according to the level of the lesion.48
Diagnosis
Accurate diagnosis of NCC is possible with proper interpretation of clinical data together with neuroimaging findings and results of immunologic tests.49 Neuroimaging studies provide objective evidence about the location of lesions and the degree of the host inflammatory response against the parasites. The most typical findings are cystic lesions showing the scolex and parenchymal brain calcifications.50
