Parasitic Infections of the Nervous System

Abstract

Purpose of Review:

This article reviews how parasites affect the human nervous system, with a focus on four parasitic infections of major public health importance worldwide, two caused by protozoa (malaria and toxoplasmosis) and two by helminths (neurocysticercosis and schistosomiasis).

Recent Findings:

Parasitic infections in humans are common, and many may affect the central nervous system where they may survive unnoticed or may cause significant pathology or even lead to the death of the host. Neuroparasitoses should be considered in the differential diagnosis of neurologic lesions, particularly in individuals from endemic regions or those with a history of travel.

Summary:

Cerebral malaria is a significant cause of mortality, particularly in African children, in whom infected red blood cells affect the cerebral vessels causing severe encephalopathy. Neurocysticercosis is the most common cause of acquired epilepsy worldwide and has varied clinical presentations, depending on the number, size, and location of the parasites in the nervous system as well as on the hostś inflammatory response. Toxoplasmosis is distributed worldwide, affecting a significant proportion of the population, and may reactivate in patients who are immunosuppressed, causing encephalitis and focal abscesses. Schistosomiasis causes granulomatous lesions in the brain or the spinal cord.

INTRODUCTION

A parasite is an organism that lives on or in another organism from a different species, taking its nourishment from the host. Parasites do not always harm the host, and a typical vertebrate is the host of many species of parasites. The human nervous system can be invaded by multiple parasite species, which, in some cases, cause a significant burden of morbidity and mortality.

Endoparasites (those living inside the host) are classified as protozoa or helminths. Protozoa are unicellular microscopic species, whereas helminths are more complex organisms and may reach several meters in length Some parasites (such as Toxoplasma gondii or Toxocara canis) are distributed worldwide, whereas others (such as Plasmodium, Schistosoma, and Taenia solium) occur in particular endemic regions but may be diagnosed in nonendemic areas because of travel and migration of infected individuals.¹ This article reviews how parasites affect the human nervous system and the types of pathology they cause, focusing on four parasitic infections of major public health importance worldwide, two caused by protozoa (malaria and toxoplasmosis) and two by helminths (neurocysticercosis and schistosomiasis). Other parasitic infections that can rarely be seen in neurologic practice are also briefly discussed.

MECHANISMS OF PARASITE INVASION AND PATHOLOGY

Parasites use multiple mechanisms to overcome the physical and immunologic barriers that vertebrates have evolved to protect their nervous systems. Some parasites, such as free-living amoebas, can enter the central nervous system (CNS) via the olfactory nerve.² Others, such as most nematodes and cestodes, enter the host via the bloodstream and thus require prior successful breaching of the skin or mucosa³ either by the bite of a vector organism or secretion of proteolytic enzymes. To enter the CNS, parasites must then traverse the blood-brain barrier via a paracellular or transcellular route from the bloodstream or by being transported in a macrophagic cell.³ Once the parasite enters the host, the host immune system will attempt to destroy it; the parasite will try to avoid destruction using immune mechanisms such as molecular mimicry, invasion of host cells, and secretion of agents able to modulate the host immune response.

Entry of a parasite into the CNS does not necessarily mean CNS damage, although, in most cases, it does result in pathology. CNS damage by parasites may occur in diverse forms. Tissue damage may result from the presence of the parasite, parasite products (ie, parasite proteases), or the host inflammatory response to these products, for example to dying and degenerating T. solium cysts in neurocysticercosis. Larval and adult nematodes or cestodes may also cause pathology by actively migrating through the host tissues, as in Gnathostoma infections or other eosinophilic meningitis.

CNS parasitoses can result in a variety of lesions, including granulomatous or cystic lesions, abscesses, encephalitis, meningitis, or myelitis, any of which may occur alone or in combination. These can present with diverse clinical manifestations, including seizures, focal deficits, mass effect, and intracranial hypertension, and can also cause complications such as vasculitis, stroke, hydrocephalus, and others.⁴

CEREBRAL MALARIA

Malaria is the most common parasitic disease of humans and the most common parasitic cause of mortality and morbidity worldwide. Annually, malaria causes more than 400,000 deaths in endemic regions, mostly in African children.⁵ Although it is usually considered a “tropical” disease, it is not restricted to the tropics, and approximately 10,000 cases are diagnosed every year in travelers.⁶ Although four species of Plasmodium can cause human malaria, only Plasmodium falciparum affects the CNS, resulting in the most severe form of disease, cerebral malaria. Cerebral malaria may be the most common cause of nontraumatic encephalopathy in the world.^6,7

Life Cycle

Transmission of P. falciparum to humans occurs by the bite of an infected Anopheles species mosquito. The parasite has a very complex life cycle. After being injected under the skin, the infective sporozoites reach the liver and infect hepatocytes. In the hepatocytes, they reproduce to significant numbers to form a hepatic schizont, after which the cell breaks and releases merozoites. Merozoites infect red blood cells and alter their shape and function. In the red cell, the parasites (now in the trophozoite stage) reproduce again to form schizonts and rupture the erythrocyte, releasing a new generation of merozoites that infect new erythrocytes and continue the blood cycle. Synchronization of this blood cycle and erythrocyte rupture causes the regularly spaced characteristic cyclical fever and malaise (Figure 6-1).

Figure 6–1.

Life cycle of the malaria parasite.

Modified from malariasite.com/life-cycle.

Clinical Presentation

Severe malaria is defined by one or more of the following: impaired consciousness, prostration, multiple seizures, acidotic breathing, acute pulmonary edema and acute respiratory distress syndrome, circulatory collapse or shock, low systolic blood pressure, acute kidney injury, clinical jaundice plus evidence of other vital organ dysfunction, or abnormal bleeding.^8,9 Cerebral malaria, and severe malarial anemia are the major causes of mortality in severe malaria. Cerebral malaria primarily affects children and nonimmune adults (such as travelers to endemic regions). In children, cerebral malaria manifests as a febrile encephalopathy with seizures (in more than 70%), with the usual case definition involving coma associated with acute infection with P. falciparum in the absence of other identifiable causes.⁶ The most vulnerable age group is between 6 months and 5 years old (other age groups are protected by maternal immunity or a previous exposure to the parasite). In the initial days of infection, nonspecific symptoms develop (eg, fever, cough, and vomiting), with the child subsequently falling into a deep coma with associated seizures. In adults, the progression to coma is gradual, seizures are less frequently observed (in 15% to 20%) and multiorgan system failure develops.¹⁰

Untreated cerebral malaria is lethal in all cases. Even under appropriate care, short-term mortality may approach 15% to 30%. Approximately 30% of survivors of cerebral malaria develop neurologic complications, such as epilepsy, cognitive and behavioral disorders, or neurologic deficits.^11,12 Adult survivors generally have fewer neurologic complications but can rarely develop postmalaria neurologic syndrome, which is similar to acute disseminated encephalomyelitis (ADEM).

Although the disease is called cerebral malaria, the parasite never invades the brain tissues. The pathogenesis is not completely understood, but the principal factor is the obstruction of blood vessels caused by intravascular sequestration of infected red cells, with subsequent cytokine release, blood-brain barrier disruption, brain edema, and metabolic alterations (Figure 6-2).^6,13,14

Figure 6–2. Pathology of cerebral malaria.

A, Macroscopic pathology of cerebral malaria (left) compared to a normal brain (right) B, Close-up view of the brain demonstrating the typical “flea-bitten” appearance resulting from multiple ring hemorrhages in the white matter.

Diagnosis

The diagnosis of malaria is based on the demonstration of parasite forms on blood microscopy. However, a significant proportion of people in endemic regions have asymptomatic parasitemia and thus the coexistence of parasitemia and neurologic disease may be falsely diagnosed as cerebral malaria. Detection of malaria retinopathy is highly sensitive (95%) and specific (90%) in identifying children whose comas are due to cerebral malaria; therefore, funduscopy should be performed in all suspected cases to look for retinal whitening, retinal hemorrhages, papilledema, and vascular changes (Figure 6-3).⁹ CSF examination is usually normal but helps to exclude other causes of encephalopathy, such as bacterial meningitis in cases with increased CSF white cell counts.¹⁵ Lumbar puncture does not increase the risk of mortality in clinically stable patients with cerebral malaria despite evidence of brain edema. MRI can demonstrate increased brain volume as well as abnormal T2 signal intensity and diffusion-weighted imaging abnormalities in the cortical, deep gray, and white matter structures.¹⁶ Unfortunately, the availability of MRI is limited in malaria-endemic regions.

Figure 6–3.

Malarial retinopathy in pediatric patients from Malawi showing white-centered hemorrhages (A), vessel color changes (B), and perimacular whitening (C, circle).

Reprinted from Taylor TT and Molyneux ME, Ann NY Acad Sci.¹⁰ © 2015 New York Academy of Sciences.

Treatment

Treatment of cerebral malaria requires IV antimalarials, with artesunate performing better than quinine.^9,17 Side effects of artesunate are infrequent, although delayed hemolysis may occur a week after treatment.¹³ Seizures are usually managed with phenobarbital and benzodiazepines, with respiratory suppression a common complication. Enteral levetiracetam may provide an effective and safe alternative,¹⁸ although availability is limited in endemic areas. Otherwise, treatment is supportive, with patients often requiring intensive care unit–level care.

TOXOPLASMOSIS

Toxoplasmosis is seen worldwide and is likely the most common parasitic infection of the human CNS. Up to one-third of the worldś population is infected with latent toxoplasmosis (usually asymptomatic), and disease occurs when latent brain infections are reactivated in patients who become immunocompromised. Toxoplasmosis is the most common opportunistic infection in patients with human immunodeficiency virus (HIV), with highest risk when CD4+ counts are less than 100 cells/mm³.^19,20

Life Cycle

Toxoplasmosis infection is caused by the ingestion of the tissue cysts or oocysts of T. gondii in contaminated food or water. Cats are definitive hosts for Toxoplasma. Oocysts are shed in the cat’s stools but are not infectious immediately (they become infectious 1 to 5 days after being shed). Considering the risks of primary infections during pregnancy, it is recommended that pregnant women do not clean litter boxes to avoid exposure. Primary infections in other immunocompetent individuals are usually asymptomatic. In low-income countries, the majority of the population has specific antibodies, compared to 10% to 50% of the population in developed countries.^21,22 Before the antiretroviral treatment era, toxoplasmosis reactivation rates in the United States and United Kingdom varied between 16% and 40%, whereas in Brazil, France, and Spain, rates were even higher. Although neurotoxoplasmosis is still a frequent cause of morbidity and mortality among patients infected with HIV, especially in lower-income countries, mortality has decreased substantially since the introduction of antiretroviral therapy.²³

Clinical Presentation

The clinical manifestations of cerebral toxoplasmosis are usually subacute and depend on the topography and number of lesions. The main symptoms are fever, headache, seizures, focal deficits, confusion, lethargy, and visual alterations related to retinal toxoplasmosis. Less frequent symptoms can include persistent cognitive impairment and involuntary movements.¹

Diagnosis

On neuroimaging, cerebral Toxoplasma lesions can be unifocal or multifocal and are most commonly located in the basal ganglia or subcortical white matter. On CT, they usually appear as hypodense ring-enhancing lesions with significant perilesional edema (Case 6–1), whereas on MRI they appear as T1-hypointense, T2-hyperintense lesions with ring enhancement. These lesions may have small hemorrhagic foci, or, more rarely, toxoplasmosis may present as isolated single or multiple cerebral hemorrhagic lesions. Two radiologic signs are highly specific for the diagnosis. One is the eccentric target sign (a ring-shaped zone of peripheral enhancement with a small eccentric nodule along the wall, observed in <30% of cases), and the other is the concentric target sign (concentric alternating zones of hypointensity and hyperintensity seen on T2-weighted MRI) (Figure 6-4).²⁴ These need to be distinguished from the target sign, which has been described as a central nidus of calcification or central enhancement surrounded by a ring of enhancement and is considered characteristic of CNS tuberculoma.

Figure 6–4.

Eccentric target sign in neurotoxoplasmosis (axial post contrast T1-weighted MRI, left) and target sign in neurotuberculosis, CT before (center) and after contrast (right). Panel A reprinted from Kumar GG, Mahadevan A, Guruprasad AS, et al. Eccentric target sign in cerebral toxoplasmosis: neuropathological correlate to the imaging feature. J Magn Reson Imaging 2010;31(6):1469–1472. doi:10.1002/jmri.22192

Panels B and C reprinted from Van Dyk A, Neuroradiology. © 1988 Springer-Verlag.

Case 6–1

A 49-year-old man presented with a generalized seizure after a week of headache. He reported a history of weight loss in the past 3 months. On examination, the patient had normal mental status but left hemiparesis with left-sided hyperreflexia.

Contrast-enhanced brain CT revealed three low-attenuation parenchymal lesions. The largest lesion was in the right basal ganglia associated with perilesional edema (Figure 6-5A). The results of a serum enzyme-linked immunosorbent assay (ELISA) and Western blot for human immunodeficiency virus (HIV) were positive. Serum ELISA for Toxoplasma gondii was positive, and the CD4+ count was 84 cells/mm³. Trimethoprim-sulfamethoxazole, dexamethasone, and valproic acid were initiated. After 2 weeks of treatment, the patient had complete neurologic recovery and showed partial resolution of his lesion burden on brain CT (Figure 6-5B); antiretroviral therapy was started.

Figure 6–5.

Imaging of the patient in Case 6–1. Axial CT shows a large rim enhancing lesion in the right basal ganglia associated with perilesional edema and midline shift (A) with marked improvement seen after 2 weeks of anti-Toxoplasma treatment (B).

Comment

Cerebral toxoplasmosis is the most common cause of expansive brain lesions in people living with HIV/acquired immunodeficiency syndrome (AIDS) and continues to cause high morbidity and mortality in individuals who are severely immunosuppressed. The most common characteristics are focal subacute neurologic deficits and ring-enhancing brain lesions in the basal ganglia, but the spectrum of clinical and neuroradiologic manifestations is broad. Early initiation of anti-Toxoplasma therapy defines the outcome. Trimethoprim-sulfamethoxazole and pyrimethamine-based regimens seem to have similar efficacy, but trimethoprim-sulfamethoxazole shows potential practical advantages. Most experts wait for 2 to 4 weeks after initiation of antiparasitic therapy before starting antiretroviral therapy in this setting to decrease the risk of immune reconstitution inflammatory syndrome.

Given the frequency of toxoplasmosis in the general population, a positive IgG serology does not confirm the diagnosis. Acutely rising serum IgG antibodies or a positive IgM serology suggest acute infection. IgM serology is less specific as it may cross react with other protozoa and may be positive in patients with autoimmune disease, On the contrary, negative serology in a patient with HIV and suspected toxoplasmosis should raise doubts about the diagnosis. However, negative serology does not exclude the diagnosis, especially in the presence of compatible clinical and radiologic findings. Negative serology may represent a low titer below the test cutoff and so does not exclude latent infection and risk of reactivation in the setting of immune reconstitution; this is not common and occurs in about 5% of cases. CSF polymerase chain reaction (PCR) is a useful tool for diagnosis of T. gondii with specificity between 96% and 100%. However, lumbar puncture is not advisable for patients with cerebral lesions with significant edema.^25,26

The diagnosis of toxoplasmosis is usually confirmed with a favorable response to anti-Toxoplasma treatment. Within 14 days of specific treatment, a good clinical and neuroimaging response is expected. If patients do not respond to therapy, a biopsy of the lesion is indicated to look for an alternative diagnosis, although nuclear imaging studies (eg, positron emission tomography [PET] or single-photon emission computed tomography [SPECT]) may be considered to differentiate toxoplasmosis from primary CNS lymphoma.

The most common differential diagnosis of neurotoxoplasmosis in lower-income countries is tuberculoma, whereas in higher-income countries primary CNS lymphoma should be considered. In patients infected with HIV, other infections, such as cryptococcosis, aspergillosis, microsporidiosis, and Chagas disease, should also be considered in the differential diagnosis of single or multifocal brain lesions.²⁰ Individuals who are immunocompetent may very rarely develop neurotoxoplasmosis, mostly as an acute diffuse encephalitis due to overwhelming primary infection. This is extremely rare, and such patients should be carefully evaluated for undiagnosed immunodeficiency.

Treatment

Therapy with pyrimethamine-based treatment or trimethoprim-sulfamethoxazole is usually effective, with clinical and radiologic improvement in 80% to 90% of patients receiving one of these regimens. In patients with sulfadiazine intolerance, either clindamycin or atovaquone can be used in combination with pyrimethamine. Treatment is continued for at least 6 weeks; if immunosuppression is present, secondary prophylaxis with trimethoprim-sulfamethoxazole or pyrimethamine-sulfadiazine is continued indefinitely. Recent data suggest that trimethoprim-sulfamethoxazole can be used for primary therapy in place of pyrimethamine-sulfadiazine with good outcomes. Potential advantages of trimethoprim-sulfamethoxazole over pyrimethamine-based protocols include lower pill burden and less-frequent dosing, the availability of IV formulations (important for patients who are critically ill), the availability of multiple generic formulations with the consequent impact on cost, and increased accessibility in poor regions. Additionally, trimethoprim-sulfamethoxazole prevents Pneumocystis jirovecii pneumonia, other bacterial infections, and malaria and simplifies the early initiation of combination antiretroviral therapy, increasing the survival of patients infected with HIV with most opportunistic diseases. Steroids may be useful if the lesions have mass effect or when diffuse or significant cerebral edema is seen.^19,27

NEUROCYSTICERCOSIS

Cysticercosis is the most common helminthic infection of the CNS, affecting patients in not only lower-income countries but also higher-income countries because of migration and travel. Neurocysticercosis represents a significant cause of morbidity and mortality, causing approximately 30% of cases of epilepsy in endemic regions,^28–30 making it the most common preventable risk factor for adult acquired epilepsy.¹²

Life Cycle

Cysticercosis is caused by the cystic larval form of the pork tapeworm T. solium, the life cycle of which involves pigs as the usual intermediate host (cysticercosis, larval infection) and humans as the sole definitive host, harboring the adult tapeworm in the small intestine when acquired from eating undercooked pork (taeniasis). Humans develop neurocysticercosis when ingesting the eggs of the tapeworm via fecal-oral transmission. Although the immune response of the host works to destroy the infective embryos that are distributed in diverse tissues, cysticerci have developed a series of immune evasion mechanisms, including localizing in protected sites (such the cerebral parenchyma, protected by the blood-brain barrier), secreting molecules able to block the complement system, affecting the cellular response, degrading attacking immunoglobulins, or even covering themselves with host immunoglobulins. Established cysts may survive for years or even decades in the human brain, but they eventually begin to degrade, losing their ability to evade the host’s immune response. The evolution of the cyst goes from a quiescent viable state to a degenerating cyst and then to complete resolution or calcification, generating focal inflammation throughout the process.^31,32??

Clinical Presentation

Neurocysticercosis varies in clinical and radiologic presentation depending on the location, size, and number of lesions and host immune response (Figure 6). Seizures and headaches are the most common symptoms in neurocysticercosis and may occur in relation to parenchymal cysts in any stage (Case 6–2). Extraparenchymal cysts in the cerebral ventricles or in the subarachnoid spaces (racemose cysts) can cause mass effect, hydrocephalus, intracranial hypertension, and chronic arachnoiditis (Case 6–3)³³ and are associated with a poorer prognosis.²⁸ Spinal cord cysticercosis occurs less commonly but may be an underrecognized cause of myelopathy in endemic regions because of limited access to neuroimaging. Asymptomatic involvement of the muscle and subcutaneous tissue also occurs.

Case 6–2

A 25-year-old man who worked as a teacher presented because of an episode that occurred while he was teaching a class when he developed sudden loss of consciousness, fell to the ground, and developed a rigid posture followed by involuntary movements of all four limbs for approximately 3 minutes. After the episode, he regained consciousness but was still drowsy when brought to the emergency department. He had a 2-year history of sporadic episodes of visualization of multiple colored lights followed by headache. He lived in a major city in Peru and rarely traveled; however, his family from the highlands regularly visited and stayed at his house.

On examination, he was awake and oriented in time, place, and person. He had a bite wound of his tongue. He had generalized muscle weakness but no focal findings or any other neurologic finding.

Brain MRI showed one left occipital cystic lesion with surrounding edema (Figure 6-7A). Two parietal cystic lesions without edema were also observed, suggesting cysticercosis cyst with scolex (Figure 6-7B). Serum enzyme-linked immunoelectrotransfer blot (EITB) assay for Taenia solium was positive. Levetiracetam was started, and after a few days, a 2-week course of albendazole and praziquantel with concomitant dexamethasone was initiated. Over 2 years of follow up, no relapses occurred.

Figure 6–7.

Imaging of the patient in Case 6–2. A, Coronal T2-weighted MRI shows a cortical cystic lesion with surrounding edema in the left occipital lobe. B, Axial fast imaging employing steady state acquisition (FIESTA) MRIs demonstrate two additional cysts, one near the midline and another near convexity, both with a hyperintense liquid content and a central hypointense scolex.

Comment

Intraparenchymal neurocysticercosis is a common cause of adult-onset epilepsy in endemic regions. EITB is highly sensitive in patients with more than one cyst. Cases in urban areas outside endemic regions are not uncommon because of the high influx of migration and complex population dynamics. After infection, patients are usually asymptomatic for long periods of time before presenting with symptoms, and symptoms frequently occur by the time one or more of the cysts begin to degenerate because of local inflammation. Corticosteroids are recommended along with antiparasitic treatment to control inflammation and its complications.

Case 6–3

A 55-year-old woman presented with 1-year history of headaches that partially improved with analgesics. One week earlier, the headache had worsened, did not improve with oral analgesics, and was accompanied by nausea and vomiting. In the morning of the day of admission, she was somnolent and did not recognize her husband, so she was brought to the hospital.

On examination, she was lethargic and disoriented with respect to person, place, and time. She had no focal neurologic deficits, and her vital signs were normal.

Initial brain CT showed ventriculomegaly with transependymal edema, suggesting acute hydrocephalus. Ventriculoperitoneal shunt placement was performed. The patient recovered, and follow-up MRI demonstrated resolution of hydrocephalus but revealed anterior temporal, pontocerebellar, and pontine cystic mass subarachnoid lesions (Figure 6-8). Serum enzyme-linked immunoelectrotransfer blot (EITB) assay for Taenia solium was strongly positive. A monoclonal antibody–based enzyme-linked immunosorbent assay (ELISA) for circulating antigen was also strongly positive. She received a 30-day course of albendazole and dexamethasone with slow tapering of steroids.

Figure 6–8.

Imaging of the patient in Case 6–3. A, Initial head CT reveals diffuse ventriculomegaly with transependymal edema. Cystic lesions are not clearly defined. B, Axial fast imaging employing steady state acquisition (FIESTA) MRI reveals multiple parasitic lesions in the cysts in the right perimesencephalic cistern and the lower left sylvian fissure.

Comment

Subarachnoid neurocysticercosis can be life-threatening because of intracranial hypertension with or without hydrocephalus by direct mass effect or arachnoiditis, or both. Serology commonly shows very strong antigen levels and antibody responses. MRI is usually required for the diagnosis because CT may only show enlarged or distorted ventricles or subarachnoid spaces without a clear demonstration of parasitic lesions. Management requires long-term antiparasitic treatment but may also require surgical excision of large lesion conglomerates. Higher doses of steroids help to reduce complications before, during, and early after antiparasitic treatment.

Diagnosis

The diagnosis of neurocysticercosis is based on neuroimaging and is supported by immunodiagnostic tests.³⁴ Neuroimaging is key for the diagnosis and provides data on the number, size, localization, and stage of lesions as well as perilesional inflammation. Guidelines published by the Infectious Disease Society of American and the American Society of Tropical Medicine and Hygiene for the diagnosis of neurocysticercosis recommend that patients should be assessed with both CT and MRI.³⁵ Brain CT provides clinicians the capacity to visualize lesions in the brain parenchyma, and MRI represents a more sensitive technique that improves imaging definition for parenchymal lesions and sensitivity for extraparenchymal lesions, although its sensitivity to detect calcified lesions is limited. Parenchymal cysts go through a series of evolutive (involutive) stages, beginning with a viable, non-inflamed cyst (vesicular stage) that later demonstrates degenerative changes, including increased density of its fluid contents (colloidal stage), local inflammation with edema, and contrast enhancement, and ultimately collapse into an inflammatory nodule (granular-nodular stage) and disappear, followed by subsequent reappearance as a calcified scar (nodular calcified stage) in 30% to 40% of cases. The tapeworm head (scolex) is frequently seen as an eccentric nodule in the interior of the cyst. Rarely, some patients (particularly young women) may present with hundreds or thousands of cysts with a diffuse inflammatory reaction and brain edema, a condition called cysticercotic encephalitis. Subarachnoid lesions frequently grow and infiltrate neighboring spaces; uncontrolled growth of the parasitic membrane in subarachnoid neurocysticercosis, leads to large parasite clusters that resemble a bunch of grapes called racemose neurocysticercosis (Figure 6-6, Panel H). Routine hematologic tests are mostly noncontributory, and eosinophilia is infrequent. CSF cellularity and biochemistry findings are also nonspecific, including moderate pleocytosis with lymphomononuclear predominance, increased protein, and, in severe cases, low glucose.

Figure 6–6.

Types and stages of neurocysticercosis. Top: A. Multiple viable parenchymal cysts (axial MRI); B. Large occipital cyst with contrast enhancement (axial MRI); C. Enhancing lesion with contrast enhancement and edema (sagittal MRI), and D, Multiple parenchymal calcifications (non-contrasted CT). Bottom: E. Cysticercotic encephalitis (axial MRI); F. Cyst in the left lateral ventricle (axial MRI); G. Subarachnoid neurocysticercosis of the Sylvian fissure (axial MRI), and H. Subarachnoid neurocysticercosis in the basal cisterns (axial MRI). Modified from García HH, et al, Current consensus guidelines for treatment of neurocysticercosis. Clin Microbiol Rev. 2002 Oct;15(4):747–56).

When neuroimaging tests are not conclusive, specific serology plays a major role in confirming the diagnosis. Antibody detection is frequently used because of its higher sensitivity, whereas antigen detection provides information on the presence of living parasites. The EITB assay using lentil-lectin purified glycoprotein parasitic antigens in serum is the assay of choice for antibody detection, with 98% sensitivity in those with more than one live brain cyst and a specificity close to 100%. In patients with a single brain cyst, the sensitivity drops and may be as low as 70%. No advantage is seen in using CSF for EITB antibody detection. The viability of the lesion is a major factor affecting antibody responses. Antigen detection is less sensitive than antibody detection on EITB, but when it is positive it confirms the presence of living parasites and helps monitor the efficacy of antiparasitic treatment.^36,37

Standard diagnostic criteria for neurocysticercosis were first developed in 1996 and last updated in 2017 (Table 6-1)^34,38; they include absolute (confirmatory by itself), neuroimaging, and clinical/exposure criteria, prioritizing neuroimaging diagnosis as the key tool for establishing the diagnosis.³⁴

Table 6–1.

Revised Diagnostic Criteria and Degrees of Diagnostic Certainty for Neurocysticercosis^a

Diagnostic criteria

Absolute criteria

Histologic demonstration of the parasite from biopsy of a brain or spinal cord lesion

Visualization of subretinal cysticercus

Conclusive demonstration of a scolex within a cystic lesion on neuroimaging studies

Neuroimaging criteria

Major neuroimaging criteria

Cystic lesions without a discernible scolex

Enhancing lesionsb

Multilobulated cystic lesions in the subarachnoid space

Typical parenchymal brain calcificationsb

Confirmative neuroimaging criteria

Resolution of cystic lesions after cysticidal drug therapy

Spontaneous resolution of single small enhancing lesionsc

Migration of ventricular cysts documented on sequential neuroimaging studiesb

Minor neuroimaging criteria

Obstructive hydrocephalus (symmetric or asymmetric) or abnormal enhancement of basal leptomeninges

Clinical/exposure criteria

Major clinical/exposure

Detection of specific anticysticercal antibodies or cysticercal antigens by well-standardized immunodiagnostic testsb

Cysticercosis outside the central nervous systemb

Evidence of a household contact with Taenia solium infection.

Minor clinical/exposure

Clinical manifestations suggestive of neurocysticercosisb

Individuals coming from or living in an area where cysticercosis is endemicb

Degree of diagnostic certainty

Definitive diagnosis

One absolute criterion

Two major neuroimaging criteria plus any clinical/exposure criteria

One major and one confirmative neuroimaging criterion plus any clinical/exposure criteria

One major neuroimaging criterion plus two clinical/exposure criteria (including at least one major clinical/exposure criterion), together with the exclusion of other pathologies producing similar neuroimaging findings

Probable diagnosis

One major neuroimaging criterion plus any two clinical/exposure criteria

One minor neuroimaging criterion plus at least one major clinical/exposure criterion

^aReprinted from Del Brutto OH, et al, J Neurol Sci.³⁸ © 2016 The Authors.

^bOperational definitions. Cystic lesions: rounded, well defined lesions with liquid contents of signal similar to that of CSF on CT or MRI; enhancing lesions: single or multiple, ring- or nodular-enhancing lesions of 10 mm to 20 mm in diameter, with or without surrounding edema, but not displacing midline structures; typical parenchymal brain calcifications: single or multiple, solid, and most usually <10 mm in diameter; migration of ventricular cyst: demonstration of a different location of ventricular cystic lesions on sequential CTs or MRIs; well-standardized immunodiagnostic tests: so far, antibody detection by enzyme-linked immunoelectrotransfer blot assay using lentil lectin-purified T. solium antigens, and detection of cysticercal antigens by monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA); cysticercosis outside the central nervous system: demonstration of cysticerci from biopsy of subcutaneous nodules, x-ray films or CT showing cigar-shaped calcifications in soft tissues, or visualization of the parasite in the anterior chamber of the eye; suggestive clinical manifestations: mainly seizures (often starting in individuals aged 20 to 49 years; the diagnosis of seizures in this context is not excluded if patients are outside of the typical age range), but other manifestations include chronic headaches, focal neurologic deficits, intracranial hypertension and cognitive decline; cysticercosis-endemic area: a place where active transmission is documented.

^cThe use of corticosteroids makes this criterion invalid.

Treatment

Therapy for neurocysticercosis includes treatment of seizures and elevated intracranial pressure, if present, and antiparasitic drugs (often with steroids) if viable or degenerating cysts are present. On the basis of studies in pigs and human pathology samples, a cyst is considered viable if it has liquid contents, and these appear similar to CSF on MRI (hypointense on T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, hyperintense on T2-weighted images). Degenerating cysts may have lost their ability to produce an adult tapeworm, but these lesions still contain live parasitic tissue and cells. After a long controversy regarding whether the use of antiparasitic treatment was of benefit or whether it was unnecessary,³⁹ most experts now agree that it destroys parasitic cysts and results in fewer seizure recurrences^40,41; therefore, it is of benefit in most patients with neurocysticercosis. Antiparasitic treatment, however, may temporarily worsen neurologic symptoms because of the resulting inflammation around a damaged cyst. It is contraindicated in patients with uncontrolled elevated intracranial pressure and is usually administered with concomitant steroid therapy. For a single parenchymal cyst, albendazole at 15 mg/kg/d for 7 to 15 days is the regimen of choice. In cases with multiple viable cysts, the combination of albendazole plus praziquantel at 50 mg/kg/d for 10 days has demonstrated superior efficacy.^35,40–43 Surgical management is limited to the placement of ventriculoperitoneal shunts in patients with hydrocephalus and neuroendoscopic removal of intraventricular cysts, and occasionally large cysts or cystic masses are surgically excised.⁴⁴

Neurocysticercosis represents a significant burden worldwide and accounts for tens of thousands of deaths per year. Significant advances have been achieved in the past decade, including the demonstration that active interventions, such as antiparasitic treatment of the human and porcine population as well as pig vaccination, can interrupt transmission and lead to focal elimination.⁴⁵ Larger elimination efforts should demonstrate the feasibility of sustained elimination and potential eradication.

SCHISTOSOMIASIS

Schistosomiasis is a chronic parasitic disease caused by trematode blood flukes of the genus Schistosoma. It is endemic to sub-Saharan Africa, South America, the Caribbean, Southwest Asia, and the Middle East.^4,46,47 Three species of the Schistosoma genus account for most cases of human schistosomiasis: Schistosoma mansoni (Africa; Southeast Asia; and parts of Brazil, Venezuela, and the Caribbean), Schistosoma haematobium (Africa, Southeast Asia, and the Middle East), and Schistosoma japonicum (China, Indonesia, and the Philippines).^1,15 Schistosomal infection of the CNS (neuroschistosomiasis) is a rare complication of schistosomiasis presenting with myelopathy or encephalopathy; it can present months to years after exposure.

Life Cycle

Humans are the definitive hosts for schistosomes. Infection occurs when the skin of the individual is penetrated by cercariae, the free-swimming larval form of the parasite, following exposure to fresh water infested with these parasites.^46,47 Cercariae then migrate through capillaries and lymphatics to the portal venous system, where they mature to adult worms over a few weeks. These then migrate to the venous system of either the gastrointestinal tract (S. mansoni, S. japonicum) or bladder (S. haematobium), and in 4 to 12 weeks, the adult parasites begin to lay eggs, which typically lodge in the intestine or bladder mucosa and are shed in the feces or urine, respectively. Neuroschistosomiasis is caused by ectopic deposition of eggs in the brain and spinal cord by retrograde flow from the iliac veins and inferior vena cava through the valveless Batson venous plexus into the cerebral veins and spinal cord. The eggs are immunogenic, and the host response leads to granulomatous inflammation, with local edema, congestion, and varying degrees of fibrosis.^15,47 Cerebral schistosomiasis is more common with S. japonicum, as it has smaller eggs that are able to migrate to the brain. The eggs of S. mansoni and S. haematobium are larger and more frequently migrate to the lumbosacral spinal cord, although they may occasionally affect the brain.¹

Clinical Presentation

Acute cerebral neuroschistosomiasis may produce a nonspecific encephalopathy that generally resolves within a few days or weeks. Chronic infection can present as a slowly expanding intracranial mass (pseudotumor), which can be a solitary mass or multiple mass lesions because of the development of parenchymal brain granulomas.^1,15,47 The most common manifestation of neuroschistosomiasis is headache, and other symptoms vary depending on the location of the lesion in the brain (motor deficits, visual abnormalities, seizures, altered mental status, vertigo, sensory impairment, speech disturbances, cognitive impairment, vomiting, and ataxia). Parenchymal brain and subarachnoid hemorrhages may occur in some cases and are related to segmental damage of small leptomeningeal or parenchymal blood vessels induced by the parasites. Signs of systemic schistosomiasis are typically absent.^1,15,48,49

On CT and MRI, cerebral neuroschistosomiasis lesions appear as solitary or multiple subcortical mass lesions surrounded by hypodense or T2-hyperintense edema, with heterogeneous contrast enhancement and irregular borders. A linear enhancement pattern surrounded by multiple enhancing nodules (the arborized pattern) is suggestive but nonspecific for neuroschistosomiasis (Figure 6-9).^{1,2,4,47–51}

Figure 6–9.

Axial postcontrast T1-weighted MRI shows patchy enhancement in an arborized pattern in cerebral schistosomiasis. Reprinted with permission from Cho T, Continuum (Minneap Minn).⁴⁷ © 2018 American Academy of Neurology.

Transverse myelitis is the most common presentation of spinal neuroschistosomiasis and is related to granulomatous lesions with inflammatory necrosis of the spinal cord. Symptoms usually progress in an acute to subacute time course, with peak at 15 days after the onset of symptoms. Granulomas may form in the spinal cord, nerve roots, or, most commonly, both. The lower spinal cord is most frequently affected, specifically at the levels of T11 through L1, possibly because of increased anastomoses between the Batson venous plexus with the portal venous system at this location.^46,47,52 The most common initial symptoms are low back pain (in 79% to 100% of individuals) or pain in the lower limbs, which can be symmetric or asymmetric. Lower spinal cord or cauda equina or conus medullaris involvement is common, causing weakness of the lower limbs (Case 6–4), lower limb sensory disturbance, sphincter dysfunction, sexual dysfunction, and abnormal reflexes.^{1,47, 52} Eventually, acute paraplegia may result from occlusion of the anterior spinal artery by the parasites. CSF analysis usually reveals mild mononuclear pleocytosis and increased protein level. MRI typically reveals enlargement of the lower spinal cord or of the conus medullaris on T1-weighted images, signal hyperintensity on T2-weighted images, and heterogenous nerve root patterns of contrast enhancement.^1,46,47 Neuroschistosomiasis should be suspected in patients who originated from or traveled to an endemic area and who present with a compatible clinical syndrome.

Case 6–4

A 22-year-old man traveled to Malawi. Three months after returning to the United States, he noticed back pain and progressive weakness in both legs that progressed to evident paraparesis. A spinal MRI demonstrated an intramedullary lesion at the T11-T12 level (Figure 6-10A). Hematologic and biochemical blood examinations were all normal, and no parasite eggs were found in stools or urine. Surgery was performed, and pathologic examination of the excised tissue revealed an inflammatory granuloma around a crenated Schistosoma egg (Figure 6-10B). Postsurgical evolution was favorable with complete recovery.

Figure 6–10.

Imaging of the patient in Case 6–4. Spinal schistosomiasis. A, Sagittal post-contrast T1-weighted MRI of the spine shows an intramedullary lesion in the lower thoracic spine. B, Pathologic (H&E) specimen from the same lesion shows a granuloma around a Schistosoma egg.

Comment

Spinal schistosomiasis should be suspected in travelers to endemic regions who develop compatible neurologic, particularly spinal, manifestations. The finding of Schistosoma eggs in feces or urine establishes the diagnosis, although the sensitivity of parasitologic diagnosis is not high.

Diagnosis

Diagnosis requires the evidence of active Schistosoma infection. Direct visualization of eggs in stool or urine, punch biopsy from the rectal mucosa (higher sensitivity),⁴⁶ or indirect assays measuring antibodies against schistosomal antigens have variable sensitivity depending on the timing and burden of infection. Serologic testing is not useful in individuals from endemic regions because schistosomiasis may cause asymptomatic infection and schistosomal antibodies may persist for years. Since the radiographic pattern in cerebral schistosomiasis is nonspecific, brain biopsy may be required to confirm the diagnosis.^46,47

Treatment

Both cerebral and spinal cord neuroschistosomiasis are managed almost exclusively medically and only rarely require surgical intervention (eg, decompressive laminectomy, mass excision, liberation of roots for larger granulomas in spinal cord neuroschistosomiasis). Praziquantel is effective in patients with brain or spinal cord involvement, but dosing and timing lack evidence-based guidelines (recommended dose varies by species).^47,48 Some investigators have reported improved outcomes from maximal surgical resection followed by praziquantel. Steroids should be initiated if neuroschistosomiasis is suspected, followed by praziquantel once the diagnosis is confirmed. Corticosteroids can mitigate the process of endarteritis, which can lead to progressive brain and spinal cord damage. In general, the outcome tends to be worse for spinal cord neuroschistosomiasis than cerebral neuroschistosomiasis.^1,47

OTHER PARASITIC INFECTIONS THAT MAY AFFECT THE HUMAN NERVOUS SYSTEM

A variety of parasitic infections may affect the human CNS less frequently. Epidemiologic suspicion based on country of origin or travel history, particularly in the setting of atypical clinical presentations of neurologic disease, should alert the clinician to consider parasitic infections of the CNS. Parasites that may cause encephalitis, meningoencephalitis, and multiple brain abscesses include free-living amoebas (Acanthamoeba species, Balamuthia mandrillaris, Naegleria fowleri), Trypanosoma (sleeping sickness in African trypanosomiasis), Angiostrongylus cantonensis (eosinophilic meningitis); Gnathostoma spinigerum (gnathostomiasis), Strongyloides stercoralis (disseminated strongyloidiasis), Trichinella spiralis (trichinosis), and Paragonimus (paragonimiasis). Focal noncystic lesions can be found in Chagas disease (American trypanosomiasis); toxocariasis (T. canis, Toxocara cati), paragonimiasis or sparganosis (Spirometra species), whereas cystic lesions occur in coenuriasis (Taenia multiceps) and hydatid disease (Echinococcus granulosus). Hemorrhagic or ischemic stroke can be caused by gnathostomiasis (G. spinigerum), disseminated strongyloidiasis (S. stercoralis), and trichinosis (T. spiralis). Spinal disease can be caused by toxocariasis and gnathostomiasis.

CONCLUSION

Parasitic infections affect the human CNS with relative frequency and should be considered in the differential diagnosis of neurologic lesions, particularly in individuals from endemic regions or those with a history of travel. Cerebral malaria, toxoplasmosis, neurocysticercosis, and neuroschistosomiasis are among the most common parasitic infections of the nervous system, but many other diseases are caused by pathogenic parasites in the human host.