NCC 2011

584 | OCTOBER 2011 | VOLUME 7 www.nature.com/nrneurol

Gastrointestinal Parasites Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 4, Room B1‑01, Bethesda, MD 20892, USA (T. E. Nash). Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas, Jr Ancash 1271, Lima, Perú (H. H. Garcia).

Correspondence to: H. H. Garcia [email protected]

Diagnosis and treatment of neurocysticercosisTheodore E. Nash and Hector H. Garcia

Abstract | Neurocysticercosis is a parasitic disease caused by the larval (cystic) form of the pork cestode tapeworm, Taenia solium, and is a major cause of acquired seizures and epilepsy worldwide. Development of sensitive and specific diagnostic methods, particularly CT and MRI, has revolutionized our knowledge of the burden of cysticercosis infection and disease, and has led to the development of effective antihelminthic treatments for neurocysticercosis. The importance of calcified granulomas with perilesional edema as foci of seizures and epilepsy in populations where neurocysticercosis is endemic is newly recognized, and indicates that treatment with anti‑inflammatory agents could have a role in controlling or preventing epilepsy in these patients. Importantly, neurocysticercosis is one of the few diseases that could potentially be controlled or eliminated—an accomplishment that would prevent millions of cases of epilepsy. This Review examines the rationale for treatment of neurocysticercosis and highlights the essential role of inflammation in the pathogenesis of disease, the exacerbation of symptoms that occurs as a result of antihelminthic treatment, and the limitations of current antihelminthic and anti‑inflammatory treatments.

Nash, T. E. & Garcia, H. H. Nat. Rev. Neurol. 7, 584–594 (2011); published online 13 September 2011; doi:10.1038/nrneurol.2011.135

IntroductionAdult Taenia solium tapeworms reside only in the small intestine of humans, their definitive host. Humans become infected with these tapeworms by eating pork products containing viable T. solium cysts; however, humans (as well as pigs) that ingest T. solium ova develop cysticercosis —that is, infection with the larval form of the T. solium tapeworm (Figure 1).

Neurocysticercosis occurs when ingested eggs hatch and the resulting embryos (onchoshperes) become larvae that invade the nervous system, and is a major cause of epilepsy acquired in adulthood and other neurological morbidity in many areas of the world.1,2 Approximately 29% of all cases of epilepsy in cysticercosis-endemic regions are thought to be caused by neurocysticercosis3—a value that closely approximates the proportion of individuals with epilepsy who have neurocysticercosis in Latin America.4–7 However, the prevalence of T. solium infection and disease has been determined in relatively few regions, and thus knowledge of the worldwide burden of neuro cysticercosis is limited.8 Overall, 1.7–3.0 million people worldwide are (conserva-tively) estimated to have epilepsy resulting from neuro-cysticercosis, and cysticercosis in humans is endemic in many regions of the world (Figure 2).9–15 Although taeniasis and cysticercosis are absent or rare in the USA and most of Europe, neurocysticercosis is still frequently diagnosed in people who have migrated to these regions from endemic areas.16–19 Seizures are still the most common manifestation of neurocysticercosis, but a substantial number of infected individuals present with complicated subarachnoid or ven-tricular disease, which requires costly, sophisticated, and often long-term treatment.

Despite impressive advances in the diagnosis of disease and the increased availability of antihelminthic treatments, large gaps remain in our knowledge about T. solium cysticer-cosis and the host responses to it. Factors such as the lack of clinically appropriate models of infection, the inability to maintain the life cycle of the parasite experimentally, and reliance on naturally infected humans as a source of infec-tious ova, are hindering further advances in our knowledge of the disease. Rodent models of infections with other tape-worms are available, but these are generally of limited use in T. solium-related disease since they differ markedly from natural infection. Although studies of pigs with cysticercosis can be helpful, these animals do not develop seizures, which limits their rele vance to human neurocysticercosis. The study of neuro cysticercosis is, therefore, most appropriately conducted in infected humans. These studies are long and difficult, requiring sophisticated imaging, special tests, and a large number of personal and financial resources, which have not been forthcoming. Neurocysticercosis, similar to echinococ cosis (another disease caused by a tapeworm), is a neglected disease.

Human carriers of T. solium tapeworms are at a very high risk of autoinfection with cysticercosis through fecal–oral transmission. The very large number of T. solium eggs passed by tapeworm carriers can result in high levels of autoexposure to the infective embryos contained in the eggs, which occasionally results in heavy cysticercosis infec-tions.20–22,23 Family members and people in close contact with tapeworm carriers are also at consider able risk from cysticercosis. In India, poor sanitation can cause contami-nation of food and water with T. solium ova, resulting in widespread low-level environ mental exposure, which could account for the high preva lence of individuals who have a single enhancing lesion (SEL) in this country.24

Competing interestsThe authors declare no competing interests.

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This Review highlights the key role of inflammation in the pathogenesis of neurocysticercosis, the exacerba-tion of symptoms that occurs as a result of antihelminthic treatment, and the rationale for and limitations of current antihelminthic and anti-inflammatory treatments.

Pathogenesis and evolutionAfter they have been ingested by humans, T. solium onco-spheres (liberated from the ova) pass through the stomach wall and are carried by the bloodstream to various organs, where they lodge in small blood vessels and may develop into viable cysts after 2–3 months (Figure 1). In the brain, the distribution of cysts generally follows the distribution of blood, resulting in parenchymal disease (within the brain tissue) and/or extra parenchymal dis ease (most commonly in the subarachnoid spaces, ventricles, and spine). Paren-chymal cysts are most common, and in patients with heavy infections they are frequently located in the watershed areas between the white and gray matter. Why and how some cysts develop into large basal sub arachnoid lesions is unknown, but this type of disease might occur following degeneration of the cyst or after loss of growth inhibition. Cysts that lodge in the choroid plexus often become dis-lodged while they are still small, and pass into the ventricu-lar system, where they are termed ventricular cysts. Such cysts can pass through the ventricular system, or become stuck, most commonly in the fourth ventricle.

The signs and symptoms of neurocysticercosis are par-ticularly diverse and depend on the number, location, growth, and stage of degeneration of the cysts, host factors (including the degree of inflammation), and parasite geno-type.2,25 Parenchymal and extraparenchymal disease differ in a number of important ways (Table 1). However, a single

Key points

■ Taenia solium neurocysticercosis is a common cause of seizure disorders worldwide

■ Intraparenchymal neurocysticercosis is mostly associated with seizures; extraparenchymal neurocysticercosis can cause mass effects and hydrocephalus, and has a poor prognosis

■ Management of patients with neurocysticercosis commonly involves antiepileptic drugs and steroids to treat the neurological and inflammatory symptoms, plus antihelminthic drugs to kill any viable parasites (in most cases)

■ Most treatment recommendations for neurocysticercosis are based on expert opinion or anecdotal evidence; only a few controlled studies of antihelminthic drugs or steroids exist

■ Neurocysticercosis could provide a useful model to study susceptibility to and pathogenesis of epilepsy

■ Neurocysticercosis is a preventable, and probably eradicable, cause of seizures and epilepsy

patient might have multiple parenchymal, ventricular or extraparenchymal cysts, some of which might be viable with little inflammation, whereas others may be in various stages of degeneration and associated with different degrees of inflammation, calcification and hydrocephalus. The states of individual lesions are independent of each other, at least to some extent. Most of the pathophysiology of cysticercosis results (directly or indirectly) from acute or chronic inflammatory responses against the membranes and residual antigens of degenerating cysts. Controlling inflam mation is, therefore, a cornerstone of approaches to limit the morbidity and mortality of neurocysticercosis. Mass effects and mechanical obstruction of cerebrospinal fluid (CSF) flow are other, less frequently encountered pathological features of the disease.26 The initial approach

Ingestion byhuman host

Ingestionby pigs

Porcine cysticercosis■ Ova hatch and invade intestinal wall■ Oncospheres are carried, via bloodstream, throughout the body

Pig(intermediate host)

Human(de�nitive host)

Ingested cysts evaginate inthe upper small intestine

Ingestion of raw or undercooked pork

Matureproglottids

Ova

Human cysticercosis■ Cysts mature in 2–3 months■ Cysts commonly found in muscle and brain■ Cysts in the brain cause neurological disease, termed neurocysticercosis

Mature Taenia solium tapeworm■ 2–4 m long■ Head (scolex) contains four suckers and a rostellum of hooks for grasping■ Liberated ova and/or proglottids are shed in human feces■ Proglottids contain 30,000–50,000 ova

Figure 1 | Life cycle of Taenia solium, the ‘pork tapeworm’.

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to treatment is dictated by the most severe manifestation of neurocysticercosis.

The symptoms of patients who present with neuro-cysti cercosis are variable, and depend on the location and number of cysts, as well as the degree of inflam-mation. A systematic review, which analyzed studies that reported the clinical manifestations of patients with neuro cysticercosis, found that 78.8% of patients presented with seizures, 37.9% presented with headaches, 16% had focal neurological deficits, 11.7% showed signs of intra-cranial hypertension, 7.9% had meningitis, 6% had gait abnormalities, 5.6% reported visual changes, 4.5% had an altered mental state, and 2.8% had cranial nerve palsies.27 Seizures are usually of the general ized tonic–clonic type, and most frequent between the second and fifth decades of life.10 Children can also develop neuro-cysticercosis, ranging from a single degenerating cyst to heavy infection; however, children rarely develop calcifi-cations, and seldom present with hy drocephalus or basal subrachnoid neurocysticercosis.28,29

SubtypesParenchymal neurocysticercosisPatients with parenchymal neurocysticercosis most commonly present with seizures. Parenchymal neuro-cysticercosis is relatively easy to treat, and (except in indivi-duals with heavy infections) has a fairly good prognosis. Initially viable cysts degenerate with treatment and then disappear, or the lesion might remain as a calcified scar.30

Viable cystsViable cysts that are not degenerating are not associated with evident inflammation (Figure 3a). For reasons that

are unclear, perhaps as a result of the natural evolution of the parasite or as a consequence of antihelminthic treat-ment, viable cysts are eventually recognized by the host, and an intense inflammatory response is initiated, which causes a stepwise series of degenerative changes.31

Degenerating cystsAs inflammation increases, the cyst contents become more dense and opaque in terms of macroscopic appearance (Figure 3b). A granuloma forms around the cyst, first as a cellular infiltrate around and then within the cyst, with an inner epithelioid cellular layer. Over time the cyst becomes more disorganized with varying degrees of cyst remnants, including recognizable cyst membranes and/or membranous-like ribbons, characteristic cal careous corpuscles, and varying degree of inflammatory reac-tion. Later, the granuloma decreases in size and becomes nodular instead of cystic. These degenerative changes result in varying amounts of enhancement on MRI, and, in some cases, edema, which gradually resolves; at this point the cyst has a reduced propensity to cause seizures.30,32

An SEL is a single degenerating cyst, which usually cause seizures in the infected individual. Although neither imaging nor serology can define the etiology of these lesions unless typical cyst morphology is evident, studies in India (where presentation with an SEL is particularly common) have determined that if a lesion is <20 mm in diameter and does not have gross edema with midline shift, if no other cause (such as tuber culosis) is evident, and if the lesion shows no subsequent growth, then it is likely to be a degenerating cysticercus.65 Individuals with an SEL have a good prognosis compared with patients with multiple-cyst infections, but the risk of having recurrent

Endemic (full life-cycle)

Suspected endemic

Imported cases (possible human cysticercosis transmission)

No data available

Figure 2 | World map showing the distribution of taeniasis and Taenia solium cysticercosis in humans. Adapted from http://gamapserver.who.int/mapLibrary/Files/Maps/Global_cysticercosis_2009.png, accessed May 2011.

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http://gamapserver.who.int/mapLibrary/Files/Maps/Global_cysticercosis_2009.png


seizures is increased in patients with calcified lesions and/or perilesional gliosis.33–36

Calcified cystsCysts can become undetectable by CT or MRI and appar-ently resolve, or the granuloma and cyst contents might hyalinize. Most degenerating cysts calcify, as best visualized by CT imaging (Figure 3c).37 In some patients, intermit-tent flares of edema (most probably caused by inflam-mation) occur, and are associated with seizures.38–40 The reason for occurrence of these flares remains unknown, but one possibility is enhanced antigen accessibility, which could drive host inflammation and/or loss of suppression of the host’s cellular immune response.32,41,42 Develop-ment of peri lesional gliosis, which almost certainly occurs secondarily to inflammation in the surrounding brain, increases the risk of epilepsy.43,44 Only a few documented descriptions of the pathology of calcifications exist; they mostly describe hyalinized, calcified lesions, with variable perilesional inflammation (Figure 3d).30,40,45–48

Extraparenchymal neurocysticercosisExtraparenchymal neurocysticercosis is less common, less well-studied, more difficult to treat, and in general has a worse prognosis than parenchymal neuro cystice cosis.49,50 Extraparenchymal disease can be further divided into ven-tricular and subarachnoid locations; the latter has various presentations, which differ according to whether the lesions affect the surface of the brain hemispheres (con-vexity cysts), the Sylvian fissure, or the basal subarachnoid space and cisterns (Figure 4).

Ventricular neurocysticercosisCysts frequently lodge in the ventricles (Figure 4a) and cause mechanical obstruction of CSF flow and/or some degree of inflammation, which might result in hydro-cephalus if the inflammatory response is not adequately suppressed. Cysts are most frequently found in the fourth ventricle, although entrapment of cysts in the lateral or third ventricles can also occur. Cysts that are not attached to the ventricle wall can cause sudden or gradual onset of mechanical obstruction of the CSF outflow. In the fourth ventricle, such obstruction can cause acute nausea, vomit ing

and vertigo (Brun’s syndrome), or have an indolent pre-sentation with nausea, vomiting, headache, and symptoms associated with hydrocephalus. A cyst in the fourth ven-tricle of a pregnant woman can mimic emesis of pregnancy, but vomiting is usually accompanied by headache when the symptoms are caused by neurocysticercosis.25

Subarachnoid disease of the brain convexityConvexity cysts on the surface of the brain hemispheres usually behave like intraparenchymal cysts, (Figure 4b) in that they are associated with seizures, and pass through the usual degenerative stages. However, convexity cysts might occasionally grow and become mass-occupying lesions.

Subarachnoid disease of the Sylvian fissureSubarachnoid disease of the Sylvian fissure usually pres-ents with clumps of multiple cysts (Figure 4c) or giant cysts that result in mass effects. Calcifications along the course of the middle cerebral artery are suggestive of chronic, long-standing disease. Inflammation adjacent to the brain (or other brain structures), fibrosis, nerve impingement, infarcts, and (less commonly) cerebral hemorrhage, further contribute to the manifestations of this form of neurocysticercosis.51

Basal subarachnoid neurocysticercosisThe most severe form of neurocysticercosis occurs when cysts become lodged in the basal subarachnoid space. At this location, cysts can enlarge and their tissues acquire the ability to proliferate.52 This aberrant growth of the cyst results in vesicular enlargement and continuously pro-liferating cyst membranes within the spaces of the brain, resulting in a complex vesicular–membranous structure with a ‘grape-like’ appearance—hence the alternative term, racemose neurocysticercosis—and usually lacking a scolex (Figure 4d). Basal subarachnoid neuro cysticercosis can become extensive and invade other spaces of the brain, resulting in mass effects and/or inflammation. The inflammatory response is initially directed against the cyst tissues in the arachnoid space, but can spread to involve the meninges, foramina, adjacent brain tissue, and nerves and vessels that course through the arachnoid space, all of which can cause focal or diffuse arachnoiditis

Table 1 | Characteristics of intraparenchymal and extraparenchymal neurocysticercosis

Characteristic Intraparenchymal neurocysticercosis Extraparenchymal neurocysticercosis

Pathology Typical cyst or granuloma, calcification Giant cysts of the Sylvian fissure, ventricular cysts, basal subarachnoid cysts. Chronic inflammation, fibrosis

Presentation Seizures caused by inflamed cyst or degenerating lesion, headache, focal neurological findings

Mass effects, hydrocephalus from mechanical obstruction, noncommunicating hydrocephalus, headache, visual problems, cranial nerve deficits, infarcts

Diagnosis Imaging shows characteristic cysts, calcifications and multiple compatible lesions

Characteristic cyst in ventricles. Other sites are nondiagnostic, unless simultaneous intraparenchymal involvement is evident

Treatment Short‑course antihelminthic drugs, short‑course corticosteroids

Might require long‑term and repeated antihelminthic therapy as well as long‑term corticosteroids (or methotrexate as a possible steroid‑sparing agent)

Response Usually cysticidal, cure rates low but patients respond well to re‑treatment

Variable, relapse common

Prognosis Good, possible seizure, relapses Poor. Shunt obstruction is common, sizeable mortality

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in the brain and spine. Eventually, the racemose cysts and resulting inflammation cause mass effects, parenchymal swelling, and fibrosis, which in turn can cause infarcts, hydrocephalus, and nerve entrapments. Involvement of the optic chiasm might lead to blindness. Some patients with basal subarachnoid neurocysticercosis have been reported to develop meningitis, but the cause of this con-dition was unclear because no identifying features, such as vesicular membranous or cyst structures, were present in these patients.53

Basal subarachnoid neurocysticercosis can also spread throughout the subarachnoid space and involve the spinal cord.54 Although this presentation is considered unusual, our research group found spinal involvement, which in most cases was asymptomatic, in 50–70% of patients who had basal subarachnoid disease (T. Nash & H. Garcia, unpublished work). The severity of spinal involvement in patients with spinal neurocysticercosis can vary from arachnoiditis (mostly in the cauda equina), to one or a few cysts with minimal spinal involvement, to mass effects that result in paralysis or, uncommonly, involve numerous cysts.55

DiagnosisDiagnosis of neurocysticercosis rests on a combination of often nonspecific findings, including epidemiology, symptoms, signs, serology, brain imaging, and pathol-ogy (if available). Although some findings in patients

with neuro cysticercosis are diagnostic, many are not; however, the combination of findings is so unlikely to be seen in a patient with any other disease that the etiology of neuro cysticercosis is practically certain. Diagnostic criteria for neurocysticercosis have been proposed56 and, although these are helpful, they have not been systematical ly validated.

EpidemiologyMost patients with neurocysticercosis have lived for long periods of time in cysticercosis-endemic regions; these areas are usually resource-poor countries where human–human transmission of disease is ongoing. In patients from nonendemic regions who have neurocysticercosis-like symptoms, the lack of significant exposure to T. solium ova means that a diagnosis of neurocysticercosis is unlikely and the clinician should suggest either an alternative eti-ology for seizures or question whether the patients had nontraditional exposures to the parasite, such as short-term travel to endemic areas. Individuals with no discern-ible exposure who present with neurocysticercosis-like symptoms should be investigated for taeniasis or proxim-ity to a tapeworm carrier, which can result in infection. For example, a number of Orthodox Jews in New York, USA, were diagnosed with neurocysticercosis, although they had never travel led to an endemic region. They had been accidentally infected by contact with domestic employ-ees who had come from Central America and who were infected with T. solium.57

History and physical examinationWith the exception of ocular cysts, which can be charac-teristic (or diagnostic) of neurocysticercosis, signs and symptoms that are caused by neurocysticercosis are often not specific to the disease. The most common symp-toms are seizures, focal neurological deficits, headache and intracranial hypertension. Seizures in patients with neuro cysticercosis are usually either focal with generaliza-tion, or generalized; in a large majority of patients, sei-zures are associated with degenerating cysts or calcified granulomas; in patients with subarachnoid involvement, seizures can also (albeit rarely) be caused by infarcts.58 Focal neuro logical deficits are an unusual and non-specific finding that are associated with various types of lesions and caused by both host and disease mechanisms. Headaches are a frequent but also non specific finding that is commonly associated with seizures. In a community study, neurocysticercosis was more common in patients with migrainous headaches than in those without such headaches.59 Hydrocephalus and intracranial hyper tension are common in patients with complicated neurocysticer-cosis and might manifest as nausea, vomiting, headache, wide-based gait, and loss of consciousness. Cognitive deficits and dementia are also frequently found in patients with neurocysticercosis.60

ImagingCNS imaging is essential to establish a definitive diagnosis of the disease and to determine the type of neuro cysti-cercosis. This information enables the clinician to identify

a

c d

b

Figure 3 | Intraparenchymal neurocysticercosis. The arrows show: a | viable cysts on T1‑weighted MRI. The eccentric dots visible in two of the cysts represent the scolex; b | a degenerating cyst on T1‑weighted contrast MRI. The prominent white ring represents contrast enhacement around the cyst membrane; c | calcified lesions on noncontrast CT; d | perilesional edema around a calcified lesion on MRI (fluid‑attenuated inversion recovery protocol).

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the necessary emergency measures and to decide which treatments are required, including the duration and degree of immunosuppressive therapy. MRI is much su perior to CT for visualizing brain structures and anatomy, as well as cysts; however, CT is superior to MRI for the detec-tion of calcifications. Ideally, non contrast CT imaging (to detect calcification) and a full MRI study with fast imaging employing steady state acquisition (FIESTA) or related MRI protocols should both be performed to ascer tain the extent of sub arachnoid and ventricular disease.61,62

Imaging findings can be classified as consistent with neuro cysticercosis, or can establish either a probable or definitive diagnosis of the disease (reviewed elsewhere63). In the context of clinical findings suggestive of neuro-cysticer cosis, roundish cysts that are 1–2 cm in dia meter, have smooth walls, and contain an eccentric dot (repre-senting the scolex) are diagnostic of neuro cysticercosis. The presence of multiple similar lesions, or multiple lesions of a range of types of compatible with neuro cysticercosis, is helpful in confirming the diagnosis.

Viable cysts appear clear on gross tissue examination, but the process of cyst degeneration is best visualized on MRI. Degenerating cysts are hypointense on T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. The first indication of cyst degeneration is the presence of enhancement (best visualized using MRI), which indicates dysfunction of the blood–brain barrier, most probably caused by inflammation around a cyst that is still viable. As degenerating cysts become opaque on gross tissue exami-nation, the MRI appearance changes from no signal to a bright signal on T1-weighted and FLAIR sequences, and is accompanied by marked enhancement.63

Diagnosis of neurocysticercosis in patients who have an SEL is difficult, because the morphology of these lesions is inconclusive, and serological testing (to identify the presence of antibodies to the parasite) commonly pro-duces negative results.64 Calcified cysts are typically small, punctate and round, although in some patients they can be large, chunky and irregular in shape. A single calcification is common in patients from endemic regions, but rare in patients from nonendemic areas; however, a single calcified lesion can be assumed to be caused by neurocysti cercosis if the rest of the clinical findings are consistent with this diag-nosis. By contrast, identification of multiple calcifications is strongly suggestive of neurocysticercosis.32

SerologyNumerous serological tests for T. solium-specific anti-bodies have been developed. The best-documented and most useful test is a western blot to detect antibodies in the serum that recognize a range of specific antigens that were identified and cloned from T. solium cysts. The test is very specific for identifying exposure to T. solium and for confirming the diagnosis of neurocysticercosis.65–69 However, this test lacks sensitivity in patients who have a low disease burden—defined as individuals with one viable or degenerating cyst, or those who have only calcified cysts.64 In endemic regions, western blot sero logical testing is useful to rule out neurocysticercosis as a diagnosis, but positive results can occur in a substantial proportion of

indivi duals who have been exposed to T. solium but do not have cysticercosis.70–72

ELISA-based antigen-detection tests that use mono-clonal antibodies against the closely related tapeworm T. saginata have been developed. These tests can identify patients who have a current, viable neurocysticercosis infection, but are not as sensitive as western-blot-based antibody assays. T. solium antigens are commonly present in patients who have subarachnoid disease, but are detected less frequently in patients with parenchymal disease. The concentration of antigen is higher in the CSF than in serum, and antigen titers in serum or CSF correlate with the gross extent of CNS involvement.73,74

A major clinical issue that has not yet been settled is when to stop antihelminthic treatment in patients who have complicated subarachnoid disease. Serial measure-ments of antigen levels in these patients could help to establish the efficacy of treatment, indicate clearance of parasites from the patient, and suggest when anti-helminthic treatment can be stopped.75 Assays that can detect cyst antigens in the serum and CSF might provide a useful tool for monitoring drug efficacy for follow-up of treated individuals.75,111

a

c d

b

Figure 4 | Extraparenchymal neurocysticercosis. a | Viable intraventricular cysts (arrowheads) with intraparenchymal degenerating enhancing cysts (white arrows) on contrast T1‑weighted MRI. b | Subarachnoid neurocysticercosis of the brain convexity (black arrow) with a viable intraparenchymal cyst (white arrow) and calcified intraparenchymal cysts (black arrowheads) on noncontrast CT. c | Arrow showing subarachnoid neurocysticercosis of the Sylvian fissure on MRI (fluid‑attenuated inversion recovery protocol). d | Basal subarachnoid neurocysticercosis on contrast T1‑weighted MRI.

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TreatmentThe choice of treatment for patients with neurocysti cercosis depends on the type and degree of CNS involvement, the acute ness and severity of the presenting symptoms, the stage of cyst degeneration and accompanying inflam-mation, and the potential risk of future complications.23,76–78 Treatment options include immediate measures to prevent morbidity or death (such as administration of mannitol or high-dose steroids), surgical procedures to remove the cysts or to relieve blockages or hydrocephalus, anti epileptic drugs to control seizures, corticosteroids to control inflam-mation, and anti helminthic medications to kill the cysts. Few treatment modalities have been subjected to ran-domized studies; therefore, the amount of benefit derived from individual treatments, and their optimal indication and use, remain unclear. However, reasonable evidence and a great deal of anecdotal experience support the use of anti helminthic medications, usually accompanied with corticosteroids, to treat patients with viable cysts.

Symptomatic treatmentPatients with severe disease and life-threatening compli-cations of neurocysticercosis (status epilepticus, intra-cranial hypertension with or without hydrocephalus, infarcts, mass effects, and focal neurological deficits) require emergency treatment. The importance of iden-tifying and promptly relieving intracranial hypertension should be stressed. If the symptoms indicate an inflamma-tory component (such as a degenerating cyst with edema and inflammation, or acute or chronic hydrocephalus), large doses of corticosteroids along with other supportive measures, such as shunt placement, are indicated.

Antihelminthic therapy is rarely required before the patient is stabilized. Indeed, in some cases, administra-tion of such drugs before stabilization of the patient could aggravate their already critical condition.

Analgesics and/or antiepileptic drugsHeadache is a frequent symptom in patients with neuro-cysticercosis, and can be experienced alone, with intra-cranial hypertension, or in the postictal period (in patients with seizures). Standard analgesics (such as paracetamol or tramadol) represent the first line of treatment for head-ache, and patients usually have a good clinical response to these medications. Antiepileptic drug therapy is indicated in most patients with neuro cysticercosis and seizures, since the seizures are secondary to an organic focus; carba-mazepine or phenytoin are the most commonly used agents in endemic countries, mainly owing to their availability and low cost. No formal studies have investigated the relative efficacies of different anti epileptic drugs in the treatment of patients with seizures caused by neuro cysticercosis, but anecdotal evidence suggests that these agents have similar efficacy to that observed in patients with idiopathic epi-lepsy. Seizures in patients with neurocysticercosis are usually well-controlled by antiepileptic monotherapy at the standard dose for the specific agent.79,80 Patients with acute, symptomatic seizures, or seizures caused by inflammation, might also benefit from treatment with cortico steroids or other anti-inflammatory medications.

Anti-inflammatory drugsCorticosteroids are commonly administered to patients with neurocysticercosis to control the inflammation induced by antihelminthic treatment and, in many cases, to suppress the inflammation that occurs during the natural course of disease. Corticosteroid therapy for neuro cysticercosis has not been specifically studied, except in the treatment of patients with an SEL. Several studies have shown that a short course of corticosteroids in combination with antiepileptic treatment decreased the number of subsequent seizures when compared with anti-epileptic drugs alone.78,81 No standard anti-inflammatory treatment regimen exists for multicystic disease; strat-egies range from no corticosteroid therapy until seizures begin or other symptoms develop, to high-dose, long-term administration of corticosteroids before, during and after antihelminthic treatment.81

A trial in patients with parenchymal neurocysticer cosis is underway to determine whether an increased dose of cortico steroids (8 mg for 28 days, followed by tapering to 0 mg over 2 weeks) results in decreased seizures compared with standard corticosteroid dosing (6 mg for 10 days) with no tapering. The results of this trial are expected shortly. This study is the first attempt to determine the utility, effective ness and adverse effects of corticosteroid use as a treatment for inflammation in patients with intra-parenchymal neuro cysticercosis. Although short courses of cortico steroids are considered reasonably safe in this setting, patients with subarachnoid cysticercosis (and, occasionally, those with complicated neuro cysticercosis) might require long-term, high-dose corticosteroids, which could result in potentially life-threatening adverse effects. Methotrexate is useful as a corticosteroid-sparing agent; doses ≤20 mg per week of this agent enabled the reduction of corticosteroid use in patients with neurocysticercosis.82

Seizures are a common presentation in patients with neurocysticercosis who have calcifications and peri lesional edema.41,42 Although the physician’s natural inclination might be to treat these patients with high-dose cortico-steroids, the clinical benefit of this treatment regime has not yet been proven. However, emerging evidence suggests that exacerbation of the original lesion, and even involve-ment of previously uninvolved calcifications, might occur when treatment with corticosteroids is tapered too quickly or stopped.41 This rebound inflammation, which seems to be caused by overcompensation of the host immune response following the removal of immuno suppression, also occurs when treatment with anti helminthic drugs or high-dose cortico steroids is stopped abruptly in patients with viable cysts.

Antihelminthic treatmentEvidence of the clinical efficacy of antihelminthic therapy is based on the results of double-blinded, random-ized studies in patients with single-cyst and multicystic parenchymal disease, the favorable clinical outcomes seen in nonrandomized series or controlled studies, and anecdotal experi ence of good clinical responses follow-ing anti helmithic treatment in patients with severe and life-threatening forms of neurocysticercosis.83 The data

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showing a benefit of antihelminthic drugs in the treat-ment of patients with an SEL are conflicting, and some trials found no significant benefit of such treatment.84 The two antihelminthic drugs that are most used (albendazole and praziquantel) are cysticidal and result in either cyst degenera tion, followed by clearance, or eventual calcifica-tion of the cyst.85,86 How ever, despite reasonable proof of their cysti cidal effects, the clinical benefit of treatment with cysti cidal agents was, until recently, not generally accepted, because many patients developed treatment-related exacer bations of disease.83,84 In addition, many clinicians were critical of the flawed design of early studies.84,87

Most studies have shown a clinical benefit of anti-helminthic therapy in patients with parenchymal disease.83 The therapeutic approach to cystic disease or SELs differs from that of extraparenchymal neurocysticercosis. A well-designed, double-blinded, randomized study that compared antihelminthic treatment with no treatment in patients with cystic disease showed a significant decrease in generalized seizures and a decrease in partial seizures in the first month after treatment; this study confirmed the conclusions of a number of earlier, less conclusive, studies.58,88,89 A meta-analysis of treatment studies also concluded that cysticidal drugs are clinically benefi-cial in patients with neurocysticercosis.83 Whether anti-helminthic treatment is efficacious in patients with an SEL is currently unclear, owing to the disparity in results from many studies.90–95

Albendazole and praziquantelAlbendazole might be superior to praziquantel when given to patients at usual doses. Uncomplicated parenchymal disease is commonly treated with 15 mg/kg albendazole in two divided doses of up to 400 mg each with meals, for 8 days to 2 weeks, although this treatment regime may result in underdosing for some patients. Praziquantel at 50 mg/kg daily is taken with meals for 1–2 weeks, usually with cimetidine to prevent metabo lism of the active parent drug in the liver.96 A short-duration, high-dose regimen of 100 mg/kg praziquantel in three divided doses every 2 h, followed by corticosteroids, was efficacious in patients with a single cyst, but the efficacy of this treat-ment regime is controversial in patients with multicystic disease.97,98 Although both albendazole and praziquantel are cysticidal, they often show only partial efficacy when administered at the doses noted above.

All commonly used antihelminthic treatment regi-mens yield disappointingly low cure rates—only 40% of untreated patients show complete clearance of all cysts, although around 60% of cysts resolve after one course of treatment. Consequently, patients often require retreat-ment. The levels of praziquantel and albendazole sulfoxide (a metabo lite of albendazole) in patients receiving these agents vary considerably from person to person. In addi-tion, the levels of both drugs are decreased in patients who are also taking antiepileptic drugs, and praziquantel levels are reduced when this drug is administered in combina-tion with cortico steroids.79,80,99,100 A potential approach to avoid these effects would be to treat the patient with anti helminthic drugs until the MRI scan shows initial

degeneration of all the cysts, and then follow the patient with imaging to confirm cyst disappearance. Initial reports indicate that combined albendazole and praziquantel therapy is safe and promising.80,101,102

Controlling treatment-induced inflammationIn patients with untreated neurocysticercosis, cysts may degenerate at different times and rates. However, anti-helminthic treatment can potentially initiate an inflam-matory response against all viable cysts at the same time. When cysts are numerous, large areas of the brain may be affected by this inflammatory response, potentially leading to severe morbidity and death. Patients with many viable lesions should, therefore, be treated with particu-lar caution; antihelminthic treatment is contraindicated in patients with disseminated disease or ocular cysts. Furthermore, antihelminthic treatment is not indicated in patients with calcified neurocysticer cosis, because calci-fied lesions are nonviable and consist only of encapsulated cyst remnants, along with varying degrees of host-derived inflammatory infiltrate.

Neurocysticercosis encephalitis is treated primarily with corticosteroids. Patients who have cysts lodged in critical areas, such as the medulla and spine, require immuno-suppressive doses of corticosteroids and may also require antihelminthic treatment until the lesions resolve. High-dose corticosteroids in combination with antihelminthic drugs administered for 1–3 months (or more) may be con-sidered in patients with ventricular cysts who cannot be treated surgically. Nonobstructing cysts in the lateral ven-tricles can also be treated medically, but ventricle entrap-ment syndromes can sometimes ensue. Continuation of anti-inflammatory drugs, such as corticosteroids or metho-trexate, might suppress the ongoing inflammation that leads to scarring and hydrocephalus in these patients.

If cysts are killed and the resulting inflammation (that causes seizures) is supressed, then the number of total sei-zures will decrease in the short-term. As all viable cysts that could degenerate will have been eliminated, long-term seizure activity in the patient will also be reduced.

Treating subarachnoid diseaseNo controlled trials have investigated the treatment of subarachnoid disease. In patients with this type of neuro-cysticercosis, the response to antihelminthic drugs is vari-able, but success usually requires long-term treatment and repeated assessments of the patient. Improvement is gauged by changes in clinical, radiological and CSF param-eters. One large study that investigated medical treatment of individuals who had giant cysts in the Sylvian fissure showed that the patients had good responses to repeated courses of antihelminthic medication.51

Basal subarachnoid neurocysticercosis is usually diffi-cult to treat, and relapses commonly occur, even years after apparent stabilization of disease. Nevertheless, in contrast to the severe morbidity of neurocysticercosis and the high frequency of autopsy descriptions of this disease before the availability of antihelminthic drugs, patients who receive persistent care and fastidious follow-up after treatment with these drugs will usually show clinical improvement,

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and survive with relatively little morbidity. Our current approach is to treat patients with antihelminthic drugs at the usual doses for 2–3 months, and then re-treat until no viable parasites are seen. Although not yet supported by controlled trials, increasing the dose of praziquantel to 100 mg/kg, or even combined albendazole plus prazi-quantel therapy at usual concentrations and dosing, might improve cysticidal efficacy and could be considered for the treatment of patients with recurrent disease.80,103–109 Short-term use of albendazole at a dose of 30 mg/kg daily has also been tried in some patients with neurocysticercosis, without any obvious increase in adverse effects.110

SurgerySurgical procedures, including neuroendoscopy, open sur gery and shunt placement, are central to the treatment of complicated neurocysticercosis.111 Neuroendoscopy is useful to remove cysts that can be easily accessed; this treat ment may reduce the symptoms caused by the cyst and could also avoid the prolonged use of cortico steroids and antihelminthic drugs. No randomized studies have investigated the treatment of ventricular disease; how-ever, the general consensus is that ventricular cysts that do not adhere to the ependyma should be removed, prefer ably by neuroendoscopy. One consideration is that neuro endoscopical or open removal of large cysts that cause symptoms of neurocysticercosis is itself likely to cause symptoms.112–116 Even if cyst removal is successful, hy drocephalus will sometimes develop anyway.

Whether the postsurgical inflammatory response (to any remaining cysts, membranes or antigens) contributes to the risk of subsequent hydrocephalus is not known. A study that investigated a large series of patients who had cysts lodged in the fourth ventricle has suggested that medical therapy could successfully be employed without the need for surgical removal of cysts, but that these patients sometimes require subsequent shunt place-ment to control hydrocephalus. Most experts, there fore, recom mend endoscopic or surgical removal of ventricu-lar cyst whenever possible. The advantages of surgery in the treatment of ventricular cysts include immediate removal of the obstruction and control of inflammation (as the source of antigen has been removed), which reduces the chance that the patient will develop obstructive and communicating hydrocephalus.111

ConclusionsBefore 1970, neurocysticercosis was not commonly recog nized by clinicians, was infrequently diagnosed, and was, essentially, untreatable. At present, neuro cysti-cer cosis is recog nized as a common infection, at least in endemic regions, where it has been identified as a major cause of seizures. Neurocysticercosis can usually be

easily diagnosed by brain imaging, and effective medical tr eatment is available.

Despite these advances in the diagnosis and treatment of neurocysticercosis, large gaps persist in our knowledge about the worldwide burden of disease and infection, our understanding of the pathophysiology of disease and genesis of epilepsy, and our ability to devise improved and highly effective treatments. The burden of disease is only known for the restricted populations that have been studied and, consequently, the global prevalence of neuro-cysticercosis is grossly underestimated. The best way to use cysticidal agents is still not understood; cure rates are low, and long-term antihelminthic therapy is frequently required for patients with complicated disease. Moreover, the use of such drugs can be a double-edged sword because, while they kill the parasites, the initiation of widespread cyst degeneration also invokes an intense and injurious host inflammatory response that needs to be suppressed. Inflammation is primarily responsible for most manifesta-tions of the disease, and how best to suppress this process remains, for the most part, unstudied. Furthermore, treat-ment with anti-inflammatory agents can potentially reduce the efficacy of antihelminthic therapy.

In endemic populations, calcified lesions are strongly associated with seizures, and 50% of individuals with cal-cified cysts show perilesional edema at the time of seizure recurrence.42 The pathophysiology in these patients is unclear, but some calcified lesions probably act as foci of inflammation, which suggests that anti-inflammatory therapy might be useful to treat and/or prevent seizures in these patients. Effective corticosteroid-sparing agents need to be identified and incorporated into the long-term manage ment of patients with ventricular and subarachnoid disease—the most severe types of neurocysticercosis—as treatment of patients with these forms of the disease is presently based solely on anecdotal experience. Over the past three and a half decades, a revolution has taken place in the ability to treat and diagnose neurocysticercosis. However, more data quantifying the substantial burden of disease associated with neurocysticercosis, and more-effective drugs with better and safer treatment regimens, are still urgently needed.

Review criteria

Most information for this Review was obtained from MEDLINE, through searches of the authors’ extensive personal collections of files, or from their ongoing work. MEDLINE searches were performed for the period between 1969 and 2011, using the search terms “cysticercosis”, “neurocysticercosis”, or “Taenia solium”. Papers published in English or Spanish were reviewed. The final reference list was generated on the basis of relevance to the topics covered in this Review, and publication date.

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AcknowledgmentsThis work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institutes of Allergy and Infection Diseases. H. H. Garcia is a Wellcome Trust International Senior Research Fellow.

Author contributionsT. E. Nash and H. H. Garcia contibuted equally to researching the data for the article, discussion of the article content, writing the article and reviewing and/or editing the manuscript before submission.

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