Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 97

Neurocysticercosis OSCAR H. DEL BRUTTO* School of Medicine, Universidad de Especialidades Espiritu Santo and Department of Neurological Sciences, Hospital Clinica Kennedy, Guayaquil, Ecuador

HISTORY Taeniasis and cysticercosis have been mentioned since the beginning of the recorded history. Tapeworms and cysticerci have been found in mummies from Ancient Egypt (Bruschi et al., 2006). Arab writers, during the first millennium AD, recognized tapeworm proglottids and called them “cucurbitine,” because of their similarity with pumpkin seeds (Cucurbita pepo). The occurrence of swine cysticercosis (measly pork) was common knowledge among the Ancient Greeks and Romans (Nieto, 1982). Indeed, swine were considered impure in Ancient Greece, and it may have been for that reason that the Qur’an prohibited the consumption of pork, since many Greek ideas were adopted by the prophet Muhammad (570–632 AD), the founder of the Islamic religion. The first human cases of neurocysticercosis were described during the 16th century. By that time, however, vesicles found in some autopsied brains were not identified as parasites (Nieto, 1982). The association between taeniasis and cysticercosis in the same individual was probably first described by the Peruvian Hipo´lito Unanue in 1792, as he published the case of a soldier with taeniasis who died following a seizure (Deza, 1987). During the 19th century, morphologic similarities between the head of the adult Taenia solium and the scolex of cysticercus were recognized. In Germany, K€ uchenmeister (1855) demonstrated that oral consumption of cysticercus from pork meat resulted in intestinal taeniasis. A few days before a convict’s death, a man was fed with cysticerci obtained from a pig slaughtered 60 hours previously. At autopsy, performed 48 hours after execution, the author found a Taenia attached with its rostellum to the duodenal mucosa. This report suggested that human taeniasis is acquired by consumption of cysticercus from infected pork.

Knowledge of the life cycle of Taenia solium was completed during the second half of the 19th century by experiments demonstrating than when Taenia eggs obtained from proglottids passed by infected humans were fed to pigs, the animals develop cysticercosis. Relevant advances during those years included the description of meningeal cysticercosis, the first classification of the clinical syndromes of cysticercosis, and the description of cysticercotic angiitis (Trelles and Trelles, 1978). The prestigious Handbuch der Neurologie included a chapter on cysticercosis that listed more than 200 references mainly from Europe, where this pathology was well recognized at the turn of the 20th century (Henneberg, 1912). The work of Yoshino (1933), who infected himself with Taenia solium cysticerci to study the life cycle of the cestode, must also be mentioned. With the introduction of the complement fixation test, the diagnosis of cysticercosis could, for the first time, be established without the need of histologic demonstration of the parasite. (Weinberg, 1909). The extensive work of Dixon and Lipscomb (1961) described in detail the public health consequences of mass travel to endemic areas and its impact on the prevalence of cysticercosis in Western countries, and contributed to our current knowledge about the natural history of this parasitic disease. Thereafter, the introduction of computed tomography (CT) allowed the visualization of intracranial cysticerci and improved the diagnosis of neurocysticercosis (Carbajal et al., 1977). Finally, the advent of specific therapy for human cysticercosis (Robles and Chavarrı´a, 1979) heralded a new era in the history of this ancient scourge.

EPIDEMIOLOGY With the exception of Muslim countries, cysticercosis is endemic in most of the developing world. While the exact

*Correspondence to: Oscar H. Del Brutto, M.D., Air Center 3542, P.O. Box 522970, Miami, FL 33152-2970, USA. Tel: þ593-42-2857-90, E-mail: [email protected]

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prevalence of neurocysticercosis is largely unknown, it is estimated that millions of people living in Latin America, Africa, and Asia are infected by this parasite, and that many of them, at any point of their lives, experience the clinical consequences of this infection (Ndimubanzi et al., 2010). Population-based studies carried out in rural villages of endemic countries have shown that neurocysticerosis is the principal cause of the excess fraction of epilepsy seen in these areas, when compared to the prevalence of epilepsy in developed countries (Del Brutto et al., 2005; Medina et al., 2005; Montano et al., 2005). The disease is also a health problem in urban centers of developing countries, where neurocysticercosis is still a major cause of hospital admissions to neurologic centers (Fleury et al., 2010). Neurocysticercosis (NCC) was rare in the US and Europe up to 30 years ago. Together with the growing number of immigrants from endemic areas, there has been an increase in the number of patients with NCC in these countries. In the US, most cases have been reported from the southwestern states where more than 20 million Mexican Americans live. Almost 90% of neurocysticercosis patients diagnosed in the US are immigrants from Mexico or South America (White, 2000; Serpa et al., 2011). However, some cases have been recognized in American citizens with no history of travel to endemic areas. Most of these patients acquired the disease through a household contact infected with Taenia solium (Sorvillo et al., 2011). A similar scenario has been observed in Canada, Australia, and some European countries, where mass immigration of people from South America has caused a recent increase in the prevalence of this parasitic disease (Esquivel et al., 2005; MassSese et al., 2008; Del Brutto, 2012a, b, c). It has also been noted that there is an increased prevalence of NCC among international travelers from nonendemic to diseaseendemic areas; most of these patients develop the disease months to years after returning home and present with benign forms of NCC (single cysticercus granulomas), strongly suggesting that the most common form of disease acquisition was through sporadic contact with a Taenia carrier while abroad (Del Brutto, 2012d).

proglottids. T. solium inhabits the small intestine of humans, where it is attached to the intestinal wall by its suckers and hooks. Every day, some gravid proglottids are detached from the distal end of the worm and are passed with the feces. Each proglottid liberates thousands of fertile eggs which are resistant to the environment. In places with deficient disposal of human feces, pigs are fed with human feces containing T. solium eggs. Once in the intestinal tract of the pig, the eggs lose their coat and liberate embryos (oncospheres) which cross the intestinal wall and enter the bloodstream, from where they are carried to the tissues and evolve forming larvas (cysticercus). Under these circumstances, pigs become intermediate hosts in the life cycle of T. solium (Del Brutto et al., 1988c). Human consumption of improperly cooked infected pork (Fig. 97.1) results in release of cysticerci in the small intestine where, by the action of digestive enzymes, their scolices evaginate and attach to the intestinal wall. After the scolex is attached, the proglottids begin to multiply and will become mature approximately 4 months after infection. Humans can also act as intermediate hosts for T. solium after ingesting its eggs. Under these circumstances, human cysticercosis develops. The mechanisms by which eggs cross the intestinal wall and lodge in human tissues are the same as those described in the pig. Humans acquire cysticercosis from ingestion of food contaminated with T. solium eggs and by the fecal-oral route in individuals harboring the adult

ETIOPATHOGENESIS Life cycle of Taenia solium The tapeworm T. solium has a complex life cycle involving two hosts, humans and pigs. Humans are the only definitive hosts for the adult cestode, whereas both pigs and humans may act as intermediate hosts for the larval form called cysticercus. The adult T. solium has a head (scolex) that consists of four suckers and a double crown of hooks, a narrow neck, and a large body formed by several hundred

Fig. 97.1. Infected pork meat showing multiple cysticerci.

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parasite in the intestine. While the former was considered the most common form of transmission, recent epidemiologic studies showing clustering of patients with cysticercosis around taeniasic individuals have changed previous concepts crediting the environment as the main source of human contamination with T. solium eggs. Human cysticercosis should now be considered as a disease mostly transmitted from person to person, and the role of infected pigs is to perpetuate the infection (Gonzalez et al., 2006).

Characteristics of cysticerci Cysticerci are small vesicles that consist of two parts, the vesicular wall and the scolex (Willms, 2008). The scolex has an armed rostellum and a rudimentary body. In some cysticercus the scolex cannot be identified. These parasites are composed of membranes attached to each other that tend to group in clusters resembling a bunch of grapes. This form is often called the racemose form of cysticerci, and is usually observed in parasites located within the cerebrospinal fluid (CSF) cisterns at the base of the brain, where they may attain a large size. While the mechanisms responsible for the transformation of cysticerci from single vesicles to the racemose form are not totally understood, it is likely that the scolices disappear as the result of a degenerative process, called hydropic degeneration, caused by the continuous entrance of CSF inside the vesicles (Escobar and Weidenheim, 2002).

Stages of involution of cysticerci After entering the central nervous system (CNS), cysticerci are in a vesicular (viable) stage in which the parasites have a transparent membrane, a clear vesicular fluid, and a normal invaginated scolex. Cysticerci may remain viable for years or, as the result of the host’s immunologic attack, enter in a process of degeneration that ends with their transformation into inert nodules. The first stage of involution of cysticerci is the colloidal stage, in which the vesicular fluid becomes turbid, and the scolex shows signs of hyaline degeneration. Thereafter, the wall of the cyst thickens and the scolex is transformed into mineralized granules; this stage, in which the cysticercus is no longer viable, is called the granular stage. Finally, the parasite remnants appear as a mineralized nodule (calcified stage) (Escobar and Weidenheim, 2002). The duration of each of these stages has not been established, although it is believed that considerable differences exist among individuals. Furthermore, pathologic studies have shown cysticerci in different stages of involution in the same individual (Fig. 97.2). Whether this represents cysts of different ages from recurrent infections or a single infection in which only some cysts have been attacked by the host’s

Fig. 97.2. Brain slice showing parenchymal cysticerci in different stages of involution.

immune system remains unknown. It has recently been suggested that not all cysticerci go through these four orderly stages of involution. Indeed, it is possible that some metacestodes are attacked by the host’s immune system as soon as they enter the nervous system, and are transformed into granulomas without going through the vesicular and colloidal stages. This alternative hypothesis of cysticerci involution is supported by the younger age of patients with cysticercus granulomas (when compared with those with vesicular cysts), by the higher prevalence of a single cysticercus granuloma in populations who are exposed to low parasite loads, and by the low sensitivity of serologic assays in patients with a single cysticercus granuloma (Garcia et al., 2010).

Tissue reaction around cysticerci Parenchymal brain cysticerci in the vesicular stage elicit a scarce inflammatory reaction in the surrounding tissue that is mainly composed of plasma cells, lymphocytes, and eosinophils. Colloidal cysticerci are surrounded by a thick collagen capsule and by a mononuclear inflammatory reaction that usually includes the parasite itself. The surrounding brain parenchyma shows an astrocytic gliosis associated with microglial proliferation, edema, neuronal degenerative changes, and perivascular cuffing of lymphocytes. When parasites enter into the granular and calcified stages, the edema subsides but the astrocytic changes in the vicinity of the lesions may become more intense, and epithelioid cells appear and coalesce to form multinucleated giant cells (Pittella, 1997). Meningeal cysticerci usually elicit a severe inflammatory reaction in the subarachnoid space with formation of an exudate composed of collagen fibers, lymphocytes,

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Fig. 97.3. Cysticerci membranes in subarachnoid space (black arrows) surrounded by inflammatory reaction (white arrowheads).

multinucleated giant cells, eosinophils, and hyalinized parasitic membranes leading to abnormal thickening of the leptomeninges (Fig. 97.3). This inflammation may be disseminated, inducing damage in structures distant to the site where the parasites lodge. The optic chiasm and cranial nerves arising from the brainstem are encased in this leptomeningeal thickening. The foramina of Luschka and Magendie may also be occluded by the thickened leptomeninges and parasitic membranes with the subsequent development of obstructive hydrocephalus. Small penetrating arteries arising from the circle of Willis may also be affected by the subarachnoid inflammatory reaction. This may cause occlusion of the lumen of the vessel with the subsequent development of a cerebral infarction (Del Brutto, 2008). Ventricular cysticerci may also elicit an inflammatory reaction if they are attached to the choroid plexus or to the ventricular wall. The ependymal lining is disrupted and proliferating subependymal glial cells protrude toward the ventricular cavities blocking the transit of CSF, particularly when the site of protrusion is at or near the foramina of Monro or the cerebral aqueduct (Pittella, 1997).

Immune response against cysticerci Some cysticercal antigens stimulate the production of specific antibodies that form the basis for the immunologic diagnosis of cysticercosis, while others play a role in the evasion of the immune surveillance against cysticerci. One of these antigens, a paramyosin called antigen B, has affinity for collagen and may bind to C1q, inhibiting the classic pathway of complement activation. As destruction of cysticerci seems to be mediated by activation of the complement cascade, antigen B could play a role in the protection of cysticerci against the host’s

immunologic attack. Despite the presence of specific antibodies against cysticerci in most patients with neurocysticercosis, there is no correlation between the severity of parasite destruction and the overall titers of such antibodies. Indeed, immunoglobulins have been more frequently found around living parasites than surrounding dead cysts, suggesting that cysticerci use the host’s immunoglobulins as a screen to avoid recognition from the immune system (Del Brutto et al., 1988c; Flisser et al., 2002). Some reports suggest the presence of cellular immune dysfunction in patients with neurocysticercosis. This impairment results from an increase in the subpopulations of CD8 T lymphocytes, impaired proliferation of lymphocytes, and abnormal concentration of cytokines. The depressed cellular immunity may be responsible for the reported association of neurocysticercosis with conditions resulting from immunodeficiency states. In addition, some studies showed a higher prevalence of cerebral glioma among neurocysticercosis patients than in the general population (Del Brutto et al., 1997). In these patients, the intense glial proliferation around the parasites, along with the suppression of the cellular immune responses may cause inhibition of the immunologic surveillance against cancer, leading to malignant transformation of astrocytes (Del Brutto et al., 2000).

CLINICAL MANIFESTATIONS Neurocysticercosis may present with a variety of clinical manifestations, a pleomorphism that is related to individual differences in the number and location of the lesions within the CNS, and to variations in the severity of disease activity. In endemic areas, neurocysticercosis is considered the “great imitator” as it may mimic almost any other neurologic disease (Del Brutto et al., 1988c). Seizures, focal neurologic signs, cognitive impairment, and intracranial hypertension, are the most common clinical manifestations of neurocysticercosis (Table 97.1).

Seizures Epileptic seizures are the most common clinical manifestation of neurocysticercosis and usually represent the primary manifestation of the disease in up to 70% of patients (Del Brutto et al., 1992). Neurocysticercosis is a leading cause of adult-onset epilepsy in areas where the disease is endemic and, as noted before, is partly responsible for the increased prevalence of epilepsy seen in developing countries (Medina et al., 2005). Seizures are more prevalent in patients with parenchymal neurocysticercosis than in those with subarachnoid or ventricular disease (Garcia and Del Brutto, 2005). While some series have shown that most patients with epilepsy due to neurocysticercosis have generalized seizures, it is most

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Table 97.1 Clinical manifestations of neurocysticercosis according to parasite location and disease activity Location/form of the disease Brain parenchyma Vesicular cysts Colloidal cysts Granulomas/calcifications Cysticercotic encephalitis Subarachnoid space Giant cysts in CSF cisterns Diffuse arachnoiditis Hydrocephalus Angiitis Ventricular system Ventricular cysts Ependymitis Spinal cord Arachnoiditis Parenchymal cysts Other forms of the disease Suprasellar cysticercosis Ophthalmic cysticercosis Muscle cysticercosis

Usual clinical manifestations

Seizures; may be asymptomatic Seizures; headache; vomiting; focal signs Seizures, may be recurrent Coma; seizures; intracranial hypertension Seizures; intracranial hypertension; focal signs; cognitive impairment Focal signs; intracranial hypertension Intracranial hypertension; cognitive impairment Acute stroke syndromes Focal signs; intracranial hypertension Seizures; intracranial hypertension Root pain; weakness; meningitis (rare) Motor and sensory signs below the level of the lesion Ophthalmologic and endocrinologic disturbances Visual loss; extraocular muscle paralysis Muscle pseudohypertrophy

likely that those patients actually presented with partial seizures with secondary generalization. The problem of neurocysticercosis and epileptogenesis has been a subject of debate. It has been suggested that seizures occur when the parasite begins to degenerate (White, 2000). However, large series of patients with neurocysticercosis-related epilepsy include patients who only have vesicular (viable) cysts at the time of diagnosis (Del Brutto et al., 1992). On the other end of the spectrum is the debate about the risk of seizures in patients with calcified parenchymal brain cysticerci (Nash et al., 2004). While calcifications have been usually considered inert lesions, recent data strongly suggest that calcified cisticerci are not clinically inactive, but may cause recurrent seizures when parasitic antigenic epitopes trapped in the calcium matrix are exposed to the host immune system due to a process of calcification remodeling (Nash et al., 2008; Mahanty and Garcia, 2010). In these cases, recurrent seizures may be the cause of hippocampal sclerosis, thus perpetuating the risk of seizures in these patients.

Focal neurologic signs A variety of focal neurologic signs related to the size, number, and location of the parasites have been described in patients with neurocysticercosis. Pyramidal tract signs predominate, but sensory deficits, language disturbances, involuntary movements, parkinsonian

rigidity, and signs of brainstem dysfunction may occur in these patients (Del Brutto et al., 1988c). Focal neurologic signs in neurocysticercosis usually follow a subacute or chronic course resembling that of a brain tumor, and are most often seen in patients with large subarachnoid cysts compressing the brain parenchyma (Fleury et al., 2011). Stroke syndromes, including transient ischemic attacks, cerebral infarcts, and intracranial hemorrhages – all causing focal neurologic deficits – have been described in patients with neurocysticercosis (Cantu and Barinagarrementeria, 1996). These infarcts are usually located in the posterior limb of the internal capsule, the corona radiata, or the brainstem, and produce typical lacunar syndromes such as pure motor hemiparesis and ataxic hemiparesis (Del Brutto, 2008).

Intracranial hypertension Some patients with neurocysticercosis present with increased intracranial pressure associated or not with seizures, focal neurologic signs, or dementia. The most common cause of this syndrome is acute or subacute hydrocephalus, which may be either related to cysticercotic arachnoiditis, granular ependymitis, or ventricular cysts (White, 2000; Fleury et al., 2011). Intracranial hypertension may be punctuated by episodes of sudden loss of consciousness related to movements of the head (Bruns syndrome) when the cause of hydrocephalus is a

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fourth ventricle cyst. Increased intracranial pressure also occurs in cysticercotic encephalitis, a severe form of neurocysticercosis that occurs as the result of a massive cysticerci infection of the brain parenchyma inducing an intense immune response from the host. This condition is more frequent among children and young women, and is characterized by clouding of consciousness, seizures, diminution of visual acuity, headache, vomiting, and papilledema (Rangel et al., 1987).

Psychiatric disturbances Patients with neurocysticercosis may present psychiatric manifestations ranging from poor performance on neuropsychological testing to a severe dementia (Forlenza et al., 1997). The latter may be found in 6–15% of cases. In the past, some of these patients were admitted to psychiatric hospitals for several years until the correct diagnosis was done at autopsy (Nieto, 1982). Psychotic episodes characterized by confusion, paranoid ideation, psychomotor agitation, and violent behavior have also been described in patients with parenchymal brain lesions. Conceivably, some of these episodes could represent attacks of psychomotor epilepsy or postictal psychosis.

Other clinical manifestations Spinal arachnoiditis is characterized by root pain and weakness of subacute onset, and cysts in the spinal cord parenchyma usually present with motor and sensory deficits that vary according to the level of the lesion (Venkataramana et al., 1989; Alsina et al., 2002). Widespread use of magnetic resonance imaging (MRI) has improved the detection of cysticercosis of the spinal cord. Indeed, the high frequency of spinal cysticerci among patients with intracranial subarachnoid NCC, which may coexist in 60% of cases, has recently been demonstrated (Callacondo et al., 2012). It is likely that this study will change the diagnostic approach to patients with intracranial subarachnoid NCC, since all of them will probably need MRI investigation of the spine to detect hidden lesions. The association of NCC and headache has been considered anecdotal in the past. However, a recent casecontrol study suggests a significant increased prevalence of NCC among patients with a “primary headache disorder” compared to subjects with other diseases of the CNS (Del Brutto and Del Brutto, 2012). Calcifications may experience periodic morphologic changes related to a mechanism of remodeling. This may expose parasitic antigenic material to the host, causing transient inflammatory changes in the brain parenchyma that may be the cause of transient and recurrent headache episodes mimicking a primary headache disorder in some patients.

Patients with cysticerci located in the sellar region present with ophthalmologic and endocrinologic disturbances (Del Brutto et al., 1988b). Intraocular cysticerci are most often located in the subretinal space and produce a progressive decrease of visual acuity or visual field defects. The cysts may induce vitritis, uveitis, and endophthalmitis; the latter is the most severe complication of ocular cysticercosis and may lead to phthisis bulbi (Madigubba et al., 2007). Massive cysticercal infection of striated muscles may produce generalized weakness associated with progressive muscle enlargement (Wadia et al., 1988).

DIAGNOSIS Laboratory findings Peripheral eosinophilia is the most common hematologic abnormality in patients with neurocysticercosis, and has been reported in up to 37% of cases (Loo and Braude, 1982). The frequency of positive stool examinations for Taenia solium eggs among patients with neurocysticercosis has varied from one series to another, and seems to be related to the severity of infection (Garcia and Del Brutto, 1999; Gilman et al., 2000). Recognition of Taenia eggs is not easy and many patients may escape detection when coproparasitologic studies are performed (Richards and Schantz, 1991). Specific coproantigen detection by ELISA and PCR will greatly improve the screening for Taenia solium carriers among healthy individuals from endemic areas (Mahanty and Garcia, 2010). Nonspecific abnormalities in the cytochemical composition of CSF have been reported in a number of patients with neurocysticercosis. These abnormalities directly correlate with the activity of the disease and with whether or not the parasites are located in the subarachnoid space. The most common finding is a moderate mononuclear pleocytosis, with cell counts rarely exceeding 300 per mm3. A moderate increase in CSF protein counts, usually in the range of 50–300 mg/dL, is common in these patients. CSF glucose levels are usually normal despite active meningeal disease (Del Brutto et al., 1988a). Hypoglycorrhachia, observed in a few patients, is associated with a poor prognosis (McCormick et al., 1982).

Neuroimaging CT and MRI provide objective evidence on the number and topography of lesions, their stage of involution, and the degree of the host’s inflammatory reaction against the parasites (Garcia and Del Brutto, 2003). In many cases, intracranial calcifications represent the only evidence of the disease. The sensitivity of conventional MRI for the detection of calcified lesions is poor, and thus CT appears as the best screening neuroimaging

NEUROCYSTICERCOSIS procedure for patients with suspected neurocysticercosis. There is recent evidence, however, that the use of susceptibility-weighted imaging may improve the identification of calcifications by MRI (Wu et al., 2009). MRI is the imaging modality of choice for the evaluation of patients with cystic lesions located in the ventricular system, the brainstem, and over the convexity of cerebral hemispheres.

PARENCHYMAL NEUROCYSTICERCOSIS CT and MRI findings in parenchymal neurocysticercosis depend on the stage of involution of the parasites (Fig. 97.4). Vesicular cysticerci appear on CT and MRI as small and rounded cysts that are well demarcated from the surrounding brain parenchyma. There is no edema and no contrast enhancement. Many of these lesions have in their interior an eccentric hyperdense nodule representing the scolex, giving them a pathognomonic “hole-with-dot” appearance. Colloidal cysticerci appear as ill-defined lesions surrounded by edema. Most of them show a ring pattern of enhancement after contrast medium administration. While the scolex is not usually visualized in colloidal cysticerci, the practice of diffusion-weighted images, may allow the recognition of the scolex, facilitating the diagnosis in selected cases (do Amaral et al., 2005) (Fig. 97.5). A particular neuroimaging pattern of parenchymal neurocysticercosis is observed in patients with cysticercotic encephalitis. In this severe form of the disease, both CT and MRI show diffuse brain edema and collapse of the ventricular system without midline shift. After contrast enhancement, multiple small ring-like or nodular lesions appear disseminated within the brain parenchyma (Rangel et al., 1987). Parenchymal brain cysticerci may also appear on CT or MRI as nodular lesions surrounded by edema after contrast administration. This pattern corresponds to the granular stage of cysticerci and is commonly referred to as “cysticercus granuloma” (Singh et al., 2010). On MRI, granular cysticerci are visualized as areas of signal void on both T1- and T2-weighted images surrounded by edema or gliosis with hyperintense rims around the area of signal void. Calcified (dead) cysticerci normally appear on CT as small hyperdense nodules without perilesional edema or abnormal enhancement after contrast medium administration.

SUBARACHNOID NEUROCYSTICERCOSIS The most common neuroimaging finding in patients with subarachnoid neurocysticercosis is hydrocephalus caused by inflammatory occlusion of Luschka and Magendie foramina. The fibrous arachnoiditis that is responsible for the development of hydrocephalus is seen on CT or MRI as areas of abnormal leptomeningeal

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enhancement at the base of the brain. Cystic subarachnoid lesions may be small when located within cortical sulci or may reach a large size if they are located in the Sylvian fissure or within the basal CSF cisterns (Fig. 97.6). Small cysts within cortical sulci usually follow the same stages of involution that were described for parenchymal brain cysts and may be found in the vesicular, colloidal, granular, or calcified stage. On the other hand, cystic lesions located within CSF cisterns usually have a multilobulated appearance, displace neighboring structures, and behave as mass occupying lesions (Fleury et al., 2011). Cerebrovascular complications of neurocysticercosis are well visualized with CT or MRI. While the neuroimaging appearance of cysticercosis-related infarcts is the same as cerebral infarcts from other causes, the association of subarachnoid cystic lesions (particularly at the suprasellar cistern) and abnormal enhancement of basal leptomeninges suggests the correct diagnosis (Del Brutto, 2008). Angiographic findings in subarachnoid neurocysticercosis include segmental narrowing or occlusion of the major intracranial arteries in patients with cysticercotic-related cerebral infarcts or even in patients lacking clinical or neuroimaging evidence of a cerebral infarct (Cantu and Barinagarrementeria, 1996). MRA is a valuable noninvasive imaging method to demonstrate segmental narrowing or occlusion of intracranial arteries in patients with subarachnoid neurocysticercosis.

VENTRICULAR NEUROCYSTICERCOSIS Ventricular cysticerci appear on CT as hypodense lesions that distort the ventricular system causing asymmetric obstructive hydrocephalus. Ventricular cysts are isodense with CSF; therefore, they only can be inferred on the basis of distortion on the shape of the ventricular cavities (Madrazo et al., 1983). In contrast, most ventricular cysts are readily visualized on MRI because the signal properties of the cystic fluid or the scolex differ from those of the CSF (Singh et al., 2003; do Amaral et al., 2005). Cyst mobility within the ventricular cavities in response to movement of the head, the “ventricular migration sign,” facilitates the diagnosis of ventricular cysticercosis in some cases (Rangel-Guerra et al., 1988).

SPINAL CORD NEUROCYSTICERCOSIS Using CT, anecdotal reports have described symmetric enlargement of the cord in a patient with intramedullary cysts and pseudoreticular formations within the spinal canal in a patient with leptomeningeal cysts. On MRI, intramedullary cysticerci appear as rounded or septated lesions that may have an eccentric hyperintense nodule representing the scolex (Garcia and Del Brutto, 2003). The periphery of the cyst usually shows abnormal

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Fig. 97.4. Imaging findings in parenchymal neurocysticercosis, including vesicular cysts (A), colloidal cysts (B), granular cysts (C), and calcifications (D).

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Fig. 97.5. Contrast-enhanced MRI (A) showing ring-enhancing lesions corresponding to colloidal cysts. Using diffusionweighted images (B), scolex are easily visualized.

mobile within the spinal subarachnoid space and may change their position during the examination according to movements of the patient on the table.

Immunologic diagnosis

Fig. 97.6. MRI showing abnormal enhancement of leptomeninges and racemose cysticerci at Sylvian fissures and basal CSF cisterns.

enhancement after contrast medium administration. The spinal cord is seen enlarged and if the scolex is not identified it is difficult to differentiate this condition from spinal tumors. Leptomeningeal cysts may be freely

Immunologic diagnostic tests are used to assess the prevalence of cysticercosis in populations and to exclude or confirm the diagnosis of neurocysticercosis in neurologic patients with inconclusive neuroimaging findings. The complement fixation test and the enzyme-linked immunosorbent assay (ELISA) are time-honored tests that have been used for the decades to diagnose cysticercosis (Richards and Schantz, 1991; White, 2000). However, both tests have been faced with problems inherent to poor sensitivity or specificity. False-negative results are related to local production of antibodies within the CNS without a parallel increase of antibodies in peripheral blood, or to immune tolerance to the parasite without production of anticysticercal antibodies, and false-positive results are due to previous contact with the adult T. solium or to cross-reactivity with other helminths (Garcia et al., 2005). The demonstration that antibodies to species-specific antigens of T. solium can be detected by enzyme-linked immunoelectrotransfer blot (EITB) assay stimulated investigators to develop highly purified antigens of cysticercus to be used in a new immunologic diagnostic test for cysticercosis (Tsang et al., 1989). The EITB has been

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extensively evaluated in different hospital-based and population-based studies (Garcia et al., 2005). While some reports suggested that serum EITB is from 94% to 98% sensitive and 100% specific for the diagnosis of human cysticercosis, results from other studies have been disappointing. One weakness of the test is the high number of false-negative results in patients with a single cerebral cyst; in such cases, the sensitivity of EITB falls significantly (Singh et al., 2010). In addition, patients with calcified lesions are less likely to test positive on EITB than those with active disease. Another weakness of the serum EITB is that it may be positive in patients who have been exposed to the adult parasite without developing cysticercosis. A recent preliminary study suggested that the use of conformation-sensitive immunoassay may detect almost 50% of patients with a single cysticercal granuloma who were negative with the EITB, thus improving the sensitivity of the test (Prabhakaran et al., 2007). Detection of circulating parasitic antigens using monoclonal antibodies is another immune diagnostic technique that has been used in some field studies (Garcia et al., 2000). However, detection of circulating antigens is possible only in patients with active disease. While the sensitivity of this test as a screening tool for the diagnosis of neurocysticercosis is poor, it may be of value to monitor the response to cysticidal drug therapy (Mahanty and Garcia, 2010).

Diagnostic criteria Despite the above mentioned advances in neuroimaging and immune diagnostic tests, the diagnosis of neurocysticercosis is a challenge in many patients. Clinical manifestations are nonspecific, neuroimaging findings are most often not pathognomonic, and serologic tests are faced with problems related to relatively poor specificity and sensitivity. A set of diagnostic criteria based on the objective evaluation of clinical, radiologic, immunologic, and epidemiologic data has been proposed to provide the physicians with elements to diagnose patients with suspected neurocysticercosis (Del Brutto et al., 2001). This set includes four categories of criteria – absolute, major, minor, and epidemiologic – stratified according to their individual diagnostic strength. Absolute criteria allow unequivocal diagnosis of neurocysticercosis, major criteria strongly suggest the diagnosis but cannot be used alone to confirm the disease, minor criteria are frequent but non-specific manifestations of the disease, and epidemiologic criteria refer to circumstantial evidence favoring the diagnosis of cysticercosis. Interpretation of these criteria result in two categories of diagnostic certainty – definitive and probable – according to the likelihood that neurocysticercosis is present in a given patient (Table 97.2).

Table 97.2 Diagnostic criteria and degrees of diagnostic certainty for neurocysticercosis Diagnostic Criteria Absolute: ● Histologic demonstration of the parasite from biopsy of a brain or spinal cord lesion ● Evidence of cystic lesions showing the scolex on neuroimaging studies ● Direct visualization of subretinal parasites by fundoscopic examination Major: ● Evidence of lesions highly suggestive of neurocysticercosis on neuroimaging studies ● Positive serum immunoblot for the detection of anticysticercal antibodies ● Resolution of intracranial cystic lesions after therapy with albendazole or praziquantel ● Spontaneous resolution of small single enhancing lesions MINOR: ● Evidence of lesions suggestive of neurocysticercosis on neuroimaging studies ● Presence of clinical manifestations suggestive of neurocysticercosis ● Positive CSF ELISA for detection of anticysticercal antibodies or cysticercal antigens ● Evidence of cysticercosis outside the central nervous system Epidemiologic: ● Individuals coming from or living in an area where cysticercosis is endemic ● History of frequent travel to disease-endemic areas ● Evidence of household a contact with T. solium infection Degrees of Diagnostic Certainty Definitive: ● Presence of one absolute criterion ● Presence of two major plus one minor or one epidemiologic criteria Probable: ● Presence of one major plus two minor criteria ● Presence of one major plus one minor and one epidemiologic criteria ● Presence of three minor plus one epidemiologic criteria (Modified from Del Brutto et al., 2001)

TREATMENT A single therapeutic approach is not useful in every patient with neurocysticercosis (Nash et al., 2006). Characterization of the disease in terms of viability of cysts, degree of the host’s immune response to the parasite, and location and number of lesions is important for rational therapy. Therapy usually includes a combination of symptomatic and cysticidal drugs. Surgery also has a role in the management of some patients (Garcia et al., 2002).

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Cysticidal drugs Praziquantel destroys 60–70% of parenchymal brain cysticerci. The initial regimen of praziquantel at doses of 50 mg/kg/day (given every 8 hours) for 15 days was arbitrarily chosen (Sotelo et al., 1984). Since then, recommended dosages of praziquantel have ranged from 10 to 100 mg/kg for periods of 3–21 days (Bittencourt et al., 1990). Plasma levels of praziquantel decline within less than 3 hours after its administration, and it seems that the cysticidal effect observed in such studies has been reached by exposing the parasites to intermittent peaks of the drug. It has also been suggested that if cysticerci are exposed to high concentrations of praziquantel maintained for up to 6 hours by giving three individual doses of 25–30 mg/kg at 2 hour intervals, this might be sufficient to destroy the parasites. While preliminary results with this new regimen were encouraging (Del Brutto et al., 1999), it seems that the single-day course of praziquantel only works for patients with a single parenchymal brain cyst (Pretell et al., 2001). Albendazole also has cysticidal properties. This drug was initially administered at doses of 15 mg/kg/day for 1 month (Escobedo et al., 1987). Further studies showed that the length of therapy could be shortened to 1 week without lessening the efficacy of the drug (Garcia et al., 1997), and even to 3 days if the patient has a single brain cyst (Bustos et al., 2006). Albendazole destroys 70–80% of parenchymal brain cysts, and has been superior to praziquantel in trials comparing the efficacy of these drugs (Sotelo et al., 1990; Takayanagui and Jardim, 1992). Another advantage of albendazole is that it also destroys subarachnoid and ventricular cysts due to its different mechanism of action (Del Brutto, 1997). In some of these cases, particularly in patients with large subarachnoid cysts, higher doses (up to 30 mg/kg/day) or more prolonged, or even repeated, courses of albendazole may be needed (Proan˜o et al., 2001; Gongora-Rivera et al., 2006; Fleury et al., 2011). Due to the benign nature of some forms of neurocysticercosis, the use of cysticidal drugs has been questioned, leading to confusion and incorrect decisions in the management of many patients. It has been claimed that cysticidal drugs only destroy the cysts without modifying the clinical course of the disease (Salinas et al., 1999). Nevertheless, more recent studies have shown that cysticidal drugs also produce clinical improvement in most patients. In a placebo-controlled trial, albendazole was effective for therapy of viable parenchymal brain cysticerci (Garcia et al., 2004). In this study, treated patients had better seizure control than the placebo group, as reflected by a 67% reduction in the number of seizures. In addition, the number of cystic lesions that resolved was significantly higher in patients receiving

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albendazole. Other controlled trials showed that the prognosis of patients with colloidal parenchymal brain cysts is better after therapy than when the disease is left untreated (Baranwal et al., 1998; Gogia et al., 2003; Kalra et al., 2003). Two recent meta-analyses of randomized trials have evaluated the effect of cysticidal drugs on neuroimaging and clinical outcomes of patients with neurocysticercosis (Del Brutto et al., 2006; Abba et al., 2010). According to these meta-analyses, cysticidal drug therapy results in better resolution of both colloidal and vesicular cysticerci, a lower risk of seizure recurrence in patients with colloidal cysticerci, and a reduction in the rate of generalized seizures in patients with vesicular cysticerci. Some patients should not be treated with albendazole or praziquantel. The use of these drugs may exacerbate the syndrome of intracranial hypertension observed in patients with cysticercotic encephalitis. In patients with both hydrocephalus and parenchymal brain cysts, cysticidal drugs may be used only after a ventricular shunt has been placed to avoid further increases of the intracranial pressure as a result of drug therapy. Cysticidal drugs must be used with caution in patients with giant subarachnoid cysticerci because the inflammatory reaction developed by the host in response to the acute destruction of the parasite within the subarachnoid space may occlude small leptomeningeal vessels surrounding the cyst. In such patients, concomitant steroid administration is mandatory to avoid the hazard of a cerebral infarct. In patients with ventricular cysts, the use of cysticidal drugs should be individualized. While albendazole successfully destroys many ventricular cysts, the inflammatory reaction may cause acute hydrocephalus if the cysts are located within the fourth ventricle or near the foramina of Monro. Finally, patients with calcifications alone should not receive cysticidal drugs since these lesions represent already dead parasites (Garcia et al., 2002).

Symptomatic therapy The administration of antiepileptic drugs usually results in adequate control of seizures in patients with calcified cysticerci. In contrast, there is some evidence that patients with viable intracranial cysts should first be treated with cysticidal drugs to achieve an adequate control of seizures with antiepileptic drugs (Del Brutto et al., 1992; Garcia et al., 2004). The optimal length of antiepileptic drug therapy in patients with neurocysticercosis has not been settled. A prospective study showed that up to 50% of patients with parenchymal brain cysticerci successfully treated with cysticidal drugs had relapses after withdrawal of antiepileptic drugs (Del Brutto, 1994). In this study, prognostic factors associated with

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seizure recurrence included the development of parenchymal brain calcifications and the presence of both recurrent seizures and multiple brain cysts before the institution of therapy. In patients with single enhancing lesions (colloidal cysts), the development of brain calcification after therapy is also the main determinant for seizure relapse after withdrawal of antiepileptic drugs; in such cases, long-term antiepileptic treatment may be needed (Singh et al., 2010). Corticosteroids represent the primary form of therapy of some forms of neurocysticercosis, including cysticercotic encephalitis, angiitis, and arachnoiditis causing hydrocephalus and progressive entrapment of cranial nerves. In patients with intracranial hypertension due to cysticercotic encephalitis, corticosteroids may be used in association with osmotic diuretics. Simultaneous administration of corticosteroids and cysticidal drugs has been recommended to ameliorate the secondary effects of headache and vomiting that may occur during therapy (Garcia et al., 2002). Such manifestations are related to the acute destruction of parasites within the brain, and are reliable indicators of drug efficacy. Absolute indications for corticosteroid administration during cysticidal drug therapy include the management of patients with giant subarachnoid cysticerci, ventricular cysts, spinal cysts, and multiple parenchymal brain cysts. In these cases, corticosteroids must be administered before, during, and even some days after the course of anticysticercal drugs to avoid the risk of cerebral infarcts, acute hydrocephalus, spinal cord swelling, and massive brain edema, respectively (Del Brutto, 1997; Garcia and Del Brutto, 1999; Garcia et al., 2005).

Surgery Patients with hydrocephalus require placement of a ventricular shunt. The main problem in these cases is the high prevalence of shunt dysfunction; indeed, it is common for these patients to have two or three shunts revisions during their lives. Their protracted course and their high mortality rates (up to 50% in 2 years) is directly related to the number of surgical interventions to change the shunt (Sotelo and Marin, 1987). Ventricular cysts may be removed by surgical excision or endoscopic aspiration (Rajshekhar, 2010). Cyst migration between the time of diagnosis and the surgical procedure is possible, and this phenomenon must be ruled out by CT or MRI immediately before surgery to avoid unnecessary craniotomies. In the absence of ependymitis, permanent shunt placing is not necessary after removal of a ventricular cyst. In contrast, shunt placement should follow or even precede the excision of ventricular cysts associated with ependymitis (Bergsneider et al., 2000).

CONTROL MEASURES Neurocysticercosis is common in areas where conditions favoring the transmission of T. solium are found, including deficient disposal of human feces, low levels of education, slaughtering of pigs without veterinary control, and presence of free roaming pigs around households (Garcia and Del Brutto, 2005). Neurocysticercosis is a potentially eradicable disease. To be effective, however, eradication programs must be directed to all the targets for control, particularly human carriers of the adult tapeworm, infected pigs, and eggs in the environment (Keilbach et al., 1989; Pawlowski, 2006). Since these targets represent interrelated steps in the life cycle of T. solium, inadequate coverage of one of them may result in a rebound in the prevalence of taeniosis/ cysticercosis after the program has been completed (Garcia et al., 2006).

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