Historical Background

The larval stage (Cysticercus cellulosae) of the porcine tapeworm Taenia solium, has been recognized in pigs for more than two millennia, and intestinal parasites were identified as worms. In ancient Greece, Hippocrates, Aristotle, and Theophrastus called them “flat worms,” likely based on Aristotle’s Historia Animalum²⁰ due to their resemblance to a tape or band, while Celsus, Pliny, and Galen called these parasites Lumbricus latus or wide worm.²¹

The Taenia solium species of tapeworm was described initially by Villanovani with a term that reflected the notion that an individual could only carry one of these parasites.²² In 1683 Tyson described the head of taenias, and later pictures of the scolex of these parasites were published.^21,23

In 1855, Kuchenmeister identified the relationship between the ingestion of cysticerci and the development of teniasis.^21,24 In an anecdote, the method to identify cysticerci is found in a play by Aristophanes of Athens entitled, “The Knights,” where he describes “let us force a stake into his mouth as cooks do, and then, by pulling out his tongue, we will examine boldly at our ease his wide opened mouth to see if he is measled”.^21,25 van Benedem ¹⁸⁵³ demonstrated the formation of cysticerci in swine after feeding them with eggs of T. solium and finding evidence of cysticercosis in the muscle after slaughtering them.²⁶

More accurate reports of cysticercosis in the nervous system in humans were made by Rumler in 1558 when he described a “tumor in the dura mater of an epileptic patient”.^21,27 Panarolus described cysts in the corpus callosum,²⁸ as well as Wharton, who identified multiple cysts in adipose tissue and muscle, thinking that they were glands.²⁵ As a disease, Malpighi described the animal nature of this parasite as well as its cyst and scolex in 1968.²⁵

The concept of cysticercus cellulosae was described initially by Zeder; however, it was later determined that this was a phase of the larva during development of the cysticercus.^21,29 Evidence of the life cycle of the parasite, and its interaction with specific communities was clearly established in Dixon’s study where he found infestations in British soldiers 5 years after their stay in India. He found a high prevalence of neurologic symptoms associated with cysticercosis.³⁰ Currently, the international consensus defines teniasis as the intestinal infestation stage, and cysticercosis is defined as the larva infestation, which occurs in multiple tissues throughout the body.

Epidemiology

The incidence of NCC varies by continent; however, it is the most frequent parasitic disease that affects the CNS.¹⁴ It is endemic in countries of Africa, Central and South America, and Southeast Asia.^31–34 Symptoms of the disease can present between 2 months and 30 years after the initial infection.

Subcutaneous nodules may be present in infected patients. However, the extraneural form of this disease usually has a benign course. Involvement of the CNS is generally a consequence of cerebral pathology, with lesser involvement of the spine.¹¹ Neurologic implications of this disease are relevant: NCC is the cause of 12% of hospitalizations and the most common cause of acquired or late onset epilepsy in countries of Latin America.^35,36 Patients suffer severe neurologic complications at productive ages. Further, it is considered that more than 50,000 deaths worldwide are related to NCC, making this disease a major public health issue.^37,38

Parasitic Life Cycle

The etiologic agent of cysticercosis is the Taenia solium at its larval stage, the cysticercus cellulosae Taenia solium has a two-host complex life cycle. The human is the definitive host for the adult and the pig is the intermediate host for the larval cysticercus. However, the human can also serve as the intermediate host after ingestion of T. solium eggs.^6,17

Humans become infected with tapeworm after ingesting pork meat containing cysticerci, the larval form of the parasite in the first stage of infection. In the small intestine, the scolex evaginates and attaches to the mucosa where it grows into the adult form of the tapeworm in the second stage; humans develop intestinal teniasis. The adult tapeworm is hermaphrodite and has multiple segments, each containing a branched uterus laden with infective eggs called proglottids, which it sheds into the fecal matter approximately 4 months after attachment during the third stage of infection. The adult tapeworm can be live up to 25 years. They remain viable several weeks in contaminated soil after excretion. The eggs are disseminated in the environment and are later ingested by pigs and humans. This entails fecal–oral transmission of infective eggs to humans as autoinfection or transmission to other individuals. Another possible but unlikely mechanism of development of cysticercosis is by retrograde peristalsis with the subsequent penetration of the mucosa by the larvae (Fig. 147-1). All of these mechanisms occur because of poor hygiene, such as failure to wash hands before meals and after defecation, or contamination of water or food with feces of carriers of the adult tapeworm.

FIGURE 147-1 Schematic representation of the life cycle of Taenia solium.

A high proportion of tapeworm carriers as well as their family members develop cysticercosis after ingestion of the infective eggs.^13,39 In the intestine, the egg becomes the oncosphere that penetrates the intestinal mucosa entering local lymphatic and mesenteric vessels and different tissues and organs during the fourth stage. It lodges mainly in subcutaneous tissue, the brain, and muscle. The fifth stage is the postoncospheral form, followed by the sixth and last stage, the cysticerci, that gives clinical manifestations according to the tissue and location of implantation.^13,40

Cysticerci are vesicles with two main parts: the vesicular wall and the scolex. The scolex has a similar structure to the adult form of T. solium, consisting of an armed rostellum and a body. They usually lodge in anatomic sites with abundant vascular supply, such as the cortex or basal ganglia. The macroscopic view of cysticerci varies according to their location in the CNS. For example, in the brain parenchyma the cysticercus measures approximately 10 mm, but in the subarachnoid space, they can grow up to 50 mm. Meningeal cysts adhere to the pia or float freely, particularly in the sylvian fissure. With time, cysticerci tend to shrink, and the meninges become thickened and fibrotic. Some cysts appear as a grape-like cluster, attached to each other by several membranes and giving rise to the racemose form of the disease. Racemose cysticercosis consists of a large multiloculated mass of cysticerci that lack an invaginated scolex. They are usually in the basilar cisterns and the fourth ventricle. In ventricular cysticercosis, a single cyst is found adhering to the ependymal wall or the choroid plexus; however, it is possible to see them floating in cerebrospinal fluid (CSF).⁴¹

Pathogenesis and Microscopic Appearance

In the CNS, cysticerci induce an inflammatory response in surrounding tissues. Initially, in the vesicular stage of the cysticercus, inflammatory reaction is minimal; it has a transparent membrane, clear fluid inside, and integrity of the larva and scolex. In the colloidal stage, the cyst shows degenerative changes due to factors such as inflammatory reaction and pharmacologic therapy. When the disease is the colloidal stage, the scolex is lost and inflammatory cells, mainly mononuclear/macrophages, penetrate the cyst. In this stage, the fluid becomes turbid and viscous. Later, in the nodular stage, the cyst is enclosed by a zone of granulation tissue with a dense capsule of collagen, which shows astrocytic gliosis, microglial proliferation and activation, edema, perivascular cuffing, and presence of necrotic tissue and cholesterol clefts. Old nodules may be fibrotic and sometimes become mineralized (calcifications). Ventricular cysticerci usually cause granular ependymitis, especially with high doses of cysticidal treatment. Degeneration of racemose cysticerci may cause a granulomatous inflammatory reaction in the subarachnoid space with accumulation of collagen, lymphocytes, multinucleate giant cell, eosinophils, and hyalinized parasitic membranes that have as a consequence leptomeningitis, chronic basilar arachnoiditis, opto-chiasmal arachnoiditis, or hydrocephalus. Consequently, CSF absorption capacity declines, causing hydrocephalus.⁴² Endoscopically, it is possible to visualize an inflammatory reaction in the choroid plexus and ventricular wall in ventricular cysticercosis. Microscopically, it is possible to identify a disrupted ependymal lining that is replaced by subependymal glial cells. This is an important cause of CSF blockage in narrow spaces such as the cerebral aqueduct and interventricular foramina.

Meningeal and small cerebral arteries show vasculitis with fibroblastic or collagenous thickening of the intima and local excrescences, which may narrow the arterial lumen. The media shows fibrosis and the adventitia shows infiltration by plasma cells.

Microscopically, the parasite has a scolex has a rostellum provided with four suckers and a double row of 22-32 hooklets. The cystic wall consists of three different layers (Figs. 147-2 and 147-3):

FIGURE 147-2 Microscopic and macroscopic images of T. solium cysticerci. A, T. solium scolex in a sagittal view inside on the cyst wall, in a stain to see collagen fibers. Masson trichromic 10×. B, Section through T. solium cyst wall. The inner reticular layer, middle cellular layer, and the outer or cuticular layer with hair-like protrusions (3 μm thick) called microtrichia (arrow). H&E 20×. (Courtesy of Dr. Juan de la Cruz.) C, Macroscopic view of cysticerci after excision from ventricular cavity.

FIGURE 147-3 Light microscopy images of cysticerci. A, Wall of a ventricular cysticercus after cysticidal therapy. The inflammatory response is shown by scattered lymphocytes and granulomatous reaction. H&E 10×. B, The wall has an inflammatory lymphocytic reaction and thickening of the wall by collagen fibers. Masson trichromic 20×.

Initially the parasite is able to evade the host’s immune response by secreting humoral factors that inhibit activation of complement and lymphocytes, the secretion of cytokines, and secretion of prostaglandins that decrease inflammation and manipulate the immune reaction to activate production of T-helper 2 molecules. The cysticercus secretes proteases that cleave interleukins and structural components in its wall that inhibit complement activation.¹¹ On the other hand, patients with acquired immune deficiency syndrome (AIDS) respond differently to the parasite. It has been reported that the incidence of NCC in patients with AIDS has increased, while other reports have found that there is no predisposition of these patients to NCC, suggesting that humoral immunity is more relevant to combat NCC than cellular immunity.

Deposits of immunoglobulin (Ig) E and IgG have been found surrounding cysticerci. Moreover, there are numerous reports of patients that have lesions at different stages, suggesting that the immune reaction against these parasites is heterogeneous while also presenting the possibility of reinfection.^35,42,43

Clinical Manifestations

The vast majority of patients with neurocysticercosis are asymptomatic. Symptomatic patients do not have specific or pathognomonic clinical manifestations. Actually, due to its pathogenic characteristics, this disease can present with diverse clinical manifestations. Clinical manifestations are the result of local inflammatory reaction and mass effect as well as systemic immune reaction. Therefore, symptoms are determined by the location of the cysticercus. Seizures are the most common presentation of neurocysticercosis. Approximately 52% to 70% of patients present seizures as their opening symptom. The diversity of manifestations depends mainly on the size, number, and location of the parasites. Focal signs are frequently due to local irritation or mass effect, which resemble those of a tumor.

Leptomeningitis is the next most frequent clinical manifestation presenting with hydrocephalus or basilar arachnoiditis⁴⁴ (Fig. 147-4). Also, when cysticerci are present in the ventricles or subarachnoid space, the flow of CSF can be obstructed by granular ependymitis and by occlusion of interventricular foramina by parasites. As a consequence, patients suffer hydrocephalus and intracranial hypertension, which may become chronic and carries numerous complications and disability.^{35,41,43,45,46}

FIGURE 147-4 Endoscopic view of subarachnoid space through supraorbital key-hole surgery. A, Evidence of arachnoiditis and focal granulomatous reaction over left carotid internal artery, close to the optic nerve. B, Endoscopic view of subarachnoid sylvian space and middle cerebral artery arachnoiditis, after resection of racemose cyst.

Another important condition related to chronicity, high level of complications, and disability, is intracranial hypertension due to hydrocephalus. This condition occurs as a consequence of arachnoidits, granular ependymitis, or the presence of cysticerci in the ventricular cavity. The Bruns phenomenon is a usual condition when csycticerci are free and floating in the ventricular space, with acute clinical manifestations, requiring emergent surgical intervention. Cysticercal encephalitis is a rare presentation and is most common in children and young women.⁴⁷ It occurs as a consequence of a massive cysticercal infection accompanied with important edema probably due to the host’s immune reaction or, in our experience, also in reaction to drug therapy, with hyper-reaction after the parasite died. The clinico-topographic presentation follows: parenchymal, meningeal, ventricular, cerebrovascular disease (vasculitis), encephalitis, disseminated, neurocognitive disorders, and spinal (radicular pain, transverse myelitis or medullar syndrome).

Diagnosis

Until now the best way to understand the clinical spectrum of NCC is through diagnostic criteria, based in clinical, radiologic, immunologic, and epidemiologic data.^48,49 These diagnostic criteria are listed in Table 147-1.

TABLE 147-1 Diagnostic Criteria for NCC

CST, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance image; NCC, neurocysticercosis.

Neuroimaging Diagnosis

Radiologic diagnosis of chronic inactive NCC can be considered upon discovery of ellipsoidal calcifications in skull x-rays or computerized axial tomography scans (CT scans) (Fig. 147-5). CT scans are still the best option in radiologic studies to identify calcifications in the parenchyma as well as in the intraventricular space. Neuroimaging studies show viable cysticerci as a hyperdense nodule with the scolex included, resembling a hole with a dot (Fig. 147-6). Active cysts appear as ring-enhancing lesions in studies with contrast. When big lesions are identified with these characteristics, it is important to consider in the differential diagnosis pyogenic abscess, fungal abscess, tuberculomas, abscess by tocoplasma, and primary brain tumors.

FIGURE 147-5 Radiologic characteristics of neurocysticercosis. A, Skull, simple x-ray, with evidence of multiple calcifications in an asymptomatic patient. B, The CT scan without contrast is a good imaging tool to see calcifications, in this case resembling star “constellations.”

FIGURE 147-6 Radiologic characteristics of neurocysticercosis. A, Simple CT scan showing multiple parenchymal vesicular cysticerci. The classical image of the hole with dot (scolex). B, Magnetic resonance imaging T1 sequence, showing evidence of a mesencephalic parenchymal cysticercus, with perilesional edema and scolex.

(Courtesy of Dr. Ruben Bañuelos.)

Magnetic resonance imaging (MRI) is currently the gold standard for diagnosis by imaging. It is better than CT scan for diagnosis in patients with cysticerci lodged in the brain stem (Fig. 147-6B), skull base, intraventricular space (Fig. 147-7), and spinal lesions, but it fails to detect small calcifications. This is an important point because in some patients, calcifications are the only evidence of chronic inactive NCC. In selected cases, spectroscopy is useful to differentiate NCC from primary brain tumors. Functional MRI (fMRI) is useful in operative planning to preserve primary functional areas of the brain during resection of these lesions. It is necessary to keep in mind that characteristics of these lesions depend mainly on the developmental stage of the parasite and on the pathophysiologic form of presentation of the disease. Besides visualization of the cyst, it is possible to find hydrocephalus (Fig. 147-8), ischemic infarctions (complemented by angiography), and abnormal enhancement of the leptomeninges (Fig. 147-9). MRI is a more sensitive test for the diagnosis of active NCC since 40% of patients with active disease have normal CT scans.^35,41,43,56 Imaging findings according to different techniques are found in Table 147-2.

FIGURE 147-7 Variations of radiologic presentation of ventricular cysticerci. A, Computed tomography scan with asymmetric dilatation of the frontal horn of lateral ventricle. B, Coronal MRI showing an adherent mass (cysticerci) and hydrocephalus. C, Axial MRI with lateral ventricular cyst without hydrocephalus. D, Sagittal MRI with a cysticercus in the third ventricle and its migration through the aqueduct toward the fourth ventricle.

FIGURE 147-8 Neurocysticercosis as a cause of acute and chronic hydrocephalus. A, CT scan with acute hydrocephalus and third ventricle obstruction by a cysticercus (arrow), and periventricular interstitial edema. B, CT scan showing chronic hydrocephalus with multiple parenchymal and third ventricular calcifications. Arrest of ventricular dilatation with lack of intracranial hypertension. CT, computed tomography.

FIGURE 147-9 Arachnoiditis due to neurocysticercosis. A, Distortion of the basal cistern shown in a CT scan as hyperdensity, secondary to fibrous arachnoiditis accompanied by hydrocephalus. B, CT scan showing leptmoneningitis, basal arachnoitidis, subarachnoid cysts, and chronic ventricular dilatation secondary to cysticercosis. CT, computed tomography.

TABLE 147-2 Pathology and Neuroimaging of Neurocysticercosis

Pharmacologic Treatment

To choose the optimal pharmacologic intervention, it is necessary to be aware of the clinical condition of the patient and plan for the best timing to start treatment. For this, it is important to consider the life cycle of the parasite and the stage, quantity, location, and immune response of the host. Basic treatment addresses three areas: cysticidal therapy, anti-inflammatory therapy, and symptomatic therapy.

Cysticidal Treatment

Praziquantel (isoquinolein-pirazine) has been used to treat human cysticercosis for approximately 30 years. It has been used previously in schistosomiasis and it has adequate absorption and low toxicity. It penetrates the blood–brain barrier and reaches one-seventh of the concentration in serum in CSF. For this reason, the drug is a good choice for parenchymal and subarachnoid NCC. Praziquantel is effective in eliminating 70% of parenchymal cysticerci after a 15-day course of treatment at daily doses of 50 mg/kg. Recent studies show that a short treatment can be effective based on pharmacokinetics. The cysticidal effect is achieved by several intermittent peaks of the drug in contact with the parasite, depending on plasma level and half-life. Based on this, authors suggest high frequent doses of praziquantel for up to 6 hours (three doses of 25–30 mg/kg at 2-hour intervals on a single day) are sufficient to eliminate the parasite. Close surveillance of the patient is mandatory with this treatment due to potential toxicity of parasitic proteins released after the elimination of the parasite, which may start an acute immune reaction.^35,57,58

Albendazole (benzimidazole) is another good choice for cysticidal therapy. It is advantageous to praziquantel since it destroys subarachnoid and ventricular cysts as it reaches higher concentrations in the CSF. Also, it has less pharmacologic interactions, allowing for concomitant use of steroidal anti-inflammatory agents, and is less expensive. Albendazole therapy destroys 75% to 90% of parenchymal brain cysts, after a treatment of 15 mg/kg/day for 1 month. Similarly, studies have shown that a short course therapy of 1 week is also effective.^25,59

Sudden destruction of the parasite releases the contents of the cyst and this may exacerbate the inflammatory reaction and increase intracranial hypertension. For this reason in patients with giant intracranial, subarachnoid (racemose), aqueductal cysts or hydrocephalus, cysticidal drugs must be used with caution or avoided until the potential risk of complications after cysticidal treatment is under control.

Cysticidal agents reach lower concentrations in the CSF than in the brain parenchyma, representing a limiting factor in the treatment of intraventricular cysticerci. Further, the inflammatory reaction that ensues after the rupture of the cyst with the release of its contents secondary to pharmacologic agents determines the ependymal inflammatory and granulomatous reaction in the ventricular wall (ventriculitis), choroid plexus, and vascular structures. Therefore, immunosuppressive therapy should be considered in cases of cysticercal encephalitis, or along with cysticidal therapy to prevent inflammatory reaction, increase of intracranial hypertension, or cerebral infarction.

In patients with calcifications and without active disease, cysticidal treatment is not required. Cysticidal therapy should be maintained in a preventive manner to address intestinal infestation with T. solium, and more so in endemic areas or after visiting endemic areas.

Recently, the use of ivermectine has been proposed as an alternative treatment for parasites that demonstrate resistance to conventional treatment. However, there are only a few case reports where this has been used as cysticidal therapy and consistent evidence is lacking^46,60 (Fig. 147-10).

FIGURE 147-10 Effect of cysticidal treatment. A, CT showing vesicular cysticercus and its scolex with mild perilesional edema. B, Nodular transformation after 3 weeks of albendazol therapy in a patient with partial seizures. C, MRI with cortical cysticercus. D, After 3 weeks of albendazol treatment. MRI, magnetic resonance image; CT, computed tomography.

Surgical Treatment

Currently surgical treatment is the primary treatment for NCC in selected cases because pharmacologic treatment is not innocuous and the advent of new surgical techniques have decreased morbidity and mortality associated with surgical procedures.^35,43,46 Minimally invasive techniques have been shown to be effective as a principal strategy in many cases⁶³ that are complemented with cysticidal therapy (Fig. 147-11). Discouraging results reported in various surgical series were related to patient profiles and not to surgical morbidity. Patients had severe disease, previous attempts of treatment had failed, and had received high doses of cysticidal drugs along with secondary effects. This yielded a surgical mortality of approximately 21% in the long-term follow-up of these patients.⁴⁵ One of the most common procedures has been the control of intracranial pressure in cases of hydrocephalus with the implantation of a ventriculo-peritoneal shunt, which had a high dysfunction rate due to the high cellular and protein contents in the CSF, as well as the contents of remnants of cysticerci, secondary ependymitis, and eventually infection. Other series reported mortality as high as 50%, directly related to the number of surgical interventions necessary for shunt revision.³⁵ In patients with NCC, failure in shunt function is also related to the presence of transit inversion of CSF with inflammatory cells and granulomatous infiltration of the ependymal wall.

FIGURE 147-11 Endoscopic images of surgical treatment of neurocysticercosis through minimally invasive techniques. A, Endoscopic precoronal right approach, showing the wall of a cysticercus emerging through the foramen of Monroe from the third ventricle. B, Endoscopic extraction of a cysticercus through transcortical approach. C, Endoscopic view of microhemorrhages in the fornix (arrow) and foramen of Monroe. D, Secondary granulomatous reaction of the thalamic vein and the ependymal wall.

In our experience, patients with ventricular or subarachnoid cysticerci, or the parenquimatous racemose form of the disease should be treated surgically with endoscopy or highly selective minimally invasive microsurgery initially, if the risk benefit assessment is favorable. In this way it is possible to avoid the severe inflammatory reaction after pharmacologic treatment and rupture of the cyst. Detritus of the cysticerci are capable of inducing an inflammatory response in the ependyma, as shown in a series of our own patients, where we compared patients treated surgically before and after cysticidal treatment. We found that the ventricular walls and the obtained parasites were devoid of inflammatory response before treatment, whereas patients treated pharmacologically showed a severe inflammatory reaction.

Currently, surgical treatment should be considered as the initial treatment in the following conditions, when the clinical condition of the patient allows it:

FIGURE 147-12 Endoscopic fenestration strategies for the treatment of hydrocephalus secondary to neurocysticercosis. A, Premamilar third ventriculostomy. B, Patency and view of basilar artery and clivus. C, Septal wall fenestration in a case of asymmetric ventricular dilatation.

Surgical treatment will be complemented with cysticidal treatment in all cases. Features of poor prognosis include: location of cysts in the basal cisterns in patients younger than 40 years with severe inflammatory reaction, patients with ventricular granulomatous septa, and patients requiring multiple procedures for review and change of shunts. Patients with cysticercal encephalitis, which is more common in young adults and children,⁴⁷ may eventually require bilateral decompressive craniectomy, when the intracranial pressure is not controlled with medical treatment.

Simplified descriptions for the treatment of different types of NCC are included in Tables 147-3, 147-4, and 147-5.

TABLE 147-3 Management of Cysternal Cysts

TABLE 147-4 Management of Parenchymal Brain and Spinal Cysts

TABLE 147-5 Management of Intraventricular Cysts (Before Cysticidal Therapy)

ICP, intracranical pressure.

Prevention and Sanitary Recommendations

Neurocysticercosis is highly correlated with conditions of poverty and its social impact, and mainly in insufficient sanitary measures in developing countries. Consequently, education on sanitation and hygiene is the most important strategy for the control of this disease. It should be oriented toward control and eradication of the parasite in carriers. Hand-washing procedures before each meal and after defecation, as well as consumption of clean and boiled water in endemic areas will be paramount. Installation of latrines or other hygienic measures for disposal of human waste are pivotal to control dissemination of this disease. Adequate care of porcine herds to prevent human infection with the intestinal form will also be important. These elemental measures will have an important preventive impact and should be complemented with cysticidal treatment to endemic populations to eliminate human infection with the adult tapeworm and the subsequent infection of humans and pigs. Currently, NCC is a public health issue even in developed countries due to the migration of people carrying the parasite from endemic areas. This makes cysticercosis the parasitic disease with largest impact on the CNS.^38,64

Conclusions

Neurocysticercosis is the parasitic disease with the greatest impact on the CNS. Knowledge of the life cycle of the parasite is relevant for understanding how humans become hosts. Neurologic clinical implications are varied since patients can present symptoms at different stages of the disease. Epilepsy, intracranial hypertension, and leptomeningitis are the most common events. Medical treatment of the disease is able to resolve a large percentage of the active forms of NCC, careful and individualized care of each patient is necessary as well as long-term follow-up. Minimally invasive surgical alternatives in treating this disease are available and not only as an option to failure of pharmacologic treatment. Education on hygiene and sanitary measures is, and will continue to be, a challenge to achieve prevention and definitive eradication of this disease.