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.