Neurocysticercosis is a parasitic disease of the central nervous system caused by the larval stage of Taenia solium. Taenia solium infection and neurocysticercosis are widely endemic in most of the poor and developing countries. It is a major cause of seizures worldwide. Neurocysticercosis is endemic in Mexico, Central and South America, and parts of Africa and Asia, particularly Indian subcontinent. Seroprevalence studies indicate high rates of exposure to the parasite in these countries. World Health Organization reported that more than 50,000 deaths each year occurred due to neurocysticercosis. Cysticercosis has also been recognized as an important parasitic disease in the United States. A higher risk for acquiring neurocysticercosis has been observed in patients who have traveled to endemic countries, are of Hispanic ethnicity, and have contact with T. solium tapeworm carriers.1-3
Pathogenesis and Pathology
In the normal life cycle of T. solium, humans are the definitive host, and pigs act as intermediate host. Adult tapeworm resides in the upper part of human intestine. The pork tapeworm has a large flat body composed of hundreds of proglottids (segmental units containing eggs). Each of the proglottid carries up to 50,000 eggs. Proglottids are periodically excreted into the feces. The eggs remain viable in the soil for several months. After ingestion of eggs by the pigs, the eggs hatch to liberate hexacanth embryo (oncosphere) into the intestine. After penetrating intestinal wall, larvae lodge into various parts of the pig's body. There is a predilection for striated muscles. These cysticerci in pig muscles survive for months to years. The life cycle continues when humans eat undercooked pork that contains the viable cysticercus larvae, and larvae evolve in adult worms. Neurocysticercosis develops when humans act as the intermediate host and an individual ingests food or water contaminated with T. solium ova. Cysts in humans preferably lodge in the brain and spinal cord, eyes, skeletal muscle, and subcutaneous tissues.
After reaching inside the brain parenchyma, the larva develops into a live cyst. The cyst consists of a protoscolex surrounded by a bladder wall. This stage of viable cyst is known as vesicular cyst stage (Fig. 1). The living viable cyst evokes only a minimal inflammatory reaction. Eventually, the osmotic barrier of the cyst wall breaks down. Consequently, there is an intense inflammatory reaction in the surrounding brain tissue. At this time, the cyst wall gets thickened, and hyaline degeneration and mineralization of the cyst take place. Cyst fluid becomes opaque. The degenerating cysts are often called colloid cyst stage (Fig. 2). It is believed that the immunologic process elicited by the release of dying parasite antigens is responsible for clinical manifestations of neurocysticercosis. When the cysticercus dies, the bladder wall collapses to form a small granuloma. Months to years later, some of these dead cysts get calcified into small nodules (called calcific stage)4-8 (Fig. 3).
Neurocysticercosis can be classified into several major clinical syndromes: parenchymal, subarachnoidal, ventricular, spinal, and ocular syndromes.
The infection of brain parenchyma is the most common form of neurocysticercosis. The number of parenchymal lesions varies from single lesion to massive parasitic infection. Single parenchymatous cysts are the most frequent clinical and imaging manifestations of neurocysticercosis in Indian subcontinent. The solitary cysticercal granulomas represent colloidal stage of natural evolution of a cysticercus cyst.3
Cysts in the subarachnoid space are typically located in the basal cisterns and deep within the sulci. Cysts in the subarachnoid space may invade the sylvian fissure and grow rarely to a giant cyst measuring more than several centimeters in diameter. A large cyst in the subarachnoid space may give a false impression that it is intraparenchymal (Fig. 4). Subarachnoidal cyst obstructs the cerebrospinal fluid (CSF) circulation resulting in hydrocephalus and intracranial hypertension. Racemose (sterile cyst without scolex) cysts in the basal cisterns can cause an intense inflammatory reaction, fibrosis, and progressive thickening of the leptomeninges at the base of the brain resulting in chronic arachnoiditis, vasculitis, and periventricular infarcts.7-9
Intraventricular cysticercal cysts are often single and tend to lodge in the fourth ventricle. They can be found in the third and lateral ventricles also. In the ventricular system, cysts either float freely within the CSF or are get attached to the ependymal layer. Active and viable intraventricular cysts do not produce any inflammatory reaction in the host, but they can cause obstructive hydrocephalus. In granular ependymitis, there are inflammatory changes in the ependyma, resulting in blockage of CSF flow at the level of the cerebral aqueduct or foramina of Monro9,10 (Fig. 5).
Spinal cysticercosis is a rare form of neurocysticercosis. Spinal cysticercus most frequently lodges in the subarachnoid space, resulting in extramedullary leptomeningeal disease. Leptomeningeal cysticercosis is clinically characterized by a syndrome of radiculomyelopathy. Thoracic region is most often involved. Leptomeningeal cysticercosis is seen in association with cysticercal involvement of the posterior fossa and results due to downward migration of the cysts from basal cisterns of the brain into the spinal cord through the CSF pathway. Intramedullary cysticercosis develops via hematogenous route and presents as partial or complete transverse cord syndromes. More than 50% of patients with intramedullary neurocysticercosis had evidence of cysticercosis elsewhere9,11 (Fig. 6).
Intraocular cysticercosis occurs in approximately 3% of the cases. Cysticerci can lodge in any part of the eye. Cysticerci most commonly occur in the vitreous humor and subretinal tissues, but cysticerci may also involve the extraocular muscles, anterior chamber, conjunctiva, and other eye tissues. In extraocular muscle cysticercosis, the most common presenting features are restricted ocular motility with diplopia and recurrent pain and redness. Cysticercosis larva can be visualized in the anterior chamber of the eye using ultrasonography (Fig. 7). The host reactions to cysticerci in the eye vary from slight to severe inflammation, together with sequelae, such as retinal detachment or atrophy, chorioretinitis, and iridocyclitis. Optic nerve involvement by cysticercosis is extremely rare, but hematogenous spread along the branches of the central retinal artery may result in isolated involvement of the optic nerve.12
Muscle involvement is common, but it often remains asymptomatic. Diffuse muscle involvement may result in pseudohypertrophic myopathy-like picture. Computed tomography is used for the diagnosis of muscular cysticercosis. On computed tomography, a honeycomb appearance, produced by a large number of live cysticerci in pseudohypertrophic muscles, has been described. This appearance is produced by the low-attenuation-density cysts standing out against the muscle mass of higher density value. On plain radiographs, neurocysticercosis presents with multiple cigar-shaped calcifications. In most patients, muscular disease presents concomitant with central nervous system involvement13 (Figs. 8, 9).
In a small number of patients with neurocysticercosis, there is massive involvement of intracranial as well as extracranial structures. In disseminated cysticercosis, brain lesions are often "too numerous to count." In disseminated cysticercosis, cranial computed tomography shows a characteristic "starry-night appearance." This appearance is produced by the hypodense scolices of living cysticerci standing out against the lower attenuation density value of the brain, the tightly paced cysts contributing little to the image. These are often mistaken for dead calcified lesions13 (Fig. 10).
The clinical presentation of neurocysticercosis is highly varied and depends on the stage, number, size, and locations of the cysticercal cysts within the central nervous system and the magnitude of the host's immune response. Neurocysticercosis is the most common cause of epilepsy in developing countries. Acute inflammation around the lesions of cysticercosis manifests as acute seizure disorder. Other frequent clinical manifestations include focal deficit, intracranial hypertension, and cognitive impairment. Cysts in the subarachnoid space often manifest with intracranial hypertension, multiple cranial nerve palsies, and focal neurological deficits. Bilateral papilledema may occur as a result of intracranial hypertension.4-8 Free-floating fourth ventricular cyst has been reported to produce recurrent episodes of abrupt positional headache accompanied by sudden ataxia, vertigo, or drop attacks; this potentially life-threatening phenomenon is called Bruns syndrome. When cysticerci lodge within the ventricular system, life-threatening intracranial hypertension may acutely develop.10 Spinal cord involvement is either extramedullary leptomeningeal or intramedullary parenchymal. The patients of spinal neurocysticercosis present with radicular pain, paresthesias, paraparesis, bowel and bladder incontinence, and sensory loss.14 Manifestations of ocular involvement include visual loss, ophthalmoplegia, field defects, and orbital pseudotumor syndromes.12
Each evolutionary stage of the parenchymal cysticercosis has a characteristic image on computed tomography. In the vesicular stage, cranial computed tomography shows one or more rounded circumscribed and hypodense lesions of variable size. The vesicular lesions do not enhance after administration of contrast media. After maturation, a hyperdense eccentric scolex within the cyst may also be identified (Fig. 1). In the colloidal stage, which is characterized by inflammation in the cyst wall, computed tomography shows ring or nodular enhancing lesions. Lesions are surrounded by variable amount of vasogenic edema (Fig. 2). In the calcified stage, lesions are often small, rounded, and homogenously hyperdense. Calcified lesions do not show enhancement after administration of contrast media. Characteristically, there is no perilesional edema (Fig. 3). It has been observed that magnetic resonance imaging is more sensitive than computed tomography in identifying the cysts if they are located in the brainstem, cerebellum, subarachnoid space, spinal cord, ventricles, and subependymal regions. Magnetic resonance images a living parenchymatous cysts as a 5- to 20-mm-diameter round lesions of CSF-equivalent density on both T1- and T2-weighted images. An isodense to hyperdense scolex can be identified within most cysts, producing a "pea in the pod" appearance (Fig. 11). In the dying cysticercus, the difference between scolex and cysts becomes unclear. The cyst fluid shows greater and increasing signal intensity than the CSF in both T1- and T2-weighted images. Magnetic resonance imaging has been shown to have some superiority over computed tomography as it may reveal many cysticerci that computed tomography has missed. However, calcified lesions are better visualized with computed tomography.8,9 A racemose cysticercus can be identified as a cluster of cysts in the subarachnoidal cisterns or sylvian fissure but can be missed if isodense with CSF and can also be mistaken for cystic tumor or other intracranial cyst (Fig. 12). Magnetic resonance imaging of the brain demonstrated a "bunch of grapes" appearance in the basal cisterns, characteristic of cysticercosis.9
Currently, the most sensitive and specific diagnostic test is an enzyme-linked immunoelectrotransfer blot assay that was developed by the Centers for Disease Control and Prevention. Enzyme-linked immunoelectrotransfer blot assay has a sensitivity of 98% and specificity of 100%. Cerebrospinal fluid enzyme-linked immunosorbent assay is only 69% sensitive and 71% specific. Enzyme-linked immunosorbent assay test is extensively used for the diagnosis of cysticercosis. Dot-enzyme-linked immunosorbent assay is a simple and rapid test for the detection of cysticercus antibodies in the serum.15
Differential Diagnosis and Diagnostic Criteria
The differential diagnosis of neurocysticercosis depends on the type of clinical presentation. If cysts are identified on computed tomography or magnetic resonance imaging, major diagnoses to be considered include tuberculoma, brain abscess, arteriovenous malformation, metastatic tumor, small primary tumor, or other parasitic cysts. Tuberculomas tend to be larger than 20 mm in diameter, have an irregular outline, cause more mass effect, and have a progressive focal neurological deficit, whereas cysts tend to be less than 20 mm in diameter, have smooth regular outline, and seldom cause progressive focal neurological deficits.16 If the patient presents with a subacute or chronic meningitis or obstructive hydrocephalus, tuberculous meningitis, fungal meningitis, cerebrovascular syphilis, neurosarcoidosis, meningeal carcinomatosis, and central nervous system vasculitis need to be considered. The presence of CSF eosinophils suggests the possibility of meningeal cysticercosis.
In tropical countries, the diagnosis of neurocysticercosis is frequently difficult because several other prevalent infective disorders can present with a similar clinical and neuroimaging picture. International criteria given by Del Brutto et al17 are helpful for the diagnosis of neurocysticercosis; however, these criteria have been criticized for not being effective in differentiating several other infective and neoplastic diseases of the central nervous system, such as central nervous system tuberculosis. Later, it was suggested that in certain situations, such as middle or old age, evidence of pre-existing tuberculosis or malignancy and pre-existing HIV infection and in patients with grossly abnormal neurological examination, diagnosis of neurocysticercosis should be made with caution16 (Tables 1, 2).
The varied manifestations of neurocysticercosis need different approaches for management. The therapy for parenchymal neurocysticercosis includes use of antiparasitic drugs. A randomized controlled trial demonstrated that antiparasitic treatment with albendazole for neurocysticercosis is safe and effective in reducing the number of seizures.18 The dose of albendazole is usually 15 mg/kg per day divided into 2 doses for 8 to 30 days. Praziquantel is another antiparasitic drug used for treatment of parenchymal neurocysticercosis. The usual dose of praziquantel is 50 mg/kg per day divided into 3 doses for 15 days. The corticosteroids should always be given along with antiparasitic drugs. Dexamethasone, 8 to 24 mg per day in 4 divided doses orally, intramuscularly, or intravenously, or prednisone 1 mg/kg per day orally is usually given. Methotrexate is a beneficial corticosteroid-sparing or replacement agent for patients with neurocysticercosis who develop chronic or recurrent perilesional inflammation.19 Anticonvulsants should be administered to all patients presenting with seizures. Several neurologists do recommend antiparasitic therapy (sometimes postoperatively) in patients with subarachnoid cysticerci or intraventricular cysticerci.20
Surgical intervention is required to remove cysts causing obstruction of the ventricles, and sometimes for removal of a large or strategically located subarachnoidal or parenchymal cyst before starting antiparasitic treatment. Patients who develop obstructive hydrocephalus from a chronic arachnoiditis or blockage of intraventricular CSF pathways need placement of a shunt. Neuro-endoscopic surgery is an effective treatment modality for patients with intraventricular neurocysticercosis. Ocular and extraocular muscle cysticercosis generally requires surgical intervention.
Most patients with parenchymal neurocysticercosis with low parasitic load have an excellent prognosis. Extraparenchymatous neurocysticercosis has a poor prognosis. Antiparasitic therapy results in early and complete resolution of colloidal and vesicular cysticerci, leading to a significantly lower risk of seizure recurrence.21 Racemose cysts in the basal cisterns cause an intense inflammatory reaction in the meninges and result in lacunar infarcts, visual loss, and hydrocephalus. Some patients need long-term corticosteroid treatment. Long-term prognosis, in patients who require neurosurgery, is generally not good. The risk of death is highest in patients with very heavy parasitic load and in patients who present with intracranial hypertension.
Neurocysticercosis is a major public health problem in developing countries. Cases have frequently been reported from developed countries. The diagnosis of neurocysticercosis should be considered in patients who present with the new-onset seizures, subacute meningitis, raised intracranial tension, obstructive hydrocephalus, or cystic mass lesions. Many patients do not always show typical neuroimaging features with invaginated scolex; serology is useful for confirming some of these cases. It is important for physicians of both developing and developed countries to be familiar with all forms of neurocysticercosis. Early diagnosis and treatment are likely to benefit the majority of these patients.
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