Neurocysticercosis (NCC) is an infestation of the nervous system caused by encysted larvae of Taenia solium. NCC is an important acquired cause of epilepsy and other neurological manifestations especially in endemic areas. NCC in children has pleomorphic manifestations depending on the location, number, viability of the cysts, and host response. Even with advancing knowledge of the disease manifestations, many aspects related to diagnosis and treatment, particularly in children, still remain controversial and pose challenges to clinical practice. There is no gold standard test to diagnose NCC and the management recommendations are still emerging. This review provides an overview of diagnosis of NCC in children and its management with special focus on current challenges and future prospects.
In developing countries, NCC is important not only because of its frequency but also because of high morbidity and mortality rates associated, especially in cases in which it progresses to increased intracranial pressure. Because of its pleomorphic presentation, NCC should be considered in the differential diagnosis of a number of neurological conditions. Treatment with cysticidal therapy leads to reduction in seizure frequency and a faster resolution of lesions.
We have summarized the current approaches to diagnosis and treatment of NCC, recent advances in understanding the biology of NCC, and how one can take advantage of these new insights to formulate the next generation of clinical trials.
KeywordsBrain Cysticercosis Epilepsy Hydrocephalus Intracranial hypertension Parasitic disease Parenchymal cyst
Introduction and background
Human neurocysticercosis (NCC), an infestation caused by the larval stage (cysticercus) of the pork tapeworm Taenia solium, is the most common parasitic disease of the central nervous system worldwide . Though it affects adults commonly, pediatric infestation is also well-recognized. NCC is endemic in most developing countries, particularly Latin America, the Indian subcontinent, Southeast Asian region, and sub-Saharan Africa. Globalization and travel have increased the incidence of NCC in many nonendemic countries including USA, UK, and Australia . The rise in the number of cases of NCC in developed countries, especially in the USA, has largely been driven by the influx of immigrants from endemic to non-endemic regions and the widespread access to neuroimaging . A recent systematic review on cysticercosis and T. solium teniasis in Europe showed an increasing trend; nearly 75% of imported cases were diagnosed in migrants and 18% in European travelers . Among the symptomatic population, more than 5 million cases of preventable epilepsy worldwide are caused by NCC. In a recent systematic review, the pooled estimate of NCC among people with epilepsy was as high as 29% from Latin America, sub-Saharan Africa, and Southeast Asia . In a community-based study of over 50,000 individuals in south India, 34% of patients with active epilepsy had a diagnosis of NCC based on contrast-enhanced CT imaging and enzyme-linked immunotransfer blot (EITB) . Among patients with active epilepsy in North India, 25% of the cases tested positive for antibodies against T. solium . The point prevalence of 4.5 per 1000 population has been noted in rural Northwest India . Among children with partial seizures, NCC accounted for 50% of the cases in hospital-based series from India .
The parasite and its lifecycle
T. solium is a tapeworm belonging to cestoda class in the family Taeniida. The adult worm is found in the small intestine of humans. It is white in color and measures 2 to 3 m in length. Its head, the scolex, contains suckers and a protruding part with hooks, or rostellum, which attaches to the host intestinal wall. The body consists of several segments known as proglottids and each one acts as an independent reproductive unit containing both male and female reproductive organs.
Cysticercosis and central nervous system
The hexacanth embryo reaches the CNS, through the bloodstream, lodging in the brain parenchyma by occluding capillary vessels usually at the gray-white junction. After actively crossing the capillary wall, the embryo reaches the interstitial space where it evolves to the cystic form, transforming into cysticercus . There are two basic forms of NCC: isolated cysts or cysticercus cellulosae (CC) and racemose cysts or cysticercus racemosus (CR). CC are usually intraparenchymal and pass through a sequence of four morphological stages: vesicular, colloidal, granular nodular, and nodular calcified stage. CR are extraparenchymal (ventricles, subarachnoid space, cisterns); they tend to grow irregularly according to the available space and can elicit a strong inflammatory response especially in the sub-arachnoid spaces. This racemose form may reach enormous size without scolices and has peculiar appearances and mass effects. Intraventricular cysts may cause acute hydrocephalus due to direct or inflammatory obstruction .
The cysticerci in the brain and other tissues undergo a natural process of involution or degeneration within a variable period of ranging from a few weeks to several years. This process starts after the transformation of the hexacanth embryo into the cysticercus. The initial stage is a live or active cyst (vesicular stage) followed by a stage in which the cyst begins to undergo degenerative changes with thickening of the membrane and replacement of the clear fluid with a whitish gel (colloidal stage). With the progression of this process, the wall becomes thicker and the gel undergoes calcium deposition (granular stage), and finally, the cyst becomes completely calcified, being reduced to one third or one fourth of its original size (calcified nodular stage) . Microscopically, the demonstration of the parasite is diagnostic. A variable inflammatory process and edema are seen in the surrounding tissues and in part depend on the stage of the process. Severe inflammatory reaction can also be seen in the leptomeninges and ependyma when the cysts are in the subarachnoid spaces or the ventricles. Occlusion of small vessels in the subarachnoid spaces may result in brain infarction.
The clinical manifestations in children are pleomorphic depending on the burden of cysts, their location, and size. Clinical manifestations can vary from completely asymptomatic infestation to severe disease and death. NCC should be suspected clinically in any normally developing child with sudden-onset seizures, headache, vomiting, or focal motor deficits where there is no other evidence of an underlying neurological disorder. Seizures are a very frequent manifestation in patients with degenerating parenchymal cysts. In Indian children, the commonest presentation of NCC is in the form of a single degenerating parenchymal cyst, the solitary cysticercus granuloma (SCG) . This presentation is seen in nearly 60 to 70% of all Indian patients with NCC . Mechanisms of epileptogenesis in neurocysticercosis are the subject of debate, and likely include local inflammation and the formation of reactive gliotic scars .
However, in endemic areas, physicians should be aware of the atypical presentations of NCC such as communicating hydrocephalus, vasculitis, strokes, dorsal midbrain syndrome, brain stem dysfunction, ptosis, amaurosis fugax, dystonia, neurocognitive deficits, and psychiatric disturbs. Due to the lack of specific neurological symptoms, diagnosis on clinical grounds alone is impossible and needs to be substantiated with neuroimaging and serology . The interaction of several factors, including variations in native versus acquired immune responses and age or sex-related differences in reactivity of the immune system, could be responsible for the the patterns of disease expression .
Histological confirmation of the parasite is not possible in most cases; therefore, diagnosis is usually based on neuroimaging and confirmed by serology. Despite modern neuroimaging methods and reliable immune diagnostic tests, diagnosis of neurocysticercosis can still be a challenge because of the low specificity of clinical and neuroimaging findings and low sensitivity and specificity of immunodiagnostic tests, particularly in endemic settings . Hence, clinicians are forced to rely on diagnostic criteria. Diagnostic criteria for SCG have been defined and validated in prospective studies . These diagnostic criteria have a high sensitivity and specificity (> 99%) in endemic settings. Diagnostic criteria have also been evolved for NCC in general [3, 9]. The sensitivity and specificity of these criteria are less than those for SCG and only one has undergone some degree of validation.
The most reliable serological test, presently available, is the enzyme-linked immunoelectrotransfer blot (EITB) assay (developed by Centers for Disease Control, Atlanta, USA in 1989), which uses lentil lectin-purified glycoprotein antigens (LLGP) to detect antibodies to T. solium in serum . For the EITB, testing of serum rather than CSF is recommended. EITB sensitivity is around 98% for patients with two or more live parasites in the nervous system; thus, people with more than one viable parenchymal cyst, ventricular or subarachnoid disease at the time of testing will have a positive serology. EITB does not cross-react with heterologous infections . A major weakness of EITB is its low sensitivity (50–60%) in patients with SCG [20, 28, 29] and even lower sensitivity in those with calcific lesions; therefore, a negative test cannot exclude NCC. Another major limitation of the EITB is that a positive test only indicates exposure to the larval antigen and does not necessarily indicate disease. EITB also remains positive for up to a year after the disease has been treated. Detection of anticysticercal antibodies in the CSF by ELISA is 89% sensitive and 93% specific in patients with viable neurocysticercosis infections and is still used when EITB is not available . Parasite DNA detection by PCR has also been used for diagnosis from CSF and fecal samples . Real-time CSF PCR has been shown to confirm the diagnosis of NCC in cases suggested by clinical, imaging, immunologic, and epidemiologic features. Comparison of immunodiagnostic assays (antibody detection by ELISA and EITB and HP10 antigen detection by ELISA) with PCR-based detection of parasite DNA from CSF suggests the role of PCR primarily in NCC cases not diagnosed by the available radiological or immunological tests [16, 39].
Therapeutic approaches might include symptomatic therapy (anti-epileptic drugs (AEDs) in most patients), antiparasitic treatment, or surgery (lesion resection or shunt placement), and often more than one of these options are needed. In the vast majority of patients, surgery is not required.
Children with SCG can be managed with AEDs alone as spontaneous resolution of the granuloma is expected (Fig. 2c–f) . However, cysticidal drugs such as albendazole may hasten the resolution, and some evidence suggests that it might lead to possible better seizure outcome.
In the definitive therapy, for cyst destruction, antihelminthic drug albendazole has been used in a dose of 15 mg/kg/day in two or three divided doses for 28 days, although shorter courses of 14 to 8 days have also been used [12, 13]. Resolution of the lesion on CT scans at 3 months was seen in 68.3 and 68.8% in the 1- and 4-week treatment groups, respectively. Although resolution of the active lesions on CT was observed after 3 months of the treatment, cured patients remain seropositive even after 1 year of the treatment. It indicates that persistent seropositivity does not necessarily indicate active infection . Praziquantel is the older cysticidal drug and is used in a dose of 50 mg/kg/day for 15 days. A single-day praziquantel therapy (25 mg/kg/dose every 2 h × 3 doses) has been reported to be as effective as 7-day treatment with albendazole. Side effects of praziquantel include abdominal pain, dizziness, headache, and allergic reactions in rare cases . Cysticidal therapy at the outset is contraindicated in children with markedly elevated intracranial pressure and ophthalmic cysticercosis due to the risk of inducing an inflammatory response and clinical worsening. Corticosteroids alone are preferred in such cases. Cysticidal therapy has no effect on calcified lesions .
Pseudotumoral or Encephalitic Form-This form is characterized by increased ICP secondary to a diffuse inflammatory reaction of the brain parenchyma due to massive infestation with cysticerci, and it is more frequent in the pediatric population. Treatment of this form is primarily medical to reduce the intracranial hypertension. Osmotic diuretics and steroid agents are effective in most cases. Decompressive craniectomy can be considered for patients refractory to medical therapy.
Spinal cord cysticercosis
Prognosis and outcome
The follow-up of children with NCC needs to be individualized. In children with persistent lesions, an additional course of cysticidal therapy is usually given. The outcome depends upon the type of NCC, cyst location (parenchymal better than extraparenchymal), and numbers (single lesions better than multiple). SCG has a good prognosis with lesion disappearing within 6 months in more than 60% of the cases allowing early withdrawal of AEDs in those in whom the lesion has resolved [23, 27]. The seizures are usually well controlled with just one AED. Recurrence of seizures in children with single lesions varies from 10 to 20%, whereas multiple and calcified lesions have frequent seizure recurrences . Children with a single ventricular cyst also have a good outcome following excision of the cyst. The prognosis is poor in children with cysticercotic encephalitis and racemose NCC [13, 34].
In order to improve the management of children with NCC, it is important to develop validated criteria for diagnosis, since the current available criteria have not been validated conclusively. Newer insights into the immune mechanisms underlying symptomatic human cysticercosis and helminth-induced immune suppression are being obtained through recent studies. Toll-like receptor-4 and soluble intercellular adhesion molecule K469E polymorphisms have been suggested to predispose to symptomatic infection [33, 38]. The understanding of these immune and genetic mechanisms will help develop newer drugs such as tamoxifen and newer drug delivery systems such as lactic acid conjugated solid lipid nanoparticles bearing albendazole and prednisolone, for effective management of NCC [10, 19]. Recent studies showing up regulation of certain genes in patients with NCC associated seizures/epilepsy might lead to better understanding the biology of the disease and also contribute to the development of simple serological tests for the disease .
NCC is an important acquired cause of epilepsy and other neurological manifestations especially in endemic areas. Because of its pleomorphic presentation, NCC should be considered in the differential diagnosis of a number of neurological conditions. NCC can also be conceptualized as a human model for development of seizures and epilepsy, and properly designed studies should yield valuable information about genetic predisposition, pathological mechanisms, and potential therapeutic targets for chronic epilepsy. Finally, if local elimination of transmission is confirmed and replicated, this will open the door to cysticercosis eradication efforts worldwide. Children with single or few lesions have a good outcome. Development of newer cysticidal drugs and drug delivery systems for both human and swine population are the potential areas of research.
Compliance with ethical standards
Conflict of interest
There was no financial support nor industry affiliations involved in this work. None of the authors has any personal or institutional financial interest in drugs, materials, or devices.
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