Indian J Pediatr DOI 10.1007/s12098-014-1576-3
REVIEW ARTICLE
Neurocysticercosis Pratibha Singhi & Renu Suthar
Received: 24 April 2014 / Accepted: 25 August 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Neurocysticercosis is the commonest parasitic disease of the nervous system in humans, and constitutes a major public health problem for most of the developing world. The clinical manifestations of Neurocysticercosis (NCC) largely depend on number of lesions, site, and host immune response against the parasite. Diagnosis is mainly based upon neuro imaging studies and is supported by antibody/antigen detection in the serum and occasionally the cerebrospinal fluid. Randomized controlled trials evaluating the clinical benefit of treatment with cysticidal agents have shown hastened resolution of lesions in most, and reduced seizure recurrence in some studies. Outcome is favourable in single lesion parenchymal NCC but is guarded in multiple lesion and extra parenchymal NCC.
Keywords Epilepsy . Neurocysticercosis . Taenia solium . Cysticidal therapy
Epidemiology Taenia solium is endemic in most developing countries, particularly Latin America, Southeast Asia, and wide parts of sub-Saharan Africa. It is rare in developed countries, where it can occur in travellers or immigrants from endemic countries. CNS infection is very frequent in endemic areas, with prevalence of specific serum antibodies above 10 % in many of these populations, and 10–20 % of the general population showing residual intraparenchymal brain calcifications on CT scan [1, 2]. In a systematic review, the pooled estimate for the proportion of NCC among patients with epilepsy was 29 % [3]. Prevalence of asymptomatic NCC in pig farming community in India is about 15 % [4]. A study from North India found a point prevalence of 4.5 / 1000 for NCC in rural India [5]. Another study from North India reported 25 % patients with active epilepsy had antibody against T. solium [6]. Among children with partial seizures, NCC accounted for over 50 % cases in hospital series from India [7]. With increasing globalization and international travel, NCC is being increasingly reported from many developed countries including USA and UK [8].
Introduction Neurocysticercosis (NCC) is the commonest cause of acquired epilepsy in India. It is caused by infection of the central nervous system (CNS) with encysted larvae of Taenia solium (T. solium). Although the commonest manifestation is epilepsy, NCC can have several other neurological manifestations. It is important to know about the disease, its diagnosis and management. P. Singhi (*) : R. Suthar Department of Pediatric Neurology and Neurodevelopment, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India e-mail: [email protected]
Life Cycle of the Parasite The adult tape worm T. solium (taeniasis) is acquired in humans from pigs by ingestion of undercooked pork infected with live T. solium cysticerci. In the intestine, these cysticerci release larvae that develop into adult worms. The proglottids of the female worm along with thousands of extremely contagious eggs are passed in the human feces. In areas with poor sanitation and open defecation, the soil gets contaminated with these eggs. Pigs are the intermediate host and are infected by grazing on such contaminated soil or by coprophagia. The eggs hatch into larvae in the pig’s intestine that pass through the mucosa and reach various tissues, where they mature into cysticerci.
Indian J Pediatr
The life cycle of the parasite is completed when humans consume undercooked pork containing the cysts. When humans ingest T. solium eggs, through contaminated food or infected food handlers, the eggs hatch to release larvae that penetrate the intestinal mucosa, and migrate throughout the body to produce cysticercosis. The cysts can lodge in any tissue, however most mature cysts are found in the CNS, skeletal muscle, subcutaneous tissue, and the eyes. Thus, humans are the definitive hosts for the parasite [9]. A frequent misconception is to assume that consumption of infected pork is needed to cause cysticercosis. Ingestion of cyst-infected pork causes taeniasis and ingestion of T. solium eggs excreted by a tapeworm carrier leads to cysticercosis. Etiopathogenesis The clinical expression, management, and prognosis of NCC varies depending on the numbers of parasites in the human CNS, their stage, their size, the inflammatory response of the host, and, most importantly, their location. In general, patients with only intra-parenchymal brain parasites present with seizures which tend to resolve over the years, whereas parasites in the ventricles and basal subarachnoid space grow and infiltrate and may cause hydrocephalus and/or intracranial hypertension and are associated with a significant morbidity and mortality [10].
Types of Neurocysticercosis Intra-Parenchymal Neurocysticercosis Neurocysticercosis most commonly involves the parenchyma of the cerebral hemispheres, with lesions commonly found at the gray matter–white matter junction, presumably resulting from deposition of the larvae in terminal small vessels of this region. In India, single lesions are common but the number is highly variable and multiple lesions are also seen in some children [11]. Inside the brain parenchyma, cysticerci are rounded vesicles formed by a worm scolex surrounded by a cystic membrane (vesicular wall). They usually range in size from a few millimetres to 1 or 2 cm. Generally cysticerci lie dormant within host tissues for prolonged periods because of inherent immune protection mechanisms, however, after some time the parasite starts degenerating and an inflammatory reactions starts. In the brain parenchyma cysts evolve through 4 stages: 1. The Vesicular cyst (Metacestode): has a thin semitransparent wall, is filled with clear fluid, and has an eccentric opaque 4–5 mm scolex. There is no inflammation around it and it is usually asymptomatic. Imaging hallmark is clear fluid filled cyst with eccentric scolex without contrast enhancement.
2. Colloidal stage: After an inflammatory response is elicited, the larva undergoes hyaline degeneration and the cyst fluid becomes opaque and gelatinous. 3. Granular nodular stage: The cyst contracts and the walls are replaced by focal lymphoid nodules and necrosis. 4. Nodular calcified stage: The cyst calcifies. Although NCC is commonly seen in children above 5 years of age, it may be seen even in infants and toddlers [12]. Seizures are by far the most frequent clinical manifestation of intraparenchymal NCC. The seizures are usually short, less than 5 min; however status epilepticus has been reported in 2 % to 32 % cases [13–16]. In a series of 500 children from India, seizures were reported in 95 % cases [13]. Most studies show similar figures of 70–90 %. Seizures are usually partial (84–87 %), particularly complex partial. Seizures may present during any stage of cyst formation. However, seizures are more frequent once the parasite degeneration begins, most likely associated with local inflammation in the surrounding cortex. Seizures can also be seen with vesicular and with calcified cysts. About a third of cases have headache and vomiting usually in association with seizures [13, 16]. Papilledema has been reported in 2 to 7 % of children. Signs of raised intracranial pressure are less common in children as compared to adults. Neurological deficits are seen in ≈4– 6 % children, and depend on the location of the cyst: they include transient hemiparesis, monoparesis, and oculomotor abnormalities. In most cases, NCC-associated seizures respond well to monotherapy with first-line antiepileptic drugs [17]. Cysticercal Encephalitis It is seen in young children and adolescents who have numerous cysts and diffuse cerebral edema. They present with severe acute raised intracranial pressure which may persist for a few days. Extraparenchymal Neurocysticercosis It can present as obstructive hydrocephalous, chronic arachnoiditis or meningitis. Cysts in the subarachnoid space may enlarge considerably without scolices, become racemose and cause obstruction leading to hydrocephalous and infarcts. Halting intraventricular cysts may cause intermittent obstruction. Spinal cysts are rare and may present with radicular pain, paresthesia, sphincteric disturbances and paraplegia Ocular cysts can be found anywhere in the eyes including the extraocular muscles, subconjuctiva or anterior chamber, subretinal space or vitreous humor and cause symptoms accordingly [18]. Immunological tests, when positive corroborate the diagnosis.
Indian J Pediatr
Diagnosis
Magnetic Resonance Imaging (MRI)
Computerised Tomography (CT)
It is usually done in cases where a scolex is not seen on CT scan as MRI visualizes the scolex with greater sensitivity than CT. The scolex is seen as a nodule that is isointense or hyperintense relative to white matter, and is best seen on proton density –weighted images. Vesicular cysts appear as round lesions either isointense or slightly hyperintense to the CSF. Calcified lesions appear hypointense on all MR imaging sequences and may at times be missed. MRI is far superior to CT for the detection of intraventricular lesions, lesions in the posterior fossa and brainstem, lesions close to the skull, and small cysts. Definition of perilesional edema is also much better on MRI. Detection of neurocysticercosis lesions can be challenging even on contrast-enhanced MR imaging of the brain, especially for the intraventricular and subarachnoid forms. High resolution MR cisternography sequences such as 3D-CISS can be instrumental in the identification and characterization of neurocysticercosis, and should be added to the MR imaging protocol for evaluation of neurocysticercosis in cases where the scolex is not visible on routine MRI sequences [20]. Magnetization transfer images (MT) and magnetization transfer ratio (MTR) help in identification of lesions not visible on routine MRI images and perilesional gliosis. In T1 weighted MT images gliotic area shows low MTR as compared to grey and white matter. Persistent perilesional gliosis surrounding the cysticercus granuloma identified by MT images is associated with refractory epilepsy in patients with NCC [21].
(a) Parenchymal Neurocysticercosis The usual CT finding is a single small enhancing computed tomographic lesion (SSECTL) also called a single cysticercus granuloma (SCG) (Fig. 1), which represents a degenerating cyst. This refers to a single, small, (20 mm, lobulated irregular shape, and marked edema causing midline shift [28]. In addition, tubercular lesions are usually seen at the base of the brain whereas NCC lesion (s) are often seen at the graywhite matter junction. In cases where the scolex is not well seen, special MRI sequences such as diffusion weighted MRI and Proton Magnetic Resonance Spectroscopy (MRS) are being tried. Presence of a lactate peak and choline/creatine ratio greater than 1 in MRS is suggestive of a tuberculoma [29].
(i) Symptomatic/supportive therapy (ii) Definitive- medical/surgical treatment for cysts Symptomatic Therapy It is required for control of acute seizures and status epilepticus and raised intracranial pressure, as per standard protocol. (a) Antiepileptic therapy: A single anti-epileptic drug (AED), usually carbamazepine or phenytoin is used to control seizures due to single lesion NCC. Seizure recurrence correlates significantly with an abnormal CT (persistence or calcification of lesion) and an abnormal EEG at the time of AED withdrawal [31]. AED can be withdrawn after 1 year seizure free interval in cases where the lesion has disappeared and the EEG has normalized; longer durations of AED may be needed for those with persistent or calcified lesions [32]. (b) Corticosteroids: Oral corticosteroids are generally administered for a few days starting a day or two before cysticidal therapy so as to reduce the perilesional edema and prevent any adverse reactions that may occur due to the host inflammatory reaction. Usually oral prednisolone 1–2 mg/kg is used; I.V dexamethasone (0.1/mg/kg/d) may be used if there are features of raised ICP. In children with numerous disseminated lesions and extensive cerebral edema, steroids may be required for several weeks. Definitive Therapy Cysticidal Therapy There has been much discussion in the literature regarding whether anti-parasitic drugs effectively kill cysts and whether anthelminthic treatment improves clinical outcome, defined as fewer seizures, in patients with intra-parenchymal NCC. Intuitively, the effects and clinical benefit of anti-parasitic regimens should be more evident in patients with multiple viable cysts, and less evident in patients with lesions that have begun their degenerative process and are already being attacked by the host’s immune system. To date, evidence suggests that antiparasitic drugs hasten the resolution of live parenchymal brain cysts; however, whether a similar benefit is obtained in the treatment of degenerating cysts is not clear [33].
Indian J Pediatr
A recent meta-analysis concluded that anthelminthic treatment was associated with increased rates of both seizure control and faster resolution of lesions in cases with single lesion [34]. Hence cysticidal therapy is recommended not only for vesicular lesions, but also for enhancing NCC lesions. Recent American Academy of Neurology guidelines also recommend the use of albendazole and corticosteroids for adults and children with parenchymal NCC, both to reduce the number of active lesions on neuroimaging and to reduce long-term seizure frequency [35]. Albendazole is preferred to praziquantel as it is less expensive, has very few side effects, has better penetration into the subarachnoid space, and co-administration of phenytoin or carbamezepine does not decrease its bioavailability. Albendazole is used in a dose of 15 mg/kg/d in 2–3 divided doses, usually for 28 days particularly in multiple lesions; shorter durations of 14 days to 8 days have also been used. Praziquantel is used in a dose of 50 mg/kg/d for 15 days. Side effects of Praziquantel include abdominal pain, dizziness, headache, and allergic reactions in rare cases. Combination therapy using both Albendazole and Praziquantel has also been used [36]. However larger trials are needed to establish its efficacy. Children with markedly elevated ICP and ophthalmic NCC should be treated with steroids alone; cysticidal therapy is avoided as it may worsen the condition by inducing an inflammatory response. Cysticidal therapy has no effect on calcified lesions. For cases with obstructive hydrocephalous, endoscopic removal of cysts from the ventricles is possible and may avoid shunt placement. Usually steroids and albendazole are also used simultaneously to reduce the rate of re-obstruction [37, 38]. A CT scan is usually done after 3–6 mo to see whether the lesions have resolved. In children with persistent lesions, another course of cysticidal therapy is usually given.
Prognosis Single enhancing lesion NCC has a good prognosis - the lesion disappears within 6 mo in more than 60 % cases and seizures are well controlled. Recurrence of seizures in children with single lesions varies from 10 to 20 %, multiple and calcified lesions have frequent seizure recurrences. The prognosis is poorer in cysticercus encephalitis and extraparenchymal NCC.
Prevention NCC is an entirely preventable disease. A multipronged action plan that includes public education, proper hygiene and
sanitation, and enforcing strict animal husbandry and meat inspection procedure is needed. Mass de-worming of population with Niclosamide or Praziquantel and mass vaccination of pigs with newer effective vaccines such as TSOL18, along with treatment of pigs with Oxfendazole, have been recommended [39]. Community interventions have been found to reduce the rate of epilepsy in hyper-endemic areas. Conclusions Neurocysticercosis is an important cause of seizures and other neurological manifestations and needs to 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. Children with single or few lesions have a good outcome. Prevention of NCC is important and is feasible.
Conflict of Interest None. Source of Funding None.
References 1. Montano SM, Villaran MV, Ylquimiche L, Figueroa JJ, Rodriguez S, Bautista CT, et al; Cysticercosis Working Group in Peru. Neurocysticercosis: association between seizures, serology, and brain CT in rural Peru. Neurology. 2005;65:229–33. 2. Medina MT, Aguilar-Estrada RL, Alvarez A, Duron RM, Martinez L, Dubon S, et al. Reduction in rate of epilepsy from neurocysticercosis by community interventions: the Salama, Honduras study. Epilepsia. 2011;52:1177–85. 3. Ndimubanzi PC, Carabin H, Budke CM, Nguyen H, Qian YJ, Rainwater E, et al. A systematic review of the frequency of neurocyticercosis with a focus on people with epilepsy. PLoS Negl Trop Dis. 2010;4:e870. 4. Prasad KN, Verma A, Srivastava S, Gupta RK, Pandey CM, Paliwal VK. An epidemiological study of asymptomatic neurocysticercosis in a pig farming community in northern India. Trans R Soc Trop Med Hyg. 2011;105:531–6. 5. Raina SK, Razdan S, Pandita KK, Sharma R, Gupta VP, Razdan S. Active epilepsy as indicator of neurocysticercosis in rural northwest India. Epilepsy Res Treat. 2012;2012:802747. 6. Singh G, Bawa J, Chinna D, Chaudhary A, Saggar K, Modi M, et al. Association between epilepsy and cysticercosis and toxocariasis: a population-based case–control study in a slum in India. Epilepsia. 2012;53:2203–8. 7. Singhi P, Singhi S. Neurocysticercosis in children. J Child Neurol. 2004;19:482–92. 8. Serpa JA, White Jr AC. Neurocysticercosis in the United States. Pathog Glob Health. 2012;106:256–60. 9. Del Brutto OH, Garcia HH. Neurocysticercosis. Handb Clin Neurol. 2013;114:313–25. 10. Estanol B, Corona T, Abad P. A prognostic classification of cerebral cysticercosis: therapeutic implications. J Neurol Neurosurg Psychiatry. 1986;49:1131–4.
Indian J Pediatr 11. Amaral L, Maschietto M, Maschietto R, Cury R, Ferreira NF, Mendonca R, et al. Ununsual manifestations of neurocysticercosis in MR imaging: analysis of 172 cases. Arq Neuro-psiquiatr. 2003;61:533–41. 12. Del Brutto OH. Neurocysticercosis in infants and toddlers: report of seven cases and review of published patients. Pediatr Neurol. 2013;48:432–5. 13. Singhi P, Ray M, Singhi S, Khandelwal N. Clinical spectrum of 500 children with neurocysticercosis and response to albendazole therapy. J Child Neurol. 2000;15:207–13. 14. Singhi P. Neurocysticercosis. Ther Adv Neurol Disord. 2011;4:67–81. 15. Singhi P. Infectious causes of seizures and epilepsy in the developing world. Dev Med Child Neurol. 2011;53:600–9. 16. Talukdar B, Saxena A, Popli VK, Choudhury V. Neurocysticercosis in children: clinical characteristics and outcome. Ann Trop Paediatr. 2002;22:333–9. 17. Nash TE, Garcia HH. Diagnosis and treatment of neurocysticercosis. Nat Rev Neurol. 2011;7:584–94. 18. David S, Mathai E. Ocular cysticercosis–a review of 25 cases. J Assoc Physicians India. 2000;48:704–7. 19. Nash T. Edema surrounding calcified intracranial cysticerci: clinical manifestations, natural history, and treatment. Pathog Glob Health. 2012;106:275–9. 20. Lerner A, Shiroishi MS, Zee CS, Law M, Go JL. Imaging of neurocysticercosis. Neuroimaging Clin N Am. 2012;22:659–76. 21. de Souza A, Nalini A, Kovoor JM, Yeshraj G, Siddalingaiah HS, Thennarasu K. Perilesional gliosis around solitary cerebral parenchymal cysticerci and long-term seizure outcome: a prospective study using serial magnetization transfer imaging. Epilepsia. 2011;52:1918–27. 22. Ito A, Yamasaki H, Nakao M, Sako Y, Okamoto M, Sato MO, et al. Multiple genotypes of taenia solium–ramifications for diagnosis, treatment and control. Acta Trop. 2003;87:95–101. 23. Atluri SR, Singhi P, Khandelwal N, Malla N. Evaluation of excretory secretory and 10–30 kDa antigens of taenia solium cysticerci by EITB assay for the diagnosis of neurocysticercosis. Parasite Immunol. 2009;31:151–5. 24. Rodriguez S, Wilkins P, Dorny P. Immunological and molecular diagnosis of cysticercosis. Pathog Glob Health. 2012;106:286–98. 25. Atluri VS, Singhi PD, Khandelwal N, Malla N. 2D-PAGE analysis of taenia solium metacestode 10–30 kDa antigens for the serodiagnosis of neurocysticercosis in children. Acta Trop. 2011;118:165–9. 26. Del Brutto OH, Wadia NH, Dumas M, Cruz M, Tsang VC, Schantz PM. Proposal of diagnostic criteria for human cysticercosis and neurocysticercosis. J Neurol Sci. 1996;142:1–6. 27. Del Brutto OH, Rajshekhar V, White Jr AC, Tsang VC, Nash TE, Takayanagui OM, et al. Proposed diagnostic criteria for neurocysticercosis. Neurology. 2001;57:177–83.
28. Rajshekhar V, Haran RP, Prakash GS, Chandy MJ. Differentiating solitary small cysticercus granulomas and tuberculomas in patients with epilepsy. Clinical and computerized tomographic criteria. J Neurosurg. 1993;78:402–7. 29. Pretell EJ, Martinot C Jr, Garcia HH, Alvarado M, Bustos JA, Martinot C, et al; Cysticercosis Working Group in Peru. Differential diagnosis between cerebral tuberculosis and neurocysticercosis by magnetic resonance spectroscopy. J Comput Aassist Tomogr. 2005;29:112–4. 30. Singhi PD, Baranwal AK. Single small enhancing computed tomographic lesions in indian children–II. clinical features, pathology, radiology and management. J Trop Pediatr. 2001;47:266–70. 31. Singhi PD, Dinakaran J, Khandelwal N. Singhi SC one vs. two years of anti-epileptic therapy in children with single small enhancing CT lesions. J Trop Pediatr. 2003;49:274–8. 32. Sharma LN, Garg RK, Verma R, Singh MK, Malhotra HS. Seizure recurrence in patients with solitary cystic granuloma or single parenchymal cerebral calcification: a comparative evaluation. Seizure. 2013;22:840–5. 33. Abba K, Ramaratnam S, Ranganathan LN. Anthelmintics for people with neurocysticercosis. Cochrane Database Syst Rev. 2010;3: CD000215. 34. Otte WM, Singla M, Sander JW, Singh G. Drug therapy for solitary cysticercus granuloma: a systematic review and meta-analysis. Neurology. 2013;80:152–62. 35. Baird RA, Wiebe S, Zunt JR, Halperin JJ, Gronseth G, Roos KL. Evidence-based guideline: treatment of parenchymal neurocysticercosis: report of the guideline development subcommittee of the American academy of neurology. Neurology. 2013;80:1424–9. 36. Kaur S, Singhi P, Singhi S, Khandelwal N. Combination therapy with albendazole and praziquantel versus albendazole alone in children with seizures and single lesion neurocysticercosis: a randomized, placebo-controlled double blind trial. Pediatr Infect Dis J. 2009;28: 403–6. 37. Sinha S, Sharma BS. Intraventricular neurocysticercosis: a review of current status and management issues. Br J Neurosurg. 2012;26: 305–9. 38. Khade P, Lemos RS, Toussaint LG. What is the utility of postoperative antihelminthic therapy after resection for intraventricular neurocysticercosis? World Neurosurg. 2013;79:558–67. 39. Sikasunge CS, Johansen MV, Phiri IK, Willingham AL 3rd, Leifsson PS. The immune response in Taenia solium neurocysticercosis in pigs is associated with astrogliosis, axonal degeneration and altered blood–brain barrier permeability. Vet Parasitol. 2009;160: 242–50.
REVIEW ARTICLE
Neurocysticercosis Pratibha Singhi & Renu Suthar
Received: 24 April 2014 / Accepted: 25 August 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Neurocysticercosis is the commonest parasitic disease of the nervous system in humans, and constitutes a major public health problem for most of the developing world. The clinical manifestations of Neurocysticercosis (NCC) largely depend on number of lesions, site, and host immune response against the parasite. Diagnosis is mainly based upon neuro imaging studies and is supported by antibody/antigen detection in the serum and occasionally the cerebrospinal fluid. Randomized controlled trials evaluating the clinical benefit of treatment with cysticidal agents have shown hastened resolution of lesions in most, and reduced seizure recurrence in some studies. Outcome is favourable in single lesion parenchymal NCC but is guarded in multiple lesion and extra parenchymal NCC.
Keywords Epilepsy . Neurocysticercosis . Taenia solium . Cysticidal therapy
Epidemiology Taenia solium is endemic in most developing countries, particularly Latin America, Southeast Asia, and wide parts of sub-Saharan Africa. It is rare in developed countries, where it can occur in travellers or immigrants from endemic countries. CNS infection is very frequent in endemic areas, with prevalence of specific serum antibodies above 10 % in many of these populations, and 10–20 % of the general population showing residual intraparenchymal brain calcifications on CT scan [1, 2]. In a systematic review, the pooled estimate for the proportion of NCC among patients with epilepsy was 29 % [3]. Prevalence of asymptomatic NCC in pig farming community in India is about 15 % [4]. A study from North India found a point prevalence of 4.5 / 1000 for NCC in rural India [5]. Another study from North India reported 25 % patients with active epilepsy had antibody against T. solium [6]. Among children with partial seizures, NCC accounted for over 50 % cases in hospital series from India [7]. With increasing globalization and international travel, NCC is being increasingly reported from many developed countries including USA and UK [8].
Introduction Neurocysticercosis (NCC) is the commonest cause of acquired epilepsy in India. It is caused by infection of the central nervous system (CNS) with encysted larvae of Taenia solium (T. solium). Although the commonest manifestation is epilepsy, NCC can have several other neurological manifestations. It is important to know about the disease, its diagnosis and management. P. Singhi (*) : R. Suthar Department of Pediatric Neurology and Neurodevelopment, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India e-mail: [email protected]
Life Cycle of the Parasite The adult tape worm T. solium (taeniasis) is acquired in humans from pigs by ingestion of undercooked pork infected with live T. solium cysticerci. In the intestine, these cysticerci release larvae that develop into adult worms. The proglottids of the female worm along with thousands of extremely contagious eggs are passed in the human feces. In areas with poor sanitation and open defecation, the soil gets contaminated with these eggs. Pigs are the intermediate host and are infected by grazing on such contaminated soil or by coprophagia. The eggs hatch into larvae in the pig’s intestine that pass through the mucosa and reach various tissues, where they mature into cysticerci.
Indian J Pediatr
The life cycle of the parasite is completed when humans consume undercooked pork containing the cysts. When humans ingest T. solium eggs, through contaminated food or infected food handlers, the eggs hatch to release larvae that penetrate the intestinal mucosa, and migrate throughout the body to produce cysticercosis. The cysts can lodge in any tissue, however most mature cysts are found in the CNS, skeletal muscle, subcutaneous tissue, and the eyes. Thus, humans are the definitive hosts for the parasite [9]. A frequent misconception is to assume that consumption of infected pork is needed to cause cysticercosis. Ingestion of cyst-infected pork causes taeniasis and ingestion of T. solium eggs excreted by a tapeworm carrier leads to cysticercosis. Etiopathogenesis The clinical expression, management, and prognosis of NCC varies depending on the numbers of parasites in the human CNS, their stage, their size, the inflammatory response of the host, and, most importantly, their location. In general, patients with only intra-parenchymal brain parasites present with seizures which tend to resolve over the years, whereas parasites in the ventricles and basal subarachnoid space grow and infiltrate and may cause hydrocephalus and/or intracranial hypertension and are associated with a significant morbidity and mortality [10].
Types of Neurocysticercosis Intra-Parenchymal Neurocysticercosis Neurocysticercosis most commonly involves the parenchyma of the cerebral hemispheres, with lesions commonly found at the gray matter–white matter junction, presumably resulting from deposition of the larvae in terminal small vessels of this region. In India, single lesions are common but the number is highly variable and multiple lesions are also seen in some children [11]. Inside the brain parenchyma, cysticerci are rounded vesicles formed by a worm scolex surrounded by a cystic membrane (vesicular wall). They usually range in size from a few millimetres to 1 or 2 cm. Generally cysticerci lie dormant within host tissues for prolonged periods because of inherent immune protection mechanisms, however, after some time the parasite starts degenerating and an inflammatory reactions starts. In the brain parenchyma cysts evolve through 4 stages: 1. The Vesicular cyst (Metacestode): has a thin semitransparent wall, is filled with clear fluid, and has an eccentric opaque 4–5 mm scolex. There is no inflammation around it and it is usually asymptomatic. Imaging hallmark is clear fluid filled cyst with eccentric scolex without contrast enhancement.
2. Colloidal stage: After an inflammatory response is elicited, the larva undergoes hyaline degeneration and the cyst fluid becomes opaque and gelatinous. 3. Granular nodular stage: The cyst contracts and the walls are replaced by focal lymphoid nodules and necrosis. 4. Nodular calcified stage: The cyst calcifies. Although NCC is commonly seen in children above 5 years of age, it may be seen even in infants and toddlers [12]. Seizures are by far the most frequent clinical manifestation of intraparenchymal NCC. The seizures are usually short, less than 5 min; however status epilepticus has been reported in 2 % to 32 % cases [13–16]. In a series of 500 children from India, seizures were reported in 95 % cases [13]. Most studies show similar figures of 70–90 %. Seizures are usually partial (84–87 %), particularly complex partial. Seizures may present during any stage of cyst formation. However, seizures are more frequent once the parasite degeneration begins, most likely associated with local inflammation in the surrounding cortex. Seizures can also be seen with vesicular and with calcified cysts. About a third of cases have headache and vomiting usually in association with seizures [13, 16]. Papilledema has been reported in 2 to 7 % of children. Signs of raised intracranial pressure are less common in children as compared to adults. Neurological deficits are seen in ≈4– 6 % children, and depend on the location of the cyst: they include transient hemiparesis, monoparesis, and oculomotor abnormalities. In most cases, NCC-associated seizures respond well to monotherapy with first-line antiepileptic drugs [17]. Cysticercal Encephalitis It is seen in young children and adolescents who have numerous cysts and diffuse cerebral edema. They present with severe acute raised intracranial pressure which may persist for a few days. Extraparenchymal Neurocysticercosis It can present as obstructive hydrocephalous, chronic arachnoiditis or meningitis. Cysts in the subarachnoid space may enlarge considerably without scolices, become racemose and cause obstruction leading to hydrocephalous and infarcts. Halting intraventricular cysts may cause intermittent obstruction. Spinal cysts are rare and may present with radicular pain, paresthesia, sphincteric disturbances and paraplegia Ocular cysts can be found anywhere in the eyes including the extraocular muscles, subconjuctiva or anterior chamber, subretinal space or vitreous humor and cause symptoms accordingly [18]. Immunological tests, when positive corroborate the diagnosis.
Indian J Pediatr
Diagnosis
Magnetic Resonance Imaging (MRI)
Computerised Tomography (CT)
It is usually done in cases where a scolex is not seen on CT scan as MRI visualizes the scolex with greater sensitivity than CT. The scolex is seen as a nodule that is isointense or hyperintense relative to white matter, and is best seen on proton density –weighted images. Vesicular cysts appear as round lesions either isointense or slightly hyperintense to the CSF. Calcified lesions appear hypointense on all MR imaging sequences and may at times be missed. MRI is far superior to CT for the detection of intraventricular lesions, lesions in the posterior fossa and brainstem, lesions close to the skull, and small cysts. Definition of perilesional edema is also much better on MRI. Detection of neurocysticercosis lesions can be challenging even on contrast-enhanced MR imaging of the brain, especially for the intraventricular and subarachnoid forms. High resolution MR cisternography sequences such as 3D-CISS can be instrumental in the identification and characterization of neurocysticercosis, and should be added to the MR imaging protocol for evaluation of neurocysticercosis in cases where the scolex is not visible on routine MRI sequences [20]. Magnetization transfer images (MT) and magnetization transfer ratio (MTR) help in identification of lesions not visible on routine MRI images and perilesional gliosis. In T1 weighted MT images gliotic area shows low MTR as compared to grey and white matter. Persistent perilesional gliosis surrounding the cysticercus granuloma identified by MT images is associated with refractory epilepsy in patients with NCC [21].
(a) Parenchymal Neurocysticercosis The usual CT finding is a single small enhancing computed tomographic lesion (SSECTL) also called a single cysticercus granuloma (SCG) (Fig. 1), which represents a degenerating cyst. This refers to a single, small, (20 mm, lobulated irregular shape, and marked edema causing midline shift [28]. In addition, tubercular lesions are usually seen at the base of the brain whereas NCC lesion (s) are often seen at the graywhite matter junction. In cases where the scolex is not well seen, special MRI sequences such as diffusion weighted MRI and Proton Magnetic Resonance Spectroscopy (MRS) are being tried. Presence of a lactate peak and choline/creatine ratio greater than 1 in MRS is suggestive of a tuberculoma [29].
(i) Symptomatic/supportive therapy (ii) Definitive- medical/surgical treatment for cysts Symptomatic Therapy It is required for control of acute seizures and status epilepticus and raised intracranial pressure, as per standard protocol. (a) Antiepileptic therapy: A single anti-epileptic drug (AED), usually carbamazepine or phenytoin is used to control seizures due to single lesion NCC. Seizure recurrence correlates significantly with an abnormal CT (persistence or calcification of lesion) and an abnormal EEG at the time of AED withdrawal [31]. AED can be withdrawn after 1 year seizure free interval in cases where the lesion has disappeared and the EEG has normalized; longer durations of AED may be needed for those with persistent or calcified lesions [32]. (b) Corticosteroids: Oral corticosteroids are generally administered for a few days starting a day or two before cysticidal therapy so as to reduce the perilesional edema and prevent any adverse reactions that may occur due to the host inflammatory reaction. Usually oral prednisolone 1–2 mg/kg is used; I.V dexamethasone (0.1/mg/kg/d) may be used if there are features of raised ICP. In children with numerous disseminated lesions and extensive cerebral edema, steroids may be required for several weeks. Definitive Therapy Cysticidal Therapy There has been much discussion in the literature regarding whether anti-parasitic drugs effectively kill cysts and whether anthelminthic treatment improves clinical outcome, defined as fewer seizures, in patients with intra-parenchymal NCC. Intuitively, the effects and clinical benefit of anti-parasitic regimens should be more evident in patients with multiple viable cysts, and less evident in patients with lesions that have begun their degenerative process and are already being attacked by the host’s immune system. To date, evidence suggests that antiparasitic drugs hasten the resolution of live parenchymal brain cysts; however, whether a similar benefit is obtained in the treatment of degenerating cysts is not clear [33].
Indian J Pediatr
A recent meta-analysis concluded that anthelminthic treatment was associated with increased rates of both seizure control and faster resolution of lesions in cases with single lesion [34]. Hence cysticidal therapy is recommended not only for vesicular lesions, but also for enhancing NCC lesions. Recent American Academy of Neurology guidelines also recommend the use of albendazole and corticosteroids for adults and children with parenchymal NCC, both to reduce the number of active lesions on neuroimaging and to reduce long-term seizure frequency [35]. Albendazole is preferred to praziquantel as it is less expensive, has very few side effects, has better penetration into the subarachnoid space, and co-administration of phenytoin or carbamezepine does not decrease its bioavailability. Albendazole is used in a dose of 15 mg/kg/d in 2–3 divided doses, usually for 28 days particularly in multiple lesions; shorter durations of 14 days to 8 days have also been used. Praziquantel is used in a dose of 50 mg/kg/d for 15 days. Side effects of Praziquantel include abdominal pain, dizziness, headache, and allergic reactions in rare cases. Combination therapy using both Albendazole and Praziquantel has also been used [36]. However larger trials are needed to establish its efficacy. Children with markedly elevated ICP and ophthalmic NCC should be treated with steroids alone; cysticidal therapy is avoided as it may worsen the condition by inducing an inflammatory response. Cysticidal therapy has no effect on calcified lesions. For cases with obstructive hydrocephalous, endoscopic removal of cysts from the ventricles is possible and may avoid shunt placement. Usually steroids and albendazole are also used simultaneously to reduce the rate of re-obstruction [37, 38]. A CT scan is usually done after 3–6 mo to see whether the lesions have resolved. In children with persistent lesions, another course of cysticidal therapy is usually given.
Prognosis Single enhancing lesion NCC has a good prognosis - the lesion disappears within 6 mo in more than 60 % cases and seizures are well controlled. Recurrence of seizures in children with single lesions varies from 10 to 20 %, multiple and calcified lesions have frequent seizure recurrences. The prognosis is poorer in cysticercus encephalitis and extraparenchymal NCC.
Prevention NCC is an entirely preventable disease. A multipronged action plan that includes public education, proper hygiene and
sanitation, and enforcing strict animal husbandry and meat inspection procedure is needed. Mass de-worming of population with Niclosamide or Praziquantel and mass vaccination of pigs with newer effective vaccines such as TSOL18, along with treatment of pigs with Oxfendazole, have been recommended [39]. Community interventions have been found to reduce the rate of epilepsy in hyper-endemic areas. Conclusions Neurocysticercosis is an important cause of seizures and other neurological manifestations and needs to 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. Children with single or few lesions have a good outcome. Prevention of NCC is important and is feasible.
Conflict of Interest None. Source of Funding None.
References 1. Montano SM, Villaran MV, Ylquimiche L, Figueroa JJ, Rodriguez S, Bautista CT, et al; Cysticercosis Working Group in Peru. Neurocysticercosis: association between seizures, serology, and brain CT in rural Peru. Neurology. 2005;65:229–33. 2. Medina MT, Aguilar-Estrada RL, Alvarez A, Duron RM, Martinez L, Dubon S, et al. Reduction in rate of epilepsy from neurocysticercosis by community interventions: the Salama, Honduras study. Epilepsia. 2011;52:1177–85. 3. Ndimubanzi PC, Carabin H, Budke CM, Nguyen H, Qian YJ, Rainwater E, et al. A systematic review of the frequency of neurocyticercosis with a focus on people with epilepsy. PLoS Negl Trop Dis. 2010;4:e870. 4. Prasad KN, Verma A, Srivastava S, Gupta RK, Pandey CM, Paliwal VK. An epidemiological study of asymptomatic neurocysticercosis in a pig farming community in northern India. Trans R Soc Trop Med Hyg. 2011;105:531–6. 5. Raina SK, Razdan S, Pandita KK, Sharma R, Gupta VP, Razdan S. Active epilepsy as indicator of neurocysticercosis in rural northwest India. Epilepsy Res Treat. 2012;2012:802747. 6. Singh G, Bawa J, Chinna D, Chaudhary A, Saggar K, Modi M, et al. Association between epilepsy and cysticercosis and toxocariasis: a population-based case–control study in a slum in India. Epilepsia. 2012;53:2203–8. 7. Singhi P, Singhi S. Neurocysticercosis in children. J Child Neurol. 2004;19:482–92. 8. Serpa JA, White Jr AC. Neurocysticercosis in the United States. Pathog Glob Health. 2012;106:256–60. 9. Del Brutto OH, Garcia HH. Neurocysticercosis. Handb Clin Neurol. 2013;114:313–25. 10. Estanol B, Corona T, Abad P. A prognostic classification of cerebral cysticercosis: therapeutic implications. J Neurol Neurosurg Psychiatry. 1986;49:1131–4.
Indian J Pediatr 11. Amaral L, Maschietto M, Maschietto R, Cury R, Ferreira NF, Mendonca R, et al. Ununsual manifestations of neurocysticercosis in MR imaging: analysis of 172 cases. Arq Neuro-psiquiatr. 2003;61:533–41. 12. Del Brutto OH. Neurocysticercosis in infants and toddlers: report of seven cases and review of published patients. Pediatr Neurol. 2013;48:432–5. 13. Singhi P, Ray M, Singhi S, Khandelwal N. Clinical spectrum of 500 children with neurocysticercosis and response to albendazole therapy. J Child Neurol. 2000;15:207–13. 14. Singhi P. Neurocysticercosis. Ther Adv Neurol Disord. 2011;4:67–81. 15. Singhi P. Infectious causes of seizures and epilepsy in the developing world. Dev Med Child Neurol. 2011;53:600–9. 16. Talukdar B, Saxena A, Popli VK, Choudhury V. Neurocysticercosis in children: clinical characteristics and outcome. Ann Trop Paediatr. 2002;22:333–9. 17. Nash TE, Garcia HH. Diagnosis and treatment of neurocysticercosis. Nat Rev Neurol. 2011;7:584–94. 18. David S, Mathai E. Ocular cysticercosis–a review of 25 cases. J Assoc Physicians India. 2000;48:704–7. 19. Nash T. Edema surrounding calcified intracranial cysticerci: clinical manifestations, natural history, and treatment. Pathog Glob Health. 2012;106:275–9. 20. Lerner A, Shiroishi MS, Zee CS, Law M, Go JL. Imaging of neurocysticercosis. Neuroimaging Clin N Am. 2012;22:659–76. 21. de Souza A, Nalini A, Kovoor JM, Yeshraj G, Siddalingaiah HS, Thennarasu K. Perilesional gliosis around solitary cerebral parenchymal cysticerci and long-term seizure outcome: a prospective study using serial magnetization transfer imaging. Epilepsia. 2011;52:1918–27. 22. Ito A, Yamasaki H, Nakao M, Sako Y, Okamoto M, Sato MO, et al. Multiple genotypes of taenia solium–ramifications for diagnosis, treatment and control. Acta Trop. 2003;87:95–101. 23. Atluri SR, Singhi P, Khandelwal N, Malla N. Evaluation of excretory secretory and 10–30 kDa antigens of taenia solium cysticerci by EITB assay for the diagnosis of neurocysticercosis. Parasite Immunol. 2009;31:151–5. 24. Rodriguez S, Wilkins P, Dorny P. Immunological and molecular diagnosis of cysticercosis. Pathog Glob Health. 2012;106:286–98. 25. Atluri VS, Singhi PD, Khandelwal N, Malla N. 2D-PAGE analysis of taenia solium metacestode 10–30 kDa antigens for the serodiagnosis of neurocysticercosis in children. Acta Trop. 2011;118:165–9. 26. Del Brutto OH, Wadia NH, Dumas M, Cruz M, Tsang VC, Schantz PM. Proposal of diagnostic criteria for human cysticercosis and neurocysticercosis. J Neurol Sci. 1996;142:1–6. 27. Del Brutto OH, Rajshekhar V, White Jr AC, Tsang VC, Nash TE, Takayanagui OM, et al. Proposed diagnostic criteria for neurocysticercosis. Neurology. 2001;57:177–83.
28. Rajshekhar V, Haran RP, Prakash GS, Chandy MJ. Differentiating solitary small cysticercus granulomas and tuberculomas in patients with epilepsy. Clinical and computerized tomographic criteria. J Neurosurg. 1993;78:402–7. 29. Pretell EJ, Martinot C Jr, Garcia HH, Alvarado M, Bustos JA, Martinot C, et al; Cysticercosis Working Group in Peru. Differential diagnosis between cerebral tuberculosis and neurocysticercosis by magnetic resonance spectroscopy. J Comput Aassist Tomogr. 2005;29:112–4. 30. Singhi PD, Baranwal AK. Single small enhancing computed tomographic lesions in indian children–II. clinical features, pathology, radiology and management. J Trop Pediatr. 2001;47:266–70. 31. Singhi PD, Dinakaran J, Khandelwal N. Singhi SC one vs. two years of anti-epileptic therapy in children with single small enhancing CT lesions. J Trop Pediatr. 2003;49:274–8. 32. Sharma LN, Garg RK, Verma R, Singh MK, Malhotra HS. Seizure recurrence in patients with solitary cystic granuloma or single parenchymal cerebral calcification: a comparative evaluation. Seizure. 2013;22:840–5. 33. Abba K, Ramaratnam S, Ranganathan LN. Anthelmintics for people with neurocysticercosis. Cochrane Database Syst Rev. 2010;3: CD000215. 34. Otte WM, Singla M, Sander JW, Singh G. Drug therapy for solitary cysticercus granuloma: a systematic review and meta-analysis. Neurology. 2013;80:152–62. 35. Baird RA, Wiebe S, Zunt JR, Halperin JJ, Gronseth G, Roos KL. Evidence-based guideline: treatment of parenchymal neurocysticercosis: report of the guideline development subcommittee of the American academy of neurology. Neurology. 2013;80:1424–9. 36. Kaur S, Singhi P, Singhi S, Khandelwal N. Combination therapy with albendazole and praziquantel versus albendazole alone in children with seizures and single lesion neurocysticercosis: a randomized, placebo-controlled double blind trial. Pediatr Infect Dis J. 2009;28: 403–6. 37. Sinha S, Sharma BS. Intraventricular neurocysticercosis: a review of current status and management issues. Br J Neurosurg. 2012;26: 305–9. 38. Khade P, Lemos RS, Toussaint LG. What is the utility of postoperative antihelminthic therapy after resection for intraventricular neurocysticercosis? World Neurosurg. 2013;79:558–67. 39. Sikasunge CS, Johansen MV, Phiri IK, Willingham AL 3rd, Leifsson PS. The immune response in Taenia solium neurocysticercosis in pigs is associated with astrogliosis, axonal degeneration and altered blood–brain barrier permeability. Vet Parasitol. 2009;160: 242–50.
