SPECIAL REPORT
Neurocysticercosis: A natural human model of epileptogenesis *Theodore E. Nash, *Siddhartha Mahanty, †Jeffrey A. Loeb, ‡William H. Theodore, §Alon Friedman, ¶Josemir W. Sander, **Gagandeep Singh, ††Esper Cavalheiro, ‡‡Oscar H. Del Brutto, §§Osvaldo M. Takayanagui, ¶¶Agnes Fleury, ##Manuela Verastegui, ***Pierre-Marie Preux, †††Silvia Montano, ‡‡‡E. Javier Pretell, §§§A. Clinton White Jr, ¶¶¶Armando E. Gonzales, ###Robert H. Gilman, and ****Hector H. Garcia Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
SUMMARY
Dr. Theodore Nash is a principal investigator in the Laboratory of Parasitic Diseases, National Institutes of Health.
Objective: To develop a better understanding of mechanisms of seizures and longterm epileptogenesis using neurocysticercosis. Methods: A workshop was held bringing together experts in epilepsy and epileptogenesis and neurocysticercosis. Results: Human neurocysticercosis and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures. Inflammatory responses to degenerating forms and later-stage calcified parasite granulomas are associated with seizures and epilepsy. Other mechanisms may also be involved in epileptogenesis. Significance: Naturally occurring brain infections with neurocysticercosis offer a unique opportunity to develop treatments for one of the world’s most common causes of epilepsy and for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state. KEY WORDS: Epilepsy, Seizure, Taenia solium, Helminth.
Accepted September 24, 2014. *Laboratory of Parasitic Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, U.S.A.; †Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, Illinois, U.S.A.; ‡Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A.; §The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel, Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada; ¶NIHR UCL Hospitals Biomedical Research Centre, Department of Clinical & Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London & Epilepsy Society, Buckinghamshire, United Kingdom; Epilepsy Institute of the Netherlands Foundation, Heemstede, The Netherlands; **Department of Neurology, Dayan and Medical College, Ludhiana, India; ††Department of Neurology and Neurosurgery, Federal University of Sao Paulo, Sao Paulo, Brazil; ‡‡School of Medicine, University Espiritu Santo, Guayaquil, Ecuador; §§Department of Neurosciences and Behavior, Ribeir~ao Preto Medical School University of S~ao Paulo, Ribeir~ao Preto, Brazil; ¶¶Institute of Biomedical Research, National Autonomous University of Mexico and National Institute of Neurology and Neurosurgery (INNN), Mexico City, Mexico; ###Department of Cellular and Molecular Sciences, Faculty of Science and Philosophy, University Peruana Cayetano Heredia, Lima, Peru; ***UMR1094 INSERM, CHU Limoges, Institute of Neuroepidemiology and Tropical Neurology, University of Limoges, Limoges, France; †††US Naval Medical Research Unit 6, Callao, Peru; ‡‡‡Department of Neurology, Hospital Alberto Sabogal, Callao, Peru; §§§Infectious Disease Division, Department of Internal Medicine, University of Texas, Galveston, Texas, U.S.A.; ¶¶¶Department of Veterinary Public Health, School of Veterinary Medicine, National University of San Marcos, Lima, Peru; ###Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, U.S.A.; and ****Cysticercosis Unit, Institute of Neurological Diseases, Lima, Peru, Center for Global Health-Tumbes, University Peruana Cayetano Heredia, Department of Microbiology, Universidad Peruana Cayetano Heredia All authors participated in a conference held in Lima, Peru from October 23–24, 2013 that led to the content of the manuscript. Address correspondence to Theodore Nash, 9000 Rockville Pike, Building 4, Rm 424, Bethesda, MD 20892, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
1
2 T. E. Nash et al. Neurocysticercosis (NCC) is the most common preventable risk factor for adult-acquired epilepsy worldwide and accounts for up to 29% of all cases of epilepsy in some endemic areas.1,2 A workshop was held on October 23 and 24, 2013 in Lima, Peru, bringing together experts in the areas of parasitology and epilepsy to develop a better understanding of mechanisms of seizures and long-term epileptogenesis triggered by NCC. Inflammatory responses to degenerating forms early on, and then chronically, to specific calcified parasite granulomas are commonly associated with seizures and epilepsy. A central conclusion reached was that human NCC and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures and the transition to chronic epilepsy.
Life Cycle of Taenia solium Infection NCC is caused by the larval form of the pork tapeworm, Taenia solium, which is endemic in many regions where pigs are raised including Latin America, most of Africa, and large parts of Asia including India, Southeast Asia, and China. The adult tapeworm, which resides in the small intestine of humans, produces infectious ova found in excreted feces. After they are ingested by free-roaming pigs, emerged larvae enter the bloodstream and develop into cysts (cysticercosis), mostly in the muscles and brain of the intermediate host. Humans become infected with the tapeworm (taeniasis) following ingestion of cysts in raw or undercooked pork.3 Tapeworm carriers can infect themselves or others around them who accidently ingest ova. Almost all of the clinical manifestations of cysticercosis result from involvement of the brain and spine, although other tissues can be affected. Infection can be controlled by intervention at various stages of the complex lifecycle,4 which includes mass chemotherapy of human tapeworm carriers and infected pigs, corralling pigs, avoiding ingestion of undercooked pork, and vaccination of pigs combined with the treatment of human tapeworm carriers and pigs.4,5 The manifestations of NCC are variable, depending on the location, number, and size of the cysts in the central nervous system (CNS) as well as the degree of accompanying inflammation. Infected people may be asymptomatic but many of them present with seizures because of parenchymal brain involvement. Hydrocephalus may be caused by ventricular cysts, involvement of the basilar subarachnoid spaces, or chronic arachnoiditis. Focal neurologic deficits may be caused by cerebral infarcts, mass lesions with or without surrounding edema, or nerve entrapment.1,3
Degenerating Cysts Invoke Inflammation ?A3B2 twb=.2w?>Viable cysts in the brain parenchyma incite little inflammation and are usually asymptomatic. Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
When cysts begin to degenerate they provoke a variable inflammatory response that commonly results in one or more seizures. Magnetic resonance imaging (MRI) and computed tomography (CT) reveal varying degrees of edema and abnormal enhancement. The onset likely reflects loss of parasite suppression of the host immune response and parasite antigen–driven immune responses. Degenerating cysticerci eventually regress, but often seizures recur because of an exacerbation of the inflammation or by other mechanisms at any time point during the degradation process. Although the amount of inflammation may be sizable, inflammation itself does not invariably lead to seizures; the proportion of inflammed cysts causing seizures is unclear. Comparing individuals who do or do not develop seizures or epilepsy even though both develop inflammed cysts is one reason that NCC is a good model to study epileptogenesis.
Antiparasitic Treatment of NCC and Seizures Antiparasitic agents are generally used in the treatment of viable NCC, which usually leads to a transient increase in the inflammatory response with clinical deterioration and seizures. Treatment of NCC remains one of the very few instances in medicine in which seizures are predictably induced during a specific period. Because of this unwanted side effect, corticosteroids are commonly employed to abrogate clinical deterioration. A recent randomized-controlled trial showed that enhanced corticosteroid dosing leads to a significant decrease in seizures at the time of treatment and shortly thereafter,6 thus strengthening support for the concept that inflammation leads to seizures. This induction of inflammation and resultant increase in seizures centered on this time point offers unique opportunities to study the relationship between inflammation and seizures, to understand the genesis of chronic epilepsy, and to prevent or to control inflammation and resultant seizures.
Seizures Associated with Calcified Cysts Calcifications are important seizure foci in NCC. Calcification of degenerating cysts is common and likely occurs late in the degenerative process. Once calcified lesions are evident, they persist and tend to accumulate. As a result, calcified T. solium granulomas are the most frequent radiologic finding of NCC in general populations living in endemic regions.7 About 10–20% of randomly scanned people show brain calcifications on CT, but only a small minority of these people have epilepsy.8 Within this subset, however, calcified lesions are foci of seizure activation in about 50% of cases.9–11 Vasogenic perilesional edema, centered around calcifications that localize to seizure foci,12 commonly develops in a surprisingly large proportion of patients at the time of a seizure recurrence. In a cohort of people with only
3 NCC and Epileptogenesis calcified lesions, 36% had a seizure recurrence and half of these demonstrated perilesional edema and enhancement around one or more calcifications.13 It is likely that perilesional edema is the result of inflammation. Seizures localized to calcifications also occur without the presence of perilesional edema, which may result from a pathophysiologic mechanism different from those associated with perilesional edema. One of the major unresolved issues is the role of these calcifications in the development and maintenance of the chronic epileptic state. Although most evidence suggests that the perilesional edema is a transient inflammatory response to the calcified cyst caused by periodic antigen release, loss of immune suppression, or a combination of both mechanisms, the calcifications themselves and the effects of ongoing focal seizures may also play roles.14 How early in the degenerative process different mechanisms are involved is central to understanding how epilepsy develops.
Blood–Brain Barrier Dysfunction One hypothesis for the genesis of seizures and epilepsy in NCC centers on blood–brain barrier pathology and inflammation. This hypothesis suggests that host inflammation directed to degenerating cysts causes abnormal vascular permeability as well as neuronal dysfunction, resulting in increased cortical excitability and acute seizures (Fig. 1). How these acute effects lead to the development of a chronic, focal epileptic disorder—a common consequence of NCC—is not known. Possible mechanisms include early continuing brain inflammation, reactive astrogliosis, cellular damage, and increased blood–brain barrier breakdown, which may further contribute to inflammation by creating a positive feedback loop. These mechanisms together with changes in brain excitability might lead to the chronic epileptic state. Clinical, imaging, and pathologic evidence supports these hypotheses.1,15–17
The Availability of Animal Models of NCC The study of NCC in humans has inherent limitations, including the inability to directly sample brain tissues, hesitancy to sample cerebrospinal fluid (CSF), difficulty in obtaining parasite antigens, and the inability to maintain the life cycle experimentally. In developing and testing therapeutics for epileptogenesis, new animal models are also needed that closely parallel the human condition. For NCC, there are a number of animal model infections of T. solium and other cestodes that can be employed to focus humanbased studies. Heterologous CNS models include intracranial inoculation of Mesocestoides corti, Taenia crassiceps, or granulomas associated with T. crassiceps. These models have limitations: they employ a different intermediate host and cestode species other than T. solium and require intracranial injection. T. solium model infections include naturally infected pigs, experimental oral infection of pigs, and the injection of oncospheres (invasive larvae) directly into the brain of rats or into the tissues of nude mice or uninfected pigs. All the models have significant potential drawbacks. The naturally infected pig most closely resembles human infections. Brain involvement occurs commonly in heavily infected animals so that the natural inflammatory response to degenerating cysts or responses induced by anticysticidal treatment can be determined. Injection of T. solium oncospheres in the rat and mouse brain is easier to perform and analyze than pig studies. These small animal models offer the possibility of larger numbers of animals, an extensive repertoire of reagents, and well-studied models for epilepsy. The T. solium models are technically demanding and require a source of T. solium ova and 3–6 months for cyst maturation. The T. solium rat model also employs neonatal rats whose immune systems are still immature and lack normal adult immune responses to the invading oncosphere.
NCC as a Human Model of Epileptogenesis
Identification of Antiepileptogenic Drug Targets for NCC
NCC offers an excellent opportunity to study prospectively the natural history of the genesis of seizures and epilepsy in a human population. This is due to its unique epidemiology and timing of seizures associated with increased inflammation, a predictable occurrence of seizures in the treatment of parenchymal disease, and subsequent development of epilepsy commonly localized to calcified lesions. It is likely that information gained from studies of NCC will be applicable to other conditions in which inflammation plays a prominent causal role such as in brain trauma, infections, and strokes, since they likely share common pathways that culminate in seizure activity.
Why is NCC a good model to study epilepsy treatments? NCC is by far the most common infection that regularly triggers seizures and epilepsy because of focal brain disease in which the role of inflammation is so obviously central to the pathophysiology. Recent studies have suggested that inflammation may be an important pathophysiologic process in both epileptogenesis and associated brain injury.18 There is also considerable evidence for a critical role of inflammation in ictogenesis in NCC. The extent and intensity of perilesional inflammation and its effect on the surrounding brain tissue is easily discernible on imaging as well as in histologic studies.19,20 The lesions in NCC are less Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
4 T. E. Nash et al.
Figure 1. A proposed mechanism of development of chronic epilepsy from acute seizures occurs as a degenerating cyst (left panel) develops into a calcification (right panel, left image) associated with perilesional edema (right panel, right image) as one cause of epilepsy in these patients. Epilepsy can also occur without the presence of perilesional edema or without obvious association with observable abnormalities. Left panel shows the same lesion with enhancement (left) and edema (right) in a patient who presented with seizures and right-sided signs. The right panel has three images of another patient presenting with seizures. A CT demonstrating a single calcification (left) with enhancement (middle) and perilesional edema (right) by MRI imaging (images from the author, T.E.N.). Epilepsia ILAE
variable and generally similar to each other. Unlike NCC, other brain insults that commonly result in epilepsy, such as trauma and stroke, occur in the context of widespread, severe brain injury or systemic disease that complicates both the investigation and intervention. Cysts are frequently located at the junction of the cortical gray and subcortical white matter and are mostly limited to 1–2 cm in diameter, and consequently result in less brain damage. In a majority of instances, patients also present with a single or limited number of lesions. The seizure focus, even in the presence of multiple lesions, is usually evident because of the presence of surrounding enhancement and/or edema. Seizures caused by degenerating cysts are frequent and the most common presentation, thus facilitating selection for clinical trials. In these individuals, there usually is good localization of the epileptogenic zone. Serial imaging and electroencephalography (EEG) studies can be used as “biomarkers” of epileptogenesis, thereby facilitating clinical trial design.21 The timing of the onset of the first seizure is an ideal zero point for therapeutic trials because the factors that induce acute seizures are present at this time point in all patients. Interventions in anticipation of treatment and seizure induction may also be worthwhile. The relative similarity in presentation and lesion characteristics would facilitate trials that might include antiinflammatory, antisynaptic plasticity and neuroprotective agents. Important research questions to be considered include the following: Question 1: What methods can best measure seizure activity, blood–brain barrier dysfunction, inflammation, gliosis and brain damage in vivo? Comment: Modern neuroimaging techniques and EEG analysis methods in combination with biomarkers of inflammation or neurologic pathology may be able to predict seizure development in patients at risk, and help determine the role of underlying processes such as Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
inflammation and a compromised blood–brain barrier. As examples, increased expression of involved proteins such as matrix metalloproteases 2 and 9 or presence of polymorphisms in proteins involved in inflammation such as Toll-like receptor genes correlate with propensity for seizures in NCC.22 A better understanding of pathophysiology of epileptogenesis employing cestode brain infections may be particularly useful in discovery of measures that are predictive and/or can be manipulated to prevent or treat disease. Question 2: What factors determine whether inflammatory lesions provoke acute seizures? Comment: Seizures can occur at any stage of NCC, but they are uncommon until a cyst begins to degenerate with accompanying inflammation. Even in the presence of degenerating cysts, only some persons have overt seizures. Other lesions, even with varying degrees of inflammation, do not provoke observable seizures. The presence and frequency of subclinical seizures are unknown. Factors to consider include the extent, intensity, and duration of the vascular/inflammatory and glial responses, location and size of the lesion, and genetic disposition. Question 3: Is there a genetic predisposition in people who develop seizures in NCC? Comment: A relatively small proportion of infected people develop seizures. Genetic susceptibilities for seizures may be the consequence of enhanced ability to mount, control, or resolve inflammatory responses to the degenerating cyst22 or to altered susceptibility to develop seizures/epilepsy.22,23 A genetic propensity to become infected or have greater infection burden may also exist. Question 4: Do antiinflammatory measures prevent, decrease or control seizure activity? Comment: Because inflammation is important in the development of seizures and epilepsy, prevention or
5 NCC and Epileptogenesis control of inflammation would be expected to decrease their occurrence. Many potential drugs are available to test this hypothesis. Animal models may be helpful to determine the mechanisms involved, which should serve as a guide to decide what agents to test. On the other hand, an antiinflammatory drug that is found to decrease seizure activity in humans would be useful clinically and at the same time support the role of inflammation in the pathogenesis of epilepsy. For instance, in a T. crassiceps granuloma model of NCC, substance P, a modulator of inflammation as well as a neurotransmitter and neuromodulator, has been implicated in causing seizures.24 Medications that block the substance P receptor, which are clinically used for other indications, could be used to confirm the importance of inflammation in humans with NCC and at the same time be therapeutic. Too much immunosuppression could also be detrimental. Inflammation may control parasite growth, degrade cysts, and rid the brain of parasite products or, failing that, effectively wall it off. Questions 5: Does the amount and degree of brain damage correlate with development of seizure/epilepsy? Comment: Whether the presence and level of brain damage associated with lesions that become seizure foci correlate with the risk of seizures is unproven, but such a relationship is plausible. In some instances, people with high-grade inflammation involving specific lesions have subsequently developed gliosis and epilepsy associated with these lesions. The presence of gliosis correlates with the existence of refractory epilepsy.25 Proving that inflammation leads to brain damage that in turn leads to seizures and epilepsy is, however, essential for developing therapeutic strategies to prevent and limit further seizures and perhaps epileptogenesis. Showing a direct role of inflammation in the development of epilepsy leads to an interesting but critical question of what level of inflammation, if any, should be tolerated in NCC or other analogous processes. The predictable nature of treatment-induced seizures makes it feasible to discover and test for systemic markers of inflammation or brain damage as biomarkers for seizure risk. Some groups have reported that mesial temporal sclerosis occurs more frequently than expected in NCC.26 If confirmed, this may occur because of prolonged or recurrent seizure activity, degeneration of cysts located in that region of the brain, genetic predisposition for its development, or other variables not yet considered.27,28 Question 6: What is the role of calcified lesions in the genesis of epilepsy? Comment: In endemic population studies in rural regions, epilepsy can affect 1–2% of the population and about 29% is associated with NCC.2 Calcifications are, however, detected in 10–20% of randomly screened persons and in most people with chronic epilepsy, and NCC viable lesions are much less frequent.8 Conse-
quently, epilepsy will be associated with calcifications in a substantial majority of situations, depending on the specific epidemiology and level of transmission. The presence of intermittent perilesional edema events around calcifications implicates these lesions as foci of seizure activity and points to the pathophysiologic mechanism involved as a frequent cause of seizures and epilepsy in endemic populations. Others suggest that seizures themselves result in edema and inflammatory responses. Prospective studies of humans with perilesional edema and clinical trials to prevent inflammation are important for identifying treatments and preventions. That abrupt cessation of corticosteroids can result in rebound as well as new edema around previously uninvolved calcifications29 suggests that active immune suppression mechanisms are involved. Loss of suppression could also lead to presence of unrestrained inflammation, edema, and seizure recurrence. Recurrent seizures are also found in about half of the patients with only calcifications who do not show perilesional edema.13 Although this may suggest that the pathophysiology of epilepsy in this group is different from that in patients with perilesional edema, more sensitive imaging studies may be able to distinguish if lesions with and without perilesional edema cause seizures by unique mechanisms, or if the inflammation is not sufficient to be detected with existing methods. Question 7: How well do antiseizure medications prevent seizures in NCC and do some antiseizure medications work better in NCC than others? Comment: No differences in efficacy of any particular antiseizure medication are known. Cysticidal treatment commonly provokes seizure activity that is roughly maximal during and shortly after cysticidal treatment ceases. The ability of known or other potential antiseizure drugs to suppress seizure activity could be compared or tested during this time period to evaluate effectiveness. Question 8: What comorbidities are associated with epilepsy associated with NCC? Comment: It is well established that significant comorbidities such as depression, migraine, anxiety disorders, and altered cognition coexist in people with epilepsy. These conditions are also a risk factor for the development of epilepsy. NCC usually presents in late adolescence or in adulthood. Analyses before and after the development of epilepsy in individuals with NCC can be employed to define comorbidities that develop or are inherent in the individual.
Summary and Specific Recommendations The purpose of the workshop was to explore the idea that NCC offers a unique opportunity not only to develop treatments for one of the world’s most common causes of Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
6 T. E. Nash et al. epilepsy, but also for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state. In addition, strong epidemiologic programs both in South America and India already study fairly uniform patient populations. There are also evolving parallel animal models available for both clinical and preclinical drug development. We propose the following next steps: 1 Foster the development and use of pertinent animal models, as delineated earlier, which could shed information on pathophysiologic mechanisms and focus the nature of clinical human trials. 2 Enable synergy among neuroscientists interested in epilepsy, applied neuroscience, and neuroinflammation with physicians/scientists knowledgeable in NCC. 3 Develop, support, or enhance study centers and networks of interested investigators in regions or areas where sufficient numbers of patients exist and clinical studies can be performed. Apply state-of-the-art imaging/studies and neuroscience to NCC. 4 Perform prospective studies in patients with parenchymal NCC at the onset of treatment, when seizures are most likely to occur, employing quantitative measures of blood–brain barrier disruption, brain damage, inflammation, anatomic changes (e.g., vasogenic and cytotoxic edema), and seizure activity over the course of disease. The measures may include MRI/magnetic resonance spectroscopy (MRS), positron emission tomography (PET) inflammatory markers, and quantitative EEG. 5 Prospectively collect clinical data to better define comorbidities. 6 In defined populations, study known candidate genes associated with seizures that may predict genetic propensity for seizures in NCC.
Acknowledgments Supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, the Office of Rare Diseases Research, the National Center for Advancing Translational Sciences, and Fogarty International Center Training Grant D43 TW00114, all from the National Institutes of Health. H.G. is supported by a Wellcome Trust Senior International Research Fellowship in Tropical Medicine and Public Health.
Additional Contributions T.E. Nash was primarily responsible for writing and editing the manuscript. S. Mahanty ([email protected]) contributed to the writing and editing of the manuscript. J.A. Loeb ([email protected]) contributed to the writing and editing of the manuscript. W.H. Theodore (theodorw@ninds. nih.gov) contributed to the writing and editing of the manuscript. A. Friedman ([email protected]) contributed to the writing and editing of the manuscript. J.W. Sander ([email protected]) contributed to the writing and editing of the manuscript. G. Singh ([email protected]) contributed to the writing and editing of the manuscript. E. Cavalheiro ([email protected]) contributed to the content of the manuscript. O.H. Del Brutto ([email protected]) contributed to the writing and Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
editing of the manuscript. O. Takayanagui ([email protected]) contributed to the content of the manuscript. A. Fleury (afleury@biomedicas. unam.mx) contributed to the writing and editing of the manuscript. M. Verastegui ([email protected]) contributed to the content of the manuscript. P.M. Pruex ([email protected]) contributed to the content of the manuscript. E.J. Pretell ([email protected]) contributed to the content of the manuscript. S. Montano ([email protected]. mil) contributed to the content of the manuscript. A.C. White ([email protected]) contributed to the writing and editing of the manuscript. A. Gonzales ([email protected]) contributed to the writing and editing of the manuscript. R. Gilman ([email protected]) contributed to the writing and editing of the manuscript. H.H. Garcia ([email protected]) was primarily responsible for writing and editing the manuscript.
Disclosures There are no financial conflicts and no commercial sponsors. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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astrogliosis, axonal degeneration and altered blood–brain barrier permeability. Vet Parasitol 2009;160:242–250. Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol 2011;7:31–40. Ooi WW, Wijemanne S, Thomas CB, et al. Short report: a calcified Taenia solium granuloma associated with recurrent perilesional edema causing refractory seizures: histopathological features. Am J Trop Med Hyg 2011;85:460–463. Nash TE, Bartelt LA, Korpe PS, et al. Case report: calcified neurocysticercus, perilesional edema, and histologic inflammation. Am J Trop Med Hyg 2014;90:318–321. Engel J Jr, Pitkanen A, Loeb JA, et al. Epilepsy biomarkers. Epilepsia 2013;54(Suppl. 4):61–69. Verma A, Prasad KN, Gupta RK, et al. Toll-like receptor 4 polymorphism and its association with symptomatic neurocysticercosis. J Infect Dis 2010;202:1219–1225. Gupta RK, Awasthi R, Garg RK, et al. T1-weighted dynamic contrastenhanced MR evaluation of different stages of neurocysticercosis and its relationship with serum MMP-9 expression. AJNR Am J Neuroradiol 2013;34:997–1003.
24. Robinson P, Garza A, Weinstock J, et al. Substance P causes seizures in neurocysticercosis. PLoS Pathog 2012;8:e1002489. 25. de Souza A, Nalini A, Kovoor JM, et al. Perilesional gliosis around solitary cerebral parenchymal cysticerci and long-term seizure outcome: a prospective study using serial magnetization transfer imaging. Epilepsia 2011;52:1918–1927. 26. Bianchin MM, Velasco TR, dos Santos AC, et al. On the relationship between neurocysticercosis and mesial temporal lobe epilepsy associated with hippocampal sclerosis: coincidence or a pathogenic relationship? Pathog Glob Health 2012;106:280–285. 27. Rathore C, Thomas B, Kesavadas C, et al. Calcified neurocysticercosis lesions and antiepileptic drug-resistant epilepsy: a surgically remediable syndrome? Epilepsia 2013;54:1815–1822. 28. Bianchin MM, Velasco TR, Wichert-Ana L, et al. How frequent is the association of neurocysticercosis and mesial temporal lobe epilepsy with hippocampal sclerosis? Epilepsia 2010;51:2359– 2360. 29. Mejia R, Nash TE. Corticosteroid withdrawal precipitates perilesional edema around calcified Taenia solium cysts. Am J Trop Med Hyg 2013;89:919–923.
Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
Neurocysticercosis: A natural human model of epileptogenesis *Theodore E. Nash, *Siddhartha Mahanty, †Jeffrey A. Loeb, ‡William H. Theodore, §Alon Friedman, ¶Josemir W. Sander, **Gagandeep Singh, ††Esper Cavalheiro, ‡‡Oscar H. Del Brutto, §§Osvaldo M. Takayanagui, ¶¶Agnes Fleury, ##Manuela Verastegui, ***Pierre-Marie Preux, †††Silvia Montano, ‡‡‡E. Javier Pretell, §§§A. Clinton White Jr, ¶¶¶Armando E. Gonzales, ###Robert H. Gilman, and ****Hector H. Garcia Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
SUMMARY
Dr. Theodore Nash is a principal investigator in the Laboratory of Parasitic Diseases, National Institutes of Health.
Objective: To develop a better understanding of mechanisms of seizures and longterm epileptogenesis using neurocysticercosis. Methods: A workshop was held bringing together experts in epilepsy and epileptogenesis and neurocysticercosis. Results: Human neurocysticercosis and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures. Inflammatory responses to degenerating forms and later-stage calcified parasite granulomas are associated with seizures and epilepsy. Other mechanisms may also be involved in epileptogenesis. Significance: Naturally occurring brain infections with neurocysticercosis offer a unique opportunity to develop treatments for one of the world’s most common causes of epilepsy and for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state. KEY WORDS: Epilepsy, Seizure, Taenia solium, Helminth.
Accepted September 24, 2014. *Laboratory of Parasitic Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, U.S.A.; †Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, Illinois, U.S.A.; ‡Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A.; §The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel, Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada; ¶NIHR UCL Hospitals Biomedical Research Centre, Department of Clinical & Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London & Epilepsy Society, Buckinghamshire, United Kingdom; Epilepsy Institute of the Netherlands Foundation, Heemstede, The Netherlands; **Department of Neurology, Dayan and Medical College, Ludhiana, India; ††Department of Neurology and Neurosurgery, Federal University of Sao Paulo, Sao Paulo, Brazil; ‡‡School of Medicine, University Espiritu Santo, Guayaquil, Ecuador; §§Department of Neurosciences and Behavior, Ribeir~ao Preto Medical School University of S~ao Paulo, Ribeir~ao Preto, Brazil; ¶¶Institute of Biomedical Research, National Autonomous University of Mexico and National Institute of Neurology and Neurosurgery (INNN), Mexico City, Mexico; ###Department of Cellular and Molecular Sciences, Faculty of Science and Philosophy, University Peruana Cayetano Heredia, Lima, Peru; ***UMR1094 INSERM, CHU Limoges, Institute of Neuroepidemiology and Tropical Neurology, University of Limoges, Limoges, France; †††US Naval Medical Research Unit 6, Callao, Peru; ‡‡‡Department of Neurology, Hospital Alberto Sabogal, Callao, Peru; §§§Infectious Disease Division, Department of Internal Medicine, University of Texas, Galveston, Texas, U.S.A.; ¶¶¶Department of Veterinary Public Health, School of Veterinary Medicine, National University of San Marcos, Lima, Peru; ###Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, U.S.A.; and ****Cysticercosis Unit, Institute of Neurological Diseases, Lima, Peru, Center for Global Health-Tumbes, University Peruana Cayetano Heredia, Department of Microbiology, Universidad Peruana Cayetano Heredia All authors participated in a conference held in Lima, Peru from October 23–24, 2013 that led to the content of the manuscript. Address correspondence to Theodore Nash, 9000 Rockville Pike, Building 4, Rm 424, Bethesda, MD 20892, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
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2 T. E. Nash et al. Neurocysticercosis (NCC) is the most common preventable risk factor for adult-acquired epilepsy worldwide and accounts for up to 29% of all cases of epilepsy in some endemic areas.1,2 A workshop was held on October 23 and 24, 2013 in Lima, Peru, bringing together experts in the areas of parasitology and epilepsy to develop a better understanding of mechanisms of seizures and long-term epileptogenesis triggered by NCC. Inflammatory responses to degenerating forms early on, and then chronically, to specific calcified parasite granulomas are commonly associated with seizures and epilepsy. A central conclusion reached was that human NCC and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures and the transition to chronic epilepsy.
Life Cycle of Taenia solium Infection NCC is caused by the larval form of the pork tapeworm, Taenia solium, which is endemic in many regions where pigs are raised including Latin America, most of Africa, and large parts of Asia including India, Southeast Asia, and China. The adult tapeworm, which resides in the small intestine of humans, produces infectious ova found in excreted feces. After they are ingested by free-roaming pigs, emerged larvae enter the bloodstream and develop into cysts (cysticercosis), mostly in the muscles and brain of the intermediate host. Humans become infected with the tapeworm (taeniasis) following ingestion of cysts in raw or undercooked pork.3 Tapeworm carriers can infect themselves or others around them who accidently ingest ova. Almost all of the clinical manifestations of cysticercosis result from involvement of the brain and spine, although other tissues can be affected. Infection can be controlled by intervention at various stages of the complex lifecycle,4 which includes mass chemotherapy of human tapeworm carriers and infected pigs, corralling pigs, avoiding ingestion of undercooked pork, and vaccination of pigs combined with the treatment of human tapeworm carriers and pigs.4,5 The manifestations of NCC are variable, depending on the location, number, and size of the cysts in the central nervous system (CNS) as well as the degree of accompanying inflammation. Infected people may be asymptomatic but many of them present with seizures because of parenchymal brain involvement. Hydrocephalus may be caused by ventricular cysts, involvement of the basilar subarachnoid spaces, or chronic arachnoiditis. Focal neurologic deficits may be caused by cerebral infarcts, mass lesions with or without surrounding edema, or nerve entrapment.1,3
Degenerating Cysts Invoke Inflammation ?A3B2 twb=.2w?>Viable cysts in the brain parenchyma incite little inflammation and are usually asymptomatic. Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
When cysts begin to degenerate they provoke a variable inflammatory response that commonly results in one or more seizures. Magnetic resonance imaging (MRI) and computed tomography (CT) reveal varying degrees of edema and abnormal enhancement. The onset likely reflects loss of parasite suppression of the host immune response and parasite antigen–driven immune responses. Degenerating cysticerci eventually regress, but often seizures recur because of an exacerbation of the inflammation or by other mechanisms at any time point during the degradation process. Although the amount of inflammation may be sizable, inflammation itself does not invariably lead to seizures; the proportion of inflammed cysts causing seizures is unclear. Comparing individuals who do or do not develop seizures or epilepsy even though both develop inflammed cysts is one reason that NCC is a good model to study epileptogenesis.
Antiparasitic Treatment of NCC and Seizures Antiparasitic agents are generally used in the treatment of viable NCC, which usually leads to a transient increase in the inflammatory response with clinical deterioration and seizures. Treatment of NCC remains one of the very few instances in medicine in which seizures are predictably induced during a specific period. Because of this unwanted side effect, corticosteroids are commonly employed to abrogate clinical deterioration. A recent randomized-controlled trial showed that enhanced corticosteroid dosing leads to a significant decrease in seizures at the time of treatment and shortly thereafter,6 thus strengthening support for the concept that inflammation leads to seizures. This induction of inflammation and resultant increase in seizures centered on this time point offers unique opportunities to study the relationship between inflammation and seizures, to understand the genesis of chronic epilepsy, and to prevent or to control inflammation and resultant seizures.
Seizures Associated with Calcified Cysts Calcifications are important seizure foci in NCC. Calcification of degenerating cysts is common and likely occurs late in the degenerative process. Once calcified lesions are evident, they persist and tend to accumulate. As a result, calcified T. solium granulomas are the most frequent radiologic finding of NCC in general populations living in endemic regions.7 About 10–20% of randomly scanned people show brain calcifications on CT, but only a small minority of these people have epilepsy.8 Within this subset, however, calcified lesions are foci of seizure activation in about 50% of cases.9–11 Vasogenic perilesional edema, centered around calcifications that localize to seizure foci,12 commonly develops in a surprisingly large proportion of patients at the time of a seizure recurrence. In a cohort of people with only
3 NCC and Epileptogenesis calcified lesions, 36% had a seizure recurrence and half of these demonstrated perilesional edema and enhancement around one or more calcifications.13 It is likely that perilesional edema is the result of inflammation. Seizures localized to calcifications also occur without the presence of perilesional edema, which may result from a pathophysiologic mechanism different from those associated with perilesional edema. One of the major unresolved issues is the role of these calcifications in the development and maintenance of the chronic epileptic state. Although most evidence suggests that the perilesional edema is a transient inflammatory response to the calcified cyst caused by periodic antigen release, loss of immune suppression, or a combination of both mechanisms, the calcifications themselves and the effects of ongoing focal seizures may also play roles.14 How early in the degenerative process different mechanisms are involved is central to understanding how epilepsy develops.
Blood–Brain Barrier Dysfunction One hypothesis for the genesis of seizures and epilepsy in NCC centers on blood–brain barrier pathology and inflammation. This hypothesis suggests that host inflammation directed to degenerating cysts causes abnormal vascular permeability as well as neuronal dysfunction, resulting in increased cortical excitability and acute seizures (Fig. 1). How these acute effects lead to the development of a chronic, focal epileptic disorder—a common consequence of NCC—is not known. Possible mechanisms include early continuing brain inflammation, reactive astrogliosis, cellular damage, and increased blood–brain barrier breakdown, which may further contribute to inflammation by creating a positive feedback loop. These mechanisms together with changes in brain excitability might lead to the chronic epileptic state. Clinical, imaging, and pathologic evidence supports these hypotheses.1,15–17
The Availability of Animal Models of NCC The study of NCC in humans has inherent limitations, including the inability to directly sample brain tissues, hesitancy to sample cerebrospinal fluid (CSF), difficulty in obtaining parasite antigens, and the inability to maintain the life cycle experimentally. In developing and testing therapeutics for epileptogenesis, new animal models are also needed that closely parallel the human condition. For NCC, there are a number of animal model infections of T. solium and other cestodes that can be employed to focus humanbased studies. Heterologous CNS models include intracranial inoculation of Mesocestoides corti, Taenia crassiceps, or granulomas associated with T. crassiceps. These models have limitations: they employ a different intermediate host and cestode species other than T. solium and require intracranial injection. T. solium model infections include naturally infected pigs, experimental oral infection of pigs, and the injection of oncospheres (invasive larvae) directly into the brain of rats or into the tissues of nude mice or uninfected pigs. All the models have significant potential drawbacks. The naturally infected pig most closely resembles human infections. Brain involvement occurs commonly in heavily infected animals so that the natural inflammatory response to degenerating cysts or responses induced by anticysticidal treatment can be determined. Injection of T. solium oncospheres in the rat and mouse brain is easier to perform and analyze than pig studies. These small animal models offer the possibility of larger numbers of animals, an extensive repertoire of reagents, and well-studied models for epilepsy. The T. solium models are technically demanding and require a source of T. solium ova and 3–6 months for cyst maturation. The T. solium rat model also employs neonatal rats whose immune systems are still immature and lack normal adult immune responses to the invading oncosphere.
NCC as a Human Model of Epileptogenesis
Identification of Antiepileptogenic Drug Targets for NCC
NCC offers an excellent opportunity to study prospectively the natural history of the genesis of seizures and epilepsy in a human population. This is due to its unique epidemiology and timing of seizures associated with increased inflammation, a predictable occurrence of seizures in the treatment of parenchymal disease, and subsequent development of epilepsy commonly localized to calcified lesions. It is likely that information gained from studies of NCC will be applicable to other conditions in which inflammation plays a prominent causal role such as in brain trauma, infections, and strokes, since they likely share common pathways that culminate in seizure activity.
Why is NCC a good model to study epilepsy treatments? NCC is by far the most common infection that regularly triggers seizures and epilepsy because of focal brain disease in which the role of inflammation is so obviously central to the pathophysiology. Recent studies have suggested that inflammation may be an important pathophysiologic process in both epileptogenesis and associated brain injury.18 There is also considerable evidence for a critical role of inflammation in ictogenesis in NCC. The extent and intensity of perilesional inflammation and its effect on the surrounding brain tissue is easily discernible on imaging as well as in histologic studies.19,20 The lesions in NCC are less Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
4 T. E. Nash et al.
Figure 1. A proposed mechanism of development of chronic epilepsy from acute seizures occurs as a degenerating cyst (left panel) develops into a calcification (right panel, left image) associated with perilesional edema (right panel, right image) as one cause of epilepsy in these patients. Epilepsy can also occur without the presence of perilesional edema or without obvious association with observable abnormalities. Left panel shows the same lesion with enhancement (left) and edema (right) in a patient who presented with seizures and right-sided signs. The right panel has three images of another patient presenting with seizures. A CT demonstrating a single calcification (left) with enhancement (middle) and perilesional edema (right) by MRI imaging (images from the author, T.E.N.). Epilepsia ILAE
variable and generally similar to each other. Unlike NCC, other brain insults that commonly result in epilepsy, such as trauma and stroke, occur in the context of widespread, severe brain injury or systemic disease that complicates both the investigation and intervention. Cysts are frequently located at the junction of the cortical gray and subcortical white matter and are mostly limited to 1–2 cm in diameter, and consequently result in less brain damage. In a majority of instances, patients also present with a single or limited number of lesions. The seizure focus, even in the presence of multiple lesions, is usually evident because of the presence of surrounding enhancement and/or edema. Seizures caused by degenerating cysts are frequent and the most common presentation, thus facilitating selection for clinical trials. In these individuals, there usually is good localization of the epileptogenic zone. Serial imaging and electroencephalography (EEG) studies can be used as “biomarkers” of epileptogenesis, thereby facilitating clinical trial design.21 The timing of the onset of the first seizure is an ideal zero point for therapeutic trials because the factors that induce acute seizures are present at this time point in all patients. Interventions in anticipation of treatment and seizure induction may also be worthwhile. The relative similarity in presentation and lesion characteristics would facilitate trials that might include antiinflammatory, antisynaptic plasticity and neuroprotective agents. Important research questions to be considered include the following: Question 1: What methods can best measure seizure activity, blood–brain barrier dysfunction, inflammation, gliosis and brain damage in vivo? Comment: Modern neuroimaging techniques and EEG analysis methods in combination with biomarkers of inflammation or neurologic pathology may be able to predict seizure development in patients at risk, and help determine the role of underlying processes such as Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
inflammation and a compromised blood–brain barrier. As examples, increased expression of involved proteins such as matrix metalloproteases 2 and 9 or presence of polymorphisms in proteins involved in inflammation such as Toll-like receptor genes correlate with propensity for seizures in NCC.22 A better understanding of pathophysiology of epileptogenesis employing cestode brain infections may be particularly useful in discovery of measures that are predictive and/or can be manipulated to prevent or treat disease. Question 2: What factors determine whether inflammatory lesions provoke acute seizures? Comment: Seizures can occur at any stage of NCC, but they are uncommon until a cyst begins to degenerate with accompanying inflammation. Even in the presence of degenerating cysts, only some persons have overt seizures. Other lesions, even with varying degrees of inflammation, do not provoke observable seizures. The presence and frequency of subclinical seizures are unknown. Factors to consider include the extent, intensity, and duration of the vascular/inflammatory and glial responses, location and size of the lesion, and genetic disposition. Question 3: Is there a genetic predisposition in people who develop seizures in NCC? Comment: A relatively small proportion of infected people develop seizures. Genetic susceptibilities for seizures may be the consequence of enhanced ability to mount, control, or resolve inflammatory responses to the degenerating cyst22 or to altered susceptibility to develop seizures/epilepsy.22,23 A genetic propensity to become infected or have greater infection burden may also exist. Question 4: Do antiinflammatory measures prevent, decrease or control seizure activity? Comment: Because inflammation is important in the development of seizures and epilepsy, prevention or
5 NCC and Epileptogenesis control of inflammation would be expected to decrease their occurrence. Many potential drugs are available to test this hypothesis. Animal models may be helpful to determine the mechanisms involved, which should serve as a guide to decide what agents to test. On the other hand, an antiinflammatory drug that is found to decrease seizure activity in humans would be useful clinically and at the same time support the role of inflammation in the pathogenesis of epilepsy. For instance, in a T. crassiceps granuloma model of NCC, substance P, a modulator of inflammation as well as a neurotransmitter and neuromodulator, has been implicated in causing seizures.24 Medications that block the substance P receptor, which are clinically used for other indications, could be used to confirm the importance of inflammation in humans with NCC and at the same time be therapeutic. Too much immunosuppression could also be detrimental. Inflammation may control parasite growth, degrade cysts, and rid the brain of parasite products or, failing that, effectively wall it off. Questions 5: Does the amount and degree of brain damage correlate with development of seizure/epilepsy? Comment: Whether the presence and level of brain damage associated with lesions that become seizure foci correlate with the risk of seizures is unproven, but such a relationship is plausible. In some instances, people with high-grade inflammation involving specific lesions have subsequently developed gliosis and epilepsy associated with these lesions. The presence of gliosis correlates with the existence of refractory epilepsy.25 Proving that inflammation leads to brain damage that in turn leads to seizures and epilepsy is, however, essential for developing therapeutic strategies to prevent and limit further seizures and perhaps epileptogenesis. Showing a direct role of inflammation in the development of epilepsy leads to an interesting but critical question of what level of inflammation, if any, should be tolerated in NCC or other analogous processes. The predictable nature of treatment-induced seizures makes it feasible to discover and test for systemic markers of inflammation or brain damage as biomarkers for seizure risk. Some groups have reported that mesial temporal sclerosis occurs more frequently than expected in NCC.26 If confirmed, this may occur because of prolonged or recurrent seizure activity, degeneration of cysts located in that region of the brain, genetic predisposition for its development, or other variables not yet considered.27,28 Question 6: What is the role of calcified lesions in the genesis of epilepsy? Comment: In endemic population studies in rural regions, epilepsy can affect 1–2% of the population and about 29% is associated with NCC.2 Calcifications are, however, detected in 10–20% of randomly screened persons and in most people with chronic epilepsy, and NCC viable lesions are much less frequent.8 Conse-
quently, epilepsy will be associated with calcifications in a substantial majority of situations, depending on the specific epidemiology and level of transmission. The presence of intermittent perilesional edema events around calcifications implicates these lesions as foci of seizure activity and points to the pathophysiologic mechanism involved as a frequent cause of seizures and epilepsy in endemic populations. Others suggest that seizures themselves result in edema and inflammatory responses. Prospective studies of humans with perilesional edema and clinical trials to prevent inflammation are important for identifying treatments and preventions. That abrupt cessation of corticosteroids can result in rebound as well as new edema around previously uninvolved calcifications29 suggests that active immune suppression mechanisms are involved. Loss of suppression could also lead to presence of unrestrained inflammation, edema, and seizure recurrence. Recurrent seizures are also found in about half of the patients with only calcifications who do not show perilesional edema.13 Although this may suggest that the pathophysiology of epilepsy in this group is different from that in patients with perilesional edema, more sensitive imaging studies may be able to distinguish if lesions with and without perilesional edema cause seizures by unique mechanisms, or if the inflammation is not sufficient to be detected with existing methods. Question 7: How well do antiseizure medications prevent seizures in NCC and do some antiseizure medications work better in NCC than others? Comment: No differences in efficacy of any particular antiseizure medication are known. Cysticidal treatment commonly provokes seizure activity that is roughly maximal during and shortly after cysticidal treatment ceases. The ability of known or other potential antiseizure drugs to suppress seizure activity could be compared or tested during this time period to evaluate effectiveness. Question 8: What comorbidities are associated with epilepsy associated with NCC? Comment: It is well established that significant comorbidities such as depression, migraine, anxiety disorders, and altered cognition coexist in people with epilepsy. These conditions are also a risk factor for the development of epilepsy. NCC usually presents in late adolescence or in adulthood. Analyses before and after the development of epilepsy in individuals with NCC can be employed to define comorbidities that develop or are inherent in the individual.
Summary and Specific Recommendations The purpose of the workshop was to explore the idea that NCC offers a unique opportunity not only to develop treatments for one of the world’s most common causes of Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
6 T. E. Nash et al. epilepsy, but also for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state. In addition, strong epidemiologic programs both in South America and India already study fairly uniform patient populations. There are also evolving parallel animal models available for both clinical and preclinical drug development. We propose the following next steps: 1 Foster the development and use of pertinent animal models, as delineated earlier, which could shed information on pathophysiologic mechanisms and focus the nature of clinical human trials. 2 Enable synergy among neuroscientists interested in epilepsy, applied neuroscience, and neuroinflammation with physicians/scientists knowledgeable in NCC. 3 Develop, support, or enhance study centers and networks of interested investigators in regions or areas where sufficient numbers of patients exist and clinical studies can be performed. Apply state-of-the-art imaging/studies and neuroscience to NCC. 4 Perform prospective studies in patients with parenchymal NCC at the onset of treatment, when seizures are most likely to occur, employing quantitative measures of blood–brain barrier disruption, brain damage, inflammation, anatomic changes (e.g., vasogenic and cytotoxic edema), and seizure activity over the course of disease. The measures may include MRI/magnetic resonance spectroscopy (MRS), positron emission tomography (PET) inflammatory markers, and quantitative EEG. 5 Prospectively collect clinical data to better define comorbidities. 6 In defined populations, study known candidate genes associated with seizures that may predict genetic propensity for seizures in NCC.
Acknowledgments Supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, the Office of Rare Diseases Research, the National Center for Advancing Translational Sciences, and Fogarty International Center Training Grant D43 TW00114, all from the National Institutes of Health. H.G. is supported by a Wellcome Trust Senior International Research Fellowship in Tropical Medicine and Public Health.
Additional Contributions T.E. Nash was primarily responsible for writing and editing the manuscript. S. Mahanty ([email protected]) contributed to the writing and editing of the manuscript. J.A. Loeb ([email protected]) contributed to the writing and editing of the manuscript. W.H. Theodore (theodorw@ninds. nih.gov) contributed to the writing and editing of the manuscript. A. Friedman ([email protected]) contributed to the writing and editing of the manuscript. J.W. Sander ([email protected]) contributed to the writing and editing of the manuscript. G. Singh ([email protected]) contributed to the writing and editing of the manuscript. E. Cavalheiro ([email protected]) contributed to the content of the manuscript. O.H. Del Brutto ([email protected]) contributed to the writing and Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12849
editing of the manuscript. O. Takayanagui ([email protected]) contributed to the content of the manuscript. A. Fleury (afleury@biomedicas. unam.mx) contributed to the writing and editing of the manuscript. M. Verastegui ([email protected]) contributed to the content of the manuscript. P.M. Pruex ([email protected]) contributed to the content of the manuscript. E.J. Pretell ([email protected]) contributed to the content of the manuscript. S. Montano ([email protected]. mil) contributed to the content of the manuscript. A.C. White ([email protected]) contributed to the writing and editing of the manuscript. A. Gonzales ([email protected]) contributed to the writing and editing of the manuscript. R. Gilman ([email protected]) contributed to the writing and editing of the manuscript. H.H. Garcia ([email protected]) was primarily responsible for writing and editing the manuscript.
Disclosures There are no financial conflicts and no commercial sponsors. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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