Neurocysticercosis-related seizures: Imaging biomarkers

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Infection, symptomology, and devolution
Neurocysticercosis (NCC) is a CNS infection resulting from exposure to the embryonated eggs of the Taenia solium tapeworm, and is hypothesised to be one of the leading global causes of acquired epilepsy.
Humans, as the tapeworm's definitive host, typically ingest the cysticerci of T. solium, resulting in taeniasis. During taeniasis the tapeworm develops, producing and dispersing viable eggs contained in proglottids. Pigs, as the intermediate hosts, typically ingest these eggs and develop subcutaneous cysts. However, it is possible for humans to consume the eggs through the faecal-oral route. When consumed, the eggs hatch into oncospheres, permeate across the intestinal wall, and invade the bloodstream. After entering the bloodstream the oncospheres lodge in the musculature and subcutaneous tissue, causing cysticercosis. In NCC cysticerci lodge in and around brain tissue [1][2][3][4].
Parenchymal NCC is associated with a wide range of symptoms including headaches, meningism signs, and anomalous behaviour sufficient to earn it the nickname, the 'great imitator', and will be the focus of this review. This is owing to the high prevalence of associated symptomatic seizures and potential epileptogenesis (i.e. the development of a persistent cortical environment with a predisposition to aberrant signal propagation) leading to recurrent seizure activity [12][13][14][15][16].
Parenchymal NCC typically develops through four sequential stages, although individual cysts may vary in their maturation time course, resulting in a mixed-stage presentation [2,17]. Each stage is defined by associated imaging and symptom presentations, which can help in distinguishing between provoked (acute symptomatic) and unprovoked (spontaneous) seizures [18]. A cyst begins in the vesicular stage, then degenerates through the colloidal-where the host's inflammatory response is strongest [19]-granular, and calcified stages. After degeneration, the cyst either resolves or persists as a calcified nodule; the latter being more commonly associated with seizure activity [20,21].

Diagnosis and imaging
A definitive diagnosis of NCC has classically required the multimodal comparison of data from clinical, radiographic, and immunologic examinations (including epidemiologic factors); recently however, neuroimaging approaches have become more accessible and robust, and at present, a definitive diagnosis can be made using only imaging data--either CT or MRI [22][23][24]. The common differential diagnoses for NCC are tuberculosis, toxoplasmosis, malignancy or pyogenic cerebral abscess [23]. Identification of cysts and their stages can be made with reasonable confidence multimodal MRI data using criteria such as enhancing cell walls, scolices, and calcification ( Fig. 1) [18,[25][26][27][28][29][30]. T1-(with and without gadolinium-based contrast enhancement) and T2-weighted scans provide relatively robust methods of localising cysts in patients with suspected NCC, but to increase specificity, different sequences/techniques have also been used e.g., diffusion weighted MRI (dMRI) can demarcate between cysts and abscesses, for example [31]. It has been noted that MRI has increased the diagnostic yield, leading to more informed surgical approaches and improved prognosis [32].
Over the last two decades, susceptibility weighted imaging (SWI) has been a popular technique for detecting cysts, due to its sensitivity to diamagnetic and paramagnetic differences [25,33]. Recently, however, 3D constructive interference in steady state (CISS) sequences have been shown to be more efficacious in delineating the radiologic markers necessary for differentiating between NCC and other diseases, as well as between the devolutionary stages [14,34,35].
Radiologic features of neurocysticercosis at different stages in order of devolution: vesicular, colloidal, granular, and active calcified (calcified lesions can alternative between benign and active, with benign lesions showing no inflammatory markers). The images were acquired with T1, contrast-enhanced T1, T2, FLAIR (fluid attenuated inversion recovery), SWI, and DWI (diffusion weighted imaging) sequences, respectively.

Diagnosis and incidence in neurocysticercosis
A diagnosis of epilepsy-the general term for a multitude of disorders that present with unprovoked, non-febrile seizures-necessitates that a seizure occurs at least once and be followed by a high (>60%) risk of recurrence. For a comprehensive overview of diagnostic criteria and classification, readers are referred to the International League Against Epilepsy task force publications [36,37].
The seizures experienced by patients with NCC are typically focal in onset, rapidly progressing to bilateral tonic clonic seizure activity [3,9,20,[38][39][40][41]. Acquired epilepsy is the name given to the collection of epilepsy syndromes resulting from external/environmental or pathologic processes [42]. A significant proportion of patients with NCC experience recurrent seizures, with many meeting the criteria for an epilepsy diagnosis. Given the prevalence of NCC in endemic regions, this relationship is common enough to suggest the occurrence of NCC-related epileptogenesis [43][44][45][46]. Whilst such factors as asymptomatic pathology, diagnostic inconsistency, and non-specific clinical presentation make NCC-related epileptogenesis difficult to characterise, evidence suggests that in some endemic populations as many as 70-90% of patients with NCC experience at least one seizure during the course of the disease [1,13,15,16,[47][48][49][50].

Association with neurocysticercosis
It is uncertain whether NCC lesions presents any inherent epileptogenicity over other structural brain lesions, yet NCC and epilepsy incidence have been positively correlated in numerous studies, suggesting that the pathophysiological mechanisms of NCC may predispose to the development of an epileptogenic state [51][52][53]. The relationship is poorly understood, however, and further confounded by the distinct clinical profiles observed in paediatric and adult populations [54].
Attempts to quantify the relationship between NCC and epilepsy have yielded varied estimates, although a recent meta-analysis puts the common odds ratio of an individual with NCC developing epilepsy at 2.76 (compared to an uninfected individual); further analysis indicates that 31.54% of epilepsy cases in at-risk countries were associated with NCC [55]. The putative association between NCC infection and epileptogenesis is supported by studies showing that appropriate anthelminthic treatment of NCC can lead to a better epilepsy prognosis in some cases [56,57]. Another study concluded that serial seizures, a family history of epilepsy, and headache predicted seizure recurrence in solitary cysticercus [58].

Modulatory factors of seizures in neurocysticercosis
There is a growing body of research regarding the mechanistic origins of seizures in NCC. On a genomic/proteomic scale, specific polymorphisms of toll-like receptor 4 have been associated with recurrent seizures in NCC [59,60]. Furthermore, the hypothesised seizure-inducing neuropeptide, Substance P, has been detected in potentially epileptogenic NCC lesions, and its ictogenic effects were subsequently demonstrated on the rodent brain [61].

Seizure characteristics in the literature
Previous studies into NCC-related epileptogenesis either omit, or do not adequately detail, the participants' seizure semiology. There is insufficient discrimination between provoked/acute symptomatic and unprovoked/spontaneous seizures in the literature. This is crucial information for an epilepsy diagnosis, which is only considered if seizures are seemingly unprovoked, arising from aberrant neural propagation [62,63]. One possible reason for this absence of data is that it is common practice to exclude from research all NCC patients without a single calcified cyst/granuloma, ostensibly controlling for acute seizures. It was believed that these solitary cysts were benign, but recent reports have suggested that remodelling of the calcium matrix in persistent lesions can precipitate acute seizures via intermittent inflammation [45,46,[64][65][66][67][68]. Whilst seizures resulting from neuroinflammation in NCC may encourage epileptogenesis, they are not necessarily symptomatic of epilepsy [59,69,70]. The lack of specificity in previous reports about the seizure characteristics results in a lack of clear understanding of epileptogenicity related to NCC.
Any conclusions drawn from retrospective cases are subject to the caveat that what is reported as unprovoked may be provoked [9,[71][72][73]. Unless explicitly defined, seizure recurrence in NCC will henceforth be referred to as NCC-related ictogenesis, to avoid potentially misattributing seizure recurrence to epilepsy in retrospective cases.

Demand for prospective case-comparison research
There is a rich literature detailing case reports, cross-sectional studies, and expert opinion in NCC research. Conversely, there are few publications suitable for inference and generalisation, with many reports failing to satisfy methodological research standards. Quantitative MRI approaches in NCC-related ictogenesis research have demonstrated an overreliance on unsuitable methodology, as shown in Table 1. Comparison groups are uncommon in these studies, and cross-sectional studies/case reports comprise a large proportion of the contemporary narrative. Expert opinions and anecdotal accounts are afforded disproportionate significance over evidence-based research in previous reviews, whilst many of the primary sources still being referenced have not been updated in step with the methodology. The lack of prospective, longitudinal, cohort-based studies is a serious limitation to our understanding of epilepsy related to NCC, which is a probable factor underlying the unpredictability of the NCC disease course.
Despite the uncertainty surrounding ictogenesis and the methodological issues in NCC research, studies into the convergence of infectious and non-communicable diseases have already contributed to the understanding and treatment of disorders such as Alzheimer's disease and Lupus, and whilst biomarker research into NCC-related ictogenesis has been, as yet, inconclusive, it has been remarked that the field offers an opportunity to explore a natural human model of acquired epilepsy [1,16,40,74,75]. Moreover, Siddiqua et al. have suggested that prospective studies into the epileptogenicity of NCC will help define the devolutionary stages, allowing for more informed treatment decisions [76].

Multivariate model
A popular model of epileptogenesis in the current literature is the multivariate model, which stipulates that epileptogenesis is multifactorial, comprising three factors: the seizure threshold, the presence of epileptogenic abnormalities, and transient precipitating factors [92]. It is therefore accepted that the mechanisms underlying epileptogenesis are part of a complex network of interacting factors, and that identification of any factor in isolation would require accurate characterisation of multiple potential confounds. As such, NCC-related epilepsy research now commonly involves multivariate analyses of prognostic correlates to create models of the disease that encompass data from multiple modalities e.g., distinct biomarkers [88,93].

Semiology as a biomarker
Clinical or electrographic seizure occurrence is an established diagnostic biomarker for epilepsy; despite the high possibility of a falsepositive diagnosis (i.e. low specificity, not every seizure is a symptom of epilepsy), the sensitivity of seizures in diagnosing epilepsy is theoretically 100% [94]. But aside from being diagnostic, seizure occurrence can also be predictive and prognostic, often being indicative of anti-seizure medication (ASM) response, and importantly, seizure remission [95][96][97][98]. Indeed, a recent study suggests that the presence of convulsive status epilepticus (SE; as opposed to isolated seizures, or seizure clusters) alongside NCC could be predictive of an excellent seizure outcome [99]. Future research should utilise the predictive value offered by the individual's seizure history.

Focal epilepsy and central nervous system damage
Potential biomarkers for epileptogenesis have been identified; in (M) TLE-HA ([mesial] temporal lobe epilepsy with hippocampal atrophy) in particular, the repeated pathological insult of uncontrollable seizure activity, blood-brain barrier (BBB) damage, and inflammation has been proposed as a driving factor for the chronicity of the disorder [100]. EEG seizures and periodic EEG discharges have been identified as further risk factors for developing post-traumatic epilepsy (epilepsy acquired subsequent to traumatic brain injury, TBI) [45]. It is worth noting that the aforementioned risk factors are valid biomarkers for acquired epilepsy in all three types of CNS damage-infection, TBI, and cerebrovascular accident. These commonalities have also been identified in individuals with NCC-related ictogenesis. Epilepsy duration and multi-lobe involvement predicted worse seizure prognosis in patients with NCC and TLE-HA post resective surgery [101].

Biomarkers in neurocysticercosis 2.2.1. Multivariate model applied to neurocysticercosis
In the case of NCC-related ictogenesis, the development of an epileptogenic environment is unlikely to be attributable to a single disease characteristic. Instead, it is likely that the combined effects of brain trauma, infection, and ictogenesis are additive, all contributing semi-independently to the multifactorial alteration of the brain state. Biomarkers for NCC-related epilepsy should account for the extent to which NCC, through brain trauma and infection, contributes to the epileptogenesis, as well as to what extend epileptogenesis is selfpropagating [70,102]. Comprehensive descriptions of epilepsy chronicity and seizure characteristics are important for avoiding confounds when applying the multivariate model.

Perilesional neurocysticercosis-related epileptogenesis biomarkers
MRI positive cysticercal lesions, whilst a valuable indicator of epileptogenicity in the surrounding cortical tissue, do not necessarily represent the epileptogenic zone [103]. Neurocysticerci can occur in any number and any region of the parenchyma, but most commonly manifest as solitary lesions in the frontal lobe [104][105][106][107]. Reported ratios of solitary/multiple NCC vary and may be biased by an overrepresentation of solitary calcified granulomas (where other lesions have resolved) in the literature, described by Batta et al. as 'referral bias'. Furthermore, it is the subject of debate as to whether load or location can influence the epileptogenicity of a cysticercus. A multicystic load has been identified as a risk factor for drug refractory seizures [83]. And there are multiple papers suggesting a location relationship, but a comparable number of studies have found cyst location to be unrelated to semiology [14,20,40,47,88,108]. A recent paper demonstrated that whilst lesion lateralisation was correlated with seizure semiology, location was not, mirroring research suggesting an incongruity between neuroimaging and semiology [90,109]. Instead, it has been suggested that in NCC the EEG focus, including proximity to hippocampus, may be more of a risk factor for epileptogenesis [110]. Indeed, recent evidence suggests that a topographical overlap of the epileptogenic zone and the cyst/oedema, i. e. the location of the focal insult relative to the seizure foci, may predispose to seizure recurrence. [80] Furthermore, the ictogenic properties of a cyst are, in part, related to its current state of degeneration and calcification (i.e. devolution) [16,40,111]. The vesicular cyst is more commonly associated with asymptomatic presentation, but during the transitionary period-which includes the colloidal and granular stages-the cyst releases inflammatory material into the cortex, provoking acute seizures. Subsequent to the granular stage, the cyst can either calcify and persist as a nodule, or resolve. There are several factors thought to predispose a cyst to calcification, such as: the presence of oedema and/or residual scolex; cyst size; prolonged seizure activity; high albendazole and/or low dexamethasone load; treatment delay; incomplete treatment course; and a mild immune response [107,112,113].
A persistent cyst may precipitate periodic episodes of inflammation/ oedema through the gradual decomposition of its calcium matrix. The literature presents evidence for a temporal relationship between perilesional vasogenic oedema and seizure activity-one possible mechanism through which NCC lesions may predispose an individual to recurrent ictogenesis [35,66,72,81,[114][115][116][117][118]. Such studies have precipitated a re-evaluation of the inflammatory properties of cysts previously believed benign, and may represent initial evidence for 'increased inflammatory response' as a biomarker for NCC-related ictogenesis. It has also been suggested that in cases where the cyst resolves, gliosis can remain as epileptogenic foci, which further complicates efforts to differentiate between acute and unprovoked seizures [25,72,73,88,119,120].

Descriptive MRI
Advances in SWI sequences have significantly improved on the specificity of conventional scans in recent years, increasing the clarity of imaging in NCC. The tissue contrasts in susceptibility-weighted angiography, 3D CISS, and fast imaging employing steady-state acquisition sequences are more sensitive to cysticerci and the scolices within, superseding that of more traditional sequences [13,14,29,35,86].
But MRI also offers a wealth of clinically relevant information beyond identification of putative neurocysticerci: 3D-double-inversion recovery has been shown to outperform magnetisation transfer and fluid attenuated inversion recovery (FLAIR) imaging for the detection of gliosis, and there is evidence that high-field diffusion MRI (dMRI) may also be efficacious for this purpose; [121][122][123][124] BBB breakdown-a potential biomarker for the inflammatory strength (and therefore, ictogenic potential) of a calcified lesion-can be examined using DCE-MRI derived metrics; [47,89,114,125]; a spoiled gradient recall echo sequence has been used to differentiate between 'typical' (round/oval ring enhancement, no midline shift) and 'atypical' (coalesced, septated, or conglomerated lesions); [86] and sequences commonly found in contemporary clinical protocols, such as T2* weighted GRE or FLAIR, make it possible to identify scolices in calcified lesions-something CT is unable to do [25,48,120].
Avenues afforded by descriptive MRI methodology are not exhausted. Despite an unclear impact of the trauma caused by cysts, the possibility of an interaction between the cystic insult, oedema, and gliosis is not yet fully explored. For example, an epileptogenic abnormality may develop as a result of specific white matter aberrations that current studies have not been powerful enough to uncover [45,92]. There is also evidence that NCC lesions have a T2 relaxometry trajectory that can be used to prognosticate seizure recurrence [79,126]. Authors are now calling for research with a greater emphasis on exploring the natural history of NCC [93,118]. And expert commentary further suggests that it is not enough to rely on prevalence and incidence to establish a meaningful relationship between NCC and epilepsy-what is now needed are rigorously controlled large-sample prospective designs, using the most consistent and powerful methods available.

Quantitative MRI
While descriptive MRI methodologies produce images suitable for visual inspection and basic quantitative analyses (number and size of lesions), novel sequences and image processing/analysis methods can infer meaningful neuroanatomical properties from quantitative metrics related to biological processes/characteristics [127,128]. The potential benefits of quantitative imaging practices have been recognised in other neurological conditions, examples are primary CNS lymphoma; [129] Parkinson's disease; [130] and frontotemporal dementia [131].
(As one of the most ubiquitous and heterogenous groups of disorders) Epilepsy research has adopted quantitative MRI techniques, and the sensitivity and robustness of these pipelines makes them effective for identifying biomarkers such as neuroanatomical correlates of disease progression [132][133][134][135]. There is a wealth of imaging literature in NCC, yet the majority of this data is unsuitable for quantitative interpretation, instead providing clinically-oriented descriptive or semi-quantitative information (i.e. lesion load and location). As techniques evolve, however, and software/hardware requirements become more attainable for researchers based in endemic regions, papers detailing quantitative MRI approaches to NCC-related ictogenesis are being published with increasing frequency. Indeed, there is evidence of a contemporary shift from descriptive to quantitative research in NCC-related ictogenesis [79,84,126]. See Table 1 for an overview of studies containing putative NCC biomarkers for seizure recurrence. The relative paucity of case-comparison studies should also be noted.

Structural correlates
Identified by structural covariance studies at the group level, morphometric abnormalities of cortical regions have been extensively linked to abnormalities in the corresponding network's functioning. For example, atrophy and/or malrotation of the hippocampus are common structural findings in epileptogenic networks, and have been linked to recurrent seizure activity in NCC [78,84,91,[136][137][138][139][140][141][142]. Potential structural biomarkers of epileptogenesis include post-traumatic thalamic damage (in rats), amygdalae enlargement (in non-lesional epilepsies), and wider thalamocortical atrophy-all of which represent vulnerabilities to key epileptogenic regions, which may contribute to NCC-related ictogenesis [135,143,144].

Imaging in network neuroscience
The data acquired by quantitative MRI studies is especially valuable for use in the context of network neuroscience (NN) approaches [145,146]. NN is a relatively new field encompassing research made possible by recent advancements in both tools and experimental frameworks; to study brain (dys)function as a collection of integrative processes, NN requires sophisticated multimodal data. Reducing the characteristics of a network down to a vector of their fundamental properties facilitates comparisons between otherwise heterogenous datasets, and is a powerful way of examining both the topology (i.e. the macroscopic organisation) of the brain, and its dynamics (i.e. the generative and interactional principles) [147][148][149][150]. The ability to represent complex system interactions as abstract mathematical models is integral to NN, and is used in epilepsy research to better understand ictogenic spread, as well as epileptogenic processes and correlates.

Graph-theory
Graph-theoretical representations of cortical networks are an elegant way to isolate the organisation and connectivity of the constituent regions, without making assumptions as to the subjects' global cortical topology [151,152]. In brief, maps of either structural or functional cortical connectivity can be extracted from quantitative MRI data, used to populate correlation matrices, and adapted into generalised stick-and-ball graph-theoretical connectomic models that allow direct group-level comparisons. By predetermining the regional atlases and quantitative metrics used to construct and populate the matrices, physiologically meaningful measures of connectivity can be extracted and compared in a systematic manner.

Epilepsy as a network disorder
Epilepsy is widely accepted to be a network disorder and boasts an established NN research precedence [153][154][155][156][157][158]. Clinical practice has adapted to the new paradigm, with current trends indicating an increase in the popularity of resective surgery informed by connectome-based biomarkers [159]. The incidence of epilepsy in NCC suggests, therefore, that the associated cysts present not only a focal insult, but a network disturbance.

Introduction and disrupted connectomes
Brain network models use both nodes, the spatially/anatomically defined cortical regions, and edges, the direct pairwise connections between them. The structural description of a network is defined by the nature, quantity, and organisation of these elements [145,160,161]. NN in NCC is in its infancy, but early network analyses in epilepsy indicate that ictogenesis may be underpinned by the association between two potentially epileptogenic lesions, one hippocampal, and one extrahippocampal (dual pathology). This has reliably been demonstrated in NCC [137,[162][163][164][165][166]. In such cases, it is hypothesised that NCC may act as an initial precipitating injury, which encourages the development of an epileptogenic state consistent with MTLE-HA [167,168]. The causality of such a relationship is unclear, and several plausible alternative hypotheses have been proposed, such as a shared genetic predisposition, vasculitis-associated ischemia, an inflammatory cross-reaction, compression effects, or a cytotoxic proximity effect of the cyst to the atrophic area [77,117,169]. Evidence from surgical evaluations support the dual-pathology hypothesis, which suggests that the correlation of the cyst topography and the seizure focus (constituting the extrahippocampal lesion) can predispose the individual to epileptogenic HA independent of any cyst features [170][171][172]. The relative scarcity of evidence, alongside the promising results of exploratory studies, suggests that the clinical-topographic characteristics of NCC-related ictogenesis represent a promising direction for quantitative imaging and network analyses.

Cortical disconnection
It is understood that seizure recurrence in epilepsy, even focal epilepsies, is associated with significant alterations of the epileptogenic network's edges, constituting network reorganisation [153,[173][174][175]. The edges connecting a cortical network's nodes are constrained to the physical connections between the anatomically distinct regions. The common method of exploring the structural connectivity of a network, tractography, involves mapping and tracing these purportedly physical connections in the form of white matter fibre bundles. MRI tractography methods identify and virtualise white matter tract bundles by measuring the anisotropic/directional movement of water along tracts using dMRI sequences and are used to create a three dimensional representation of the available axonal pathways between grey matter regions [176]. In this way, the organisation of a network's edges can be examined for disruption and abnormalities, which may be revealing in otherwise normal appearing white matter. The results of epilepsy network dMRI suggest that the degree of network disorganisation is predictive of not only seizure severity, but also that response to ASM could be related to the assortativeness of a network (i.e. the tendency for nodes to create robust subnetworks by connecting with other nodes of a similar number of a edge connections) [177,178]. The robustness of diffusion-based networks is such that surgical planning using dMRI metrics to inform neurosurgery is a growing area of research, hypothesised to lead to significant improvements in post-resection quality of life, amongst other benefits [179,180].
Diffusion MRI has not met with as wide success in NCC research, due in part to its limited clinical utility when compared to traditional structural scans. Whilst select studies have, however, highlighted the value of dMRI for identifying scolices, indicating the cyst phase, distinguishing between different types of lesions/mass effects, and prognosticating calcification, further interpretation of diffusion data requires postprocessing and expert interpretation for clinical use [107,130,[181][182][183][184][185][186]. Consequently, dMRI explorations of NCC-related ictogenesis are uncommon, especially in endemic areas where the necessary resources (such as MRI facilities, computational power, and time) are less accessible or in high demand. The application of dMRI/tractographic methods to NCC currently represents a potentially informative research area, especially with growing support for the more advanced sequences with more diffusion directions and higher diffusion coding (b-values) used for diffusion kurtosis imaging, fibre-ball white matter modelling, and diffusion microstructure imaging [187][188][189].

Introduction and measurement
While structural connectivity is defined by pairwise anatomical connections, functional connectivity is defined by time-series correlations of regional functional (metabolic or electrophysiological) activity between two (or more) regions. In short, the structural connectome is a description of network organisation, the functional connectome a description of how dynamic processes propagate activations throughout the network [148,150,153,190]. Since its inception less than 30 years ago, task-free resting state functional MRI (rs-fMRI) has become a popular method for delineating functional networks; [191,192] rs-fMRI demonstrates a high degree of reproducibility and test/re-test consistency, and the resultant activations correspond with task-specific systems [193,194]. Furthermore, despite some initial complications with preprocessing and variability, there are tangible benefits to rs-fMRI over task-based fMRI, including its ease of implementation for clinical populations and disease conditions [195].

Correlates in epilepsy
Resting state fMRI approaches comprise a large part of the current literature in epilepsy research. TLE (temporal lobe epilepsy) in particular has a particularly well explored functional pathology; mesiotemporal functional connectivity impairment is a common finding ipsilateral to the seizure focus, and when co-occurring alongside increased contralateral connectivity, is suggestive of diffuse limbic reorganisation [194,196]. Indeed, a recent study identified temporal lobe functional connectivity as a potential biomarker of TLE [197]. Furthermore, aberrant mesiotemporal connectivity may be associated with widespread default mode network or thalamo-fronto-cortical functional abnormalities, which correlate with structural alterations [198]. In idiopathic generalised epilepsy (IGE), disease duration is negatively correlated with thalamo-frontal network functional connectivity (and consistent with a reduction in thalamic volume), despite higher global connectivity in IGE than controls, regardless of seizure control [199,200]. Correspondence between functional and anatomical network disruptions in epilepsy has been demonstrated, although diffusivity abnormalities (i.e. increased mean diffusivity) exhibit a focus proximity function, diminishing with anatomical distance from the epileptogenic focus [201,202].
Functional network alterations are not only reliably associated with deficits in cognition and motor activation, but recent studies have also shown a link between functional reorganisation and a predisposition to experience recurrent seizures over the following 12 months [203][204][205][206][207][208]. Functional network reorganisation in IGE has been proposed as indicative of a resting state more susceptible to transitioning to seizure state, and seizure outcomes in TLE can be predicted using functional network properties [159,200,209]. The network theory for epilepsy is an interesting perspective for NCC-related ictogenesis, which may lie in the functional correlates of the initial insult. Cortical functionality, alongside numerous other biological systems and networks, is hypothesised to be 'degenerate' (i.e. consisting of multiple structurally different parts that are capable of producing the same output/response), suggesting that the black-and-white limitations of unimodal structural analysis are unsuitable for capturing the interplay of functional integration and segregation [150,210].

Correlates in neurocysticercosis
To assess the functional impact of NCC without direct measurement of proxies would require assumptions to be made regarding the impact of the cysts, and there is little evidence to suggest that this can be done with any accuracy. Indeed, fMRI research into cortical malformations suggests that the functional correlates of neurocysticerci are non-trivial in that the functional impacts of cortical malformations are highly variable in both magnitude and modality [103]. As functional connectivity during or after NCC infection has not been explored, rs-fMRI offers a powerful method of assessing how functional networks, and therefore brain function, are impacted by neurocysticerci on an acute and residual level.

Conclusions
There is currently insufficient evidence to accurately and definitively describe the relationship between NCC and acquired epilepsy, but it can be said with confidence that there is a larger-than-odds co-occurrence of recurrent seizures following NCC infection. Current evidence cannot explain the relationship between NCC-a pleomorphic focal insult-and recurrent seizure activity, believed to be the consequence of networklevel disruptions. Trends in contemporary neuroscience, alongside expert opinions, indicate that MRI-derived network analyses are a potentially illuminating research direction.
Conventional MRI approaches provide invaluable descriptive data, but are mostly unsuitable for analyses beyond the identification of macroscopic correlates (lesion load, location, oedema, etc.). Although rarely used in NCC, quantitative measurements of physical characteristics, such as cortical thickness, volume, and curvature can elucidate correlates that might otherwise go unnoticed after radiologic examination. Moreover, diffusion metrics, which are unprecedented beyond NCC stage detection, may indicate reduced structural integrity at the microscale and predict remote involvement of cortical regions via tract reconstruction. Structural networks are a logical step forward for NCC researchers. There is also a growing body of literature which has begun to demonstrate the efficacy of rs-fMRI for both the diagnosis and prognosis of neurological disorders, suggesting that functional connectivity studies in NCC-related ictogenesis may present similar findings. In recent years, advanced imaging processing pipelines have become more accessible, and techniques have been developed to overcome many of the restrictions that have limited the utility of earlier MRI. As some have already noted, this facilitates a new perspective in NCC; MRI-derived network analyses offer a promising research direction, with potential benefits extending past NCC-related ictogenesis to include the wider population of individuals who experience recurrent seizures.

Ethics and integrity
Nothing to declare.

Declaration of Competing Interest
None