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Neurocysticercosis and pharmacoresistant epilepsy: possible role of calcified lesions in epileptogenesis Volume 22, issue 4, August 2020

Figures


  • Figure 1

  • Figure 2

Neurocysticercosis (NCC), associated with the larval phase of Taenia solium in the human central nervous system (CNS), is a neglected and usually poverty-related disease of high public importance (Coyle et al., 2012).

Acute symptomatic seizures may result from transitional or degenerating parasites as a consequence of the acute inflammatory response (Carpio and Romo, 2014). Seizures may also occur as a result of infarcts related to vasculitis and thrombosis of penetrating vessels from subarachnoid cysticercosis (Del Brutto, 1992). Encephalomalacia and gliosis, resulting from prior inflammation, accompanies the formation of granulomas with or without calcification and are potential causes of persistent seizure activity (Rathore et al., 2013).

In the chronic phase, seizures require treatment with antiseizure medication and some may progress to refractoriness to treatment (Carpio and Romo, 2015); the seizures are the basis for the diagnosis of epilepsy with inflammatory/structural aetiology.

In the specific setting of a residual calcified lesion, associated epilepsy was previously considered to be related to a remote aetiology, once the non-inflamed calcified cysts were regarded as inert (Sotelo et al., 1985). However, studies support the existence of a subset of calcified lesions that could be the source of intermittent ictal activity and of a chronic inflammatory process, often associated with the temporary presence of perilesional oedema (Nash and Patronas, 1999). Regarding this topic, only a few examples of the histopathology of calcifications are described in the literature (Gupta et al., 2002; Robinson et al., 2012).

This study aimed to measure the cellular expression of immunohistochemical (IHC) markers of epileptogenesis in a single calcified cysticercus in a girl with refractory epilepsy which started at three years old; the patient has been seizure-free for 25 months following lesionectomy.

Case study

A six-year-old, right-handed female presented with seizures that started at three years of age, with a frequency of 3 to 30/day. She presented with myoclonic seizures and brief behavioural arrest without automatisms or post-ictal symptoms, leading to an initial hypothesis of generalized epilepsy. She had been on multiple antiseizure medications, including maximally tolerated doses of levetiracetam, valproate, ethosuximide, topiramate, and cannabidiol, in addition to a ketogenic diet, on admission to our tertiary service. The patient had no neurological deficits, and her intellectual level was within the lower middle range. Long-term video-EEG monitoring showed numerous myoclonic-tonic, asymmetric tonic, and behavioural arrest seizures. The EEG also showed epileptiform activity in the right frontal region, with secondary bilateral synchrony (figure 1B). Ictal EEG revealed frontal onset seizures. Brain MRI showed a nodular calcification located in the right mid-frontal gyrus, depicted by marked hypointensity on all sequences, including susceptibility weighted imaging, surrounded by hyperintensity on T2 and FLAIR (figure 1A). After failure of treatments with carbamazepine and clobazam, the patient underwent a multidisciplinary evaluation followed by a resection of the calcified lesion. Because the lesion was close to the motor area, the initial surgical planning included intraoperative mapping of the hand motor area and acute electrocorticography. However, this delimitation was not possible intraoperatively, despite the use of different stimulation parameters. A long-term study with subdural electrodes was then performed, allowing the delineation of the irritative and ictal onset zones, as well as localization relative to the hand motor area. Histopathological analysis showed a cysticercus with necrosis, a regressive phenomenon of the vesicle wall, of which the scolex was surrounded by a non-specific chronic inflammatory process (figure 1C).

Postoperatively, the patient did not present any deficits and has been seizure-free for 25 months since surgery; in addition, her neurocognitive profile was maintained. The resected tissue was submitted for immunohistochemical study in order to evaluate the presence of neurotransmitters and inflammatory markers (figure 2).

Discussion

This case illustrates a focal frontal epilepsy with seizure semiology and EEG findings leading to an initial erroneous diagnosis of generalized epilepsy, with absences and myoclonic seizures. Myoclonia was recognized as possibly generalized or focal based only on the most recent classification of seizures (Fisher et al., 2017). Additionally, the EEG of this patient, with very frequent bilateral synchrony and rare focal frontal sharp waves, further complicated the analysis.

The epileptogenic potential of a calcified cysticercus requires further clarification. Calcified lesions are common in asymptomatic individuals, and studies report that these lesions are mainly incidental, which questions their true epileptogenicity (Leite et al., 2000). Besides being considered inert for a long time (Sotelo et al., 1985), recent studies suggest that calcifications of NCC may cause seizures when parasitic antigens retained in the calcium matrix are exposed to the immune system, inducing a recurrent inflammatory reaction (Nash et al., 2008). However, it is not clear whether the perilesional oedema frequently seen in NCC patients is the cause or the consequence of seizures (Leite et al., 2000), representing an inflammatory reaction or merely postictal vasogenic oedema (Nash and Patronas, 1999; Nash et al., 2008). In addition, the perilesional gliosis, as observed in this patient, has been considered to be suggestive of epileptogenic potential (Rathore et al., 2013).

The multifactorial concept of epilepsy is based on the triad of epileptogenic abnormality, seizure threshold, and precipitating factors (Engel et al., 2013). In the context of NCC, the epileptogenic abnormality relates to the number and localization of parasites, as well as their evolutionary phases over time. Additionally, a genetic predisposition might be responsible for a low seizure threshold hastened by precipitating factors such as the host immunologic response, with a cascade of events such as blood-brain barrier breakdown, brain inflammation, and reactive astrogliosis. The biomarkers (the increase in glutamate and pro-epileptogenic kinin B1 receptors) reported in this clinical case would correspond to the “precipitating factors”. The effect of all these factors would lead to the chronic epileptogenic process (Carpio and Romo, 2015).

A basic assumption links the pathogenesis of epilepsy and the generation of synchronized neuronal activity with an imbalance between inhibitory GABA-mediated and excitatory glutamate-mediated neurotransmission, which favours the latter. In this study, IHC staining for neurotransmitters and inflammatory markers showed increased levels of glutamate and its transporters around the lesion relative to more distant tissue; the opposite was seen for the expression of GABA markers (figure 2B).

One study showed that the activated microglia releases proinflammatory cytokines, which may lead to neuronal hyperexcitability and neurodegeneration. The microglial and astrocytic activation likely contributes to the epileptogenesis (Benson et al., 2015). In this case, immunofluorescence analysis of Iba1 (a specific calcium-binding protein for microglia/macrophage) showed a decreasing gradient of microglia density from the proximal to the distal cortex. The necrotic areas presented the highest concentration of microglia.

Furthermore, the kinin B1 receptor, weakly expressed under physiological conditions, is induced by injury or upon in vivo or in vitro exposure to pro-inflammatory mediators. The kinin B2 receptor subtype, on the other hand, is constitutively and widely expressed throughout the central and peripheral nervous system (Arganaraz et al., 2004). Accordingly, in this case, the increased B1 receptor, as a marker of kinins in the cysticercus and around the lesion, relative to B2 receptor, was suggestive of epileptogenic properties.

This case shows that the inflammatory response due to a calcified granuloma might be associated with the development of seizures and epilepsy. The increase of glutamate and pro-epileptogenic B1 receptors in proximal cortex associated with a reduction of GABA and anti-epileptogenic B2 receptors are findings that might explain the chronic epileptogenesis of the lesion, corroborating the hypothesis of neurotoxicity and inflammatory mechanisms involved in the pathophysiology of epilepsy in patients with neurocysticercosis.

A calcified cysticercus can be a cause of epilepsy refractory to medication and should be considered for surgical treatment with a potential chance of cure when the epileptogenic lesion is removed.

Supplementary data

Summary didactic slides are available on the www.epilepticdisorders.com website.

Acknowledgments and disclosures

None of the authors have any conflict of interest to declare.