Epilepsy after viral encephalitis
The main risk factors for epilepsy after viral encephalitis (VE) in 198 acute encephalitis patients in a study from the Mayo Clinic, USA (Singh et al., 2015) were:
- –seizures (particularly focal) during the acute phase of the disease;
- –status epilepticus;
- –and FLAIR/T2 hyperintensity on MRI, with “structural injury often involving the epileptogenic temporal and frontal lobes”.
Indeed, in an earlier population-based study (Annegers et al., 1988), the risk for the development of chronic epilepsy at 20 years of follow-up was 22% for patients with acute seizures compared to 10% for patients without acute seizures. Cortical injury, as for HSV-1 and less frequently HSV-2 infections, is apparently linked to higher epilepsy rates (Singh et al., 2016), compared to viral infections with damage mainly to subcortical structures, as in Japanese encephalitis (Lee et al., 2007; Misra et al., 2008). None of the patients with “pure subcortical involvement, leptomeningeal enhancement, and brain stem or spinal cord lesions” on MRI developed epilepsy after VE. Additional risk factors for chronic epilepsy after VE, as identified in a study from the Taiwan University Hospital in 54/330 (16%) children with acute encephalitis between 1984 and 2000 (Lee et al., 2007), were focal neurological signs, severe disturbance of consciousness, and neurological deterioration during the hospitalization. Epilepsy after VE presented within six months after the acute illness in 80% and within the following three years in 94% patients; 26 (50%) cases were drug-resistant.
Epilepsy after herpes simplex virus encephalitis
HSVencephalitis (HSVE) is the most common sporadic encephalitis (De Tiège et al., 2003). The estimated incidence is 1/250,000-500,000 per year with one third of cases occurring in childhood and adolescence; over 90% are caused by HSV-1 (Baringer, 2008). Epileptologists are more often confronted with epilepsies after HSVE than with epilepsies after encephalitis caused by other viral agents. For this reason, peculiarities of this virus that may be relevant to the development of chronic epilepsies are discussed in more detail.Morbidity after HSV encephalitis
In contrast to the lower mortality since the invention of acyclovir, morbidity is still high, with many affected persons subsequently suffering neurological deficits. Older age at the acute stage of disease, development of coma, the presence of restricted diffusion on brain MRI, and delay in the administration of acyclovir predicted poor outcome in 29/45 adult patients with HSVE admitted to the Mayo Clinic between 1995 and 2013 (Singh et al., 2016). In this study, 10/22 (45%) “for which this information was available” developed epilepsy during the 6-12-month follow-up. The risk of severe neurological sequelae is particularly high in very young children. In a community-based three-year prospective survey of children aged 2-23 months in Britain and Ireland (Ward et al., 2012), 13/19 children with HSV-encephalitis aged 2-11 months during the acute illness had focal abnormalities on MRI and 11/19 had long-term neurological deficits. Of the six children aged 12-35 months during the acute illness, only one had an abnormality on MRI; 3/6 suffered from neurological sequelae. After a follow-up period of over one year, 12/19 were diagnosed with developmental delay and 7/19 (37%) had epileptic seizures.Cortical injury in HSV encephalitis
Due to the necrotizing properties of the HS viruses, epilepsy following HSVE is bound to arise from areas of MRI-visible cortical damage. Extratemporal regions may often undergo damage that is unfortunately also bilateral in many cases. At the early stages of HSVE, lesions arise from damage to the blood/brain barrier with consequent cerebral oedema, characterized by hypointensity on T1-weighted and hyperintensity on T2-weighted MRI. At later stages, an evolution towards haemorrhagic and necrotic lesions is evident. The localization and extent of T2/FLAIR signal changes reflecting the damage occurring in the acute stage of the disease were recently described in detail (Singh et al., 2016) (figure 1). In this cohort, T2/FLAIR signal changes were present in >90% of cases, with a slightly lower rate of cortical involvement. Changes were seen in the temporal lobes in 88%, in the insular cortex in 70%, in the frontal lobes in 68%, and in the thalamus in 28% of cases, whereas bilateral changes were diagnosed in almost half of the patients. These high rates of brain lesions are noteworthy since 52% of patients underwent acyclovir treatment from Day 1. The oedemas will eventually resolve in a significant number of patients. However, the distribution of acute MRI changes (figure 1) matches the distribution of cortical scars, subcortical white matter changes, and atrophic changes in patients with drug-resistant epilepsy following HSVE (Misra et al., 2008; Pillai et al., 2016; Singh et al., 2016). This observation underlines that temporal lobe epilepsy following HSV-encephalitis is rarely a “pure” temporal lobe epilepsy, and far more often a “temporal plus” epilepsy (Kahane et al., 2015; Barba et al., 2016).Anti-NMDA-R encephalitis after HSV infection
Anti-NMDA-R encephalitis after HSV infection is a recently identified constellation that should be distinguished both from HSV reactivation and drug-resistant epilepsy after VE. NMDA-R antibodies have been frequently detected in patients with HSV-1 encephalitis (Prüss et al., 2012). Moreover, anti-NMDA-R encephalitis has been highlighted as a parainfectious autoimmune phenomenon, emerging within weeks of HSV-1 encephalitis (Armangue et al., 2013, 2014, 2015; Hacohen et al., 2014). Recent studies have substantiated previous suggestions that early relapse in HSV encephalitis, particularly in children, may be of autoimmune origin (De Tiège et al., 2003). The presentation is typically biphasic, with remission from VE, followed by relapse with autoimmune encephalitis within 1-7 weeks of first VE symptoms. Prompt diagnosis is crucial to initiate potentially beneficial immunotherapy (Armangue et al., 2015).
Epilepsy after cerebral viral infections other than HSV-encephalitis
The number of viruses that can cause encephalitis and subsequent chronic epilepsy is huge. Their worldwide geographical distribution is reported by Misra et al. (2008) (table 1) and discussed by Singhi (2011). In the Mayo Clinic report (Singh et al., 2014) on acute encephalitis pathogens (n=95), the following viruses were identified: HSV in 39%, varicella zoster in 23%, West Nile virus in 19%, Epstein-Barr virus in 6%, HIV in 3%, and other viruses in 10%. Factors associated with the development of epilepsy after VE were focal seizures, FLAIR/T2 abnormalities pointing to a cortical involvement, generalized seizures, and status epilepticus. Regarding epilepsy after VE, no statistically significant difference was found between HSV-encephalitis and encephalitis caused by other viruses in this study, although this has been shown in other publications (Singh et al., 2015). A similar spectrum of viruses, in cases with a positive result, has been found in the series from the Johns Hopkins Hospital in Baltimore, including 103 cases of acute encephalitis in adults (Thakur et al., 2013), although the cause was “unknown” in almost half of the patients. The aetiology remained unclear in 72% of encephalitis cases in a collaborative study with the participation of 17 hospitals in Spain (de Ory et al., 2013), as well as in 57% children with encephalitis in Taiwan (Lee et al., 2007). The significance of negative investigations for infectious agents at the time of the acute encephalitis in patients later developing drug-resistant epilepsies is discussed below under non-MTLE after viral encephalitis. The spectrum of viruses in the Taiwan study seems to be larger than in the studies from the US and Spain: enterovirus-encephalitis outnumbers varicella zoster and HSV infections, followed by infections caused by rubella, mumps, measles, and adenoviruses. In contrast to HSV, evidence for one of these other viruses was not associated with an increased risk of epilepsy after VE, notwithstanding the other known risk factors.
Epilepsy after VE is uncommon in Japanese encephalitis, the most frequent cause of encephalitis in Asia and Northern Australia. Though acute seizures tend to occur in up to 50% of affected persons (Misra et al., 2008), only 4% of patients from the Gansu province in China developed chronic epilepsy during (a relatively short) follow-up (Yin et al., 2015). Other neurological sequelae, such as various kinds of motor disturbances, dystonia and Parkinsonism, and cranial nerve symptoms, prevail along with impaired cognition and memory problems. This low rate of epilepsy after VE is due to the fact that Japanese encephalitis mainly affects the basal ganglia, the brain stem, and the spinal cord (anterior horn). Moreover, Japanese encephalitis often causes status epilepticus, which may lead to widespread cortical damage, with the subsequent development of drug-resistant epilepsy (seefigure 2ofMisra et al., 2008).
Epilepsy after bacterial meningitis
Morbidity and mortality after bacterial meningitis
The lack of antibiotics in some cases and their delayed administration in others may account for the high mortality of bacterial meningitis (BM) in several African (Pelkonen et al., 2009; Ramakrishnan et al., 2009) and other developing countries (Al Khorasani and Banajeh, 2006; Singhi, 2011). Further predictors of a severe course are:
Pathological alterations of the meninges that spare the underlying cortex do not necessarily provoke seizures. Thus, seizures during the acute phase of meningitis may indicate that the affected person is suffering from a meningoencephalitis. Moreover, seizures may be attributed to a decrease in seizure threshold by fever. Around 30-50% of children who survive acute meningitis suffer long-term sequelae, although these more often comprise hearing loss or cognitive problems than seizures. About one third of children with BM treated at a tertiary centre in Northern India had neurological sequelae after 12 months of follow-up; only 9% had seizures (Singhi et al., 2007). Numerous studies have aimed to identify the risk factors for an adverse outcome following bacterial meningitis (Grimwood et al., 1996; Pagliano et al., 2007; Vasilopoulou et al., 2011; Bargui et al., 2012; Namani et al., 2013). However, the risk factors for epilepsy after BM have not been analysed separately from those for other neurological sequelae in any of these studies.
Risk factors for epilepsy after bacterial meningitis
Overall, epilepsy after BM is considerably more infrequent than epilepsy after VE. In a meta-analysis from 1993, including 4,920 children with a history of meningitis from 19 studies published since 1955, 4% of patients had seizures at follow-up (Baraff et al., 1993). The rate of epilepsy after BM depends on the acute course (complicated vs. uncomplicated) and the length of follow-up. In a 12-year follow-up study from Australia, considering children and adolescents with early childhood meningitis, 3/49 (6%) with complicated and only 1/60 (2%) with uncomplicated acute meningitis had epilepsy after BM. At short-term follow-up (Namani et al., 2013), epilepsy after BM rates were 0% at two weeks and 1% at three months. In a population study from England and Wales with a five-year follow-up period (Bedford et al., 2001), a single-centre study from France with a medium follow-up of 10 years (Bargui et al., 2012), and a “long-term follow-up” monocentric study from Kosovo (Namani et al., 2013), epilepsy after BM rates were 7%, 9%, and 9%, respectively. “Long-term follow-up“ studies usually lack the duration necessary to include adults with the syndrome of MTLE after acute bacterial meningitis in early childhood. The duration of a “silent period” after the insult to the mesial structures in early childhood can extend to three decades (table 2). However, the inclusion of these adult cases is not expected to increase the rate of epilepsy after BM. Temporal lobe epilepsies with an onset of chronic seizures without a “silent period” of at least six months after the acute infection do not correspond to pure MTLE. Interestingly, seizures during the acute phase of meningitis in the neonatal period do not cause typical hippocampal sclerosis. This may be attributed to the reduced vulnerability of the hippocampus in neonates, due to the immature expression of excitatory synapses at this developmental stage (discussion in Holthausen, 1994).
Surgery for epilepsy caused by bacterial meningitis
In a large surgical series from the Freiburg Epilepsy Centre, Germany, from 1999 to 2015 (Ramantani et al., 2013a, 2013b, 2013c, 2017), only nine of 369 children underwent surgery for drug-resistant epilepsy after BM. Cerebral infections leading to brain scarring and subsequent refractory epilepsy occurred within the first year of life in all but one patient. In most cases, the MRI-visible cortical damage was extensive, including three cases with hemispheric and one with bilateral pathology. The rate of neurological deficit matched the extent of brain damage; five patients had a hemiparesis, and four had a visual field deficit. All patients were drug-resistant to five or more AEDs (mean: eight AEDs), much higher than for any other aetiology (Ramantani et al., 2014) within the same large surgical series. This was in line with an overall very long latency of epilepsy onset to surgery (mean: 10 years). A total of 3/9 patients underwent functional hemispherectomy and another three underwent multilobectomies: temporo-parieto-occipital, fronto-temporal, and temporo-occipital, in one case each. The remaining three patients underwent anterior temporal lobectomy with amygdalohippocampectomy. Interestingly, three of these patients had a positive histopathology for FCD; two FCD 1b and one FCD 2a. Hippocampal sclerosis was shown in 7/9 patients. After a mean follow-up period of six years, 4/9 had an Engel I outcome, two had Engel II, and three had Engel III. It should be noted that in all five cases with seizure recurrence, this occurred within the first weeks after surgery.
Overall, two main types of epilepsy may develop after BM, similar to those following viral infection: (1) MTLE and (2) neocortical, predominantly extratemporal epilepsy.Patients with MTLE after bacterial meningitis
Most patients with drug-resistant epilepsy after BM, who undergo epilepsy surgery, suffer from MTLE with hippocampal atrophy (table 2), associated with meningitis in infancy or early childhood (Marks et al., 1992; Donaire et al., 2007). Patients with a history of meningitis in early childhood, mesial temporal sclerosis on MRI, and an epilepsy course concordant with the syndrome of MTLE (“silent period”!) are excellent surgical candidates (Lancman and Morris, 1996; Lee et al., 1997; Trinka et al., 2000; Donaire et al., 2007; Sellner and Trinka, 2013). It is postulated that febrile seizures during the acute phase of meningitis in early childhood cause hippocampal atrophy, whereas seizures during neonatal meningitis do not cause this type of damage. Bilateral hippocampal atrophy in epilepsy after BM beyond the neonatal period, without marked damage in other parts of the brain, is highly unlikely to occur. The six-case series with hippocampal atrophy after meningitis from Barcelona, Spain (Donaire et al., 2007), may give a different impression. Two patients in this study were offered temporal lobectomies and one had a functional hemispherectomy; all three became seizure-free. The other three were excluded from surgery because of bilateral memory deficits, bilateral sharp waves, and/or “extratemporal” semiology. With a single exception, none of these patients had meningitis in early childhood (in contrast to the patients in the other three publications listed in table 2), whereas all had a prolonged epilepsy course. The higher rate of bilateral temporal pathology after a cerebral infection later in life has been previously reported (Lancman and Morris, 1996). In this study, in that of Marks et al. (1992), as well as the studies listed in table 2, successfully operated patients with epilepsy after BM and unilateral MTLE had meningitis in early childhood.
The reported high rates of invasive recordings in studies of epilepsy surgery in patients with epilepsy after BM (Sellner and Trinka, 2012) may reflect a more cautious approach in patients with MTLE following bacterial meningitis. However, these rates may also be attributed to the fact that some of these publications are somewhat older, representing an era of more generous indication for invasive recordings in MTLE than nowadays. Experienced epileptologists should be able to classify an epilepsy post BM correctly as “pure MTLE”, “temporal lobe epilepsy plus” (Kahane et al., 2015; Barba et al., 2016), a neocortical temporal lobe epilepsy, or an epilepsy linked to “dual pathology”. Of particular value for the diagnosis of MTLE after BM is the history of a “silent period” after the acute seizures occurring during meningitis in early childhood. Of concern is the long duration of epilepsy to surgery in all four reports dealing with meningitis in early childhood and the onset of epilepsy at school age (latency between 21 and 26 years; table 2), which is considerably longer than for other MTLE patients. The benefits of epilepsy surgery for patients with epilepsy after BM in early childhood presenting with symptoms, signs and MRI findings (hippocampal atrophy) concordant with the diagnosis of MTLE are still not as widely known as they deserve to be. In the only report dealing exclusively with epilepsy after BM during the first 4 years of life, 12/13 underwent an anterior temporal lobectomy, resulting in seizure freedom in all cases (Davies et al., 1996).Non-MTLE after bacterial meningitis
Neocortical epilepsies after BM are focal, multifocal, or even hemispheric, and the presumed epileptogenic lesions are MRI-visible. These correspond to neocortical scars as a result of a meningoencephalitis with a severe course or as a result of meningitis with late or ineffective antibiotic treatment. With the exception of patients with dramatic, widespread bi-hemispheric brain damage, a correlation of seizure semiology, interictal and ictal EEG findings with the localization of the MR-visible epileptogenic neocortical scars is feasible in most cases.
It should be noted that the extent of the epileptogenic zone in neocortical epilepsy after BM and its full or partial overlap with the extent of MRI-visible cortical scar(s) may differ considerably between postnatal meningitis and meningitis occurring later in life. Despite the lack of conclusive publications on this topic, there is some evidence that the epileptogenic zone in postnatal epilepsy after BM is larger than the visible cortical scar, due to “acquired cortical dysplasia” (Marín-Padilla, 1999). This observation is analogous to the patterns of cortical scarring encountered in pre-/perinatal stroke and to watershed lesions after hypoxic-ischaemic events in mature neonates. This consideration should be kept in mind when discussing the indication of invasive recordings in patients with neocortical epilepsy after BM. Further analogies to the two other aetiologies mentioned above are evident in the presence of widespread white matter damage in some cases and, possibly, in the additional presence of benign focal epileptiform discharges of childhood. If clinicians fail to appreciate these interictal discharges as benign, a child with refractory epilepsy after BM might be unjustifiably rejected for epilepsy surgery.
In some cases, brain damage due to the acute meningitis itself or due to the prolonged hemiconvulsions during the acute illness is so extensive as to consider hemispherectomy/hemispherotomy. Children with refractory epilepsy and contralateral hemiparesis related to hemispheric post-infectious scarring may profit from a hemispheric resection or disconnection. In a recent hemispherotomy cohort (Ramantani et al., 2013c), only one of 52 children and adolescents had a porencephalic cyst due to meningitis at the age of 4 years.
Epilepsy after neurocysticercosis
Neurocysticercosis (NCC) is most prevalent in Middle and South America, sub-Saharan regions of Africa, South-East Asia, particularly areas of China, and northern India. However, there are huge regional variations (Winkler, 2012), not only from continent to continent, but also from region to region in a given country, from rural areas to cities in the same province, from regions with a predominantly Muslim population to neighbouring areas with a different religion or prevalent ethnic group. NCC is practically non-existent in the province of Kerala that has a very high rate of literacy, but was the underlying aetiology of symptomatic focal epilepsy in 48% of 558 children from another province in south India (Murthy and Yangala, 2000). It should be noted that young children are less often and less severely affected in comparison to adults.
Due to the increased streams of migration from countries in which NCC is endemic to non-endemic countries, it is likely that physicians in more developed parts of the world will see mores patients with this disease in the near future (Serpa and White, 2012). Despite the availability of NCC treatment recommendations, NCC patients may not be correctly diagnosed and treated in the developed world. This is due to the limited exposure of physicians in the developed world to this disease (Garcia and Del Brutto, 2005; Nash et al., 2006; Singhi, 2011; Del Brutto, 2012a; Del Brutto and García, 2012). Nevertheless, according to a recent review (Del Brutto, 2012b), the risk of acquiring the disease for people travelling between countries to endemic areas is low, though it may increase for long-term stays.
The gold standard in NCC diagnostics is neuroimaging. MRI is superior to CT (Singhi, 2011; Verma and Lalla, 2012), but MRI is far less available than CT in developing countries (which, however, is sufficient in most cases). Patients with NCC from the Indian subcontinent present more often with single lesions, whereas those from Africa, Middle- and South America present more often with multiple lesions (Winkler, 2012). There are absolute, major, minor and epidemiological criteria for the diagnosis of NCC (Del Brutto et al., 2001; Del Brutto, 2012a). The main differential diagnoses are metastases, toxoplasmosis, and tubercula in the brain. In the diagnostic workup, diffusion weighted images and MRI-spectroscopy may be useful (Del Brutto et al., 1996; Carpio, 1998).
The majority of NCC cases are asymptomatic (Sanchez et al., 1999; Singhi et al., 2000; Fleury et al., 2003; Montano et al., 2005; de Almeida and Torres, 2011; Prasad et al., 2011). However, epileptic seizures are the main neurological manifestation, present in over 90% of symptomatic NCC (Monteiro et al., 1992; Singhi et al., 2000; Medina et al., 2005). Seizures in NCC, particularly new-onset seizures, seem to occur more often during the active and transitional stages than during the degenerative stage of NCC (Carpio, 1998), although regional differences may again be noted (Singhi, 2011).
Incidence and prevalence of epilepsy after neurocysticercosis
NCC resulting from infection with the larvae of the porcine tapeworm Taenia solium is the most frequent cause of new-onset epilepsies in many parts of the world, mainly in developing countries (Relationship between epilepsy and tropical diseases, 1994; Román et al., 2000; Garcia and Del Brutto, 2005). NCC is reportedly the underlying cause in up to 30% of epilepsies in the developing world (Burneo et al., 2009). Particularly grim figures regarding the burden of NCC-associated chronic epilepsy in sub-Saharan countries are outlined in a recent review (Winkler, 2012). These figures are high because, among other reasons, many affected persons in resource-poor countries do not take AEDs or do not take them regularly. Extremely puzzling is the considerable variability in chronic epilepsy prevalence in countries where NCC is endemic. NCC was the cause of new-onset epilepsy in 50% of affected persons in a population-based study from a rural area in Peru (Villarán et al., 2009), and the cause of symptomatic epilepsy in only 12/346 (4%) patients in a report from West-China. Figures of around 30%, 37%, and 37% are reported in publications from Peru and Honduras (Gaffo et al., 2004; Medina et al., 2005; Montano et al., 2005, respectively). A total of 48% of children with epilepsy seen at the university hospital in Hyderabad, India, had epilepsies associated with NCC (Murthy and Yangala, 2000).
Drug-resistance in NCC
Most publications on NCC-related epilepsy support that seizures are controlled by AEDs more successfully than for most other aetiologies. This holds true especially for some recently reported paediatric cases from India. Features contributing to this favourable course are the presence of predominantly non-calcified lesions in children (15% calcified lesions vs. 55% in adults), as well as the tendency of lesions to disappear during follow-up in a quarter to a third of cases (Gadgil and Udani, 2011). The recurrence rate after AED withdrawal is higher in patients with multiple and calcified lesions (Singhi, 2011). However, it is difficult to get a clear picture regarding the prevalence of drug-resistant epilepsies. Only 8/512 (2%) patients with drug-resistant epilepsies seen at the outpatient clinic in Ribeirao Preto in Brazil had “isolated neurocysticercosis” due to calcified lesions. Calcified lesions were found in 27% of patients with MTLE. However, according to the physiciańs view in this renowned epilepsy centre, these lesions were unrelated to the MTLE.
Two major issues remain unanswered regarding epilepsy after NCC. It is still unclear whether, in patients with NCC, hippocampal sclerosis results from recurrent seizure activity from a local or distant focus or chronic recurrent inflammation (Singla et al., 2007; Del Brutto et al., 2016). In either case, hippocampal sclerosis may become the pathological substrate of subsequent MTLE. The role of calcified NCC lesions in epilepsy pathogenesis and their inter-relations with co-existing hippocampal sclerosis are yet to be clarified (Singh et al., 2000; Nash et al., 2004; Velasco et al., 2006; Singla et al., 2007; Bianchin et al., 2013; de Oliveira Taveira et al., 2015). Four different hypotheses have been considered:
- –coincidence, since both entities are relatively common in endemic areas;
- –calcified NCC lesions and MTLE related to hippocampal sclerosis are associated, but not causally related;
- –NCC may directly cause MTLE related to hippocampal sclerosis by inflammation and structural damage to the hippocampi or cortex by the acute phase of cysticerci located in the vicinity -apparently not applicable for non-temporal NCC;
- –and NCC is rather a trigger than the direct cause of the epileptogenic process leading to MTLE.
Surgery for epilepsy after neurocysticercosis
For a condition so often linked to chronic epilepsy, one would expect that a significant proportion of patients would undergo epilepsy surgery, especially since there are excellent epilepsy surgery centres in countries where NCC is endemic, such as China, Brazil, India, and South Africa. Nevertheless, the numbers of operated patients with refractory epilepsy caused by NCC are very low, whereas most of them have MTLE (Leite et al., 2000; da Gama et al., 2005; Chandra et al., 2010; Bianchin et al., 2013; Rathore et al., 2013; Meguins et al., 2015).
In a study from the epilepsy centres in Ribeirao Preto and Campinas, Brazil, no clinical or electroencephalographic differences were found between patients with MTLE and those with MTLE linked to NCC-related calcified MRI lesions (da Gama et al., 2005; Leite et al., 2000). Furthermore, these two groups did not differ in surgical outcome. Therefore, it was concluded that the calcified lesions in these patients were coincidental findings in a population where NCC is endemic and where most affected persons are asymptomatic. This conclusion has been recently challenged in a study with favourable postsurgical outcomes linked to the resection of calcified lesions, located within the temporal lobe, in addition to the resection of the mesial temporal structures (Rathore et al., 2013). Furthermore, although there was no difference regarding Engel I outcomes, more patients with MTLE alone had Engel Ia outcomes compared to patients with MTLE plus NCC. An excellent discussion about the issue of whether NCC-related calcified lesions are causative or not in MTLE can be found in a recent review (Singh and Chowdhary, 2014).
Reports of extratemporal epilepsy surgery in patients with NCC and epilepsy are exceedingly rare. In a study from India, 4/5 patients were seizure-free after extratemporal epilepsy surgery (Rathore et al., 2013). In a case report from Malaysia, the resection of a cysticercotic granuloma within the left frontal lobe led to seizure freedom (Hasan et al., 2011). The paucity of data on extratemporal surgery for NCC-related epilepsy may be attributed to the fact that even experienced epilepsy centres may hesitate to proceed to surgery when multiple lesions are present. Another reason may be that epilepsies caused by singular extratemporal NCC-related calcified lesions usually respond to AEDs. Several authors have discussed the pathophysiological mechanisms responsible for rendering NCC-related calcified lesions epileptogenic. One possible mechanism is immunoreaction by the host leading to a (subtle) inflammatory “perifocal reaction”. Perfusion MRI may help to differentiate epileptogenic from non-epileptogenic calcified lesions (Gupta et al., 2012).
Surgery for epilepsy caused by rare infectious agents
On very rare occasions, patients with cerebral tuberculomas, schistosomiasis, and other rare infectious agents may undergo epilepsy surgery.
In a five-case epilepsy surgery series from Bangladesh (Chowdhury et al., 2010), one of the patients suffered from a tuberculoma. The patient presented typical mesial temporal seizures with increasing frequency for over almost a year without any neurological deficit or deterioration of general condition or cognitive functions. MRI showed a hyperintense lesion in the anterior/mesial temporal lobe, initially attributed to meningioma or ependymoma. The patient underwent standard anterior temporal lobectomy with amygdalohippocampectomy. Histopathology revealed brain tuberculosis. At the last follow-up visit, at five months, the patient was seizure-free without taking AEDs. Tuberculosis is not rare in Bangladesh, but its presentation with MTLE without any systemic symptoms and signs is unusual. A study on epilepsy surgery for post-infectious encephalitis from New Delhi, India (Chandra et al., 2010) included three patients with tuberculosis, as well as a case of gliotic scars and multiloculated hydrocephalus following tuberculosis meningitis in the first year of life. This patient with the extensive tuberculosis-related brain damage underwent hemispherotomy. The remaining three patients underwent a resection of the mesial temporal structures, a neocortical temporal resection, and a frontal resection. At the last follow-up visit, at over a year after surgery, all four patients were seizure-free.
Schistosomiasis is the most common trematode infection, widely distributed in Asia, Africa, and Latin America. Schistosomal granuloma results from a host-to-pathogen interaction that triggers an immune response and manifests similarly to a brain tumour. In a large surgical series from the Wuhan Tongji Hospital, China in 1955-2004 (Lei et al., 2008), 250 patients with seizures as the initial symptom of cerebral granulomas caused by Schistosoma japonicum and drug-resistant epilepsy later on underwent surgery 2-12 years after epilepsy onset. After 4-5 years of follow-up, four patients died as a result of the schistosomal liver cirrhosis and ten died of natural causes; of the remaining 196 cases, 180 (92%) were seizure-free. All patients in this series presented chronic schistosomiasis with hepatosplenomegaly, ascites, and esophagogastric varices in more than half of the cases.