Does gender influence susceptibility and consequences of acquired epilepsies?

YNBDI-03220; No. of pages: 6; 4C: Neurobiology of Disease xxx (2014) xxx–xxx

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Does gender influence susceptibility and consequences of acquired epilepsies? Piero Perucca a,b,c,⁎, Peter Camfield d, Carol Camfield d a

Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia Department of Neurology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia d Department of Pediatrics, Dalhousie University and IWK Health Centre, Halifax, Nova Scotia, Canada b c

a r t i c l e

i n f o

Article history: Received 25 February 2014 Revised 11 May 2014 Accepted 17 May 2014 Available online xxxx Keywords: Acquired epilepsy Symptomatic epilepsy Cryptogenic epilepsy Gender Incidence Prognosis Stroke Traumatic brain injury Tumor Hippocampal sclerosis

a b s t r a c t Gender differences in the incidence and clinical course of acquired and “cryptogenic” epilepsy are reviewed based on a literature search. We emphasized incidence and population-based studies because they are best suited to assess the effect of gender on susceptibility and clinical evolution of these epilepsies and may control for potential confounding factors. However, such studies were only available for a few acquired etiologies. These included tumor, prenatal and perinatal brain insults, cerebrovascular disease, infection, trauma, neurodegenerative disease, and autoimmune disorders. None of these acquired causes has been consistently shown to affect women or men to a greater or lesser degree, although some of the literature is contradictory or inadequate. There is almost no literature that addresses the effect of gender on the clinical course of epilepsy associated with these acquired causes. In addition, most studies of acquired causes do not take into account the incidence of the cause in the population with or without associated epilepsy. In children, “cryptogenic” epilepsy (non-syndromic and without causative MRI lesion) does not appear to have a gender preference and gender does not seem to affect the likelihood of remission. As further population-based studies of the etiology and clinical course of epilepsy are undertaken, it may be worthwhile to more specifically define the role of gender. © 2014 Elsevier Inc. All rights reserved.

Introduction Epidemiological data suggest that gender may affect susceptibility to epilepsy and its prognosis. Most studies found that the overall incidence of epilepsy is slightly higher in men than women, both in developing and industrialized countries (Benn et al., 2008; Christensen et al., 2007; Hauser et al., 1993; Lavados et al., 1992; Tekle-Haimanot et al., 1997), although this difference rarely reaches statistical significance (Joensen, 1986). In a systematic review and meta-analysis of incidence studies, the median annual incidence of epilepsy was 50.7/100 000 for men and 46.2/100 000 for women (p value not significant) (Kotsopoulos et al., 2002). Pediatric population-based studies find the ratio of males and females essentially equal (Arts et al., 2004; Berg et al., 2001; Camfield et al., 1996; Ross et al., 1980; Sidenvall et al., 1993; Wirrell et al., 2011b). The likelihood of seizure remission does not differ significantly between men and women (Cockerell et al., 1997), but male gender is

⁎ Corresponding author at: Departments of Medicine and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia. Fax: +61 3 93428628. E-mail address: [email protected] (P. Perucca). Available online on ScienceDirect (www.sciencedirect.com).

associated with a greater risk of premature death (Forsgren et al., 2005), including sudden unexpected death in epilepsy (SUDEP) (Hesdorffer et al., 2011). In a pooled analysis of case–control studies (Hesdorffer et al., 2011), male gender carried a 1.42-fold increased risk for SUDEP (95% C.I.: 1.07–1.88). In pediatric populations, gender may not exert an effect on mortality. In a recent combined analysis of four population-based pediatric cohorts including 2239 children with newly diagnosed epilepsy followed N 30000 person-years, 69 deaths occurred (37 males and 32 females) (Berg et al., 2013). Male and female subjects were approximately equally represented across cause of death categories (SUDEP; seizurerelated, not SUDEP; other natural; non-natural). However, given the small numbers involved, formal statistical tests were not conducted. Gender differences are also identifiable at the level of specific forms of epilepsy, particularly those in which genetic predisposition has a central role in the development of the disease (genetic epilepsies) (Christensen et al., 2005; Dibbens et al., 2008; Kleveland and Engelsen, 1998; Scheffer et al., 2008). Despite the wide range of environmental factors leading to the development of epilepsy, limited research has investigated the influence of gender in acquired epilepsies (Berg et al., 2010; Christensen et al., 2005; Hauser et al., 1993). Some etiologies of acquired epilepsies, such as traumatic brain injury (TBI), are more common in one gender. As a group, symptomatic epilepsies, which according to the 1989 International

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Please cite this article as: Perucca, P., et al., Does gender influence susceptibility and consequences of acquired epilepsies?, Neurobiol. Dis. (2014), http://dx.doi.org/10.1016/j.nbd.2014.05.016

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League Against Epilepsy (ILAE) terminology also included acquired epilepsies (Commission on Classification and Terminology of the International League Against Epilepsy, 1989), are slightly more common in men (Christensen et al., 2005; Hauser et al., 1993; Manford et al., 1992). Symptomatic epilepsies are associated per se with excess mortality (Hauser and Beghi, 2008), but no significant differences have been observed between sexes (Sillanpaa and Shinnar, 2010; Strauss et al., 2003). The combined analysis of four large populationbased pediatric cohorts of newly diagnosed patients demonstrated an excess mortality among the symptomatic epilepsies, but no differences in gender (Berg et al., 2013). In this article, we will review available evidence on the impact of gender in different types of acquired epilepsies, highlight limitations of the current literature, and provide recommendations for future studies. For the purposes of this review, “acquired epilepsies” are defined as epilepsies due to external or environmental causes (e.g. traumatic brain injury) as well as internal pathological processes (e.g. autoimmune disorders), in which no clear genetic component is involved. In addition, we will focus on population-based and incidence studies, as prevalence estimates can be misleading if used for etiologic studies or to provide information on prognosis (Hauser et al., 1993). This is not a systematic review and reflects our own assessment of the literature available in this area. We searched PubMed up to January 31st, 2014, using the terms “epilepsy”, “seizures”, “incidence”, and “population-based”. These were combined with specific causes of acquired epilepsy, such as “hippocampal sclerosis”, “febrile status epilepticus”, “tumor”, “glioma”, “meningioma”, “prenatal brain insults”, “perinatal brain insults”, “birth asphyxia”, “birth ischemia”, “birth infection”, “cerebrovascular disease”, “stroke”, “hemorrrhage”, “infection”, “meningitis”, encephalitis”, “trauma”, “traumatic brain injury”, “neurodegenerative disease”, “dementia”, “Alzheimer’s disease”, and “autoimmune disorders”. A separate search was done for “cryptogenic epilepsy”. Additional studies were sought in reference lists of retrieved articles and in our personal files. Of note, the term cryptogenic epilepsy is used here to reflect the inclusion criteria of studies performed prior to the most recent ILAE classification of epilepsies (Berg et al., 2010). Causes of acquired epilepsies and gender differences Hippocampal sclerosis/febrile status epilepticus Hippocampal sclerosis is the most common histopathological finding in adults with drug-resistant temporal lobe epilepsy (Blumcke et al., 2013). Febrile status epilepticus has been associated with hippocampal injury and subsequent hippocampal sclerosis and temporal lobe epilepsy (Lewis et al., 2002; Provenzale et al., 2008). In a U.K. population-based study of convulsive status epilepticus in childhood, the incidence of first ever episodes of febrile status epilepticus was comparable in boys and girls (5.5/100 000/year vs 4/100 000/year) (Chin et al., 2006). In a prospective, multicenter, case–control study comparing children with a first febrile status epilepticus (n = 169) and those with a first simple febrile seizure (n = 102), female gender was found to be a risk factor for febrile status epilepticus (multivariate OR [95% C.I.] = 2.2 [1.14–4.43]) (Hesdorffer et al., 2013). The development of epilepsy in these cohorts, as well as any associated gender differences, has yet to be assessed. To our knowledge, no incidence study has explored gender differences in patients with epilepsy and hippocampal sclerosis. Retrospective studies mostly from tertiary epilepsy care centers suggest that hippocampal sclerosis occurs with equal frequency in men and women with epilepsy (Blumcke et al., 2002; Briellmann et al., 1999). In another retrospective study, female gender was found to be a predictor of poorer outcome following surgery for temporal lobe epilepsy associated with hippocampal sclerosis (Burneo et al., 2006); this was not confirmed in a subsequent investigation by the same group (Burneo et al., 2008). In an MRI study including 60 patients with drug-resistant temporal lobe

epilepsy (70% of whom had hippocampal sclerosis), men were found to have more brain atrophy than women (Briellmann et al., 2000). Seizure frequency was a factor contributing to reduced brain volumes in men but not in women, suggesting that male gender may be associated with greater vulnerability to seizure-related brain damage. Overall, these findings should be interpreted with caution, as they were obtained retrospectively in highly selected patient samples. Tumor Brain tumors account for 4–8% of cases with newly diagnosed epilepsy (Hauser et al., 1993; Olafsson et al., 2005). In patients with brain tumors, epileptic seizures occur in 10–100% depending on tumor type (van Breemen et al., 2007). A Swedish study assessing the incidence of unprovoked seizures in a catchment area of N100 000 people found that tumor-related seizures were five times as common in men compared to women (10/100 000/year vs 2/100 000/year, calculated from study results) (Forsgren et al., 1996). However, in the few other studies exploring gender differences in tumor-related epilepsy, similar rates were found in men and women (Adelow et al., 2009; Beilmann et al., 1999; Forsgren, 1990). It should be noted that none of the studies controlled for gender differences in the incidence of tumors in the investigated populations. To our knowledge, there are no other data from incidence studies on the effect of gender in tumor-related epilepsies. Small, retrospective, single-center, cohort studies of patients with tumors have found no significant differences in the male-to-female ratio between patients developing unprovoked seizures and those who did not (Alajbegovic et al., 2009; Lieu and Howng, 2000). Gender was not correlated with post-operative seizure control in retrospective series of patients with tumor-related epilepsy who underwent tumor resection (Luyken et al., 2003; Zaatreh et al., 2003). Prenatal and perinatal insults Prenatal and perinatal insults, including infections, asphyxia and hemorrhage, are important risk factors for the development of epilepsy (Beilmann et al., 1999; Larsson and Eeg-Olofsson, 2006). In a population-based study from Estonia, the incidence of childhood epilepsy due to perinatal factors was similar in boys and girls (11/100000/year vs 12/100000/year) (Beilmann et al., 1999). Comparative assessments for individual types of factors were not carried out. In a Swedish study assessing the incidence of epilepsy and unprovoked seizures in a catchment area of ~1 million people, rates of seizures attributable to hypoxic–ischemic encephalopathy were comparable between men and women (0.4/100 000/year vs 0.5/100 000/year, calculated from study results) (Adelow et al., 2009). It should be noted that neither study adjusted for potential gender differences in the incidence of perinatal insults in the investigated populations. To our knowledge, there are no other data on the influence of gender on epilepsies due to prenatal or perinatal insults. Cerebrovascular disease Stroke is a leading cause of epilepsy in adults, accounting for up to 15% of all etiologies in patients aged 34–64 years (Hauser et al., 1993). Its relevance is even greater in the elderly, in which almost one-third of cases with newly diagnosed epilepsy appear to be stroke-related (Hauser et al., 1993). Available evidence indicates that gender does not influence susceptibility to post-stroke epilepsy. Gender was not associated with the development of post-stroke epilepsy in large, population-based, cohort studies of patients with stroke (Chen et al., 2012; Fox et al., 2013; Graham et al., 2013; Jungehulsing et al., 2013; Kammersgaard and Olsen, 2005; So et al., 1996). In three of these studies, results were adjusted for potential confounders, including age, vascular risk factors, stroke type, severity and location, and acute

Please cite this article as: Perucca, P., et al., Does gender influence susceptibility and consequences of acquired epilepsies?, Neurobiol. Dis. (2014), http://dx.doi.org/10.1016/j.nbd.2014.05.016

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symptomatic seizures (Chen et al., 2012; Fox et al., 2013; Jungehulsing et al., 2013). The relationship between gender and susceptibility to post-stroke epilepsy was also investigated in three population-based incidence studies of epilepsy and unprovoked seizures (Adelow et al., 2009; Forsgren, 1990; Forsgren et al., 1996). In two of these, rates of seizures attributable to a prior ischemic and/or hemorrhagic stroke were similar in both sexes (Adelow et al., 2009; Forsgren et al., 1996). In the third study, which assessed the incidence of unprovoked seizures in a catchment area of N100 000 adults, seizures due to hemorrhagic stroke were three times as common in men as in women (3/100 000/year vs 1/100 000/year, calculated from study results), but numbers were too small to allow meaningful comparisons (Forsgren, 1990). It should be noted that none of three studies accounted for potential gender differences in the incidence of stroke in the investigated population. To our knowledge, no incidence study has explored the effect of gender on consequences of post-stroke epilepsy. In a small, retrospective, single-center study of patients with late post-stroke seizures, there were no significant differences in the male-to-female ratio between patients who experienced persistent worsening of stroke sequelae following a seizure and those who did not (Bogousslavsky et al., 1992). Infection Infections of the central nervous system (CNS) account for 1–5% of cases with newly diagnosed epilepsy (Hauser et al., 1993; Murthy and Prabhakar, 2008). In survivors of CNS infections, the risk of developing unprovoked seizures ranges between 6.8% and 8.3% (Annegers et al., 1988; Rantakallio et al., 1986). Limited data are available on gender differences in epilepsies due to prior CNS infections. In two populationbased incidence studies of epilepsy and unprovoked seizures, rates of seizures attributable to CNS infections were almost twice as high in men as in women, but numbers were too small to allow meaningful comparisons (Adelow et al., 2009; Beilmann et al., 1999). Of note, neither study adjusted for potential gender differences in the incidence of CNS infections in the investigated populations. Moreover, comparative assessments for specific types of infections were not performed. To our knowledge, there are no other data from incidence studies on the effect of gender in epilepsies related to CNS infections. A retrospective study of 108 patients treated for brain abscess at a single center found a higher proportion of men subsequently developing epilepsy than women (69% vs 22%, p b 0.05) (Koszewski, 1991). These findings were not confirmed in another, yet smaller, study (Kilpatrick, 1997). Trauma Traumatic brain injury (TBI) is a major cause of acquired epilepsy in adults, accounting for about 30% of identified etiologies in patients aged 16–34 years (Hauser et al., 1993). The risk of developing unprovoked seizures is directly related to the severity of TBI (Annegers et al., 1998; Lowenstein, 2009). Evidence on the effect of gender in post-traumatic epilepsy is conflicting. In a Danish population-based study of posttraumatic epilepsy including N 1.6 million children and young adults, the relative risk of developing epilepsy after mild brain injury was slightly, yet significantly, higher in women than in men (2.49 [95% C.I.: 2.25–2.76] vs 2.01 [1.83–2.22]) (Christensen et al., 2009). There was no significant interaction with gender for patients with skull fractures or severe brain injury. In a Taiwanese population-based study of N19 000 TBI patients and N 540 000 non-TBI subjects, men were found to be at significantly higher risk of post-traumatic epilepsy than women (hazard ratio = 1.7 [95% C.I., 1.3–2.1]) (Yeh et al., 2013). The interaction between gender and TBI severity was not assessed. In a U.S. population-based cohort study of N2000 patients with TBI, gender was not significantly associated with post-traumatic epilepsy, while adjusting for several variables including age, TBI severity, early post-

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traumatic seizures, etiology of the injury, and comorbidities (Ferguson et al., 2010). The relationship between gender and post-traumatic epilepsy has also been explored in four population-based incidence studies of epilepsy and unprovoked seizures (Adelow et al., 2009; Beilmann et al., 1999; Forsgren, 1990; Forsgren et al., 1996). In three of these (Adelow et al., 2009; Beilmann et al., 1999; Forsgren, 1990), seizures due to a prior head injury were two to six times as common in men as in women. In the fourth study (Forsgren et al., 1996), the incidence of post-traumatic seizures was almost three times higher in women than in men. None of these studies accounted for potential gender differences in the incidence of TBI and its severity in the investigated populations. In addition, the number of cases with post-traumatic seizures was generally small. To our knowledge, there are no data on the effect of gender on consequences of post-traumatic epilepsy. Neurodegenerative disorders Neurodegenerative disorders, including Alzheimer's disease and other types of dementia, account for almost 4% of cases with newly diagnosed epilepsy (Hauser et al., 1993; Hesdorffer et al., 1996). This rate increases to ~ 10% in patients aged 65 years or older (Hauser et al., 1993). In a UK population-based cohort study of ~7000 patients with Alzheimer's disease and N 4000 patients with vascular dementia, the incidence of epilepsy/unprovoked seizures did not differ significantly between men and women with Alzheimer's disease (5.1/1000 person-years [95% C.I.: 3.4–7.4] vs 5.9/1000 person-years [4.7–7.4]) or vascular dementia (8.7/1000 person-years [5.9–12.8] vs 6.7/1000 person-years [4.6–9.5]) (Imfeld et al., 2013). A three-center, prospective, cohort study of patients with Alzheimer's disease failed to find an association between gender and the development of unprovoked seizures in Alzheimer's disease, adjusting for potential confounders such as age, race/ethnicity, educational achievement, duration of illness, baseline function, cognition, depression, and medical comorbidities (Scarmeas et al., 2009). Neurodegenerative pediatric disorders have a variety of genetic patterns of inheritance (most commonly recessive or sex linked) which may lead to a slight male predominance. However, it is difficult to document due to the numerous types of neurodegenerative conditions. The relationship between gender and susceptibility to epilepsy due to neurodegenerative disorders was also explored in three populationbased incidence studies of epilepsy and unprovoked seizures (Adelow et al., 2009; Beilmann et al., 1999; Forsgren et al., 1996). In two of these, seizures attributable to neurodegenerative diseases (Beilmann et al., 1999) or dementia (Adelow et al., 2009) were almost twice as common in men as in women. In the third study, rates of seizures due to Alzheimer's disease were about two times higher in women compared to men (Forsgren et al., 1996). None of these studies controlled for potential gender differences in the incidence of neurodegenerative disorders and their risk factors in the investigated populations. In addition, the number of cases with seizures due to neurodegenerative disorders was small. To our knowledge, there are no data from incidence studies on the effect of gender on consequences of epilepsy due to neurodegenerative disorders. Autoimmune disorders The pathogenic role of autoimmune processes in epilepsy is increasingly being recognized (Bien and Scheffer, 2011). This is supported by the increased risk of seizures in certain autoimmune disorders (e.g. systemic lupus erythematosus and Hashimoto’s encephalopathy) as well as the efficacy of immunomodulating treatments in some forms of epilepsy (Bien and Scheffer, 2011). Specific autoantibodies have also been identified in a number of neurologic conditions often presenting with recurrent seizures (Bien and Scheffer, 2011). There are very limited data on the influence of gender in epilepsies related to autoimmune

Please cite this article as: Perucca, P., et al., Does gender influence susceptibility and consequences of acquired epilepsies?, Neurobiol. Dis. (2014), http://dx.doi.org/10.1016/j.nbd.2014.05.016

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processes. In a population-based Swedish study of N100 000 adults, the incidence of unprovoked seizures related to immunological etiologies was twice as high in men as in women (2/100 000/year vs 1/100 000/year, calculated from study results), but numbers were too small to allow meaningful comparisons (Forsgren et al., 1996). Moreover, this study did not account for potential gender differences in the incidence of immunological factors in the investigated population. To our knowledge, there are no other data from incidence studies on the effect of gender in epilepsies due to autoimmune disorders. An initial small cohort study suggested that, in systemic lupus erythematosus, seizures might be more common in men than in women (Ward and Studenski, 1990). However, these findings were not confirmed by subsequent larger multi-center investigations (Hanly et al., 2012; Molina et al., 1996). Unknown cause (cryptogenic epilepsy) The assessment of the influence of gender on susceptibility and consequences of acquired epilepsies of unknown cause is fraught with difficulties, as it largely relies on studies on “cryptogenic epilepsy”. First, cryptogenic epilepsies as defined by the 1989 ILAE Classification (Commission on Classification and Terminology of the International League Against Epilepsy, 1989) were not restricted to acquired forms of epilepsy, and therefore results of studies conducted in this category of patients may have been confounded by inclusion of patients in whom epilepsy had a non-identified genetic etiology. Second, many epidemiological studies conducted in the last two decades combined cryptogenic and idiopathic epilepsies into one group, thereby precluding any assessment of incidences rates or outcomes specific for cryptogenic epilepsy. Third, the ability to identify structural or metabolic etiologies (which would exclude a diagnosis of cryptogenic epilepsy) is dependent on local expertise and facilities, and is strongly influenced by the period in which the study was performed. For example, in the pre-MRI era, many cases of focal cortical dysplasia, for which modern imaging techniques would clearly reveal the underlying cause, would have been misclassified as having cryptogenic epilepsy. Taking these limitations into account, three population-based incidence studies of childhood epilepsy conducted in the MRI era have assessed the effect of gender on cryptogenic epilepsy, separately from idiopathic cases. In all these studies, incidences of cryptogenic epilepsy were comparable in both genders (Beilmann et al., 1999; Dura-Trave et al., 2008; Wirrell et al., 2011b).

Information on the effect of gender on susceptibility to cryptogenic epilepsy can be also extrapolated from two other pediatric incidence studies. The first is the Nova Scotia population-based study of incident cases of childhood-onset epilepsy, which has been the subject of previous reports (Camfield and Camfield, 2007, 2013; Camfield et al., 1996). This consisted of 692 cases, 131 of which (19%) had non-syndromic, non-lesional epilepsy (i.e. cryptogenic epilepsy). Of these, 58 (44%) were males and 78 (56%) were females (unpublished data). The second study consisted of a community-based cohort of 613 cases with onset of epilepsy between ages of 1 month and 16 years (Berg et al., 2011). In the 294 cases with non-syndromic epilepsy and ≥ 10 years of followup (81% with a normal MRI), males and females were almost equally represented (51% vs 49%). Overall, these findings suggest that gender does not influence susceptibility to cryptogenic epilepsy. Gender may also not have an effect on the prognosis of cryptogenic epilepsy. In a U.S. population-based cohort study of children with cryptogenic focal epilepsy, gender was not found to be a predictor of remission of seizures or development of drug-resistant epilepsy (Wirrell et al., 2011a). Limitations of current literature This review highlighted the scarcity of available data on sex differences in the susceptibility to acquired epilepsies. Even less information exists on the influence of gender on consequences of acquired epilepsies. The above shortcomings are compounded by the fact that the few existing data are derived from studies which are not free from limitations. Most of these are population-based incidence studies of epilepsy and unprovoked seizures, which are suboptimal to assess gender differences in acquired epilepsies for the following reasons: a) they do not account for potential gender differences in the incidence of causes of acquired epilepsies (or their risk factors) in the investigated populations; b) their sample size is often too small to allow assessment of gender differences in uncommon etiologies, such as CNS infections or autoimmune disorders; c) they do not usually provide information on specific subtypes of etiologies, such as different types of perinatal insults or CNS infections. Some of these limitations may also explain why some of these studies reported inconsistent or conflicting results. Population-based cohort studies of incident cases with specific causes of acquired epilepsy are the ideal design to assess the effect of gender on susceptibility and consequences of these, as they allow for

Table 1 Summary of the evidence from incidence studies providing data on gender differences in the susceptibility to acquired epilepsies and their consequences. Underlying epilepsy etiology

Susceptibility

Consequences

References

Hippocampal sclerosis/febrile status epilepticus Tumor

No data

No data

n/a

No apparent gender differences in the incidence of tumor-related epilepsy No apparent gender differences in the incidence of epilepsy due to perinatal insults No gender differences in the incidence of post-stroke epilepsy

No data

(Adelow et al., 2009; Beilmann et al., 1999; Forsgren, 1990; Forsgren et al., 1996) (Adelow et al., 2009; Beilmann et al., 1999)

Infection Trauma

Insufficient data to draw conclusions Conflicting data on the effect of gender on post-traumatic epilepsy

No data No data

Neurodegenerative disorders

Conflicting data on the effect of gender on epilepsy due to neurodegenerative disorders Insufficient data to draw conclusions No apparent gender differences in the incidence of childhood cryptogenic epilepsy

No data

Prenatal and perinatal insults Cerebrovascular disease

Autoimmune disorders Unknown cause (cryptogenic epilepsy)

No data No data

No data No effect of gender on seizure remission or development of drug-resistance in childhood cryptogenic focal epilepsy

(Adelow et al., 2009; Chen et al., 2012; Forsgren, 1990; Forsgren et al., 1996; Fox et al., 2013; Graham et al., 2013; Jungehulsing et al., 2013; Kammersgaard and Olsen, 2005; So et al., 1996) (Adelow et al., 2009; Beilmann et al., 1999) (Adelow et al., 2009; Beilmann et al., 1999; Christensen et al., 2009; Ferguson et al., 2010; Forsgren, 1990; Forsgren et al., 1996; Yeh et al., 2013) (Adelow et al., 2009; Beilmann et al., 1999; Forsgren et al., 1996; Imfeld et al., 2013) (Forsgren et al., 1996) (Beilmann et al., 1999; Berg et al., 2011; Dura-Trave et al., 2008; Forsgren et al., 1996; Wirrell et al., 2011a; Wirrell et al., 2011b)

n/a = not available.

Please cite this article as: Perucca, P., et al., Does gender influence susceptibility and consequences of acquired epilepsies?, Neurobiol. Dis. (2014), http://dx.doi.org/10.1016/j.nbd.2014.05.016

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control of potential confounding factors. However, such studies are only available for a few selected etiologies, i.e. stroke, TBI and neurodegenerative disorders. Conclusions Limited research has been dedicated to the impact of gender on susceptibility to acquired epilepsies and their consequences. Most data are derived from studies which have not been primarily designed to address this topic. For several forms of acquired epilepsies (related to tumors, perinatal insults, cerebrovascular disease, and unknown cause), gender does not appear to influence susceptibility (Table 1). For others, data are completely missing, inadequate to draw conclusions or conflicting (Table 1). Large well-designed ad-hoc studies are ultimately needed to address the question of whether gender does have an influence on acquired epilepsies. Conflict of interest None of the authors has any conflict of interest to disclose. Acknowledgment Dr. Piero Perucca is supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS). References Adelow, C., et al., 2009. Newly diagnosed single unprovoked seizures and epilepsy in Stockholm, Sweden: first report from the Stockholm Incidence Registry of Epilepsy (SIRE). Epilepsia 50, 1094–1101. Alajbegovic, A., et al., 2009. Characteristics of symptomatic epilepsy in patients with brain tumours. Bosn J. Basic Med. Sci. 9, 81–84. Annegers, J.F., et al., 1988. The risk of unprovoked seizures after encephalitis and meningitis. Neurology 38, 1407–1410. Annegers, J.F., et al., 1998. A population-based study of seizures after traumatic brain injuries. N. Engl. J. Med. 338, 20–24. Arts, W.F., et al., 2004. Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood. Brain 127, 1774–1784. Beilmann, A., et al., 1999. Incidence of childhood epilepsy in Estonia. Brain Dev. 21, 166–174. Benn, E.K., et al., 2008. Estimating the incidence of first unprovoked seizure and newly diagnosed epilepsy in the low-income urban community of Northern Manhattan, New York City. Epilepsia 49, 1431–1439. Berg, A.T., et al., 2001. Two-year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia 42, 1553–1562. Berg, A.T., et al., 2010. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 20052009. Epilepsia 51, 676–685. Berg, A.T., et al., 2011. Complete remission in nonsyndromic childhood-onset epilepsy. Ann. Neurol. 70, 566–573. Berg, A.T., et al., 2013. Mortality risks in new-onset childhood epilepsy. Pediatrics 132, 124–131. Bien, C.G., Scheffer, I.E., 2011. Autoantibodies and epilepsy. Epilepsia 52 (Suppl. 3), 18–22. Blumcke, I., et al., 2002. Ammon's horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy. Brain Pathol. 12, 199–211. Blumcke, I., et al., 2013. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 54, 1315–1329. Bogousslavsky, J., et al., 1992. Persistent worsening of stroke sequelae after delayed seizures. Arch. Neurol. 49, 385–388. Briellmann, R.S., et al., 1999. Occurrence of hippocampal sclerosis: is one hemisphere or gender more vulnerable? Epilepsia 40, 1816–1820. Briellmann, R.S., et al., 2000. Men may be more vulnerable to seizure-associated brain damage. Neurology 55, 1479–1485. Burneo, J.G., et al., 2006. Race/ethnicity, sex, and socioeconomic status as predictors of outcome after surgery for temporal lobe epilepsy. Arch. Neurol. 63, 1106–1110. Burneo, J.G., et al., 2008. Kaplan–Meier analysis on seizure outcome after epilepsy surgery: do gender and race influence it? Seizure 17, 314–319. Camfield, P., Camfield, C., 2007. Long-term prognosis for symptomatic (secondarily) generalized epilepsies: a population-based study. Epilepsia 48, 1128–1132. Camfield, C.S., Camfield, P.R., 2013. The adult seizure and social outcomes of children with partial complex seizures. Brain 136, 593–600. Camfield, C.S., et al., 1996. Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia 37, 19–23.

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Chen, T.C., et al., 2012. The incidence rate of post-stroke epilepsy: a 5-year follow-up study in Taiwan. Epilepsy Res. 102, 188–194. Chin, R.F., et al., 2006. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 368, 222–229. Christensen, J., et al., 2005. Gender differences in epilepsy. Epilepsia 46, 956–960. Christensen, J., et al., 2007. Incidence and prevalence of epilepsy in Denmark. Epilepsy Res. 76, 60–65. Christensen, J., et al., 2009. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet 373, 1105–1110. Cockerell, O.C., et al., 1997. Prognosis of epilepsy: a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 38, 31–46. Commission on Classification and Terminology of the International League Against Epilepsy, 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389–399. Dibbens, L.M., et al., 2008. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat. Genet. 40, 776–781. Dura-Trave, T., et al., 2008. Incidence of epilepsies and epileptic syndromes among children in Navarre, Spain: 2002 through 2005. J. Child Neurol. 23, 878–882. Ferguson, P.L., et al., 2010. A population-based study of risk of epilepsy after hospitalization for traumatic brain injury. Epilepsia 51, 891–898. Forsgren, L., 1990. Prospective incidence study and clinical characterization of seizures in newly referred adults. Epilepsia 31, 292–301. Forsgren, L., et al., 1996. Incidence and clinical characterization of unprovoked seizures in adults: a prospective population-based study. Epilepsia 37, 224–229. Forsgren, L., et al., 2005. Mortality of epilepsy in developed countries: a review. Epilepsia 46 (Suppl. 11), 18–27. Fox, C.K., et al., 2013. Acute seizures predict epilepsy after childhood stroke. Ann. Neurol. 74, 249–256. Graham, N.S., et al., 2013. Incidence and associations of poststroke epilepsy: the prospective South London Stroke Register. Stroke 44, 605–611. Hanly, J.G., et al., 2012. Seizure disorders in systemic lupus erythematosus results from an international, prospective, inception cohort study. Ann. Rheum. Dis. 71, 1502–1509. Hauser, W.A., Beghi, E., 2008. First seizure definitions and worldwide incidence and mortality. Epilepsia 49 (Suppl. 1), 8–12. Hauser, W.A., et al., 1993. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 34, 453–468. Hesdorffer, D.C., et al., 1996. Dementia and adult-onset unprovoked seizures. Neurology 46, 727–730. Hesdorffer, D.C., et al., 2011. Combined analysis of risk factors for SUDEP. Epilepsia 52, 1150–1159. Hesdorffer, D.C., et al., 2013. Risk factors for febrile status epilepticus: a case–control study. J. Pediatr. 163, 1147–1151. Imfeld, P., et al., 2013. Seizures in patients with Alzheimer's disease or vascular dementia: a population-based nested case–control analysis. Epilepsia 54, 700–707. Joensen, P., 1986. Prevalence, incidence, and classification of epilepsy in the Faroes. Acta Neurol. Scand. 74, 150–155. Jungehulsing, G.J., et al., 2013. Incidence and predictors of post-stroke epilepsy. Acta Neurol. Scand. 127, 427–430. Kammersgaard, L.P., Olsen, T.S., 2005. Poststroke epilepsy in the Copenhagen stroke study: incidence and predictors. J. Stroke Cerebrovasc. Dis. 14, 210–214. Kilpatrick, C., 1997. Epilepsy and brain abscess. J. Clin. Neurosci. 4, 26–28. Kleveland, G., Engelsen, B.A., 1998. Juvenile myoclonic epilepsy: clinical characteristics, treatment and prognosis in a Norwegian population of patients. Seizure 7, 31–38. Koszewski, W., 1991. Epilepsy following brain abscess. The evaluation of possible risk factors with emphasis on new concept of epileptic focus formation. Acta Neurochir. (Wien) 113, 110–117. Kotsopoulos, I.A., et al., 2002. Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia 43, 1402–1409. Larsson, K., Eeg-Olofsson, O., 2006. A population based study of epilepsy in children from a Swedish county. Eur. J. Paediatr. Neurol. 10, 107–113. Lavados, J., et al., 1992. A descriptive study of epilepsy in the district of El Salvador, Chile, 1984–1988. Acta Neurol. Scand. 85, 249–256. Lewis, D.V., et al., 2002. Do prolonged febrile seizures produce medial temporal sclerosis? Hypotheses, MRI evidence and unanswered questions. Prog. Brain Res. 135, 263–278. Lieu, A.S., Howng, S.L., 2000. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res. 38, 45–52. Lowenstein, D.H., 2009. Epilepsy after head injury: an overview. Epilepsia 50 (Suppl. 2), 4–9. Luyken, C., et al., 2003. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 44, 822–830. Manford, M., et al., 1992. The National General Practice Study of Epilepsy. The syndromic classification of the International League Against Epilepsy applied to epilepsy in a general population. Arch. Neurol. 49, 801–808. Molina, J.F., et al., 1996. Systemic lupus erythematosus in males. A study of 107 Latin American patients. Medicine (Baltimore) 75, 124–130. Murthy, J.M., Prabhakar, S., 2008. Bacterial meningitis and epilepsy. Epilepsia 49 (Suppl. 6), 8–12. Olafsson, E., et al., 2005. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol. 4, 627–634.

Please cite this article as: Perucca, P., et al., Does gender influence susceptibility and consequences of acquired epilepsies?, Neurobiol. Dis. (2014), http://dx.doi.org/10.1016/j.nbd.2014.05.016

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P. Perucca et al. / Neurobiology of Disease xxx (2014) xxx–xxx

Provenzale, J.M., et al., 2008. Hippocampal MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis. AJ. Am. J. Roentgenol. 190, 976–983. Rantakallio, P., et al., 1986. Incidence and prognosis of central nervous system infections in a birth cohort of 12,000 children. Scand. J. Infect. Dis. 18, 287–294. Ross, E.M., et al., 1980. Epilepsy in childhood: findings from the National Child Development Study. Br. Med. J. 280, 207–210. Scarmeas, N., et al., 2009. Seizures in Alzheimer disease: who, when, and how common? Arch. Neurol. 66, 992–997. Scheffer, I.E., et al., 2008. Epilepsy and mental retardation limited to females: an underrecognized disorder. Brain 131, 918–927. Sidenvall, R., et al., 1993. A community-based prospective incidence study of epileptic seizures in children. Acta Paediatr. 82, 60–65. Sillanpaa, M., Shinnar, S., 2010. Long-term mortality in childhood-onset epilepsy. N. Engl. J. Med. 363, 2522–2529. So, E.L., et al., 1996. Population-based study of seizure disorders after cerebral infarction. Neurology 46, 350–355.

Strauss, D.J., et al., 2003. Remote symptomatic epilepsy: does seizure severity increase mortality? Neurology 60, 395–399. Tekle-Haimanot, R., et al., 1997. Incidence of epilepsy in rural central Ethiopia. Epilepsia 38, 541–546. van Breemen, M.S., et al., 2007. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 6, 421–430. Ward, M.M., Studenski, S., 1990. Systemic lupus erythematosus in men: a multivariate analysis of gender differences in clinical manifestations. J. Rheumatol. 17, 220–224. Wirrell, E.C., et al., 2011a. A population-based study of long-term outcomes of cryptogenic focal epilepsy in childhood: cryptogenic epilepsy is probably not symptomatic epilepsy. Epilepsia 52, 738–745. Wirrell, E.C., et al., 2011b. Incidence and classification of new-onset epilepsy and epilepsy syndromes in children in Olmsted County, Minnesota from 1980 to 2004: a population-based study. Epilepsy Res. 95, 110–118. Yeh, C.C., et al., 2013. Risk of epilepsy after traumatic brain injury: a retrospective population-based cohort study. J. Neurol. Neurosurg. Psychiatry 84, 441–445. Zaatreh, M.M., et al., 2003. Temporal lobe tumoral epilepsy: characteristics and predictors of surgical outcome. Neurology 61, 636–641.

Please cite this article as: Perucca, P., et al., Does gender influence susceptibility and consequences of acquired epilepsies?, Neurobiol. Dis. (2014), http://dx.doi.org/10.1016/j.nbd.2014.05.016