sex differences in human epilepsy
TRANSCRIPT
Experimental Neurology xxx (2014) xxx–xxx
YEXNR-11700; No. of pages: 6; 4C:
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Experimental Neurology
j ourna l homepage: www.e lsev ie r .com/ locate /yexnr
Review
Sex differences in human epilepsy
Ivanka Savic ⁎Karolinska Institute, Department of Women's, Children's Health, Neurology Clinic Karolinska Hospital, Q2:07, SE-171 76 Stockholm, Sweden
⁎ Fax: +46 8 517 773 49.E-mail address: [email protected].
http://dx.doi.org/10.1016/j.expneurol.2014.04.0090014-4886/© 2014 Published by Elsevier Inc.
Please cite this article as: Savic, I., Sex differe
a b s t r a c t
a r t i c l e i n f oArticle history:Received 26 November 2013Revised 5 April 2014Accepted 9 April 2014Available online xxxx
Keywords:BrainEpilepsyMTLESex differenceMRI
In the majority of neuropsychiatric conditions, marked gender-based differences have been found in the epide-miology, clinical manifestations, and therapy of disease. Emerging data suggest that gender differences exist alsoin the epidemiology, and pathophysiology of epilepsy. The present review summarizes the current informationregarding gender and epilepsy. These differences are regarded from the perspective of innate sex differences incerebral morphology, structural and functional connections, and assuming that these differences may rendermen and women differently vulnerable to epileptogenicity.
© 2014 Published by Elsevier Inc.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Sex differences in the epidemiology of epilepsies in humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Cerebral sex differences in the healthy brain and the tentative mechanisms underlying these differences . . . . . . . . . . . . . . . . . . . . . . . 0Possible implications of cerebral sex dimorphism for genetic generalized epilepsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Childhood absence epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Juvenile myoclonic epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Possible implications of cerebral sexual dimorphism for temporal lobe epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Sex differences in the amygdala connections — can they affect the ictal and interictal behaviors in patients with MTLE? . . . . . . . . . . . . . . 0
Psychiatric comorbidities with epilepsy — impact of gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Introduction
Epileptic seizures are generated by specific cerebral networks. De-pending on the networks involved the semiology of seizures, as well asthe interictal behavioral, cognitive, and emotional changesmay vary. Dif-ferent regions in the brain seem to have a different propensity to gener-ate and sustain seizure activity in humans (Engel, 2013). During the lastdecade there has been a rapid increase of reports on sex differences incerebral structure and function (Giedd et al., 2006; Savic, 2010). These
nces in human epilepsy, Exp.
newdata highlight the possibility that in epilepsy, similarly to other neu-ropsychiatric conditions, epidemiological and phenomenological sexmay exist, and that some of these differencesmay be explained by inher-ent sex differences in cerebral structure, connectivity, and function. Suchdifferences are important to identify, as they may potentially offer valu-able information when trying to understand the mechanisms ofepileptogenesis, and develop new treatment strategies.
The present review discusses possible sex differences in epilepsy inhumans addressing four different issues. First of all, is the general sensi-tivity to develop epileptic seizures different in women compared tomen? Secondly, is there a sex difference in the epidemiology of variousepilepsy syndromes? Third, given the described sex differences in
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cerebral anatomy, is the location of the region of seizure onset different-ly distributed in male and female epilepsy patients, in other words,could there exist a sex difference in regional liability to generate sei-zures? Fourth, are there any sex differences in primary projections ofthe epileptogenic region, in the spread of epileptic seizures and their se-miology? Finally, are there sex differences in interictal behaviors, cogni-tive deficits and psychiatric comorbidity?
Sex differences in the epidemiology of epilepsies in humans
According to a large epidemiological report (Hauser et al., 1993) anda subsequent meta-analysis (Kotsopoulos et al., 2002), the prevalenceof epilepsy is slightly lower in females compared to males (46.2 vs.50.7 per 100,000). This difference seems to be constituted by the higherpreponderance inmales to develop partial epilepsies (Christensen et al.,2005;McHugh and Delanty, 2008), and partial epilepsiesmost commonamong the various types of epilepsies. The male excess in prevalence ofpartial epilepsies is often explained by the higher prevalence of lesionalepilepsy in men (i.e. epilepsy associated with detectable changes in ce-rebral morphology which are co-localized with the region generatingepileptic seizure), (Christensen et al., 2005). Lesional epilepsy is morecommon in men either because lesions are more prevalent in men, or,because men are more prone to lesion-associated epileptogenesis. Thefirst alternative is supported by an early theory launched by Taylor stat-ing that the cerebral maturation is slower in boys, and therefore, thetime frame for a potential seizure-producing insult (which is more like-ly to affect a brain still undergoing maturation), is longer in boys(Taylor, 1969). The second is supported by findings from some animalmodels of mesial temporal lobe epilepsy (MTLE), showing a higher vul-nerability to develop epilepsy in male rats when the model is based onlesion and hyperthermia, or lesion and early life stress (Desgent et al.,2012). To the contrary, when the model is not associated with lesion,for example, when seizures are induced by amygdala kindling+ stress,the vulnerability is found to be higher in females, (Salzberg et al., 2007).This latter observation is compatible with some epidemiological reportsfrom humans, according to which cryptogenic temporal lobe epilepsy(defined by a lack of obvious etiological factors and lesions) is morecommon in females (62% vs. 38%, p b 0.001), (Christensen et al., 2005;McHugh and Delanty, 2008).
A significantly higher female prevalence has in several surveys beenfound also in idiopathic generalized epilepsies (IGE), which representsome 15–20% of all epilepsies. For example, childhood absence epilepsy(CAE) is reported to be 2–5 times more common in females, with somedifferences depending on whether early onset typical CAE is described(Asadi-Pooya et al., 2012;Waaler et al., 2000). Juvenile absence epilepsy(JAE) is three times more common among females, and juvenile myo-clonic epilepsy (JME) about 1.5 times more common among females(Christensen et al., 2005; Kleveland and Engelsen, 1998). The mecha-nisms underlying this uneven gender distribution are unknown. Never-theless, it needs to be pointed out that, although IGE is not associatedwith any lesions, the cerebral networks processing IGE show changesin both white and gray matter as well as areas of functional hyper andhypo-connectivities in the affected subjects. Whether these structuraland functional changes differ between male and female IGE patients ispresently uncertain. Most of the studies of cerebral anatomy and func-tion in various forms of epilepsy have been carried outwith brain imag-ing methodology and were often limited by low numbers of subjects.Furthermore, they were either based on gender-matched populationswithout specifically investigating possible gender difference, or, thegroup differences were calculated using gender as a nuisance variable.Of clear interest is, however, that the reported structural correlates toMTLE as well as IGE seem confined to networks in the brain that showstructural differences among male and female healthy controls. Thisraises the general question as towhether sex differences in the architec-ture of various brain regions, and in the functional connections betweenthese regions could be involved in the genesis of the observed sex
Please cite this article as: Savic, I., Sex differences in human epilepsy, Exp
differences in the epidemiology of epilepsy. Theoretically, the regionalcyto-organization could influence the regional susceptibility to devel-op/generate seizures in males vs. females, whereas sex differences infunctional and structural connections could be important for themodal-ity of seizure spread in the brain. To provide background to this discus-sion, the major sex differences in the healthy human brain will bediscussed in the next paragraph.
Cerebral sex differences in the healthy brain and the tentativemechanisms underlying these differences
There is increasing evidence for sexual differences in the humanbrain. They have been found in structural volumes, in regional gray(GM) and white matter (WM) volumes, in cortical thickness, as wellas in the structural and functional connections. In general, the amygdalaand thalamus volume is found to be larger inmen, thehippocampus andcaudate volume larger in women (Filipek et al., 1994; Giedd et al., 1997,2006; Murphy et al., 1996; Neufang et al., 2009; Paus et al., 1996; Razet al., 1995). The GM volumes are reported to be greater in men in themesial temporal lobe, the cerebellum, and the lingual gyrus (Carneet al., 2006; Good et al., 2001; Lentini et al., 2013; Savic and Arver,2011), and greater in women in the precentral gyrus, the orbitofrontaland anterior cingulate gyri, and the right inferior parietal lobe (Goodet al., 2001; Lentini et al., 2013; Luders et al., 2005, 2009a,b; Nopouloset al., 2000; Savic and Arver, 2011; Strange et al., 1999). Women seemalso to have generally thicker cortex, (reflecting dendritic connections,neuronal size and packing) particularly in the motor strip, and the oc-cipital and parietal lobes (Luders et al., 2006; Savic and Arver, 2013).In contrast, the white matter connections between cortical regions arefound to be stronger in men, as shown in higher fractional anisotropy(FA) values (reflecting myelinization, the axonal size, and packing) in,for example, the corticospinal tract and the thalamic radiation, (Allenet al., 2011; Filippi et al., 2013; Gong et al., 2011; Hsu et al., 2008; Ohet al., 2007; Rametti et al., 2011; Wang et al., 2014; Westerhausenet al., 2011). These findings might suggest a higher local clustering inwomen, and more long-distance connections in men.
The described sex differences are believed to derive from specificprocesses that shape brain morphology during development. Recently,it has been suggested that themotor-networks could be affected by pro-cesses coded by genes expressed on the X-chromosome, whereas themesial temporal and occipito-parietal networks could be influencedby testosterone and estrogen (Lentini et al., 2013; Savic and Arver,2013). Sex differences detected in these networks may have implica-tions for the prevalence and expression in several disorders of cerebralconnections, including epilepsy. The observed sex differences inthalamo-cortical and cortico-spinal tracts as well as in themotor cortex,thus in the networks, which are fundamental in IGE, may influence thedevelopment and expression of both JME and CAE. The described sex di-morphism in the limbic networks, on the other hand, is of interest fortemporal lobe epilepsy, and MTLE in particular. Of special relevance isthe observation of a sex differentiated functional connectivity fromthe amygdala with greater right amygdala connectivity in men, andgreater left amygdala connectivity in women (Kilpatrick et al., 2006;Savic and Lindstrom, 2008). Of further interest is that the brain regionsshowing stronger functional connectivity with the right amygdala inmen (the sensorimotor cortex, striatum, and pulvinar) are differentfrom those showing stronger functional connectivity with the leftamygdala in women (the subgenual cortex and hypothalamus). Asshown in the next paragraphs, these sex differences in functional con-nectivity may shape both ictal expression and the interictal behaviors.
Possible implications of cerebral sex dimorphism for geneticgeneralized epilepsies
Many of thewell-described epilepsy syndromes in idiopathic gener-alized epilepsies have a genetic predominance (Table 1). The so-called
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Table 1Epilepsy syndromes with gender differences.Derived from Engel (2013).
Female predominanceEarly myoclonic epilepsyWest syndromeMyoclonic epilepsy in non-progressive disordersChildhood absence epilepsyEpileptic encephalopathy with continuous spike-and-wave during sleepLandau-Kleffner syndromeJuvenile absence epilepsyJuvenile myoclonic epilepsyIdiopathic photosensitive occipital lobe epilepsyPhotosensitive epilepsy
Male predominanceMyoclonic epilepsy of infancyDravet syndromeEpilepsy with myoclonic atonic seizuresBenign epilepsy with centrotemporal spikesEpilepsy with myoclonic absences
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genetic generalized epilepsies, (GGE), which represent about 15% of allepilepsies, are considered to be primarily Mendelian, monogenic orcomplex, non-Mendelian (Gardiner, 2005). There is also evidence formaternal inheritance in JME due to imprinting (Pal et al., 2006).
The mechanisms underlying the uneven gender distribution in GGEare currently unknown. The GGE network has been defined bymeans ofsimultaneous EEG and functional magnetic resonance imaging (EEG-fMRI), (Gotman et al., 2005; Moeller et al., 2008). These studies haveshown that during epileptogenic discharges there is a relative increasein the BOLD signal in the thalamus along with a decrease in the “de-fault-mode network” (Wang et al., 2012). GGE patients also show in-creased cortical excitability between the paroxysmal events (Badawyet al., 2007) and display mild ongoing cognitive impairments (Henkinet al., 2005; Pavone et al., 2001), which suggest that the activity andfunction of GGE brain networksmay also be affected during the baselinestate between the generalized spike and wave events. MRI studies ofGGE patients have shown an atrophy of the thalamus, and dependingon the syndrome, also changes in regional cerebral graymatter volumesand densities (Ciumas and Savic, 2006; Koepp et al., 2013; Wang et al.,2012). Whether these structural and functional changes are more com-mon in women compared to men with GGE is presently uncertain, butdeserves to be investigated. The following two paragraphs providesome speculations about the possible impact of gender on the functionaland structural correlates of two common forms of GGE, which are moreprevalent among females — childhood absence epilepsy, and juvenilemyoclonic epilepsy.
Childhood absence epilepsy
While epileptic seizures of CAE are considered to be “generalized,”evidence suggests that in reality spike and wave discharges in CAE pa-tients emerge from focal abnormal circuits in both hemispheres(Blumenfeld, 2005). In particular, there seems to be an engagement ofthe orbitofrontal circuits. Using EEG-fMRI Bai and colleagues comparedbetween-hemisphere resting-state functional connectivity in 16 pa-tients vs. 16 matched controls and found increased connectivity be-tween the right and left orbitofrontal cortices in CAE patients, with nosignificant differences observed in the other 15 ROIs examined (Baiet al., 2011). In some MRI studies with voxel-based morphometry theleft orbitofrontal graymatter volumewas found to be smaller in CAE pa-tients compared with agematched controls, thus, supporting the possi-bility of a more localized orbitofrontal abnormality (Caplan et al., 2009;Chan et al., 2006). Other structural changes reported are a decreased agerelated thinning of the left frontal lobe cortex, and increased thinning inthe right posterior central and the paracentral gyri (Tosun et al., 2011).In addition, thalamic atrophy has been found in CAE (Betting et al.,2006) as in several other forms of GGE (Helms et al., 2006; Koepp
Please cite this article as: Savic, I., Sex differences in human epilepsy, Exp.
et al., 2013;Mory et al., 2003). None of the structural and functional ab-normalities reported in CAE provides an obvious explanation to the fe-male predominance in this condition.
Juvenile myoclonic epilepsy
Structural frontal lobe abnormalities also have been described inJME. They are characterized by an increase in the concentration ofgray matter and thickness of the cortex (Betting et al., 2006;Vulliemoz et al., 2011), along with reductions in N-acetyl aspartate(Savic et al., 2004) and increases in glutamate (de Araujo Filho et al.,2009; Simister et al., 2003). Like in other GGE syndromes a reductionin the thalamic volume has been detected (primarily in the dorsomedi-al nucleus), and also decreases in the concentration of NAA (Helms et al.,2006; Koepp et al., 2013). Congruent with the clinical observation thatphotic stimuli and cognitive efforts may trigger myoclonic jerks, it hasbeen reported that, in patients with JME, the functional connections be-tween the motor cortex and areas within the frontal and parietal lobeare increased, as are the FA values (reflecting axonal diameter, packingdensity andmyelination) between the supplementarymotor cortex andthe occipital cortex (Vollmar et al., 2011; Vulliemoz et al., 2011). Someof the described findings have been detected already one year after sei-zure onset, and are unlikely to be a mere effect of seizures. They couldreflect migrational changes including cortical dysplasia. In some JMEfamilies linkage has been detected to a susceptibility gene at the EJM1locus of chromosome 6 (Pal et al., 2006). This gene has now beenpreliminarily identified as BRD2, a putative transcriptional regulator(Pal et al., 2003), and mutations of this gene are reported to lead tomicrodysgenesis.
Again, none of the aforementioned brain imaging studies paid spe-cial attention to gender aspects, and themechanisms behind the report-ed female excess in JME are unknown. One interesting notion, however,is that themajority of regions described to be involved in JME constituteparts of the motor network. Recent studies suggest that this networkdiffers between males and females, and is modified by X-chromosomegenes, as well as by testosterone and estrogen (Lentini et al., 2013;Neufang et al., 2009; Savic, 2010; Savic and Arver, 2013). Consideringthe pubertal onset of JME, it is possible that the expression of genes pro-moting susceptibility to myoclonic seizures could be up-regulated bysex-steroids at puberty, and perhaps more by estrogen than testoster-one. An additional possibility is that sex hormone related shaping of ax-onal and dendritic connections in the seizure-generating network couldfacilitate the onset of JME. Indeed, estrogen is reported to delay dendrit-ic pruning, whereas testosterone promotes it (Savic, 2010). Low testos-terone levels are associated with lower FA values (Rametti et al., 2012).Thus, the described frontal lobe increases in the graymatter volume, re-ductions in the thalamic volume, and connectivity changes in JME, areall compatible with known sex hormone effects (Neufang et al., 2009;Witte et al., 2010) and provide a context for female dominance in the li-ability to develop JME. It should, however, be emphasized that JME is aheterogeneous epilepsy syndrome, in which frontal lobe dysfunctionseems present only in a subgroup of patients (Helms et al., 2006). Onefuture project addressing the mechanisms underlying the reported sexdifference in the prevalence of JMEwould contribute to the understand-ing on whether this distribution varies among the different subtypes ofJME, as reported in CAE (Asadi-Pooya et al., 2012).
Possible implications of cerebral sexual dimorphism for temporallobe epilepsy
Thehippocampus, amygdala, and the temporal neocortex are pivotalfor the processing of temporal lobe seizures. The development of theseregions and their functional and structural connections is shaped by tes-tosterone and estrogen, and shows known pubertal perturbations(Neufang et al., 2009; Nguyen et al., 2013). Testosterone and estrogenboth modulate the susceptibility to temporal lobe seizures with
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testosteronehaving primarily protective and estrogen proconvulsive ef-fects (Verrotti et al., 2010). Temporal lobe seizures, in turn, lead to re-duced testosterone levels. Together, these factors provide a rathercomplicated and intricate context for temporal lobe epileptogenesis.
Reports of gender comparisons in tissue pathologywithin the area ofseizure onset have hitherto been limited to patients withmesial tempo-ral lobe epilepsy (MTLE). These reports do not suggest any sex differ-ences in the distribution and extent of hippocampal sclerosis(Briellmann et al., 1999) nor in the degree of amygdala atrophy(Bower et al., 2003; Silva et al., 2010). Neither are there any available re-ports specifically investigating the regional liability to develop seizuresamong male and female patients with partial epilepsy. Interestingly,and at variance to this gender similarity with respect to the seizure gen-erating region in MTLE, differences between genders have been report-ed in the areas of seizure spread, the areas of epileptogenic dysfunctionand the regional atrophy outside the zone of seizure onset.
Using FDG-PET we detected “extramesiotemporal” (primarily thefrontal lobe) decreases in glucose metabolism in men, but not inwomen with MTLE (Savic and Engel, 1998). This gender differencereflected a difference in the spread pattern of seizures. In a differentstudy of a similar population, it was observed that women with MTLEhad temporal hypometabolism contralateral to the zone of ictal onset,while ipsilateral frontal hypometabolism was seen in men (Nickelet al., 2003). Together, these findings might explain the observationthat hippocampal seizures are more prone to generalize in men com-pared to women (Janszky et al., 2004). The findings are supported bya recent, and rather extensive MRI investigation (comprising 120 pa-tients with MTLE) and showing that the extra temporal tissue loss wasmore pronounced in male patients, particularly in the frontal cortex,whereas the contralateral temporal cortexwasmore affected in females(Santana et al., 2014).
The possibility of gender dissimilarity in seizure spread deservesspecial attention, as consequences of spread patterns may, potentially,explain some ictal semiology, as well as the interictal behavioral andemotional problems in patients with MTLE. Of particular interest hereare potential effects of the sex differentiated amygdala connections.
Sex differences in the amygdala connections— can they affect the ictal andinterictal behaviors in patients with MTLE?
The amygdala has historically been strongly implicated in the neuro-biology of emotion, and an extensive corpus of research has establishedthe amygdala as being critical for a variety of social and emotion-relatedprocesses. The amygdala is important for the detection and recognitionof emotional facial expressions, for the processing of social informationmore generally, as well as for the enhancement of memory by emotion(Anderson et al., 2003; LaBar et al., 1998; Vuilleumier et al., 2001). Re-cently, it has been discovered that emotional responses obtained duringelectrical stimulation of drug resistant epilepsy patients undergoingpresurgical video–stereo–EEG occur more often in women than inmen (Meletti et al., 2006). Using a review of charts and video electroen-cephalography documentation of seizures of 2530 epilepsy patientsChiesa et al. reported that prevalence of ictal fear was higher in femalepatients despite matched locations of seizure onset (which in about70% of subjects was in the temporal lobe) (Chiesa et al., 2007). A poten-tial explanation might be that there is a gender-related lateralization inamygdala involvement in emotional memory, with a leftward domi-nance in women (Cahill et al., 2001). Due to left lateralization of amyg-dala projections it might be that in females fear, which is mediated bythe amygdala and its projections in the left hemisphere, is easier verbal-ized and encoded in the verbal memory networks.
Processing of emotions in general is related to the amygdala connec-tions to themesial prefrontal cortex (mPFC) (Courtin et al., 2013; Garciaet al., 2006). This network is also involved in the modulation of psycho-social stress stimuli (Jovanovic et al., 2011; Savic, 2013). The amygdala–mPFC connections are reported to be stronger in women (Kilpatrick
Please cite this article as: Savic, I., Sex differences in human epilepsy, Exp
et al., 2006; Savic and Lindstrom, 2008). One theoretical consequenceof this sex difference is that possible excitotoxic changes, which couldoccur in response to seizure induced glutamate release along the projec-tions to themesial temporal lobe (Bagetta et al., 2004; Savic et al., 2000),could in mPFC be more pronounced in female compared with maleMTLE patients. This, in turn,would provide context for a higher sensitiv-ity to psychosocial stress among females with MTLE, implying a possi-bility for a higher prevalence of stress related psychiatric illness,primarily mood and anxiety disorders. Overall, there is an impressionthat although the investigations of possible gender differences inMTLE are still in an early phase, the initial reports about differences inseizure spread are of great interest, because theymay influence the psy-chiatric comorbidity, reported in about 30% of patients with MTLE,where the underlying mechanisms remain unclear.
Psychiatric comorbidities with epilepsy — impact of gender
Psychiatric comorbidity with epilepsy is inherently multifactorial.Thus, when discussing gender differences in this comorbidity even if re-ducing epilepsy to a connectivity disorder, there are several importantfactors needing consideration. The most prominent are:
(1) The type of epilepsy — epilepsy syndrome that is described(2) The specific cerebral structures that are primarily involved in
that type of epilepsy/epilepsy syndrome(3) The specific neuronal networks that are connected to these struc-
tures and potentially involved in seizure propagation(4) The vulnerability of these networks to possible seizure associated
excitotoxic events (the duration, and frequency of seizures)(5) The age at onset of epilepsy(6) The antiepileptic medication(7) The psychiatric history and heredity.
Due to space limitations, only two conditions co-morbidwith epilepsywill be mentioned: depression and obsessive compulsive disorders.
Among epilepsy patients affective disorders are most common inthose with intractable MTLE, although a higher prevalence comparedto the general population has been reported also in frontal lobe epilepsy(Helmstaedter and Witt, 2010) and in IGE (Piazzini et al., 2001). Basedon the preliminary observations of gender differences in amygdala con-nectivity, one could expect that sex differences in the prevalence of de-pression would be most frequent among female patients with MTLE.However, whereas the majority of epidemiological studies fromthe general population show that depression is two–three times morefrequent in females, the reports about gender distribution of epilepsy-associated depression are less conclusive. In one large population-based study examining nearly 37,000 people of which 0.6% were diag-nosed with epilepsy of heterogeneous types, the overall odds ratio foranxiety disorders or suicidal thoughts among epileptic patients were2.4 and 2.2, respectively (Tellez-Zenteno et al., 2007). Major depressivedisorder showed a significant age by sex interaction, such that male ep-ilepsy patients became more susceptible to depression with age, whilewomen became less susceptible (Tellez-Zenteno et al., 2007). Thisstudy did, however, not factor for the type of epilepsy. Some studies,carried out in MTLE specifically, report a male-specific vulnerability todepression when the epileptogenic region is left sided (Altshuler et al.,1990; Strauss et al., 1992). These studies suffer, on the other hand,from low effect size, and are incompatible with the general view of amore pronounced right hemisphere dysfunction in depression, particu-larly in men (Bruder et al., 2012), although amore recent and extensivesurvey of data fromMTLE patients whowere admitted for epilepsy sur-gery, failed to show any interaction between the prevalence of depres-sion and the side of seizure onset (Devinsky et al., 2005). Overall,female gender seems to be a less prominent vulnerability factor whendepression is comorbid with epilepsy, (Helmstaedter and Witt, 2010).It is possible that while females show a baseline vulnerability to depres-sion, they are somewhat protected from increased vulnerability due to
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altered noradrenergic and serotonergic signaling caused by seizure ac-tivity, perhaps due to the effects of ovarian hormones (or their metabo-lites) (Nemeth et al., 2013).
Obsessive compulsive disorders (OCD) are also common (10–20%)and, often under diagnosed in patients with epilepsy (Kaplan, 2010).Male sex, age, seizure focus, its lateralization, and intractability toantiepileptogenic drugs (AED) are the main risks, but, notably, not theAED treatment in itself (Hamed et al., 2013). Interestingly, OCD are pri-marily reported in IGE, and in patients who suffer from partial seizureswith secondary generalization— in both conditions there is an engage-ment of the basal ganglia. A possible role of basal ganglia in the co-morbidity betweenOCD and generalized tonic clonic epilepsy is intrigu-ing given the pivotal role of these structures in OCD, and the reportsabout changes in basal ganglia structural volumes (Ciumas and Savic,2006), and in dopamine transporter binding sites (Odano et al., 2012)in generalized epilepsies. Why OCD seem to be more common amongmale epilepsy patients is currently unclear.
Conclusion
Like in other neuropsychiatric conditions, sex differences are foundin epilepsies. These differences are not prominent, and exist in onlysome forms of epilepsy. In MTLE gender seems to matter primarilywith regard to the primary projections from the epileptogenic region,and may reflect innate sex differences in networks supporting seizurepropagation, as well as in the manner in which these networks arereorganized due to seizures themselves. In CAE and JME, two conditionswhere the pathophysiology is less clear, and perhaps less homogenous,the higher prevalence in females might be related to the inherent sexdifferences in seizure generating motor circuits. Contrary to the expec-tations, when associated with epilepsy, the prevalence psychiatric dis-orders do not show the usual uneven sex distribution. Whether this isbecause there is a sex difference in the severity of seizures, because ofan interaction between seizure induced biochemical perturbations andtestosterone and estrogen acting as exacerebrators or protectors of psy-chiatric manifestations is currently unknown. Overall, the current infor-mation of the effect of gender on epilepsy is still limited and warrantsfurther investigations. Independent of the exact underlying mecha-nisms the observed sex differences in some aspects, as well as the lackof sex differences in other aspects, deserve further attention as theymight have clinical relevance and help generate important insights inthe biology of seizure disorders, and well as in the biology of genderdifferences.
Acknowledgments
The Insurance Council forWorking Life and Social Science (FAS), theSwedish Research Council, AFA Insurance and VINNOVA (2007–2061)are acknowledged for their financial support.
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