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Peri-ictal vegetative symptoms in temporal lobe epilepsy
Epilepsy & Behavior 11 (2007) 125–129 www.elsevier.com/locate/yebeh
Peri-ictal vegetative symptoms in temporal lobe epilepsy J. Janszky a,b,*, A. Fogarasi a,c, V. Toth b, V. Magalova a, C. Gyimesi a,b, N. Kovacs b, R. Schulz a, A. Ebner a a Epilepsy Center Bethel, Bielefeld, Germany Department of Neurology, University of Pe´cs, Pe´cs, Hungary Epilepsy Center, Bethesda Children’s Hospital, Budapest, Hungary b
c
Received 8 March 2007; revised 14 April 2007; accepted 17 April 2007 Available online 20 June 2007
Abstract We investigated peri-ictal vegetative symptoms (PIVS) in 141 patients with adult temporal lobe epilepsy (TLE) and assessed frequency, gender effect, and lateralizing value of peri-ictal autonomic signs. We recorded abdominal auras in 62%, goosebumps in 3%, hypersalivation in 12%, spitting in 1%, cold shivering in 3%, urinary urge in 3%, water drinking in 7%, postictal nose wiping (PNW) in 44%, and postictal coughing in 16%. At least one vegetative sign appeared in 86% of the patients. The presence of PIVS did not have a significant lateralizing value. PNW occurred in 52% of women and in 33% of men, whereas any PIVS was present in 93% of women and 77% of men. In summary, contradictory to previous studies, the presence of PIVS has no lateralizing value, which may be linked to a low frequency of occurrence of PIVS. PIVS, especially PNW, occurred more frequently in women, supporting the gender differences in epilepsy. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Temporal lobe epilepsy; Autonomic symptoms; Lateralizing signs; Gender differences
1. Introduction Peri-ictal vegetative symptoms (PIVS) are common in adult epilepsy, but also frequent in pediatric epilepsy [1]. PIVS during epileptic seizures have both clinical and theoretical importance. PIVS can help us better understand the central representation of the autonomic nervous system [2] and some of them can add additional information in the assessment of the epileptogenic focus, which is especially useful in presurgical evaluation of intractable epilepsy [3]. PIVS may play a role in sudden unexpected death in epilepsy (SUDEP) [4]. A variety of PIVS have been described in adults, including cardiovascular, respiratory, gastrointestinal, cutaneous, pupillary, oroalimentary, genital, sexual, and urinary manifestations [4–8]. Some vegetative signs have been found to have lateralizing value [4,8–14]. *
Corresponding author. Address: Department of Neurology, University of Pe´cs, Ret u. 2, 7623 Pe´cs, Hungary. Fax: +36 72535911. E-mail address: [email protected] (J. Janszky). 1525-5050/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2007.04.015
Postictal nose wiping has no lateralizing value; however, the hand used to wipe the nose is usually ipsilateral to the seizure focus; thus, nose wiping is a highly reliable, clinical lateralizing sign pointing to the ipsilateral hemisphere [15,16]. Male gender is a strong predictor of SUDEP [17]. Consequently, possible gender differences in PIVS can be partially responsible for a gender difference in SUDEP. Indeed, some studies have found that gender may have an effect on peri-ictal vegetative changes. Right-sided seizures are accompanied by an increase in heart rate, but this lateralization difference occurs only in male patients [18]. Sexual auras are more frequent in women than in men [19]. Genital automatisms are more common in men than in women [20]; this gender difference is true also for children and infants [21]. In this study we systematically investigated videorecorded PIVS in adult temporal lobe epilepsy to assess the (1) frequency, (2) gender effect, and (3) lateralizing value of PIVS in patients who consecutively underwent
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presurgical evaluation and surgery for intractable temporal lobe epilepsy.
Table 1 Association of peri-ictal vegetative symptoms with lateralization
2. Methods In this retrospective study, we reviewed video recordings of 141 patients (81 women: age range, 16–59; mean age, 34.1 ± 10; mean age at epilepsy onset, 10.9; range, 1–37) who had consecutively undergone the adult presurgical evaluation program with ictal video/EEG recordings from 1995 to 2002 in Epilepsy Center Bethel, Bielefeld, Germany. All patients had epilepsy surgery due to intractable medial temporal lobe epilepsy (TLE) with video-recorded complex partial seizures (CPS) caused by unilateral medial temporal lobe lesions. Histopathological examination revealed hippocampal sclerosis in 127, benign brain tumor in 13 (eight gangliogliomas, two dysembryoplastic neuroepithelial tumors, two lowgrade astrocytomas, and one oligodendroglioma), cortical dysplasia in one, and cavernoma in another case. For 111 patients, the 2-year postoperative evaluation was available, and 84 (76%) had become seizure-free (Engel 1 outcome). To reevaluate the archived seizures, we selected one to three consecutively recorded CPS for each patient. Isolated auras were not analyzed. If the patient had more than three recorded seizures, then we reevaluated only the first three. The video recordings were reviewed by one of the authors blinded to all of the patients’ clinical data except the diagnosis of medial TLE. In total, 310 archived seizures were analyzed. A clinical sign was considered to be present in a particular patient if it occurred in at least one of the recorded seizures. All patients and (where possible) their relatives were asked about their auras and postictal signs on admission to the inpatient unit. Patients underwent continuous video/scalp EEG monitoring lasting more than 2 days. The electrodes were placed according to the 10–10 system; 32–64 channels were used. Patients were instructed to signal their aura by pushing the alarm button. Detailed ictal and postictal interventions and examinations in which patients were asked about their preictal signs were performed by trained EEG technicians specialized in presurgical evaluation according to a written protocol. All patients underwent high-resolution MRI examinations with a 1.5- or 1.0-T Siemens Magnetom MR machine using a special protocol for detecting epileptogenic lesions. In some patients, determination of speech dominance was necessary. The Wada test or speech-activated fMRI was used; methodological details are described elsewhere [22,23]. We analyzed the occurrence of vegetative symptoms and whether various vegetative symptoms were associated with side of surgery and gender. For statistical evaluation of categorical variables, v2 and Fisher’s exact tests were carried out. For statistical evaluation of continuous variables, the Mann–Whitney test was performed. Error probabilities <0.05 were considered significant.
3. Results We recorded an abdominal aura in 62%, goose bumps in 3%, hypersalivation in 12%, spitting in 1%, cold shivers in 3%, peri-ictal urinary urge in 3%, peri-ictal water drinking in 7%, postictal nose wiping in 44%, and postictal coughing in 16% of the patients. No ictal vomiting was observed. Eighty percent of the patients manifested at least one vegetative sign. Table 1 outlines the difference in the occurrence of peri-ictal vegetative phenomena in patients with right-sided versus left-sided epilepsy. Determination of speech dominance during the presurgical evaluation process was necessary in 97 patients. Table 2 illustrates the difference in the occurrence of peri-ictal vegetative phenomena in patients with dominant versus nondominant seizures. PIVS did not have significant lateralizing value in our patients. Table 3 reveals the difference in the occur-
Abdominal aura Goose bumps Hypersalivation Ictal spitting Cold shivers Peri-ictal urinary urge Peri-ictal water drinking Postictal nose wiping Postictal coughing Any peri-ictal vegetative signs
Right-sided medial TLE (N = 65)
Left-sided medial TLE (N = 76)
P value
43(66) 0(0) 10(15) 1(2) 2(3)
44(58) 4(5) 7(9) 1(1) 4(5) 2(3)
0.38 0.12 0.3 1.0 0.12 1.0
3(5)
4(5)
1.0
28(43)
34(45)
0.84
10(15) 55(85)
12(16) 65(86)
1.0 0.8
Table 2 Association of peri-ictal vegetative symptoms with hemispheric dominance in the 97 patients in whom speech dominance was determined
Abdominal aura Goose bumps Hypersalivation Ictal spitting Cold shivers Peri-ictal urinary urge Peri-ictal water drinking Postictal nose wiping Postictal coughing Any peri-ictal vegetative signs
Nondominant medial TLE (N = 47)
Dominant medial TLE (N = 50)
P value
34(72) 1(2) 5(9) 1(2) 2(4) 2(4)
29(58) 3(6) 5(10) 1(2) 2(4) 1(2)
0.14 0.62 1.0 1.0 1.0 0.52
2(4)
4(8)
0.67
21(45)
22(44)
0.95
8(17) 40(85)
9(18) 40(80)
0.89 0.6
Table 3 Association of peri-ictal vegetative symptoms with gender
Abdominal aura Goose bumps Hypersalivation Ictal spitting Cold shivers Peri-ictal urinary urge Peri-ictal water drinking Postictal nose wiping Postictal coughing Any peri-ictal vegetative signs Any peri-ictal vegetative signs except postictal nose wiping a
Women (N = 81)
Men (N = 60)
P value
53(65) 2(2) 10(12) 1(1) 4(9) 4(9) 5(6) 42(52) 13(16) 75(93) 68(84)
34(57) 2(3) 7(12) 1(1) 0(0) 0(0) 2(3) 20(33) 9(15) 46(77) 40(67)
0.3 1.0 1.0 1.0 0.14 0.14 0.7 0.028a 1.0 0.007 0.017
Boldface indicates significance.
rence of peri-ictal vegetative phenomena in males versus females. We found that PIVS, especially postictal nose wiping, occurred more frequently in women than in men. Postictal nose wiping occurred in 52% of women and in only
J. Janszky et al. / Epilepsy & Behavior 11 (2007) 125–129
33% of men. PIVS were present in 93% of women and 77% of men. This gender difference remained even when PIVS other than nosewiping were considered (see Table 3). There were no relationships between PIVS and other clinical phenomena including etiology (e.g., tumor vs hippocampal sclerosis), age, age at epilepsy onset, and duration of epilepsy. 4. Discussion In the present study, we investigated PIVS—different ictal and postictal clinical signs that can be considered as sympathic or parasympathic vegetative phenomena. These signs are supposed to result from activation of the central autonomic nervous system [4]. We found that PIVS are very common during TLE seizures, being manifested by 86% of the patients. The most common vegetative symptoms are abdominal auras and postictal nose wiping. Previous studies reported that ictal urinary urge [10], peri-ictal water drinking [11], ictal spitting [12], and ictal vomiting [13] are clinical ictal lateralizing signs pointing to the nondominant hemisphere, whereas cold shivers and goose bumps lateralize to the dominant hemisphere [14]. Some studies have found that postictal coughing may lateralize to the right hemisphere [24,25], but others have not [26]. Contradictory to previous studies, PIVS did not exhibit significant lateralizing value in our patients in right/left or dominant/nondominant relationships. The abdominal aura occurred more often in right TLE, without reaching statistical significance. This trend can be explained by ictal speech disturbance and postictal amnesia in leftsided seizures. We did not investigate the ipsilateral/contralateral correlation, for example, in the case of nose wiping [15,16]. The lack of association between hemispheric lateralization and PIVS may be partially related to the relatively small number of patients included in this study, because the signs found to have lateralizing value in previous studies occurred relatively infrequently in our consecutive patient group. For example, no ictal vomiting was observed at all. This was also true for gustatory auras, which were investigated intensively by the Bancaud group [27], and ictal spitting, which occurred in only two patients. Goose bumps or cold shivers were present only in patients with a left-sided epileptogenic region, but again, the number of patients was two small to reach statistical significance. Another explanation for the difference between our results and those of previous studies can be derived from the different patient populations. In the present study, we examined only patients with medial TLE, that is, a homogenous patient population, whereas in the studies examining ictal urinary urge [10] and peri-ictal water drinking [11], patients with all forms of TLE were included. Our study suggests that the lateralizing value of PIVS is limited in everyday practice, in agreement with our previous work, in which we systematically analyzed the lateral-
127
izing value of PIVS in childhood partial epilepsies and found that the presence of various PIVS did not have lateralizing value [1]. PIVS, especially postictal nose wiping, occurred more frequently in women than in men. This gender difference remained even when we considered PIVS other than nose wiping (see Table 3). Our data support the existence of gender differences in human epileptic seizures. Previous studies have demonstrated that sexual auras are more frequent in women than in men [19,28,29]. Cardiovascular effects of seizures also reflect gender differences, because right-sided seizures are accompanied by an increase in heart rate, but this lateralization difference occurs only in male patients [18]. Others found that men may be more vulnerable to seizure-associated brain damage [30]. We recently reported that men have secondarily generalized tonic–clonic seizures more often than women, whereas women have isolated auras and lateralized EEG seizure patterns more often, suggesting that the seizure spread is more extended or occurs more frequently in men than in women [31]. Experimental data also support the hypothesis that temporal lobe seizures in male animals are more severe than those in female animals. These gender differences may be related to the testosterone level [32]. The gender differences in PIVS may be related to the physiological sex differences of the autonomic nervous system. Women have a preponderance of vagal over sympathetic responsiveness, whereas males have a preponderance of sympathetic over vagal control of cardiac function [33,34]. Women have reduced baroreflex sensitivity, measured during the Valsalva maneuver [35]. Experimental data suggest that there are already sex differences in the autonomic nervous system prenatally. For instance, the distribution of neuropeptides in the brain differs in the brains of premature male and female rats [36], female rats have fewer ganglionic neurons [37], and acetylcholinesterase (AChE) activity is higher in newborn males compared with females [38]. The sex differences in the autonomic system may be a manifestation of sex differences observed in various pathological conditions. There is the well-known male predominance in coronary heart disease. Conversely, women are more likely to have Raynaud’s phenomenon and to experience syncopal episodes. Conclusively, the experimental, human physiological and pathological data suggest that parasympathetic responsiveness is greater in females and sympathetic responsiveness is greater in males [34]. In our study, however, both parasympathic PIVS (e.g., urinary urge) and sympathetic PIVS (e.g., cold shivering) occurred more frequently in women. Finally, whether gender differences in PIVS have any relationship to the higher risk of SUDEP in men remains unknown. Some speculate that the gender differences in the autonomic nervous system are due to developmental differences or to the effects of prevailing levels of male and/or female sex hormones [34]. Our results revealed gender differences in autonomic symptoms during epileptic seizures. These
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rapidly changing phenomena caused by abnormal brain activity may partially contradict this theory and support the existence of gender differences not only on the hormonal level but also on the level of the central autonomic system. We did not investigate autonomic parameters (e.g., breathing or heart functions), which cannot be determined by reviewing ictal video recordings. Conversely, some authors have reported that ictal bradycardia is associated mainly with left temporal seizures [39,40], whereas others have suggested that ictal bradycardia is related to bitemporal seizure activity [41]. Ictal tachycardia is associated with right-sided temporal seizures [42]; however, there may be gender differences in this phenomenon, because in women, there is no lateralization difference for ictal heart rate elevation [18]. Acknowledgments This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG-Eb 111/2-2), the Hungarian Research Council (ETT 219/2006), and the Hungarian Scientific Research Fund (OTKA T043045 and F 68720). J.J. was supported by the Humboldt Foundation and the Bolyai Scholarship. A.F. was supported by Grant D 048517 from the Hungarian Scientific Research Fund. We gratefully acknowledge Terri Shore Ebner, a native English speaker who carefully reviewed the article. References [1] Fogarasi A, Janszky J, Tuxhorn I. Autonomic symptoms during childhood partial seizures. Epilepsia 2006;47:584–8. [2] Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993;68:988–1001. [3] Rosenow F, Luders H. Presurgical evaluation of epilepsy. Brain 2001;124:1683–700. [4] Baumgartner C, Lurger S, Leutmezer F. Autonomic symptoms during epileptic seizures. Epileptic Disord 2001;3:103–6. [5] Freeman R, Schachter SC. Autonomic epilepsy. Semin Neurol 1995;15:158–66. [6] Liporace JD, Sperling MR. Simple autonomic seizures. In: Engel Jr J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott–Raven; 1997. p. 549–55. [7] Janszky J, Fogarasi A, Magalova V, Tuxhorn I, Ebner A. Hyperorality in epileptic seizures: periictal incomplete Klu¨ver–Bucy syndrome. Epilepsia 2005;46:1235–40. [8] Fogarasi A, Janszky J, Tuxhorn I. Ictal pallor is associated with left temporal seizure onset zone in children. Epilepsy Res 2005;67:117–21. [9] Kirchner A, Pauli E, Hilz MJ, Neundo¨rfer B, Stefan H. Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2002;73:73–5. [10] Baumgartner C, Gro¨ppel G, Leutmezer F, et al. Ictal urinary urge indicates seizure onset in the nondominant temporal lobe. Neurology 2000;55:432–4. [11] Trinka E, Walser G, Unterberger I, et al. Peri-ictal water drinking lateralizes seizure onset to the nondominant temporal lobe. Neurology 2003;60:873–6. [12] Voss NF, Davies KG, Boop FA, et al. Spitting automatism in complex partial seizures: a nondominant temporal localizing sign? Epilepsia 1999;40:114–6.
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Peri-ictal vegetative symptoms in temporal lobe epilepsy J. Janszky a,b,*, A. Fogarasi a,c, V. Toth b, V. Magalova a, C. Gyimesi a,b, N. Kovacs b, R. Schulz a, A. Ebner a a Epilepsy Center Bethel, Bielefeld, Germany Department of Neurology, University of Pe´cs, Pe´cs, Hungary Epilepsy Center, Bethesda Children’s Hospital, Budapest, Hungary b
c
Received 8 March 2007; revised 14 April 2007; accepted 17 April 2007 Available online 20 June 2007
Abstract We investigated peri-ictal vegetative symptoms (PIVS) in 141 patients with adult temporal lobe epilepsy (TLE) and assessed frequency, gender effect, and lateralizing value of peri-ictal autonomic signs. We recorded abdominal auras in 62%, goosebumps in 3%, hypersalivation in 12%, spitting in 1%, cold shivering in 3%, urinary urge in 3%, water drinking in 7%, postictal nose wiping (PNW) in 44%, and postictal coughing in 16%. At least one vegetative sign appeared in 86% of the patients. The presence of PIVS did not have a significant lateralizing value. PNW occurred in 52% of women and in 33% of men, whereas any PIVS was present in 93% of women and 77% of men. In summary, contradictory to previous studies, the presence of PIVS has no lateralizing value, which may be linked to a low frequency of occurrence of PIVS. PIVS, especially PNW, occurred more frequently in women, supporting the gender differences in epilepsy. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Temporal lobe epilepsy; Autonomic symptoms; Lateralizing signs; Gender differences
1. Introduction Peri-ictal vegetative symptoms (PIVS) are common in adult epilepsy, but also frequent in pediatric epilepsy [1]. PIVS during epileptic seizures have both clinical and theoretical importance. PIVS can help us better understand the central representation of the autonomic nervous system [2] and some of them can add additional information in the assessment of the epileptogenic focus, which is especially useful in presurgical evaluation of intractable epilepsy [3]. PIVS may play a role in sudden unexpected death in epilepsy (SUDEP) [4]. A variety of PIVS have been described in adults, including cardiovascular, respiratory, gastrointestinal, cutaneous, pupillary, oroalimentary, genital, sexual, and urinary manifestations [4–8]. Some vegetative signs have been found to have lateralizing value [4,8–14]. *
Corresponding author. Address: Department of Neurology, University of Pe´cs, Ret u. 2, 7623 Pe´cs, Hungary. Fax: +36 72535911. E-mail address: [email protected] (J. Janszky). 1525-5050/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2007.04.015
Postictal nose wiping has no lateralizing value; however, the hand used to wipe the nose is usually ipsilateral to the seizure focus; thus, nose wiping is a highly reliable, clinical lateralizing sign pointing to the ipsilateral hemisphere [15,16]. Male gender is a strong predictor of SUDEP [17]. Consequently, possible gender differences in PIVS can be partially responsible for a gender difference in SUDEP. Indeed, some studies have found that gender may have an effect on peri-ictal vegetative changes. Right-sided seizures are accompanied by an increase in heart rate, but this lateralization difference occurs only in male patients [18]. Sexual auras are more frequent in women than in men [19]. Genital automatisms are more common in men than in women [20]; this gender difference is true also for children and infants [21]. In this study we systematically investigated videorecorded PIVS in adult temporal lobe epilepsy to assess the (1) frequency, (2) gender effect, and (3) lateralizing value of PIVS in patients who consecutively underwent
126
J. Janszky et al. / Epilepsy & Behavior 11 (2007) 125–129
presurgical evaluation and surgery for intractable temporal lobe epilepsy.
Table 1 Association of peri-ictal vegetative symptoms with lateralization
2. Methods In this retrospective study, we reviewed video recordings of 141 patients (81 women: age range, 16–59; mean age, 34.1 ± 10; mean age at epilepsy onset, 10.9; range, 1–37) who had consecutively undergone the adult presurgical evaluation program with ictal video/EEG recordings from 1995 to 2002 in Epilepsy Center Bethel, Bielefeld, Germany. All patients had epilepsy surgery due to intractable medial temporal lobe epilepsy (TLE) with video-recorded complex partial seizures (CPS) caused by unilateral medial temporal lobe lesions. Histopathological examination revealed hippocampal sclerosis in 127, benign brain tumor in 13 (eight gangliogliomas, two dysembryoplastic neuroepithelial tumors, two lowgrade astrocytomas, and one oligodendroglioma), cortical dysplasia in one, and cavernoma in another case. For 111 patients, the 2-year postoperative evaluation was available, and 84 (76%) had become seizure-free (Engel 1 outcome). To reevaluate the archived seizures, we selected one to three consecutively recorded CPS for each patient. Isolated auras were not analyzed. If the patient had more than three recorded seizures, then we reevaluated only the first three. The video recordings were reviewed by one of the authors blinded to all of the patients’ clinical data except the diagnosis of medial TLE. In total, 310 archived seizures were analyzed. A clinical sign was considered to be present in a particular patient if it occurred in at least one of the recorded seizures. All patients and (where possible) their relatives were asked about their auras and postictal signs on admission to the inpatient unit. Patients underwent continuous video/scalp EEG monitoring lasting more than 2 days. The electrodes were placed according to the 10–10 system; 32–64 channels were used. Patients were instructed to signal their aura by pushing the alarm button. Detailed ictal and postictal interventions and examinations in which patients were asked about their preictal signs were performed by trained EEG technicians specialized in presurgical evaluation according to a written protocol. All patients underwent high-resolution MRI examinations with a 1.5- or 1.0-T Siemens Magnetom MR machine using a special protocol for detecting epileptogenic lesions. In some patients, determination of speech dominance was necessary. The Wada test or speech-activated fMRI was used; methodological details are described elsewhere [22,23]. We analyzed the occurrence of vegetative symptoms and whether various vegetative symptoms were associated with side of surgery and gender. For statistical evaluation of categorical variables, v2 and Fisher’s exact tests were carried out. For statistical evaluation of continuous variables, the Mann–Whitney test was performed. Error probabilities <0.05 were considered significant.
3. Results We recorded an abdominal aura in 62%, goose bumps in 3%, hypersalivation in 12%, spitting in 1%, cold shivers in 3%, peri-ictal urinary urge in 3%, peri-ictal water drinking in 7%, postictal nose wiping in 44%, and postictal coughing in 16% of the patients. No ictal vomiting was observed. Eighty percent of the patients manifested at least one vegetative sign. Table 1 outlines the difference in the occurrence of peri-ictal vegetative phenomena in patients with right-sided versus left-sided epilepsy. Determination of speech dominance during the presurgical evaluation process was necessary in 97 patients. Table 2 illustrates the difference in the occurrence of peri-ictal vegetative phenomena in patients with dominant versus nondominant seizures. PIVS did not have significant lateralizing value in our patients. Table 3 reveals the difference in the occur-
Abdominal aura Goose bumps Hypersalivation Ictal spitting Cold shivers Peri-ictal urinary urge Peri-ictal water drinking Postictal nose wiping Postictal coughing Any peri-ictal vegetative signs
Right-sided medial TLE (N = 65)
Left-sided medial TLE (N = 76)
P value
43(66) 0(0) 10(15) 1(2) 2(3)
44(58) 4(5) 7(9) 1(1) 4(5) 2(3)
0.38 0.12 0.3 1.0 0.12 1.0
3(5)
4(5)
1.0
28(43)
34(45)
0.84
10(15) 55(85)
12(16) 65(86)
1.0 0.8
Table 2 Association of peri-ictal vegetative symptoms with hemispheric dominance in the 97 patients in whom speech dominance was determined
Abdominal aura Goose bumps Hypersalivation Ictal spitting Cold shivers Peri-ictal urinary urge Peri-ictal water drinking Postictal nose wiping Postictal coughing Any peri-ictal vegetative signs
Nondominant medial TLE (N = 47)
Dominant medial TLE (N = 50)
P value
34(72) 1(2) 5(9) 1(2) 2(4) 2(4)
29(58) 3(6) 5(10) 1(2) 2(4) 1(2)
0.14 0.62 1.0 1.0 1.0 0.52
2(4)
4(8)
0.67
21(45)
22(44)
0.95
8(17) 40(85)
9(18) 40(80)
0.89 0.6
Table 3 Association of peri-ictal vegetative symptoms with gender
Abdominal aura Goose bumps Hypersalivation Ictal spitting Cold shivers Peri-ictal urinary urge Peri-ictal water drinking Postictal nose wiping Postictal coughing Any peri-ictal vegetative signs Any peri-ictal vegetative signs except postictal nose wiping a
Women (N = 81)
Men (N = 60)
P value
53(65) 2(2) 10(12) 1(1) 4(9) 4(9) 5(6) 42(52) 13(16) 75(93) 68(84)
34(57) 2(3) 7(12) 1(1) 0(0) 0(0) 2(3) 20(33) 9(15) 46(77) 40(67)
0.3 1.0 1.0 1.0 0.14 0.14 0.7 0.028a 1.0 0.007 0.017
Boldface indicates significance.
rence of peri-ictal vegetative phenomena in males versus females. We found that PIVS, especially postictal nose wiping, occurred more frequently in women than in men. Postictal nose wiping occurred in 52% of women and in only
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33% of men. PIVS were present in 93% of women and 77% of men. This gender difference remained even when PIVS other than nosewiping were considered (see Table 3). There were no relationships between PIVS and other clinical phenomena including etiology (e.g., tumor vs hippocampal sclerosis), age, age at epilepsy onset, and duration of epilepsy. 4. Discussion In the present study, we investigated PIVS—different ictal and postictal clinical signs that can be considered as sympathic or parasympathic vegetative phenomena. These signs are supposed to result from activation of the central autonomic nervous system [4]. We found that PIVS are very common during TLE seizures, being manifested by 86% of the patients. The most common vegetative symptoms are abdominal auras and postictal nose wiping. Previous studies reported that ictal urinary urge [10], peri-ictal water drinking [11], ictal spitting [12], and ictal vomiting [13] are clinical ictal lateralizing signs pointing to the nondominant hemisphere, whereas cold shivers and goose bumps lateralize to the dominant hemisphere [14]. Some studies have found that postictal coughing may lateralize to the right hemisphere [24,25], but others have not [26]. Contradictory to previous studies, PIVS did not exhibit significant lateralizing value in our patients in right/left or dominant/nondominant relationships. The abdominal aura occurred more often in right TLE, without reaching statistical significance. This trend can be explained by ictal speech disturbance and postictal amnesia in leftsided seizures. We did not investigate the ipsilateral/contralateral correlation, for example, in the case of nose wiping [15,16]. The lack of association between hemispheric lateralization and PIVS may be partially related to the relatively small number of patients included in this study, because the signs found to have lateralizing value in previous studies occurred relatively infrequently in our consecutive patient group. For example, no ictal vomiting was observed at all. This was also true for gustatory auras, which were investigated intensively by the Bancaud group [27], and ictal spitting, which occurred in only two patients. Goose bumps or cold shivers were present only in patients with a left-sided epileptogenic region, but again, the number of patients was two small to reach statistical significance. Another explanation for the difference between our results and those of previous studies can be derived from the different patient populations. In the present study, we examined only patients with medial TLE, that is, a homogenous patient population, whereas in the studies examining ictal urinary urge [10] and peri-ictal water drinking [11], patients with all forms of TLE were included. Our study suggests that the lateralizing value of PIVS is limited in everyday practice, in agreement with our previous work, in which we systematically analyzed the lateral-
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izing value of PIVS in childhood partial epilepsies and found that the presence of various PIVS did not have lateralizing value [1]. PIVS, especially postictal nose wiping, occurred more frequently in women than in men. This gender difference remained even when we considered PIVS other than nose wiping (see Table 3). Our data support the existence of gender differences in human epileptic seizures. Previous studies have demonstrated that sexual auras are more frequent in women than in men [19,28,29]. Cardiovascular effects of seizures also reflect gender differences, because right-sided seizures are accompanied by an increase in heart rate, but this lateralization difference occurs only in male patients [18]. Others found that men may be more vulnerable to seizure-associated brain damage [30]. We recently reported that men have secondarily generalized tonic–clonic seizures more often than women, whereas women have isolated auras and lateralized EEG seizure patterns more often, suggesting that the seizure spread is more extended or occurs more frequently in men than in women [31]. Experimental data also support the hypothesis that temporal lobe seizures in male animals are more severe than those in female animals. These gender differences may be related to the testosterone level [32]. The gender differences in PIVS may be related to the physiological sex differences of the autonomic nervous system. Women have a preponderance of vagal over sympathetic responsiveness, whereas males have a preponderance of sympathetic over vagal control of cardiac function [33,34]. Women have reduced baroreflex sensitivity, measured during the Valsalva maneuver [35]. Experimental data suggest that there are already sex differences in the autonomic nervous system prenatally. For instance, the distribution of neuropeptides in the brain differs in the brains of premature male and female rats [36], female rats have fewer ganglionic neurons [37], and acetylcholinesterase (AChE) activity is higher in newborn males compared with females [38]. The sex differences in the autonomic system may be a manifestation of sex differences observed in various pathological conditions. There is the well-known male predominance in coronary heart disease. Conversely, women are more likely to have Raynaud’s phenomenon and to experience syncopal episodes. Conclusively, the experimental, human physiological and pathological data suggest that parasympathetic responsiveness is greater in females and sympathetic responsiveness is greater in males [34]. In our study, however, both parasympathic PIVS (e.g., urinary urge) and sympathetic PIVS (e.g., cold shivering) occurred more frequently in women. Finally, whether gender differences in PIVS have any relationship to the higher risk of SUDEP in men remains unknown. Some speculate that the gender differences in the autonomic nervous system are due to developmental differences or to the effects of prevailing levels of male and/or female sex hormones [34]. Our results revealed gender differences in autonomic symptoms during epileptic seizures. These
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rapidly changing phenomena caused by abnormal brain activity may partially contradict this theory and support the existence of gender differences not only on the hormonal level but also on the level of the central autonomic system. We did not investigate autonomic parameters (e.g., breathing or heart functions), which cannot be determined by reviewing ictal video recordings. Conversely, some authors have reported that ictal bradycardia is associated mainly with left temporal seizures [39,40], whereas others have suggested that ictal bradycardia is related to bitemporal seizure activity [41]. Ictal tachycardia is associated with right-sided temporal seizures [42]; however, there may be gender differences in this phenomenon, because in women, there is no lateralization difference for ictal heart rate elevation [18]. Acknowledgments This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG-Eb 111/2-2), the Hungarian Research Council (ETT 219/2006), and the Hungarian Scientific Research Fund (OTKA T043045 and F 68720). J.J. was supported by the Humboldt Foundation and the Bolyai Scholarship. A.F. was supported by Grant D 048517 from the Hungarian Scientific Research Fund. We gratefully acknowledge Terri Shore Ebner, a native English speaker who carefully reviewed the article. References [1] Fogarasi A, Janszky J, Tuxhorn I. Autonomic symptoms during childhood partial seizures. Epilepsia 2006;47:584–8. [2] Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993;68:988–1001. [3] Rosenow F, Luders H. Presurgical evaluation of epilepsy. Brain 2001;124:1683–700. [4] Baumgartner C, Lurger S, Leutmezer F. Autonomic symptoms during epileptic seizures. Epileptic Disord 2001;3:103–6. [5] Freeman R, Schachter SC. Autonomic epilepsy. Semin Neurol 1995;15:158–66. [6] Liporace JD, Sperling MR. Simple autonomic seizures. In: Engel Jr J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott–Raven; 1997. p. 549–55. [7] Janszky J, Fogarasi A, Magalova V, Tuxhorn I, Ebner A. Hyperorality in epileptic seizures: periictal incomplete Klu¨ver–Bucy syndrome. Epilepsia 2005;46:1235–40. [8] Fogarasi A, Janszky J, Tuxhorn I. Ictal pallor is associated with left temporal seizure onset zone in children. Epilepsy Res 2005;67:117–21. [9] Kirchner A, Pauli E, Hilz MJ, Neundo¨rfer B, Stefan H. Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2002;73:73–5. [10] Baumgartner C, Gro¨ppel G, Leutmezer F, et al. Ictal urinary urge indicates seizure onset in the nondominant temporal lobe. Neurology 2000;55:432–4. [11] Trinka E, Walser G, Unterberger I, et al. Peri-ictal water drinking lateralizes seizure onset to the nondominant temporal lobe. Neurology 2003;60:873–6. [12] Voss NF, Davies KG, Boop FA, et al. Spitting automatism in complex partial seizures: a nondominant temporal localizing sign? Epilepsia 1999;40:114–6.
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