- Email: [email protected]
The semiology of febrile seizures: Focal features are frequent
Epilepsy & Behavior 73 (2017) 59–63
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
The semiology of febrile seizures: Focal features are frequent Michihiko Takasu a, Tetsuo Kubota b, Takeshi Tsuji c, Hirokazu Kurahashi a, Shingo Numoto a, Kazuyoshi Watanabe d, Akihisa Okumura a,⁎ a
Department of Pediatrics, Aichi Medical University, Japan Department of Pediatrics, Anjo Kosei Hospital, Japan Department of Pediatrics, Okazaki City Hospital, Japan d Department of Pediatrics, Nagoya University Graduate School of Medicine, Japan b c
a r t i c l e
i n f o
Article history: Received 12 January 2017 Revised 15 April 2017 Accepted 13 May 2017 Available online xxxx Keywords: Febrile seizures Focal features Aura Facial expressions Behavioral changes
a b s t r a c t Objective: To clarify the semiology of febrile seizures (FS) and to determine the frequency of FS with symptoms suggestive of focal onset. Methods: FS symptoms in children were reported within 24 h of seizure onset by the parents using a structured questionnaire consisting principally of closed-ended questions. We focused on events at seizure commencement, including changes in behavior and facial expression, and ocular and oral symptoms. We also investigated the autonomic and motor symptoms developing during seizures. The presence or absence of focal and limbic features was determined for each patient. The associations of certain focal and limbic features with patient characteristics were assessed. Results: Information was obtained on FS in 106 children. Various events were recorded at seizure commencement. Behavioral changes were observed in 35 children, changes in facial expression in 53, ocular symptoms in 78, and oral symptoms in 90. In terms of events during seizures, autonomic symptoms were recognized in 78, and convulsive motor symptoms were recognized in 68 children. Focal features were evident in 81 children; 38 children had two or more such features. Limbic features were observed in 44 children, 9 of whom had two or more such features. There was no significant relationship between any patient characteristic and the numbers of focal or limbic features. Significance: The semiology of FS varied widely among children, and symptoms suggestive of focal onset were frequent. FS of focal onset may be more common than is generally thought. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Seizure semiology is the most effective way to identify the type of seizure experienced by patients with epilepsy. It has been intensively studied in such patients, especially those with focal epilepsies, which may be susceptible to surgical treatment. Some specific semiological features can be used to identify the location of seizure onset. Tonic movement without impaired consciousness suggests an origin in the primary motor cortex or the supplementary sensorimotor area of the contralateral hemisphere, and a visual aura suggests an origin in the primary visual cortex. In contrast, there have been few studies on the semiology of febrile seizures (FS) [1], FS are the most common seizure disorders in children. FS have been classified into simple and complex seizures. Most FS are usually considered to be generalized tonic–clonic seizures of short ⁎ Corresponding author at: Department of Pediatrics, Aichi Medical University, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan. E-mail address: [email protected] (A. Okumura).
http://dx.doi.org/10.1016/j.yebeh.2017.05.004 1525-5050/© 2017 Elsevier Inc. All rights reserved.
duration occurring only once during a single episode of febrile illness. Complex FS are usually defined as FS with one or more of the following features; focal onset, duration N10 min, or multiple seizures during a single episode of illness. Of these features, the presence or absence of focal features is not easy to determine. Indeed, the definitions are ambiguous, and subtle focal features can easily be missed by observers (such as parents) who are surprised and frightened when a child suffers a seizure. Additionally, several ictal electroencephalographic studies (ictal EEGs) of epileptic seizures have shown that generalized features are not uncommon during focal seizures in infants and younger children [2–4]. Diffuse tonic postures are common during focal seizures (even symmetric seizures) in infants. Therefore, focal seizures in infants and young children can be mistaken for generalized seizures. Neville and Gindner recently suggested that most FS, especially those that originate in the mesial temporal lobe, may be of focal origin [1]. The cited authors prospectively studied 10 consecutive children with FS. Detailed seizure histories were taken, focusing on phenomena evident before the motor events. A clear preliminary phase, or aura, compatible with a seizure origin in the temporal lobe, was evident in
60
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63
seven children. Hamelin and Vercueil reported ictal videotape-recorded EEG findings during an example of “simple” FS of focal onset [5]. The patient opened his eyes and began to cry in association with the development of rhythmic activity in the right centrotemporal region. The cited authors considered the possibility that even simple FS may be focal (possibly hippocampal) in nature. Thus, we hypothesized that FS of focal onset may be more frequent than presently thought. We therefore prospectively surveyed FS semiology focusing on manifestations at seizure commencement. Our aim was to clarify the semiology of FS and to determine the frequency of FS with symptoms suggestive of focal onset.
The rates of events at the commencement of FS and those during FS were compared according to the presence or absence of past history of FS, because observation of a first FS could be more emotionally challenged and less reliable than that of a second or later FS. We also performed statistical analyses comparing differences in patient characteristics according to frequency of non-specific focal and limbic features. We used the chi-square and the Kruskal–Wallis tests to compare categorical and numerical variables, respectively. A P-value b 0.05 was considered to reflect statistical significance. All statistical analyses were performed with the aid of EZR ver. 1.33 software (available at http:// www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) [7].
2. Patients and methods
3. Results
This prospective study was performed from May 2014 to October 2015 in the Departments of Pediatrics of Aichi Medical University Hospital, Anjo Kosei Hospital, and Okazaki City Hospital. Children with FS who visited these hospitals immediately after their seizures were consecutively included. FS were defined as seizures in children aged 6 months to 5 years associated with a fever N38.0 °C and without central nervous system infection or acute metabolic derangement. Children with any previous evidence of neurological or developmental abnormalities were excluded. The study was approved by the ethics committee of Aichi Medical University Hospital. Manifestations of FS were described by the parents using a structured questionnaire as soon as possible after arrival at the hospital (at the latest, within 24 h). The questionnaire consisted principally of closed-ended questions. The parents or caregivers were allowed to choose two or more answers for each question and to add whatever comments they wished. The attending pediatricians assisted the parents if necessary. Seizure duration was numerically recorded. We focused on events at seizure commencement, including changes in behavior and facial expression, and ocular and oral symptoms. Changes in facial expression were evaluated using a facial action coding system [6]. We showed parents pictures of various facial expressions: disgust, fear, anger, contempt, sadness, surprise, and happiness. Parents were asked to choose the picture that was most similar to the child's facial expression at seizure onset. We also asked whether the child was awake or asleep before seizure onset, and documented the autonomic and motor symptoms during seizure and responsiveness after seizure. We explored the focal and limbic features of all patients. Focal features were defined as seizure symptoms that were presumed to arise from specific brain regions. The following items were classified as focal features:
We obtained data about 106 children (60 boys and 46 girls) with FS. The median patient age was 24 months (range, 8–71 months). Fortyone children (39%) had histories of FS. Nineteen children (18%) had experienced two or more episodes of FS. Family histories of FS (in parents and siblings) were recorded for 39 children (37%). Seizure duration was b1 min in 10 children (9%), 1–4 min in 60 (57%), 5–9 min in 16 (15%), 10–19 min in 11 (10%), ≥ 20 min in 3 (3%), and undetermined in 6 (6%). Before seizures, 63 children (59%) were awake, and 43 (41%) were asleep. After seizures, 28 children (26%) were alert, 45 (42%) were drowsy, and 33 (31%) fell asleep. Table 1 summarizes events at the commencement of FS. Behavioral changes were observed in 35 children (32%). Nineteen 19 (18%) cried or screamed; 10 (9%) were poorly responsive (9%); and 4 exhibited motion arrest (4%). One child developed motion arrest followed by crying,
1) Any change in behavior; 2) Changes in facial expression: fear, sadness, anger, or laughter; 3) Ocular symptoms: lateral deviation or eyelid flutter; 4) Oral symptoms: at least one of the following: drooling, oral automatism, cheek twitching, or mouth deviation; 5) Events during a seizure: both specific autonomic symptoms (at least one of the following: pallor, cyanosis, or vomiting) and nonconvulsive motor symptoms (atonicity or no obvious movement) were evaluated. Limbic features were defined as seizure symptoms that were very likely of mesial temporal onset. The following items were classified as limbic features: 1) Changes in behavior: crying or screaming; 2) Changes in facial expression: fear or sadness; 3) Oral symptoms: oral automatism. No ocular, autonomic, or motor symptom was considered to be a limbic feature. The numbers of focal and limbic features were counted for each patient.
Table 1 Events at the commencement of febrile seizure.
Change in behavior Cry or scream Poor responsiveness Motion arrest Rough breathing Irritability Complaint of pain Unremarkable Change in facial expression Surprise Fear Sadness Disgust Anger Laugh Contempt Blank face Unremarkable Ocular symptoms Upgaze Staring Blank eyes Lateral deviation Crossed eyes Eyelid flutter Multidirectional movement Unremarkable Oral symptoms Open slightly Drooling Clenching teeth Oral automatism Open widely Cheek twitching Mouth deviation Unremarkable NS: not significant.
All (N = 106)
No past history of FS (N = 65)
With past history of FS (N = 41)
19 (18%) 10 (9%) 4 (4%) 2 (2%) 1 (1%) 1 (1%) 71 (67%)
13 (20%) 6 (9%) 3 (5%) 0 1 (2%) 1 (2%) 43 (66%)
6 (15%) 4 (10%) 1 2 (5%) 0 0 28 (68%)
NS NS NS NS NS NS NS
24 (23%) 19 (18%) 6 (6%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 27 (26%) 36 (33%)
15 (23%) 13 (20%) 4 (6%) 0 1 (2%) 1 (2%) 0 16 (25%) 25 (38%)
9 (22%) 6 (15%) 2 (5%) 1 (2%) 0 0 1 (2%) 11 (27%) 11 (27%)
NS NS NS NS NS NS NS NS NS
38 (36%) 32 (30%) 21 (20%) 8 (8%) 4 (4%) 3 (3%) 2 (2%) 18 (17%)
24 (37%) 19 (29%) 15 (23%) 3 (5%) 2 (3%) 2 (3%) 1 (2%) 13 (20%)
14 (34%) 13 (32%) 6 (15%) 5 (13%) 2 (5%) 1 (2%) 1 (2%) 5 (12%)
NS NS NS NS NS NS NS NS
37 (35%) 30 (28%) 21 (20%) 15 (14%) 10 (9%) 6 (6%) 3 (3%) 16 (15%)
25 (38%) 16 (25%) 10 (15%) 8 (12%) 6 (9%) 5 (8%) 1 (2%) 13 (20%)
12 (29%) 14 (34%) 11 (27%) 7 (14%) 4 (10%) 1 (2%) 2 (5%) 3 (7%)
NS NS NS NS NS NS NS NS
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63 Table 2 Events during febrile seizure.
Autonomic symptoms Pallor Cyanosis Flushing Vomiting Unremarkable Motor symptoms Clonic movement No obvious movement Tonic–clonic movement Atonic Tonic movement Uncertain
All (N = 106)
No past history of FS (N = 65)
With past history of FS (N = 41)
57 (54%) 12 (11%) 8 (8%) 4 (4%) 28 (26%)
36 (55%) 7 (11%) 6 (9%) 2 (3%) 15 (23%)
21 (63%) 5 (12%) 2 (5%) 2 (5%) 13 (32%)
NS NS NS NS NS
39 (37%) 16 (15%) 16 (15%) 14 (13%) 13 (12%) 8 (8%)
21 (32%) 11 (17%) 11 (17%) 8 (12%) 9 (14%) 5 (8%)
18 (44%) 5 (12%) 5 (12%) 6 (15%) 4 (10%) 3 (7%)
NS NS NS NS NS NS
61
in behavior/facial expression and oral symptoms were observed at seizure commencement in 19 (18%)/19 (18%), and 15 (14%) children, respectively. Table 4 summarizes the relationships between focal features and patient characteristics. Thirty-eight children (36%) had two or more focal features. Twelve children (11%) had three or more such features. No patient characteristic had any significant effect on the number of focal features. Table 5 summarizes the relationships between limbic features and patient characteristics. Forty-four children (42%) exhibited at least one limbic feature. Only nine children (8%) exhibited two or more features. No patient characteristic had any significant effect on the number of limbic features.
4. Discussion
NS: not significant.
and another demonstrated poor responsiveness followed by screaming. Changes in facial expression at seizure commencement were noted in 53 children (50%). Facial expressions were rated as surprise in 24 children (23%), fear in 19 (18%), and sadness in 6 (6%). Other facial expressions were rare. Ocular symptoms were noted in 78 children (74%). Upgazing and staring were frequent at seizure commencement. Lateral deviation was evident in eight children (8%), and eyelid flutter was evident in three (3%). Two types of ocular symptom were noted in 20 children (19%). Oral symptoms were recognized in 90 children (85%). Slight mouth-opening and drooling were frequent. Oral automatism (lipsmacking and chewing) was observed in 15 children (14%). Cheek twitching and mouth deviation were recognized in six (6%) and three (3%) children, respectively. Twenty-nine children (27%) had two or more types of oral symptom. The rate of any events at the commencement of FS was not different according to the presence or absence of past history of FS. Table 2 summarizes events noted during seizures. Autonomic symptoms were recognized in 78 children (74%). Pallor and cyanosis were evident in 57 (54%) and 12 (11%), respectively. Vomiting was recorded in four children (4%), three of whom also exhibited pallor or cyanosis. In terms of motor symptoms, convulsive movements were observed in 68 children (64%), but tonic–clonic movements were observed in only 16 (15%). Sixteen children (15%) exhibited no obvious movements, and 14 (13%) became atonic. The rate of any events during FS was not different according to the presence or absence of past history of FS. Table 3 lists the numbers of children with focal and limbic features. Eighty-one children (76%) had one or more focal features. Of these, changes in behavior or facial expression and oral symptoms were observed at seizure commencement in 35 (33%), 27 (25%), and 48 (45%) children, respectively. Ocular symptoms at seizure commencement and events during seizures were relatively infrequent. Forty-four children exhibited one or more limbic features. Of these, changes
We found that the semiology of FS varied widely among children. Various events were observed at seizure commencement. Symptoms suggestive of focal seizure origin were frequently observed at seizure commencement. In terms of events during seizures, tonic–clonic movement was infrequent. Thus, any suggestion that most FS are generalized tonic–clonic seizures may be inaccurate. Notably, most children with FS exhibited one or more manifestations suggestive of focal onset. Eighty-one (76%) of the 106 children exhibited at least one focal feature, and 38 (36%) exhibited two or more. These results support the suggestion that FS are often of focal onset. Currently, FS with focal features are classified as complex FS. If focal onset FS is not uncommon, classification of FS by the presence or absence of focal features may be unnecessary. FS are frequent from infancy through to young childhood (age 1–2 years), at which time primary generalized epilepsies are rather rare. If FS and epilepsy (unprovoked seizures) share a similar pathogenesis, dependent on age-related brain maturation, it is rational to suggest that FS are often of focal onset, although the presence of focal features does not always mean that a seizure is, in fact, of focal onset. Of seizure symptoms suggestive of focal onset, events at seizure commencement are important, because they contain clues allowing focal and generalized seizures to be distinguished. We consider changes in behavior and facial expression to be possible surrogates of aura, which is a subjective ictal phenomenon preceding observable seizure symptoms [8,9]. Auras are frequent in adults with focal seizures [10]. Infants and young children cannot verbalize the presence of aura because it is a subjective ictal phenomenon. However, the observed changes in behavior and facial expression suggest the presence of a subjective phenomenon. Indeed, we observed various changes in behavior and facial expression, some of which were suggestive of focal onset seizures. We believe that seizures associated with changes in behavior and/or facial expression that are attributable to activation of the emotional network (fear, sadness, anger, or laughter) are likely to be of focal onset. In our present study, one-third of children exhibited changes in behavior,
Table 3 Focal and limbic features.
Events at the beginning of a seizure Change in behavior Change in facial expression Ocular symptoms Oral symptoms
Focal features
Number of cases
Limbic features
Number of cases
Any Fear, sadness, anger, or laugh Lateral deviation or eyelid flutter At least one of following items; drooling, oral automatism, cheek twitching, or mouth deviation
35 (33%) 27 (25%) 11 (10%) 48 (45%)
Cry or scream Fear or sadness Not assessed Oral automatism
19 (18%) 19 (18%)
19 (18%)
Not assessed
Events during a seizure Both autonomic and motor symptoms listed below Autonomic; at least one of pallor, cyanosis, or vomiting Motor; atonic or no obvious movement
15 (14%)
62
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63
Table 4 Focal features and patient characteristics. Number of focal features
Male Age (months)a Past history of FS Family history of FS Sz during wakefulness Duration of Sz ~5 min
0 N = 25
1 N = 43
2 N = 26
3 N=9
4 N=3
18 (72%) 21 (8–61) 9 (36%) 8 (32%) 13 (52%) 18 (72%)
20 (47%) 27 (10–71) 19 (44%) 19 (44%) 23 (53%) 27 (63%)
16 (62%) 22.5 (10–47) 10 (38%) 8 (31%) 18 (69%) 16 (62%)
4 (44%) 23 (12–62) 3 (33%) 3 (33%) 6 (67%) 8 (89%)
2 (67%) 15 (13–18) 0 1 (33%) 3 (100%) 1 (33%)
NS NS NS NS NS NS
FS: febrile seizures, Sz: seizure, NS: not significant. a Data are shown as median (range).
and one-fourth developed relevant facial expressions (fear, sadness, anger, or laughter). Certain ocular symptoms evident at seizure commencement are presumed to be localizing or lateralizing in nature [11,12]. We included lateral eye deviation and eyelid flutter among the symptoms suggestive of focal onset [11]. However, most ocular symptoms are present in patients experiencing both focal and generalized seizures. Upgazing or staring is observed at the commencement of both generalized tonic– clonic and focal seizures, and this is combined with impairments in awareness. There were few children with ocular symptoms suggestive of focal onset in the present study. Oral symptoms at seizure commencement varied widely. We considered drooling, oral automatism, cheek twitching, and mouth deviation to be indicative of focal onset. Drooling, cheek twitching, and mouth deviation are often observed in child epilepsy patients, and these are often accompanied by centrotemporal spikes [13]. Drooling or hypersalivation is also observed in patients with temporal lobe epilepsy [14]. Oral automatism is a characteristic seizure symptom of those with such epilepsy [15,16]. Notably, nearly half of all children with FS had one or more oral symptoms suggestive of focal onset. Events during a seizure can sometimes be used to distinguish focal from generalized seizures. Certain autonomic changes are characteristic of focal seizures. Pallor or cyanosis associated with vomiting is characteristic of the seizures of Panayiotopoulos syndrome [17,18]. Ictal pallor has also been reported in children with temporal lobe epilepsy [19]. However, cyanosis is also evident during generalized tonic–clonic seizures [20]. Thus, pallor, cyanosis, and vomiting were considered to be suggestive of focal seizure onset in the present study, but only if they were not associated with any obvious convulsive or other movement or atony. Asymmetric motor symptoms (such as unilateral dystonic posturing) were not investigated in the present study because unsettled witnesses (such as upset parents) find these symptoms difficult to identify, although they are useful for differentiating focal from generalized seizures. It is not easy for those lacking specialized knowledge to classify motor symptoms correctly. Tonic seizures can be misinterpreted as tonic–clonic seizures. Therefore, we defined atony or absence of obvious movement (only) as motor symptoms suggestive of focal onset.
Ultimately, about one-fifth of all children were judged to exhibit events during seizures suggestive of focal onset. Neville and Gindner considered the possibility that FS was a syndrome of secondarily generalized hippocampal epilepsy based on the frequent compatibility between the semiology of FS with a mesial temporal origin of seizures [1,21]. The cited authors stressed the evidence for a preliminary phase or ‘aura.’ Fear, drooling, lip-smacking, chewing, and eye deviation were considered to be suggestive of mesial temporal epilepsy. Consistent with these ideas, we considered limbic features to be present if at least one of the following were noted at seizure commencement: crying or screaming (behavioral changes), a facial expression of fear or sadness, and/or oral automatism. Ultimately, seizure symptoms suggestive of a limbic system origin were evident in 44 of the 106 children. This suggests that limbic features may not be infrequent, although the numbers of children with such features were fewer in the present study than in the work of Neville and Gindner [1]. The differences in the proportions of limbic features are explained by the methods employed in the two studies. We asked witnesses to complete questionnaires, whereas two clinicians conducted direct or telephone interviews in the study conducted by Neville and Gindner [1]. Clinician interviews will yield more detailed information, increasing the proportion of children with limbic features. However, the diversity of FS semiology evident in our present study can be explained by differences among the children in seizure foci. Some seizure foci were located outside the mesial temporal lobe. The presence or absence of focal or limbic features was not associated with any particular patient characteristic. Of the various factors, age may be closely related to seizure manifestations. The semiology of focal seizures differs in infants and adults [22]. Automatisms developing during the focal seizures of infants are often subtle. Apparent generalized features are common during such seizures, despite the fact that well-developed secondary generalizations associated with synchronized, bilateral clonic activity are rare. The absence of any difference in seizure semiology by patient characteristics suggests that focal or limbic features may be universal in FS. Our study had several limitations. Our fundamental focus was on the presence or absence of auras, or focal seizure symptoms, in children
Table 5 Limbic features and patient characteristics. Number of limbic features
Male Age (months)a Past history of FS Family history of FS Sz during wakefulness Duration of Sz ~5 min FS: febrile seizures, Sz: seizure. a Data are shown as median (range).
0 N = 62
1 N = 35
2 N=7
3 N=2
35 (56%) 23.5 (8–71) 26 (42%) 23 (37%) 38 (61%) 39 (63%)
18 (51%) 24 (10–62) 12 (34%) 12 (34%) 19 (89%) 24 (69%)
6 (86%) 22 (16–34) 2 (29%) 3 (43%) 4 (57%) 6 (86%)
1 (50%) 15 (12–18) 1 (50%) 1 (50%) 2 (100%) 1 (50%)
NS NS NS NS NS NS
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63
with generalized seizures. Dugan et al. [23] used a detailed semistructured interview to study the frequency of auras in patients with generalized epilepsies. It was found that 21.3% of participants reported auras in response to an open-ended question, and 64.3% were presumed to have auras based on analysis of the answers to closed-ended questions. Seneviratne et al. used the validated Epilepsy Diagnostic Interview Questionnaire [24] to study the frequency of focal seizure symptoms in patients with idiopathic generalized epilepsies [25]. It was found that 70 of 135 participants exhibited focal seizure symptoms including aphasia, a visual aura, and epigastric sensations. These studies imply that auras and focal features are observable during generalized seizures. It is not easy to distinguish focal from generalized seizures based solely on semiology. The gold standard is ictal VTR-EEG recording. However, ictal recordings during FS are very difficult to obtain and do not yield realistic data. The reliability of information could be influenced by emotions of witnesses. Especially, parents who first saw FS of their children might be strongly challenged by a seizure. Thus, observation of a first FS may be less reliable than that of a second or later FS. In our study, the rates of events at the commencement of and during FS were not significantly different according to the presence or absence of past history of FS. The observation bias according to the presence or absence of past history of FS is presumed to be less strong in our study. The sensitivity of focal feature detection may have been low in our present study, as we did not conduct direct interviews. More information on seizure semiology would have been obtained had detailed interviews been performed. To this end, it would be desirable to develop an interview tool that can be used to evaluate seizures in infants and young children. The questionnaire that we used was not validated and may have been somewhat inappropriate. Our definitions of focal and limbic features are tentative. To determine the presence or absence of focal or limbic features more objectively, an appropriate questionnaire, as well as careful definitions of focal and limbic features, is essential. In summary, the semiology of FS varied widely among children, and seizure symptoms suggestive of focal onset were frequent. About onethird of children had symptoms suggestive of limbic onset. Neither the focal nor the limbic features were associated with age, a history of FS, or seizure duration. These results suggest that FS of focal onset are not uncommon and may not be necessarily regarded as complex. The semiology of FS requires further investigation, as does the relationship thereof to FS recurrence and the later development of unprovoked seizures. Disclosure None of the authors has any conflict of interest to disclose. Acknowledgements This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (26293252 and 26461551), a grant from Japan Agency for Medical Research and Development
63
(15fk0108005h0001), and a grant from the Ministry of Health, Labour and Welfare (H27-Nanji-Ippan-028). References [1] Neville B, Gindner D. Febrile seizures are a syndrome of secondarily generalized hippocampal epilepsy. Dev Med Child Neurol 2010;52:1151–3. [2] Yamamoto N, Watanabe K, Negoro T, Takaesu E, Aso K, Furune S, et al. Complex partial seizures in children: ictal manifestations and their relation to clinical course. Neurology 1987;37:1379–82. [3] Brockhaus A, Elger CE. Complex partial seizures of temporal lobe origin in children of different age groups. Epilepsia 1995;36:1173–81. [4] Dravet C, Catani C, Bureau M, Roger J. Partial epilepsies in infancy: a study of 40 cases. Epilepsia 1989;30:807–12. [5] Hamelin S, Vercueil L. A simple febrile seizure with focal onset. Epileptic Disord 2014;16:112–5. [6] Ryan A, Cohn JF, Lucey S, Saragih J, Lucey P, De la Torre F, et al. Automated facial expression recognition system. 43rd annual 2009 international carnahan conference on security technology; 2009. p. 172–7. [7] Kanda R. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013;48:452–8. [8] Blume WT, Luders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel Jr J. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001;42:1212–8. [9] Johanson M, Valli K, Revonsuo A, Wedlund JE. Content analysis of subjective experiences in partial epileptic seizures. Epilepsy Behav 2008;12:170–82. [10] So N. Epileptic auras. In: Wyllie E, editor. The treatment of epilepsy. Principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 299–308. [11] Foldvary-Schaefer N, Unnwongse K. Localizing and lateralizing features of auras and seizures. Epilepsy Behav 2011;20:160–6. [12] Rossetti AO, Kaplan PW. Seizure semiology: an overview of the 'inverse problem'. Eur Neurol 2010;63:3–10. [13] Panayiotopoulos CP, Bureau M, Caraballo RH, Dalla Bernardina B, Valeta T. Idiopathic focal epilepsies in childhood. In: Bureau M, Genton P, Dravet C, Delgado-Escueta AV, Tassinari CA, Thomas P, Wolf P, editors. Epileptic syndromes in infancy childhood and adolescence. 5th ed. Montrouge: John Libbey; 2012. p. 217–54. [14] Shah J, Zhai H, Fuerst D, Watson C. Hypersalivation in temporal lobe epilepsy. Epilepsia 2006;47:644–51. [15] Williamson PD, Thadani VM, French JA, Darcey TM, Mattson RH, Spencer SS, et al. Medial temporal lobe epilepsy: videotape analysis of objective clinical seizure characteristics. Epilepsia 1998;39:1182–8. [16] Fontana E, Negrini F, Francione S, Mai R, Osanni E, Menna E, et al. Temporal lobe epilepsy in children: electroclinical study of 77 cases. Epilepsia 2006;47:26–30 [Suppl]. [17] Panayiotopoulos CP. Extraoccipital benign childhood partial seizures with ictal vomiting and excellent prognosis. J Neurol Neurosurg Psychiatry 1999;66:82–5. [18] Koutroumanidis M. Panayiotopoulos syndrome: an important electroclinical example of benign childhood system epilepsy. Epilepsia 2007;48:1044–53. [19] Fogarasi A, Janszky J, Tuxhorn I. Ictal pallor is associated with left temporal seizure onset zone in children. Epilepsy Res 2005;67:117–21. [20] Baumgartner C, Lurger S, Leutmezer F. Autonomic symptoms during epileptic seizures. Epileptic Disord 2001;3:103–16. [21] Neville BG, Gindner D. Febrile seizures — semiology in humans and animal models: evidence of focality and heterogeneity. Brain Dev 2010;32:33–6. [22] Nordli DR, Wyllie E. Seizure semiology in infants with localization-related epilepsy. In: Engel J, Pedley T, editors. Epilepsy. A comprehensive textbook. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 635–8. [23] Dugan P, Carlson C, Bluvstein J, Chong DJ, Friedman D, Kirsch HE. Auras in generalized epilepsy. Neurology 2014;83:1444–9. [24] Seneviratne U, Woo JJ, Boston RC, Cook M, D'Souza W. Focal seizure symptoms in idiopathic generalized epilepsies. Neurology 2015;85:589–95. [25] Choi H, Winawer MR, Kalachikov S, Pedley TA, Hauser WA, Ottman R. Classification of partial seizure symptoms in genetic studies of the epilepsies. Neurology 2006;66: 1648–53.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
The semiology of febrile seizures: Focal features are frequent Michihiko Takasu a, Tetsuo Kubota b, Takeshi Tsuji c, Hirokazu Kurahashi a, Shingo Numoto a, Kazuyoshi Watanabe d, Akihisa Okumura a,⁎ a
Department of Pediatrics, Aichi Medical University, Japan Department of Pediatrics, Anjo Kosei Hospital, Japan Department of Pediatrics, Okazaki City Hospital, Japan d Department of Pediatrics, Nagoya University Graduate School of Medicine, Japan b c
a r t i c l e
i n f o
Article history: Received 12 January 2017 Revised 15 April 2017 Accepted 13 May 2017 Available online xxxx Keywords: Febrile seizures Focal features Aura Facial expressions Behavioral changes
a b s t r a c t Objective: To clarify the semiology of febrile seizures (FS) and to determine the frequency of FS with symptoms suggestive of focal onset. Methods: FS symptoms in children were reported within 24 h of seizure onset by the parents using a structured questionnaire consisting principally of closed-ended questions. We focused on events at seizure commencement, including changes in behavior and facial expression, and ocular and oral symptoms. We also investigated the autonomic and motor symptoms developing during seizures. The presence or absence of focal and limbic features was determined for each patient. The associations of certain focal and limbic features with patient characteristics were assessed. Results: Information was obtained on FS in 106 children. Various events were recorded at seizure commencement. Behavioral changes were observed in 35 children, changes in facial expression in 53, ocular symptoms in 78, and oral symptoms in 90. In terms of events during seizures, autonomic symptoms were recognized in 78, and convulsive motor symptoms were recognized in 68 children. Focal features were evident in 81 children; 38 children had two or more such features. Limbic features were observed in 44 children, 9 of whom had two or more such features. There was no significant relationship between any patient characteristic and the numbers of focal or limbic features. Significance: The semiology of FS varied widely among children, and symptoms suggestive of focal onset were frequent. FS of focal onset may be more common than is generally thought. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Seizure semiology is the most effective way to identify the type of seizure experienced by patients with epilepsy. It has been intensively studied in such patients, especially those with focal epilepsies, which may be susceptible to surgical treatment. Some specific semiological features can be used to identify the location of seizure onset. Tonic movement without impaired consciousness suggests an origin in the primary motor cortex or the supplementary sensorimotor area of the contralateral hemisphere, and a visual aura suggests an origin in the primary visual cortex. In contrast, there have been few studies on the semiology of febrile seizures (FS) [1], FS are the most common seizure disorders in children. FS have been classified into simple and complex seizures. Most FS are usually considered to be generalized tonic–clonic seizures of short ⁎ Corresponding author at: Department of Pediatrics, Aichi Medical University, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan. E-mail address: [email protected] (A. Okumura).
http://dx.doi.org/10.1016/j.yebeh.2017.05.004 1525-5050/© 2017 Elsevier Inc. All rights reserved.
duration occurring only once during a single episode of febrile illness. Complex FS are usually defined as FS with one or more of the following features; focal onset, duration N10 min, or multiple seizures during a single episode of illness. Of these features, the presence or absence of focal features is not easy to determine. Indeed, the definitions are ambiguous, and subtle focal features can easily be missed by observers (such as parents) who are surprised and frightened when a child suffers a seizure. Additionally, several ictal electroencephalographic studies (ictal EEGs) of epileptic seizures have shown that generalized features are not uncommon during focal seizures in infants and younger children [2–4]. Diffuse tonic postures are common during focal seizures (even symmetric seizures) in infants. Therefore, focal seizures in infants and young children can be mistaken for generalized seizures. Neville and Gindner recently suggested that most FS, especially those that originate in the mesial temporal lobe, may be of focal origin [1]. The cited authors prospectively studied 10 consecutive children with FS. Detailed seizure histories were taken, focusing on phenomena evident before the motor events. A clear preliminary phase, or aura, compatible with a seizure origin in the temporal lobe, was evident in
60
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63
seven children. Hamelin and Vercueil reported ictal videotape-recorded EEG findings during an example of “simple” FS of focal onset [5]. The patient opened his eyes and began to cry in association with the development of rhythmic activity in the right centrotemporal region. The cited authors considered the possibility that even simple FS may be focal (possibly hippocampal) in nature. Thus, we hypothesized that FS of focal onset may be more frequent than presently thought. We therefore prospectively surveyed FS semiology focusing on manifestations at seizure commencement. Our aim was to clarify the semiology of FS and to determine the frequency of FS with symptoms suggestive of focal onset.
The rates of events at the commencement of FS and those during FS were compared according to the presence or absence of past history of FS, because observation of a first FS could be more emotionally challenged and less reliable than that of a second or later FS. We also performed statistical analyses comparing differences in patient characteristics according to frequency of non-specific focal and limbic features. We used the chi-square and the Kruskal–Wallis tests to compare categorical and numerical variables, respectively. A P-value b 0.05 was considered to reflect statistical significance. All statistical analyses were performed with the aid of EZR ver. 1.33 software (available at http:// www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) [7].
2. Patients and methods
3. Results
This prospective study was performed from May 2014 to October 2015 in the Departments of Pediatrics of Aichi Medical University Hospital, Anjo Kosei Hospital, and Okazaki City Hospital. Children with FS who visited these hospitals immediately after their seizures were consecutively included. FS were defined as seizures in children aged 6 months to 5 years associated with a fever N38.0 °C and without central nervous system infection or acute metabolic derangement. Children with any previous evidence of neurological or developmental abnormalities were excluded. The study was approved by the ethics committee of Aichi Medical University Hospital. Manifestations of FS were described by the parents using a structured questionnaire as soon as possible after arrival at the hospital (at the latest, within 24 h). The questionnaire consisted principally of closed-ended questions. The parents or caregivers were allowed to choose two or more answers for each question and to add whatever comments they wished. The attending pediatricians assisted the parents if necessary. Seizure duration was numerically recorded. We focused on events at seizure commencement, including changes in behavior and facial expression, and ocular and oral symptoms. Changes in facial expression were evaluated using a facial action coding system [6]. We showed parents pictures of various facial expressions: disgust, fear, anger, contempt, sadness, surprise, and happiness. Parents were asked to choose the picture that was most similar to the child's facial expression at seizure onset. We also asked whether the child was awake or asleep before seizure onset, and documented the autonomic and motor symptoms during seizure and responsiveness after seizure. We explored the focal and limbic features of all patients. Focal features were defined as seizure symptoms that were presumed to arise from specific brain regions. The following items were classified as focal features:
We obtained data about 106 children (60 boys and 46 girls) with FS. The median patient age was 24 months (range, 8–71 months). Fortyone children (39%) had histories of FS. Nineteen children (18%) had experienced two or more episodes of FS. Family histories of FS (in parents and siblings) were recorded for 39 children (37%). Seizure duration was b1 min in 10 children (9%), 1–4 min in 60 (57%), 5–9 min in 16 (15%), 10–19 min in 11 (10%), ≥ 20 min in 3 (3%), and undetermined in 6 (6%). Before seizures, 63 children (59%) were awake, and 43 (41%) were asleep. After seizures, 28 children (26%) were alert, 45 (42%) were drowsy, and 33 (31%) fell asleep. Table 1 summarizes events at the commencement of FS. Behavioral changes were observed in 35 children (32%). Nineteen 19 (18%) cried or screamed; 10 (9%) were poorly responsive (9%); and 4 exhibited motion arrest (4%). One child developed motion arrest followed by crying,
1) Any change in behavior; 2) Changes in facial expression: fear, sadness, anger, or laughter; 3) Ocular symptoms: lateral deviation or eyelid flutter; 4) Oral symptoms: at least one of the following: drooling, oral automatism, cheek twitching, or mouth deviation; 5) Events during a seizure: both specific autonomic symptoms (at least one of the following: pallor, cyanosis, or vomiting) and nonconvulsive motor symptoms (atonicity or no obvious movement) were evaluated. Limbic features were defined as seizure symptoms that were very likely of mesial temporal onset. The following items were classified as limbic features: 1) Changes in behavior: crying or screaming; 2) Changes in facial expression: fear or sadness; 3) Oral symptoms: oral automatism. No ocular, autonomic, or motor symptom was considered to be a limbic feature. The numbers of focal and limbic features were counted for each patient.
Table 1 Events at the commencement of febrile seizure.
Change in behavior Cry or scream Poor responsiveness Motion arrest Rough breathing Irritability Complaint of pain Unremarkable Change in facial expression Surprise Fear Sadness Disgust Anger Laugh Contempt Blank face Unremarkable Ocular symptoms Upgaze Staring Blank eyes Lateral deviation Crossed eyes Eyelid flutter Multidirectional movement Unremarkable Oral symptoms Open slightly Drooling Clenching teeth Oral automatism Open widely Cheek twitching Mouth deviation Unremarkable NS: not significant.
All (N = 106)
No past history of FS (N = 65)
With past history of FS (N = 41)
19 (18%) 10 (9%) 4 (4%) 2 (2%) 1 (1%) 1 (1%) 71 (67%)
13 (20%) 6 (9%) 3 (5%) 0 1 (2%) 1 (2%) 43 (66%)
6 (15%) 4 (10%) 1 2 (5%) 0 0 28 (68%)
NS NS NS NS NS NS NS
24 (23%) 19 (18%) 6 (6%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 27 (26%) 36 (33%)
15 (23%) 13 (20%) 4 (6%) 0 1 (2%) 1 (2%) 0 16 (25%) 25 (38%)
9 (22%) 6 (15%) 2 (5%) 1 (2%) 0 0 1 (2%) 11 (27%) 11 (27%)
NS NS NS NS NS NS NS NS NS
38 (36%) 32 (30%) 21 (20%) 8 (8%) 4 (4%) 3 (3%) 2 (2%) 18 (17%)
24 (37%) 19 (29%) 15 (23%) 3 (5%) 2 (3%) 2 (3%) 1 (2%) 13 (20%)
14 (34%) 13 (32%) 6 (15%) 5 (13%) 2 (5%) 1 (2%) 1 (2%) 5 (12%)
NS NS NS NS NS NS NS NS
37 (35%) 30 (28%) 21 (20%) 15 (14%) 10 (9%) 6 (6%) 3 (3%) 16 (15%)
25 (38%) 16 (25%) 10 (15%) 8 (12%) 6 (9%) 5 (8%) 1 (2%) 13 (20%)
12 (29%) 14 (34%) 11 (27%) 7 (14%) 4 (10%) 1 (2%) 2 (5%) 3 (7%)
NS NS NS NS NS NS NS NS
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63 Table 2 Events during febrile seizure.
Autonomic symptoms Pallor Cyanosis Flushing Vomiting Unremarkable Motor symptoms Clonic movement No obvious movement Tonic–clonic movement Atonic Tonic movement Uncertain
All (N = 106)
No past history of FS (N = 65)
With past history of FS (N = 41)
57 (54%) 12 (11%) 8 (8%) 4 (4%) 28 (26%)
36 (55%) 7 (11%) 6 (9%) 2 (3%) 15 (23%)
21 (63%) 5 (12%) 2 (5%) 2 (5%) 13 (32%)
NS NS NS NS NS
39 (37%) 16 (15%) 16 (15%) 14 (13%) 13 (12%) 8 (8%)
21 (32%) 11 (17%) 11 (17%) 8 (12%) 9 (14%) 5 (8%)
18 (44%) 5 (12%) 5 (12%) 6 (15%) 4 (10%) 3 (7%)
NS NS NS NS NS NS
61
in behavior/facial expression and oral symptoms were observed at seizure commencement in 19 (18%)/19 (18%), and 15 (14%) children, respectively. Table 4 summarizes the relationships between focal features and patient characteristics. Thirty-eight children (36%) had two or more focal features. Twelve children (11%) had three or more such features. No patient characteristic had any significant effect on the number of focal features. Table 5 summarizes the relationships between limbic features and patient characteristics. Forty-four children (42%) exhibited at least one limbic feature. Only nine children (8%) exhibited two or more features. No patient characteristic had any significant effect on the number of limbic features.
4. Discussion
NS: not significant.
and another demonstrated poor responsiveness followed by screaming. Changes in facial expression at seizure commencement were noted in 53 children (50%). Facial expressions were rated as surprise in 24 children (23%), fear in 19 (18%), and sadness in 6 (6%). Other facial expressions were rare. Ocular symptoms were noted in 78 children (74%). Upgazing and staring were frequent at seizure commencement. Lateral deviation was evident in eight children (8%), and eyelid flutter was evident in three (3%). Two types of ocular symptom were noted in 20 children (19%). Oral symptoms were recognized in 90 children (85%). Slight mouth-opening and drooling were frequent. Oral automatism (lipsmacking and chewing) was observed in 15 children (14%). Cheek twitching and mouth deviation were recognized in six (6%) and three (3%) children, respectively. Twenty-nine children (27%) had two or more types of oral symptom. The rate of any events at the commencement of FS was not different according to the presence or absence of past history of FS. Table 2 summarizes events noted during seizures. Autonomic symptoms were recognized in 78 children (74%). Pallor and cyanosis were evident in 57 (54%) and 12 (11%), respectively. Vomiting was recorded in four children (4%), three of whom also exhibited pallor or cyanosis. In terms of motor symptoms, convulsive movements were observed in 68 children (64%), but tonic–clonic movements were observed in only 16 (15%). Sixteen children (15%) exhibited no obvious movements, and 14 (13%) became atonic. The rate of any events during FS was not different according to the presence or absence of past history of FS. Table 3 lists the numbers of children with focal and limbic features. Eighty-one children (76%) had one or more focal features. Of these, changes in behavior or facial expression and oral symptoms were observed at seizure commencement in 35 (33%), 27 (25%), and 48 (45%) children, respectively. Ocular symptoms at seizure commencement and events during seizures were relatively infrequent. Forty-four children exhibited one or more limbic features. Of these, changes
We found that the semiology of FS varied widely among children. Various events were observed at seizure commencement. Symptoms suggestive of focal seizure origin were frequently observed at seizure commencement. In terms of events during seizures, tonic–clonic movement was infrequent. Thus, any suggestion that most FS are generalized tonic–clonic seizures may be inaccurate. Notably, most children with FS exhibited one or more manifestations suggestive of focal onset. Eighty-one (76%) of the 106 children exhibited at least one focal feature, and 38 (36%) exhibited two or more. These results support the suggestion that FS are often of focal onset. Currently, FS with focal features are classified as complex FS. If focal onset FS is not uncommon, classification of FS by the presence or absence of focal features may be unnecessary. FS are frequent from infancy through to young childhood (age 1–2 years), at which time primary generalized epilepsies are rather rare. If FS and epilepsy (unprovoked seizures) share a similar pathogenesis, dependent on age-related brain maturation, it is rational to suggest that FS are often of focal onset, although the presence of focal features does not always mean that a seizure is, in fact, of focal onset. Of seizure symptoms suggestive of focal onset, events at seizure commencement are important, because they contain clues allowing focal and generalized seizures to be distinguished. We consider changes in behavior and facial expression to be possible surrogates of aura, which is a subjective ictal phenomenon preceding observable seizure symptoms [8,9]. Auras are frequent in adults with focal seizures [10]. Infants and young children cannot verbalize the presence of aura because it is a subjective ictal phenomenon. However, the observed changes in behavior and facial expression suggest the presence of a subjective phenomenon. Indeed, we observed various changes in behavior and facial expression, some of which were suggestive of focal onset seizures. We believe that seizures associated with changes in behavior and/or facial expression that are attributable to activation of the emotional network (fear, sadness, anger, or laughter) are likely to be of focal onset. In our present study, one-third of children exhibited changes in behavior,
Table 3 Focal and limbic features.
Events at the beginning of a seizure Change in behavior Change in facial expression Ocular symptoms Oral symptoms
Focal features
Number of cases
Limbic features
Number of cases
Any Fear, sadness, anger, or laugh Lateral deviation or eyelid flutter At least one of following items; drooling, oral automatism, cheek twitching, or mouth deviation
35 (33%) 27 (25%) 11 (10%) 48 (45%)
Cry or scream Fear or sadness Not assessed Oral automatism
19 (18%) 19 (18%)
19 (18%)
Not assessed
Events during a seizure Both autonomic and motor symptoms listed below Autonomic; at least one of pallor, cyanosis, or vomiting Motor; atonic or no obvious movement
15 (14%)
62
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63
Table 4 Focal features and patient characteristics. Number of focal features
Male Age (months)a Past history of FS Family history of FS Sz during wakefulness Duration of Sz ~5 min
0 N = 25
1 N = 43
2 N = 26
3 N=9
4 N=3
18 (72%) 21 (8–61) 9 (36%) 8 (32%) 13 (52%) 18 (72%)
20 (47%) 27 (10–71) 19 (44%) 19 (44%) 23 (53%) 27 (63%)
16 (62%) 22.5 (10–47) 10 (38%) 8 (31%) 18 (69%) 16 (62%)
4 (44%) 23 (12–62) 3 (33%) 3 (33%) 6 (67%) 8 (89%)
2 (67%) 15 (13–18) 0 1 (33%) 3 (100%) 1 (33%)
NS NS NS NS NS NS
FS: febrile seizures, Sz: seizure, NS: not significant. a Data are shown as median (range).
and one-fourth developed relevant facial expressions (fear, sadness, anger, or laughter). Certain ocular symptoms evident at seizure commencement are presumed to be localizing or lateralizing in nature [11,12]. We included lateral eye deviation and eyelid flutter among the symptoms suggestive of focal onset [11]. However, most ocular symptoms are present in patients experiencing both focal and generalized seizures. Upgazing or staring is observed at the commencement of both generalized tonic– clonic and focal seizures, and this is combined with impairments in awareness. There were few children with ocular symptoms suggestive of focal onset in the present study. Oral symptoms at seizure commencement varied widely. We considered drooling, oral automatism, cheek twitching, and mouth deviation to be indicative of focal onset. Drooling, cheek twitching, and mouth deviation are often observed in child epilepsy patients, and these are often accompanied by centrotemporal spikes [13]. Drooling or hypersalivation is also observed in patients with temporal lobe epilepsy [14]. Oral automatism is a characteristic seizure symptom of those with such epilepsy [15,16]. Notably, nearly half of all children with FS had one or more oral symptoms suggestive of focal onset. Events during a seizure can sometimes be used to distinguish focal from generalized seizures. Certain autonomic changes are characteristic of focal seizures. Pallor or cyanosis associated with vomiting is characteristic of the seizures of Panayiotopoulos syndrome [17,18]. Ictal pallor has also been reported in children with temporal lobe epilepsy [19]. However, cyanosis is also evident during generalized tonic–clonic seizures [20]. Thus, pallor, cyanosis, and vomiting were considered to be suggestive of focal seizure onset in the present study, but only if they were not associated with any obvious convulsive or other movement or atony. Asymmetric motor symptoms (such as unilateral dystonic posturing) were not investigated in the present study because unsettled witnesses (such as upset parents) find these symptoms difficult to identify, although they are useful for differentiating focal from generalized seizures. It is not easy for those lacking specialized knowledge to classify motor symptoms correctly. Tonic seizures can be misinterpreted as tonic–clonic seizures. Therefore, we defined atony or absence of obvious movement (only) as motor symptoms suggestive of focal onset.
Ultimately, about one-fifth of all children were judged to exhibit events during seizures suggestive of focal onset. Neville and Gindner considered the possibility that FS was a syndrome of secondarily generalized hippocampal epilepsy based on the frequent compatibility between the semiology of FS with a mesial temporal origin of seizures [1,21]. The cited authors stressed the evidence for a preliminary phase or ‘aura.’ Fear, drooling, lip-smacking, chewing, and eye deviation were considered to be suggestive of mesial temporal epilepsy. Consistent with these ideas, we considered limbic features to be present if at least one of the following were noted at seizure commencement: crying or screaming (behavioral changes), a facial expression of fear or sadness, and/or oral automatism. Ultimately, seizure symptoms suggestive of a limbic system origin were evident in 44 of the 106 children. This suggests that limbic features may not be infrequent, although the numbers of children with such features were fewer in the present study than in the work of Neville and Gindner [1]. The differences in the proportions of limbic features are explained by the methods employed in the two studies. We asked witnesses to complete questionnaires, whereas two clinicians conducted direct or telephone interviews in the study conducted by Neville and Gindner [1]. Clinician interviews will yield more detailed information, increasing the proportion of children with limbic features. However, the diversity of FS semiology evident in our present study can be explained by differences among the children in seizure foci. Some seizure foci were located outside the mesial temporal lobe. The presence or absence of focal or limbic features was not associated with any particular patient characteristic. Of the various factors, age may be closely related to seizure manifestations. The semiology of focal seizures differs in infants and adults [22]. Automatisms developing during the focal seizures of infants are often subtle. Apparent generalized features are common during such seizures, despite the fact that well-developed secondary generalizations associated with synchronized, bilateral clonic activity are rare. The absence of any difference in seizure semiology by patient characteristics suggests that focal or limbic features may be universal in FS. Our study had several limitations. Our fundamental focus was on the presence or absence of auras, or focal seizure symptoms, in children
Table 5 Limbic features and patient characteristics. Number of limbic features
Male Age (months)a Past history of FS Family history of FS Sz during wakefulness Duration of Sz ~5 min FS: febrile seizures, Sz: seizure. a Data are shown as median (range).
0 N = 62
1 N = 35
2 N=7
3 N=2
35 (56%) 23.5 (8–71) 26 (42%) 23 (37%) 38 (61%) 39 (63%)
18 (51%) 24 (10–62) 12 (34%) 12 (34%) 19 (89%) 24 (69%)
6 (86%) 22 (16–34) 2 (29%) 3 (43%) 4 (57%) 6 (86%)
1 (50%) 15 (12–18) 1 (50%) 1 (50%) 2 (100%) 1 (50%)
NS NS NS NS NS NS
M. Takasu et al. / Epilepsy & Behavior 73 (2017) 59–63
with generalized seizures. Dugan et al. [23] used a detailed semistructured interview to study the frequency of auras in patients with generalized epilepsies. It was found that 21.3% of participants reported auras in response to an open-ended question, and 64.3% were presumed to have auras based on analysis of the answers to closed-ended questions. Seneviratne et al. used the validated Epilepsy Diagnostic Interview Questionnaire [24] to study the frequency of focal seizure symptoms in patients with idiopathic generalized epilepsies [25]. It was found that 70 of 135 participants exhibited focal seizure symptoms including aphasia, a visual aura, and epigastric sensations. These studies imply that auras and focal features are observable during generalized seizures. It is not easy to distinguish focal from generalized seizures based solely on semiology. The gold standard is ictal VTR-EEG recording. However, ictal recordings during FS are very difficult to obtain and do not yield realistic data. The reliability of information could be influenced by emotions of witnesses. Especially, parents who first saw FS of their children might be strongly challenged by a seizure. Thus, observation of a first FS may be less reliable than that of a second or later FS. In our study, the rates of events at the commencement of and during FS were not significantly different according to the presence or absence of past history of FS. The observation bias according to the presence or absence of past history of FS is presumed to be less strong in our study. The sensitivity of focal feature detection may have been low in our present study, as we did not conduct direct interviews. More information on seizure semiology would have been obtained had detailed interviews been performed. To this end, it would be desirable to develop an interview tool that can be used to evaluate seizures in infants and young children. The questionnaire that we used was not validated and may have been somewhat inappropriate. Our definitions of focal and limbic features are tentative. To determine the presence or absence of focal or limbic features more objectively, an appropriate questionnaire, as well as careful definitions of focal and limbic features, is essential. In summary, the semiology of FS varied widely among children, and seizure symptoms suggestive of focal onset were frequent. About onethird of children had symptoms suggestive of limbic onset. Neither the focal nor the limbic features were associated with age, a history of FS, or seizure duration. These results suggest that FS of focal onset are not uncommon and may not be necessarily regarded as complex. The semiology of FS requires further investigation, as does the relationship thereof to FS recurrence and the later development of unprovoked seizures. Disclosure None of the authors has any conflict of interest to disclose. Acknowledgements This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (26293252 and 26461551), a grant from Japan Agency for Medical Research and Development
63
(15fk0108005h0001), and a grant from the Ministry of Health, Labour and Welfare (H27-Nanji-Ippan-028). References [1] Neville B, Gindner D. Febrile seizures are a syndrome of secondarily generalized hippocampal epilepsy. Dev Med Child Neurol 2010;52:1151–3. [2] Yamamoto N, Watanabe K, Negoro T, Takaesu E, Aso K, Furune S, et al. Complex partial seizures in children: ictal manifestations and their relation to clinical course. Neurology 1987;37:1379–82. [3] Brockhaus A, Elger CE. Complex partial seizures of temporal lobe origin in children of different age groups. Epilepsia 1995;36:1173–81. [4] Dravet C, Catani C, Bureau M, Roger J. Partial epilepsies in infancy: a study of 40 cases. Epilepsia 1989;30:807–12. [5] Hamelin S, Vercueil L. A simple febrile seizure with focal onset. Epileptic Disord 2014;16:112–5. [6] Ryan A, Cohn JF, Lucey S, Saragih J, Lucey P, De la Torre F, et al. Automated facial expression recognition system. 43rd annual 2009 international carnahan conference on security technology; 2009. p. 172–7. [7] Kanda R. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013;48:452–8. [8] Blume WT, Luders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel Jr J. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001;42:1212–8. [9] Johanson M, Valli K, Revonsuo A, Wedlund JE. Content analysis of subjective experiences in partial epileptic seizures. Epilepsy Behav 2008;12:170–82. [10] So N. Epileptic auras. In: Wyllie E, editor. The treatment of epilepsy. Principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 299–308. [11] Foldvary-Schaefer N, Unnwongse K. Localizing and lateralizing features of auras and seizures. Epilepsy Behav 2011;20:160–6. [12] Rossetti AO, Kaplan PW. Seizure semiology: an overview of the 'inverse problem'. Eur Neurol 2010;63:3–10. [13] Panayiotopoulos CP, Bureau M, Caraballo RH, Dalla Bernardina B, Valeta T. Idiopathic focal epilepsies in childhood. In: Bureau M, Genton P, Dravet C, Delgado-Escueta AV, Tassinari CA, Thomas P, Wolf P, editors. Epileptic syndromes in infancy childhood and adolescence. 5th ed. Montrouge: John Libbey; 2012. p. 217–54. [14] Shah J, Zhai H, Fuerst D, Watson C. Hypersalivation in temporal lobe epilepsy. Epilepsia 2006;47:644–51. [15] Williamson PD, Thadani VM, French JA, Darcey TM, Mattson RH, Spencer SS, et al. Medial temporal lobe epilepsy: videotape analysis of objective clinical seizure characteristics. Epilepsia 1998;39:1182–8. [16] Fontana E, Negrini F, Francione S, Mai R, Osanni E, Menna E, et al. Temporal lobe epilepsy in children: electroclinical study of 77 cases. Epilepsia 2006;47:26–30 [Suppl]. [17] Panayiotopoulos CP. Extraoccipital benign childhood partial seizures with ictal vomiting and excellent prognosis. J Neurol Neurosurg Psychiatry 1999;66:82–5. [18] Koutroumanidis M. Panayiotopoulos syndrome: an important electroclinical example of benign childhood system epilepsy. Epilepsia 2007;48:1044–53. [19] Fogarasi A, Janszky J, Tuxhorn I. Ictal pallor is associated with left temporal seizure onset zone in children. Epilepsy Res 2005;67:117–21. [20] Baumgartner C, Lurger S, Leutmezer F. Autonomic symptoms during epileptic seizures. Epileptic Disord 2001;3:103–16. [21] Neville BG, Gindner D. Febrile seizures — semiology in humans and animal models: evidence of focality and heterogeneity. Brain Dev 2010;32:33–6. [22] Nordli DR, Wyllie E. Seizure semiology in infants with localization-related epilepsy. In: Engel J, Pedley T, editors. Epilepsy. A comprehensive textbook. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 635–8. [23] Dugan P, Carlson C, Bluvstein J, Chong DJ, Friedman D, Kirsch HE. Auras in generalized epilepsy. Neurology 2014;83:1444–9. [24] Seneviratne U, Woo JJ, Boston RC, Cook M, D'Souza W. Focal seizure symptoms in idiopathic generalized epilepsies. Neurology 2015;85:589–95. [25] Choi H, Winawer MR, Kalachikov S, Pedley TA, Hauser WA, Ottman R. Classification of partial seizure symptoms in genetic studies of the epilepsies. Neurology 2006;66: 1648–53.