Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Original article
Five pediatric cases of ictal fear with variable outcomes Mari Akiyama a,b,⇑, Katsuhiro Kobayashi a, Takushi Inoue a, Tomoyuki Akiyama a, Harumi Yoshinaga a a
Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan b Department of Pediatrics, National Hospital Organization, Minami-Okayama Medical Center, Japan Received 29 March 2013; received in revised form 28 August 2013; accepted 22 November 2013
Abstract Purpose: Ictal fear is an uncommon condition in which fear manifests as the main feature of epileptic seizures. The literature has suggested that ictal fear is generally associated with poor seizure outcomes. We wanted to clarify the variability in seizure outcome of children with ictal fear. Subjects and methods: We identified five pediatric patients with ictal fear who were followed up on at Okayama University Hospital between January 2003 and December 2012. We retrospectively reviewed their clinical records and EEG findings. Results: The onset age of epilepsy ranged from 8 months to 9 years and 10 months. The common ictal symptoms were sudden fright, clinging to someone nearby, and subsequent impairment of consciousness, which were often accompanied by complex visual hallucinations and psychosis-like complaints. Ictal fear, in four patients, was perceived as a nonepileptic disorder by their parents. Ictal electroencephalograms (EEG) of ictal fear were obtained in all patients. Three showed frontal onset, while the other two showed centrotemporal or occipital onsets. Two patients were seizure free at last follow-up, while seizures persisted in the other three. A patient with seizure onset during infancy had a favorable outcome, which was considered to be compatible with benign partial epilepsy with affective symptoms. Conclusion: Ictal fear is not always associated with a symptomatic cause or a poor seizure outcome. It is quite important to make a correct diagnosis of ictal fear as early as possible to optimize treatment. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Ictal fear; Childhood; Benign partial epilepsy with affective symptoms; Frontal lobe epilepsy
1. Introduction Ictal fear is an uncommon condition in which fear manifests as the main feature of epileptic seizures. Partial seizures presenting with fear are generally considered to originate in the temporal or frontal lobe [1,2]. Ictal fear is ‘unprovoked fear without object of dread’ which spontaneously appears associated with epileptic discharges which involve neural networks that include the limbic structures responsible for emotions [3]. It has been ⇑ Corresponding author at: Department of Child Neurology, Oka-
yama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Okayama 700-8558, Japan. Tel.: +81 86 235 7372; fax: +81 86 235 7377. E-mail address: [email protected] (M. Akiyama).
empirically shown that not only ‘pure’ ictal fear but also ictal fear with fearful hallucinations exist [4]. Children with ictal fear are frequently misdiagnosed as having sleep or psychiatric disorders, such as pavor nocturnus, panic attacks and psychogenic reactions [5,6]. Cases reported in the literature show that for most patients with ictal fear, their epilepsy was symptomatic and intractable. We report on five children with ictal fear confirmed by ictal EEGs whose outcomes were more variable than expected. 2. Subjects and methods We identified five pediatric patients with ictal fear who were followed up on at Okayama University Hospital between January 2003 and December 2012.
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.11.011
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
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The details of patient #4 were reported elsewhere [7]. The inclusion criteria for ictal fear in this study were epileptic seizures which present fear as a prominent symptom and in which fear is expressed with facial expressions, behavioral changes (i.e. running away, intense crying, clinging to someone nearby), and/or verbal descriptions. All patients underwent routine EEGs at Okayama University Hospital. Four had ictal EEGs recorded at Okayama University Hospital and one at a different hospital. EEGs were recorded during waking and sleep for more than 40 min using Neurofax (Nihon Kohden, Tokyo, Japan) according to the International 10–20 Electrode Placement System. The follow-up periods were more than 5 years in all patients. We retrospectively reviewed their clinical records and EEG findings. 3. Results 3.1. Case report Patient #1 is a girl with normal psychomotor development at seizure onset. Her gestation and delivery were uneventful. There was no family history of seizure disorders. At the age of 8 months, she started having seizures consisting of generalized atonia and unresponsiveness with cyanosis and eye fixation, lasting approximately 3 min. She was referred to Okayama University Hospital after having several seizures. Physical and neurological examinations were unremarkable. Her head CT scan and interictal EEG were normal. She was clinically diagnosed as having epilepsy and treated with phenobarbital. Two months later, she experienced three afebrile generalized tonic–clonic seizures in a day. An increase in phenobarbital dosage suppressed her seizures. At the age of 1 year and 5 months, she started having events characterized by sudden intense crying for her mother without any provocation, clinging to someone nearby with a frightened expression, looking around uneasily and a subsequent mild cloudiness of consciousness. These events lasted 1–5 min. Although she was able to respond and walk at approximately 2 min after onset, once or twice she showed the unusual behavior of seeking her mother even when her mother was beside her. She fully recovered within 5 min of onset. At the age of 2 years and 1 month, while suffering from a cold, she had three similar events within a few hours. On her arrival at Okayama University Hospital, she was alert and her neurological examination was normal. She had another event during an EEG study on the same day. The ictal EEG demonstrated irregular 2–3 Hz delta activity originating from the bilateral occipital head regions, which appeared approximately 10 s prior to the clinical symptoms and built up and spread to the bilateral central head regions (Fig. 1). As the events were confirmed to be partial seizures, carbamazepine
was started and her seizures have been completely suppressed since then. Later on, her interictal EEG showed sporadic spike–wave complexes with bilateral occipital dominance (Fig. 2). Carbamazepine was discontinued at the age of six and she remained seizure-free at last follow-up. 3.2. Other results The clinical characteristics of the five patients are summarized in Table 1. The onset age of epilepsy ranged from 8 months to 9 years and 10 months. Patient #5 had a febrile status epilepticus with right hemiconvulsion at the age of 5 years and was diagnosed as having acute encephalopathy. She developed moderate mental retardation and autistic behavior as a result of acute encephalopathy. The causes of epilepsy in the other four patients were unknown, and three of them continued to show normal intelligence. Patient #4 developed mild mental retardation, attention deficit/hyperactivity disorder, and severe conduct disorder after the onset of epilepsy. Four patients had ictal fear at the onset of epilepsy. Patient #1, presented in the above case report, initially had ictal syncope. Patient #3 experienced secondarily generalized seizures concurrently with ictal fear. Patient #5 developed ictal fear followed by secondarily generalized seizures at 9 months after acute encephalopathy. The common feature of ictal fear was sudden fright and clinging to someone nearby, followed by impairment of consciousness. Patient #1 showed unusual behavior that resembled transient blindness or postictal confusion following fear expressions. Patient #2 complained of dizziness and intense fear at the same time. Two patients (patients #3 and #4) had fear sensation, complex visual hallucinations and psychosis-like complaints simultaneously. In patient #5, fear expression was the sole manifestation. All patients experienced clusters of seizures. Two of them (patients #4 and #5) had status epilepticus many times and required hospitalization. Although patient #1 showed no epileptic abnormalities on the her first EEG, subsequent EEGs showed spike–wave complexes with bilateral occipital dominance. The other four patients showed frontal spikes. Two of them (patients #2 and #5) had few spikes throughout their courses. Although the remaining two (patients #3 and #4) showed frequent frontal spikewaves intermingled with frontal background slowing, especially during the periods of frequent seizures, they did not have frequent spikes in their baseline states. In patient #1, an ictal EEG of a seizure presenting with fear showed occipital seizure onset. Three patients had frontal seizure onset, while the remaining patient had centrotemporal seizure onset. In three patients (patients #2, #3 and #4) with frontal seizure onset, ictal
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
M. Akiyama et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 1. Ictal EEG during wakefulness of patient #1. Approximately 10 s before the onset of symptoms (black arrow), irregular 2–3 Hz delta waves appeared over both occipital areas spreading to the bilateral central areas.
Fig. 2. Interictal EEG during wakefulness of patient #1 at 2 years of age. There are spike–wave complexes with bilateral occipital dominance.
EEGs consisted of fast activity in the bilateral frontal head area with increasing amplitudes and decreasing frequency, which evolved into slow activity intermingled
with spike-waves spreading from the frontal region to the entire head region. In contrast, in patient #1, the ictal EEGs consisted of slow wave activity originating
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
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Table 1 Clinical characteristics of patients. Patient #
1
2
3
4
5
Sex Etiology Onset age of epilepsy (years) Seizure type at onset Other seizure types Accompanying symptoms of IF Onset age of IF (years) Seizure frequency at onset Anti-epileptic drugs
F Unknown 8 months
M Unknown 4
F Unknown 9
M Unknown 4
F Post-encephalopathy 6
Ictal syncope GTCS Transient blindness? 1
IF
IF
IF
IF
None Dizziness
None Complex visual hallucination
sGS None
4
sGS Complex visual hallucination 9
4
6
Monthly
Monthly
Weekly
Daily
Daily
PB, CBZ
CBZ, ZNS
CBZ, VPA, LTG, LEV
5
6
7
CBZ, PHT, CZP, ZNS, AZA, VPA, ST, PRM, CLB, GBP 11
PB, VPA, CBZ, ZNS, PHT, AZA, ST, LTG, LEV 10
Suppressed
Suppressed
SPS
IF
IF, sGS MR, autism
Follow-up periods (years) Seizures at the last follow-up Development at the last follow-up Head CT/MRI
Normal
Normal
Normal
Normal/ND
ND/Normal
Functional imaging
ND
Normal/ Normal ND
Mild MR, ADHD, severe conduct disorder ND/Normal
Spike location in interictal EEG Seizure onset zone in ictal EEG
Bil. O, Cz
R F, Cz
Interictal SPECT; hypoperfusion at Rt. Fp RF
Ictal SPECT; hyperperfusion at bil. frontal cingulate Bil. Fp-F
Bil. F, R O-pT
Bil. O
Bil. F, more in R
Bil. F, more in R
Bil. F
L C-T
Minimal cerebral atrophy ND
F, female; M, male; IF, ictal fear; GTCS, generalized tonic-clonic seizure; sGS, secondarily generalized seizure; SPS, simple partial seizure; PB, phenobarbital; CBZ, carbamazepine; ZNS, zonisamide; VPA, valproic acid; LTG, lamotrigine; LEV, levetiracetam; PHT, phenytoin; CZP, clonazepam; AZA, acetazolamide; ST, sulthiame; PRM, primidone; CLB, clobazam; GBP, gabapentin; MR, mental retardation; ADHD, attention deficit/hyperactivity disorder; CT, computed tomography; MRI, magnetic resonance imaging; SPECT, single photon emission computed tomography; ND, not done; EEG, electroencephalogram; Fp, frontopolar; F, forntal; C, central; T, temporal, pT, posterior temporal; O, occipital; Cz, central midline; R, right; L left; Bil., bilateral.
from the bilateral occipital regions, and from the left centrotemporal area in patient #5 spreading to adjacent areas. Although brain magnetic resonance imaging (MRI) revealed no abnormalities in patients #3 and #4, interictal 99m Tc-ECD single photon emission computed tomography (SPECT) in patient #3 suggested a frontal epileptic focus. In addition, patient #4 showed an anterior cingulate focus on ictal SPECT and magnetoencephalography (MEG). Patient #5, a case with post-encephalopathy, showed minimal cerebral atrophy on MRI. The remaining two (patients #1 and #2) showed no abnormalities on brain computed tomography (CT) or MRI. All patients were treated with anti-epileptic drugs. Three were not seizure-free, and more than nine antiepileptic drugs had been tried in two of these patients at last follow-up (December 2012). Ictal fear in patient #3 has been suppressed since valproic acid was started, although the episodes of ‘feeling strange around the back of the head’, which might be simple partial seizures, have remained. In contrast, seizures were
suppressed immediately after carbamazepine was started in patient #1. Patient #2 was successfully treated with carbamazepine and zonisamide. Patients #1 and #2 have remained seizure-free for more than 4 years since they stopped taking medication. 4. Discussion There have been few reports of multiple pediatric cases with ictal fear, although there have been several reports of single pediatric cases [7–10]. Herein, we presented five pediatric cases with ictal fear confirmed by ictal EEGs. Ictal fear, in four patients, was perceived as a nonepileptic disorder by their parents. In particular, patient #2 frequently complained of simultaneous dizziness and a fearful feeling during his seizures. His ictal symptoms were misleading and resembled those of psychogenic seizures or benign paroxysmal vertigo. Since his interictal EEG showed few epileptic discharges, we were unable to confirm the diagnosis of epilepsy until we performed an ictal EEG.
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
M. Akiyama et al. / Brain & Development xxx (2014) xxx–xxx
Ictal fear is a rare condition that has not yet been widely recognized. It may be difficult to distinguish ictal fear from non-epileptic phenomena, even in adult cases [11,12], when intense fear with screaming and violent movements are the sole ictal manifestations. In the case of children, it may be more difficult to diagnose because of their poor expressive abilities and the variability of their associated symptoms [8–10]. It has been suggested that the fear sensation associated with epileptic seizures generally originates from temporal or frontal lobes. Analysis of intracranial ictal EEGs and observations of clinical symptoms provoked by electrical stimulation have demonstrated limbic structures, especially the amygdala, are closely tied to fear [2,13]. Limbic activation by seizure discharges or electrical stimulation may add an affective dimension to perceptual and mnemonic data processed by the temporal neocortex, which may be required for endowing them with experiential immediacy [14]. Bancaud et al. reported that seizures originating from the anterior cingulate gyrus usually consist of intense fright with facial expressions of fear, and aggressive verbalizations, often accompanied with complex gestural automatisms and autonomic symptoms [15]. They emphasized the essential involvement of the anterior cingulate gyrus for the appearance of such intense fear. It has also been argued that the anterior cingulate cortex is responsible for the regulation of autonomic systems, storage of emotional memory, and escape behavior associated with fear [16]. Orbitofrontal seizures also accompany complex gestural automatisms and frequent changes of mood [15]. It has been suggested that these manifestations are related to the propagation of the orbital discharges to the anterior cingulate gyrus. Reciprocal anatomical pathways between the orbitofrontal cortex, hippocampus, amygdala, and cingulate gyrus have also been reported [17]. In general, neither spontaneous seizures in ‘pure’ occipital lobe epilepsy nor cortical electrical stimulation applied to the occipital lobe produce a fearful feeling. Even complex visual hallucinations rarely involve emotional expressions [18,19]. On the other hand, Oehl et al. reported ictal fear originating from the occipital lobe [20]. They noted that intense fear in a patient’s habitual seizure was triggered by spontaneous epileptic activity arising in the occipital lobe and by electrical stimulation at the same location via the secondary propagation of discharges from the occipital epileptogenic area to the symptomatogenic zone in the amygdala. Other reports also demonstrated rapid propagation of epileptic discharges originating from the occipital region to the temporal lobe [19,21]. Thus, although not common, fear sensation could occur in epileptic seizures of occipital origin. Along with symptomatic cases, Dalla Bernardina et al. [22,23] reported children with benign partial
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epilepsy of childhood whose seizures had predominantly affective symptoms, particularly an expression of terror, and termed them ‘benign partial epilepsy with affective symptoms’ (BPEAS). The frequent interictal abnormalities were characterized by slow spike-wave complexes resembling Rolandic spikes involving the fronto-temporal or the parieto-temporal areas of one hemisphere. Ictal EEGs showed clear localization in the fronto-temporal, the centro-temporal or the parietal areas in some cases, whereas other cases showed diffuse distribution of epileptic discharges at seizure onset. Seizures were suppressed by anti-epileptic drugs without difficulty, and long-term outcomes were favorable. In these cases, a significant involvement of the temporal lobe was suspected because fear is generally induced by the involvement of the temporal lobe [13,24]. Nevertheless, the ictal EEG pattern remained ambiguous regarding temporal localization in the majority of the cases [23]. There have been other reports on a few cases of BPEAS [5,9]. In our study, patient #1 had seizure onset with ictal syncope and generalized tonic-clonic seizures in infancy, although the seizure frequency was low, which was compatible with BPEAS. Seizures persisted in three patients at last follow-up, while the other two have achieved seizure freedom in our case series. Although it is difficult to detect a statistical difference because of the small number of patients, seizure-free patients appeared to have infrequent seizures throughout their clinical courses. The onset age of ictal fear was relatively low in the seizure-free patients. In contrast, seizure-persistent patients, especially the two intractable patients (patients #4 and #5), experienced status epilepticus several times. Both had symptomatic frontal lobe epilepsy. While the majority of patients with ictal fear have poor outcomes, those with good outcomes, such as the ones we have reported on here, do exist. Some of the former require epilepsy surgery, while the latter can discontinue medication sooner or even go without treatment. In any case, it is quite important to make a correct diagnosis of ictal fear as early as possible to optimize treatment. References [1] Manford M, Fish DR, Shorvon SD. An analysis of clinical seizure patterns and their localizing value in frontal and temporal lobe epilepsies. Brain 1996;119:17–40. [2] Biraben A, Taussig D, Thomas P, Even C, Vignal JP, Scarabin JM, et al. Fear as the main feature of epileptic seizures. J Neurol Neurosurg Psychiatry 2001;70:186–91. [3] Gloor P. Experiential phenomena of temporal lobe epilepsy: facts and hypothesis. Brain 1990;113:1673–94. [4] Williams D. The structures of emotions reflected in epileptic experiences. Brain 1956;79:29–67. [5] Cornaggia CM, Beghi M, Giovannini S, Boni A, Gobbi G. Partial seizures with affective semiology versus pavor nocturnus. Epileptic Disord 2010;12:65–8.
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[6] Lombroso CT. Pavor nocturnus of proven epileptic origin. Epilepsia 2000;41:1221–6. [7] Inutsuka M, Ogino T, Yoshinaga H, Ohtsuka Y, Oka E. A child with ictal fear as the primary epileptic manifestation (in Japanese). No To Hattatsu 2003;35:336–41. [8] Huppertz HJ, Franck P, Korinthenberg R, Schulze-Bonhage A. Recurrent attacks of fear and visual hallucinations in a child. J Child Neurol 2002;17:230–3. [9] Wakai S, Yoto Y, Higashidate Y, Tachi N, Chiba S. Benign partial epilepsy with affective symptoms: hyperkinetic behavior during interictal periods. Epilepsia 1994;35:810–2. [10] Elmi H, Kilincßaslan A, Oztu¨rk M, Yapici Z. A case with hyperkinetic FLE presenting as a psychiatric disturbance. Turk J Pediatr 2011;53:574–8. [11] Sazgar M, Carlen PL, Wennberg R. Panic attack semiology in right temporal lobe epilepsy. Epileptic Disord 2003;5:93–100. [12] Lee DO, Helmers SL, Steingard RJ, DeMaso DR. Case study: seizure disorder presenting as panic disorder with agoraphobia. J Am Acad Child Adolesc Psychiatry 1997;36:1295–8. [13] Fish DR, Gloor P, Quesney FL, Olivier A. Clinical responses to electrical brain stimulation of the temporal and frontal lobes in patients with epilepsy. Pathophysiological implications. Brain 1993;116:397–414. [14] Gloor P, Olivier A, Quesney LF, Andermann F, Horowitz S. The role of the limbic system in experiential phenomena of temporal lobe epilepsy. Ann Neurol 1982;12:129–44. [15] Bancaud J, Talairach J. Clinical semiology of frontal lobe seizures. In: Chauvel P, Delgado-Escueta AV, Halgren E, Bancaud J, editors. Frontal lobe seizures and epilepsies. Advances in neurology, vol. 57. New York: Raven Press; 1992. p. 3–58. [16] Vogt BA. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci 2005;6:533–44.
[17] Kringelbach ML, Rolls ET. The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Prog Neurobiol 2004;72:341–72. [18] Salanova V, Andermann F, Olivier A, Rasmussen T, Quesney LF. Occipital lobe epilepsy, electroclinical manifestations, electrocorticography, cortical stimulation and outcome in 42 patients treated between 1930 and 1991. Brain 1992;115:1655–80. [19] Williamson PD, Thadani VM, Darcey TM, Spencer DD, Spencer SS, Mattson RH. Occipital lobe epilepsy: clinical characteristics, seizure spread patterns, and results of surgery. Ann Neurol 1992;31:3–13. [20] Oehl B, Schulze-Bonhage A, Lanz M, Brandt A, Altenmu¨ller DM. Occipital lobe epilepsy with fear as leading ictal symptom. Epilepsy Behav 2012;23:379–83. [21] Sturm JW, Newton MR, Chinvarun Y, Berlangieri SU, Berkovic SF. Ictal SPECT and interictal PET in the localization of occipital lobe epilepsy. Epilepsia 2000;41:463–6. [22] Dalla Bernardina B, Colamaria V, Chiamenti C, Capovilla G, Trevisan E, Tassinari CA. Benign partial epilepsy with affective symptoms (benign psychomotor epilepsy). In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence (2nd edn). London: John Libbey & Co.; 1992. p. 219–24. [23] Dalla Bernardina B, Darra F, Fontana E, Beaumanoir A. Is there a benign limbic epilepsy in children? In: Avanzini G, Beaumanoir A, Mira L, editors. Limbic seizures in children. London: John Libbey & Co.; 2001. p. 241–7. [24] Cendes F, Andermann F, Gloor P, Gambardella A, LopesCendes I, Watson C, et al. Relationship between atrophy of the amygdala and ictal fear in temporal lobe epilepsy. Brain 1994;117:739–46.
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
Original article
Five pediatric cases of ictal fear with variable outcomes Mari Akiyama a,b,⇑, Katsuhiro Kobayashi a, Takushi Inoue a, Tomoyuki Akiyama a, Harumi Yoshinaga a a
Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan b Department of Pediatrics, National Hospital Organization, Minami-Okayama Medical Center, Japan Received 29 March 2013; received in revised form 28 August 2013; accepted 22 November 2013
Abstract Purpose: Ictal fear is an uncommon condition in which fear manifests as the main feature of epileptic seizures. The literature has suggested that ictal fear is generally associated with poor seizure outcomes. We wanted to clarify the variability in seizure outcome of children with ictal fear. Subjects and methods: We identified five pediatric patients with ictal fear who were followed up on at Okayama University Hospital between January 2003 and December 2012. We retrospectively reviewed their clinical records and EEG findings. Results: The onset age of epilepsy ranged from 8 months to 9 years and 10 months. The common ictal symptoms were sudden fright, clinging to someone nearby, and subsequent impairment of consciousness, which were often accompanied by complex visual hallucinations and psychosis-like complaints. Ictal fear, in four patients, was perceived as a nonepileptic disorder by their parents. Ictal electroencephalograms (EEG) of ictal fear were obtained in all patients. Three showed frontal onset, while the other two showed centrotemporal or occipital onsets. Two patients were seizure free at last follow-up, while seizures persisted in the other three. A patient with seizure onset during infancy had a favorable outcome, which was considered to be compatible with benign partial epilepsy with affective symptoms. Conclusion: Ictal fear is not always associated with a symptomatic cause or a poor seizure outcome. It is quite important to make a correct diagnosis of ictal fear as early as possible to optimize treatment. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Ictal fear; Childhood; Benign partial epilepsy with affective symptoms; Frontal lobe epilepsy
1. Introduction Ictal fear is an uncommon condition in which fear manifests as the main feature of epileptic seizures. Partial seizures presenting with fear are generally considered to originate in the temporal or frontal lobe [1,2]. Ictal fear is ‘unprovoked fear without object of dread’ which spontaneously appears associated with epileptic discharges which involve neural networks that include the limbic structures responsible for emotions [3]. It has been ⇑ Corresponding author at: Department of Child Neurology, Oka-
yama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Okayama 700-8558, Japan. Tel.: +81 86 235 7372; fax: +81 86 235 7377. E-mail address: [email protected] (M. Akiyama).
empirically shown that not only ‘pure’ ictal fear but also ictal fear with fearful hallucinations exist [4]. Children with ictal fear are frequently misdiagnosed as having sleep or psychiatric disorders, such as pavor nocturnus, panic attacks and psychogenic reactions [5,6]. Cases reported in the literature show that for most patients with ictal fear, their epilepsy was symptomatic and intractable. We report on five children with ictal fear confirmed by ictal EEGs whose outcomes were more variable than expected. 2. Subjects and methods We identified five pediatric patients with ictal fear who were followed up on at Okayama University Hospital between January 2003 and December 2012.
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.11.011
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
2
M. Akiyama et al. / Brain & Development xxx (2014) xxx–xxx
The details of patient #4 were reported elsewhere [7]. The inclusion criteria for ictal fear in this study were epileptic seizures which present fear as a prominent symptom and in which fear is expressed with facial expressions, behavioral changes (i.e. running away, intense crying, clinging to someone nearby), and/or verbal descriptions. All patients underwent routine EEGs at Okayama University Hospital. Four had ictal EEGs recorded at Okayama University Hospital and one at a different hospital. EEGs were recorded during waking and sleep for more than 40 min using Neurofax (Nihon Kohden, Tokyo, Japan) according to the International 10–20 Electrode Placement System. The follow-up periods were more than 5 years in all patients. We retrospectively reviewed their clinical records and EEG findings. 3. Results 3.1. Case report Patient #1 is a girl with normal psychomotor development at seizure onset. Her gestation and delivery were uneventful. There was no family history of seizure disorders. At the age of 8 months, she started having seizures consisting of generalized atonia and unresponsiveness with cyanosis and eye fixation, lasting approximately 3 min. She was referred to Okayama University Hospital after having several seizures. Physical and neurological examinations were unremarkable. Her head CT scan and interictal EEG were normal. She was clinically diagnosed as having epilepsy and treated with phenobarbital. Two months later, she experienced three afebrile generalized tonic–clonic seizures in a day. An increase in phenobarbital dosage suppressed her seizures. At the age of 1 year and 5 months, she started having events characterized by sudden intense crying for her mother without any provocation, clinging to someone nearby with a frightened expression, looking around uneasily and a subsequent mild cloudiness of consciousness. These events lasted 1–5 min. Although she was able to respond and walk at approximately 2 min after onset, once or twice she showed the unusual behavior of seeking her mother even when her mother was beside her. She fully recovered within 5 min of onset. At the age of 2 years and 1 month, while suffering from a cold, she had three similar events within a few hours. On her arrival at Okayama University Hospital, she was alert and her neurological examination was normal. She had another event during an EEG study on the same day. The ictal EEG demonstrated irregular 2–3 Hz delta activity originating from the bilateral occipital head regions, which appeared approximately 10 s prior to the clinical symptoms and built up and spread to the bilateral central head regions (Fig. 1). As the events were confirmed to be partial seizures, carbamazepine
was started and her seizures have been completely suppressed since then. Later on, her interictal EEG showed sporadic spike–wave complexes with bilateral occipital dominance (Fig. 2). Carbamazepine was discontinued at the age of six and she remained seizure-free at last follow-up. 3.2. Other results The clinical characteristics of the five patients are summarized in Table 1. The onset age of epilepsy ranged from 8 months to 9 years and 10 months. Patient #5 had a febrile status epilepticus with right hemiconvulsion at the age of 5 years and was diagnosed as having acute encephalopathy. She developed moderate mental retardation and autistic behavior as a result of acute encephalopathy. The causes of epilepsy in the other four patients were unknown, and three of them continued to show normal intelligence. Patient #4 developed mild mental retardation, attention deficit/hyperactivity disorder, and severe conduct disorder after the onset of epilepsy. Four patients had ictal fear at the onset of epilepsy. Patient #1, presented in the above case report, initially had ictal syncope. Patient #3 experienced secondarily generalized seizures concurrently with ictal fear. Patient #5 developed ictal fear followed by secondarily generalized seizures at 9 months after acute encephalopathy. The common feature of ictal fear was sudden fright and clinging to someone nearby, followed by impairment of consciousness. Patient #1 showed unusual behavior that resembled transient blindness or postictal confusion following fear expressions. Patient #2 complained of dizziness and intense fear at the same time. Two patients (patients #3 and #4) had fear sensation, complex visual hallucinations and psychosis-like complaints simultaneously. In patient #5, fear expression was the sole manifestation. All patients experienced clusters of seizures. Two of them (patients #4 and #5) had status epilepticus many times and required hospitalization. Although patient #1 showed no epileptic abnormalities on the her first EEG, subsequent EEGs showed spike–wave complexes with bilateral occipital dominance. The other four patients showed frontal spikes. Two of them (patients #2 and #5) had few spikes throughout their courses. Although the remaining two (patients #3 and #4) showed frequent frontal spikewaves intermingled with frontal background slowing, especially during the periods of frequent seizures, they did not have frequent spikes in their baseline states. In patient #1, an ictal EEG of a seizure presenting with fear showed occipital seizure onset. Three patients had frontal seizure onset, while the remaining patient had centrotemporal seizure onset. In three patients (patients #2, #3 and #4) with frontal seizure onset, ictal
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
M. Akiyama et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 1. Ictal EEG during wakefulness of patient #1. Approximately 10 s before the onset of symptoms (black arrow), irregular 2–3 Hz delta waves appeared over both occipital areas spreading to the bilateral central areas.
Fig. 2. Interictal EEG during wakefulness of patient #1 at 2 years of age. There are spike–wave complexes with bilateral occipital dominance.
EEGs consisted of fast activity in the bilateral frontal head area with increasing amplitudes and decreasing frequency, which evolved into slow activity intermingled
with spike-waves spreading from the frontal region to the entire head region. In contrast, in patient #1, the ictal EEGs consisted of slow wave activity originating
Please cite this article in press as: Akiyama M et al. Five pediatric cases of ictal fear with variable outcomes. Brain Dev (2014), http://dx.doi.org/ 10.1016/j.braindev.2013.11.011
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M. Akiyama et al. / Brain & Development xxx (2014) xxx–xxx
Table 1 Clinical characteristics of patients. Patient #
1
2
3
4
5
Sex Etiology Onset age of epilepsy (years) Seizure type at onset Other seizure types Accompanying symptoms of IF Onset age of IF (years) Seizure frequency at onset Anti-epileptic drugs
F Unknown 8 months
M Unknown 4
F Unknown 9
M Unknown 4
F Post-encephalopathy 6
Ictal syncope GTCS Transient blindness? 1
IF
IF
IF
IF
None Dizziness
None Complex visual hallucination
sGS None
4
sGS Complex visual hallucination 9
4
6
Monthly
Monthly
Weekly
Daily
Daily
PB, CBZ
CBZ, ZNS
CBZ, VPA, LTG, LEV
5
6
7
CBZ, PHT, CZP, ZNS, AZA, VPA, ST, PRM, CLB, GBP 11
PB, VPA, CBZ, ZNS, PHT, AZA, ST, LTG, LEV 10
Suppressed
Suppressed
SPS
IF
IF, sGS MR, autism
Follow-up periods (years) Seizures at the last follow-up Development at the last follow-up Head CT/MRI
Normal
Normal
Normal
Normal/ND
ND/Normal
Functional imaging
ND
Normal/ Normal ND
Mild MR, ADHD, severe conduct disorder ND/Normal
Spike location in interictal EEG Seizure onset zone in ictal EEG
Bil. O, Cz
R F, Cz
Interictal SPECT; hypoperfusion at Rt. Fp RF
Ictal SPECT; hyperperfusion at bil. frontal cingulate Bil. Fp-F
Bil. F, R O-pT
Bil. O
Bil. F, more in R
Bil. F, more in R
Bil. F
L C-T
Minimal cerebral atrophy ND
F, female; M, male; IF, ictal fear; GTCS, generalized tonic-clonic seizure; sGS, secondarily generalized seizure; SPS, simple partial seizure; PB, phenobarbital; CBZ, carbamazepine; ZNS, zonisamide; VPA, valproic acid; LTG, lamotrigine; LEV, levetiracetam; PHT, phenytoin; CZP, clonazepam; AZA, acetazolamide; ST, sulthiame; PRM, primidone; CLB, clobazam; GBP, gabapentin; MR, mental retardation; ADHD, attention deficit/hyperactivity disorder; CT, computed tomography; MRI, magnetic resonance imaging; SPECT, single photon emission computed tomography; ND, not done; EEG, electroencephalogram; Fp, frontopolar; F, forntal; C, central; T, temporal, pT, posterior temporal; O, occipital; Cz, central midline; R, right; L left; Bil., bilateral.
from the bilateral occipital regions, and from the left centrotemporal area in patient #5 spreading to adjacent areas. Although brain magnetic resonance imaging (MRI) revealed no abnormalities in patients #3 and #4, interictal 99m Tc-ECD single photon emission computed tomography (SPECT) in patient #3 suggested a frontal epileptic focus. In addition, patient #4 showed an anterior cingulate focus on ictal SPECT and magnetoencephalography (MEG). Patient #5, a case with post-encephalopathy, showed minimal cerebral atrophy on MRI. The remaining two (patients #1 and #2) showed no abnormalities on brain computed tomography (CT) or MRI. All patients were treated with anti-epileptic drugs. Three were not seizure-free, and more than nine antiepileptic drugs had been tried in two of these patients at last follow-up (December 2012). Ictal fear in patient #3 has been suppressed since valproic acid was started, although the episodes of ‘feeling strange around the back of the head’, which might be simple partial seizures, have remained. In contrast, seizures were
suppressed immediately after carbamazepine was started in patient #1. Patient #2 was successfully treated with carbamazepine and zonisamide. Patients #1 and #2 have remained seizure-free for more than 4 years since they stopped taking medication. 4. Discussion There have been few reports of multiple pediatric cases with ictal fear, although there have been several reports of single pediatric cases [7–10]. Herein, we presented five pediatric cases with ictal fear confirmed by ictal EEGs. Ictal fear, in four patients, was perceived as a nonepileptic disorder by their parents. In particular, patient #2 frequently complained of simultaneous dizziness and a fearful feeling during his seizures. His ictal symptoms were misleading and resembled those of psychogenic seizures or benign paroxysmal vertigo. Since his interictal EEG showed few epileptic discharges, we were unable to confirm the diagnosis of epilepsy until we performed an ictal EEG.
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Ictal fear is a rare condition that has not yet been widely recognized. It may be difficult to distinguish ictal fear from non-epileptic phenomena, even in adult cases [11,12], when intense fear with screaming and violent movements are the sole ictal manifestations. In the case of children, it may be more difficult to diagnose because of their poor expressive abilities and the variability of their associated symptoms [8–10]. It has been suggested that the fear sensation associated with epileptic seizures generally originates from temporal or frontal lobes. Analysis of intracranial ictal EEGs and observations of clinical symptoms provoked by electrical stimulation have demonstrated limbic structures, especially the amygdala, are closely tied to fear [2,13]. Limbic activation by seizure discharges or electrical stimulation may add an affective dimension to perceptual and mnemonic data processed by the temporal neocortex, which may be required for endowing them with experiential immediacy [14]. Bancaud et al. reported that seizures originating from the anterior cingulate gyrus usually consist of intense fright with facial expressions of fear, and aggressive verbalizations, often accompanied with complex gestural automatisms and autonomic symptoms [15]. They emphasized the essential involvement of the anterior cingulate gyrus for the appearance of such intense fear. It has also been argued that the anterior cingulate cortex is responsible for the regulation of autonomic systems, storage of emotional memory, and escape behavior associated with fear [16]. Orbitofrontal seizures also accompany complex gestural automatisms and frequent changes of mood [15]. It has been suggested that these manifestations are related to the propagation of the orbital discharges to the anterior cingulate gyrus. Reciprocal anatomical pathways between the orbitofrontal cortex, hippocampus, amygdala, and cingulate gyrus have also been reported [17]. In general, neither spontaneous seizures in ‘pure’ occipital lobe epilepsy nor cortical electrical stimulation applied to the occipital lobe produce a fearful feeling. Even complex visual hallucinations rarely involve emotional expressions [18,19]. On the other hand, Oehl et al. reported ictal fear originating from the occipital lobe [20]. They noted that intense fear in a patient’s habitual seizure was triggered by spontaneous epileptic activity arising in the occipital lobe and by electrical stimulation at the same location via the secondary propagation of discharges from the occipital epileptogenic area to the symptomatogenic zone in the amygdala. Other reports also demonstrated rapid propagation of epileptic discharges originating from the occipital region to the temporal lobe [19,21]. Thus, although not common, fear sensation could occur in epileptic seizures of occipital origin. Along with symptomatic cases, Dalla Bernardina et al. [22,23] reported children with benign partial
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epilepsy of childhood whose seizures had predominantly affective symptoms, particularly an expression of terror, and termed them ‘benign partial epilepsy with affective symptoms’ (BPEAS). The frequent interictal abnormalities were characterized by slow spike-wave complexes resembling Rolandic spikes involving the fronto-temporal or the parieto-temporal areas of one hemisphere. Ictal EEGs showed clear localization in the fronto-temporal, the centro-temporal or the parietal areas in some cases, whereas other cases showed diffuse distribution of epileptic discharges at seizure onset. Seizures were suppressed by anti-epileptic drugs without difficulty, and long-term outcomes were favorable. In these cases, a significant involvement of the temporal lobe was suspected because fear is generally induced by the involvement of the temporal lobe [13,24]. Nevertheless, the ictal EEG pattern remained ambiguous regarding temporal localization in the majority of the cases [23]. There have been other reports on a few cases of BPEAS [5,9]. In our study, patient #1 had seizure onset with ictal syncope and generalized tonic-clonic seizures in infancy, although the seizure frequency was low, which was compatible with BPEAS. Seizures persisted in three patients at last follow-up, while the other two have achieved seizure freedom in our case series. Although it is difficult to detect a statistical difference because of the small number of patients, seizure-free patients appeared to have infrequent seizures throughout their clinical courses. The onset age of ictal fear was relatively low in the seizure-free patients. In contrast, seizure-persistent patients, especially the two intractable patients (patients #4 and #5), experienced status epilepticus several times. Both had symptomatic frontal lobe epilepsy. While the majority of patients with ictal fear have poor outcomes, those with good outcomes, such as the ones we have reported on here, do exist. Some of the former require epilepsy surgery, while the latter can discontinue medication sooner or even go without treatment. In any case, it is quite important to make a correct diagnosis of ictal fear as early as possible to optimize treatment. References [1] Manford M, Fish DR, Shorvon SD. An analysis of clinical seizure patterns and their localizing value in frontal and temporal lobe epilepsies. Brain 1996;119:17–40. [2] Biraben A, Taussig D, Thomas P, Even C, Vignal JP, Scarabin JM, et al. Fear as the main feature of epileptic seizures. J Neurol Neurosurg Psychiatry 2001;70:186–91. [3] Gloor P. Experiential phenomena of temporal lobe epilepsy: facts and hypothesis. Brain 1990;113:1673–94. [4] Williams D. The structures of emotions reflected in epileptic experiences. Brain 1956;79:29–67. [5] Cornaggia CM, Beghi M, Giovannini S, Boni A, Gobbi G. Partial seizures with affective semiology versus pavor nocturnus. Epileptic Disord 2010;12:65–8.
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