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Efficacy and safety of levetiracetam in the treatment of Panayiotopoulos syndrome
Epilepsy Research (2009) 85, 318—320
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
Efficacy and safety of levetiracetam in the treatment of Panayiotopoulos syndrome Carmen García ∗, Guillermo Rubio Neurology Service, Hospital Jerez, Cádiz, Spain Received 6 October 2008; received in revised form 22 March 2009; accepted 27 March 2009 Available online 6 May 2009
KEYWORDS Antiepileptic drugs; Levetiracetam; Panayiotopoulos syndrome; Epilepsy
Summary Panayiotopoulos syndrome (PS) represents the second commonest benign partial epilepsy of childhood. This study evaluated the effects of levetiracetam (LEV) in three children with this syndrome. All three children (aged 8, 12 and 10 years) had episodic autonomic symptoms for 4, 6 and 2 years, respectively. Symptoms duration varied between a few minutes and 5—7 days, reflecting an autonomic status epilepticus. Children previously controlled on valproate (VPA) but with recurring seizures, were given LEV (1000—2000 mg/day) initially as add-on therapy, and after as monotherapy. All three children received LEV monotherapy and remained seizure-free after 3, 3 and 2 years of treatment, respectively. One child, after 2 years seizure free, stopped LEV treatment. Now, he is asymptomatic for 2 years. LEV has shown efficacy on autonomic seizure control in three patients with PS where VPA was ineffective. © 2009 Elsevier B.V. All rights reserved.
PS is a common childhood-related idiopathic benign seizure disorder that has been officially recognised by the International League against Epilepsy (ILAE) (Engel, 2001). An expert consensus has defined it as a ‘‘benign age-related focal seizure disorder occurring in early and mid-childhood. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms, and by EEG that shows shifting and/or multiple foci, often with occipital predominance’’ (Ferrie et al., 2006). Prevalence of PS is high, around 6% of seizures in children 1—15 years old. In the general population 2—3/1000 children may be affected with a peak onset at 6—9 years.
∗ Corresponding author at: Avda Dr Mara˜ nón 8, 11500 El Puerto de Santa María, Cádiz, Spain. Tel.: +34 607256084; fax: +34 956851601. E-mail address: [email protected] (C. García).
The clinical features of this syndrome comprise a characteristic constellation of symptoms that start with autonomic symptoms, mainly emetic that can be followed by more conventional seizure-symptoms like impairment of consciousness, eyes deviation, hemiconvulsions or generalised convulsion, speech arrest or visual hallucinations. Patients begin with the full or partial emetic triad (nausea, retching and vomiting) and with consciousness preserved; they feel sick, look pale and mydriasis is sometimes very prominent. Nevertheless, pure autonomic seizures and pure autonomic status epilepticus (autonomic seizure that lasts for more than 30 min) occur in only about 10% of patients, because most patients develop behavioural changes (restlessness, agitation, quietness, terror) and impairment of consciousness. Two thirds of seizures occur during sleep. Fifty-four per cent of the seizures last from 1 to 30 min with a mean of 9 min and the rest last more than 30 min and can persist for hours or even days.
0920-1211/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2009.03.024
Safety of levetiracetam in children Despite similar clinical manifestations, there is significant EEG variability from normal to abnormal EEGs, with occipital or extraoccipital high or small amplitude spikes or multispikes or spike-wave complexes. PS is remarkably benign in terms of seizure frequency and evolution. Autonomic status epilepticus imparts no residual neurological deficit. The risk of developing epilepsy in adult life is probably no more than that in the general population. Nevertheless, cardio-respiratory arrest may exceptionally happen and is potentially fatal. The great majority of patients do not need treatment. However, prophylactic treatment may be desired if a child has multiple recurrences and in the event of parental insistence. We present the effect of LEV in three children with PS who needed treatment, and had received VPA for 6 months with recurrence of the seizures.
Case 1 An 8-year-old girl presented with episodes that began with nausea, retching and headache, tinnitus, felling sick and being unwell, sweating and looking pale. She vomited repeatedly and became unresponsive and confused for hours or even some days (until 7 days). The episodes started when the child was four and since then had occurred every 1—3 months. She had neither been diagnosed nor treated in that time. She was a 33-week gestation born. Developmental milestones where normal. She had no significant past medical or family history. Neurological exam and MRI were normal. The EEG revealed small, sparse spikes, and brief generalised discharges of small spikes. Treatment was started with VPA, increasing up to 1000 mg, with reduction in the duration (less than 24 h) and frequency (two in 6 months) of the attacks. She complained of important weight gain. Over the following 6 months, the frequency and initial duration of the attacks increased until the previous frequency. She was then started on LEV at 250 mg twice a day, increasing to 500 mg every 12 h after 2 weeks. After 3 months, she had an attack lasting 15 min, at which point the dose was increased to 1000 mg every 12 h. Three months later, the child was seizure free and the VPA was progressively reduced over 10 days and then stopped. She remains seizure free for 3 years and reports no side effects.
Case 2 A 12-year-old boy attended our clinic as a result of episodes involving sudden onset of headache, pallor, dizziness and the triad of emetic symptoms: retching, nausea and vomiting. These episodes began when the boy was 6 years old, and since then, he had been suffering an attack every 6 months, lasting between 10 and 15 min. Over the previous 6 months, the attacks had increased in frequency to two a month. Some of the attacks were taking longer to subside, with symptoms lasting for up to 5 days. In the last episode, before coming to the clinic, the vomiting had been so severe that it had caused bleeding in the digestive tract, as a result of Mallory Weiss Syndrome, diagnosed by endoscopy. The patient had not received any drug treatment until that time. His past medical history, family history, neurological exam and MRI
319 were negative. The EEG revealed repetitive spikes mainly from the frontal region while awake. The diagnosis was PS. He began VPA therapy (1000 mg) and was seizure free for 6 months, when he had two new episodes with VPA blood level of 96.5 g/ml. LEV was initiated at 250 mg twice a day increased to 1000 mg in a day, in 2 weeks. From the beginning of LEV therapy the boy was seizures free. One month later VPA was decreased until withdrawal. He has had no drug related adverse effects. He has been seizure free for 3 years.
Case 3 A 10-year-old boy complained of episodes of tinnitus, sweating, pallor, nausea, retching, vomiting and occipital headaches over the previous 2 years. The episodes happened mainly during sleep, and the duration was 3—6 min, and disappeared spontaneously. The frequency became once a day in the last months and happened at daytime as well. His medical history was positive only for allergic rhinitis and in the family history, his mother had migraine. His delivery and development were normal. Physical and neurological examinations were normal. Brain MRI was normal. EEG revealed multifocal spike and brief generalised discharges of multispikes and spike wave complexes. He had never been diagnosed or treated. He started on treatment with VPA (1000 mg) and was seizure free for 6 months, when the episodes returned and began to occur monthly over the next 9 months. At this point, he began taking LEV 250 mg twice in a day, increasing up to 1000 mg daily in 2 weeks, with complete control of seizures. One year later he was taller and had gained weight because he was 13 years old. He had two mild episodes. LEV dose was increased reaching 1000 mg twice a day, and he remained seizure-free again for 1 year with no drug related adverse effects. LEV was then withdrawal. Actually he is 16-year-old and he has had no further seizures. We present three patients with PS that had episodic autonomic symptoms for 4, 6, and 2 years, respectively. The most frequent manifestations were nausea, vomiting, headache, sickness, sweating and pallor. Symptom duration varied between a few minutes in 1 and 5 to 7 days in the other two, reflecting an autonomic status epilepticus. Episodes were daily in one child and one to three per month in the other two, significantly interfering with child’s life making necessary prophylactic treatment. EEG is the most useful diagnostic procedure in this syndrome even when clinical manifestations are more important. However, it should be emphasized that PS should not be equated with occipital spikes. Our patients showed small sparse spikes in one, and multi-focal spikes wave complexes with frontal predominance in the other two, with very brief bursts of generalised spike-wave discharges in two of them. All they showed abnormalities in wakefulness so they did not need sleep recording. These EEG findings reveal a big variability between different patients and in subsequent records of the same patient. They had ‘‘functional spikes’’ (Covanis, 2006), that refers to transient focal EEG abnormalities of sharp waves that occur in children with or without epileptic seizures and disappear in the late teenager years. They appear in many brain locations, often shifting from one to another region in series of EEGs. The frequency, location
320 and persistence of spikes do not determine clinical manifestation, duration, severity and frequency of seizures or prognosis. The same clinical symptoms with such different EEGs indicate that there is a diffuse cortical hyperexcitability which is maturation related. The preferential involvement of autonomic manifestation may be attributed to epileptic discharges triggering low-threshold emetic and hypothalamus centres of vulnerable children. A weak epileptic discharge irrespective of localization activates susceptible autonomic centres (Panayiotopoulos, 2005). Continuous anticonvulsant treatment is usually not recommended in PS because most children have only a single seizure or seizures are infrequent. The seizures are usually benign and focal, and the risks are small. The potential side effects of drugs appear to outweigh the benefits. However, 10—20% of patients may have frequent seizures or have persistent autonomic status epilepticus for up to some days or very intensive autonomic manifestations that need small doses of antiepileptic medication to prevent recurrences, such happened in our patients. There is no convincing evidence, that any therapy will be more effective than other to control seizures and it is reported that some patients are sometimes resistant to treatment. Most clinicians treat seizures with carbamazepine (CBZ) or VPA. However, there are two reports of atypical developments after introduction of CBZ. One with absence and myoclonic seizures that ceased immediately after discontinuation (Kikumoto et al., 2006), and the other, with absences and atonic seizures (drop attacks) that did not improve after the drug was stopped (Ferrie et al., 2002). In our patients, seizures disappeared under VPA therapy for 6 months, but all of them had new recurrences. It is likely that the efficacy of this drug decrease with time, with a ‘‘tolerance’’ effect, not described until now. Of the newer drugs, LEV has been reported as therapeutic in three cases of benign epilepsy of childhood with centrotemporal spikes (Bello-Espinosa and Roberts, 2003) but to our knowledge, it has never been reported in patients with PS. Potential advantages of LEV for the paediatric population include lack of non-linear elimination kinetics, autoinduction, drug interactions, significant protein binding or reactive metabolites such as epoxides -enes or oxides (Leppik, 2001). LEV does not cause the weight gain, polycystic ovarian syndrome and thinning of hair seen with VPA nor has the risk of rash of CBZ (10%) (Konishi et al., 1993) or lamotrigine (LMT) (6%) (Barron et al., 2000). LEV also takes a relatively short time to achieve therapeutic dose, unlike LMT that can take 5—6 weeks. All patients in our study became seizure free with LEV alone or as add-on therapy. There are some evidences of
C. García, G. Rubio behavioural adverse reactions in children treated with this drug (Mula et al., 2004). Therefore, we started with small doses (250 mg) and titration was slow (250 mg per week), with a maintenance dose of 1000—2000 mg in two divided doses daily and we did not find any adverse event. LEV had excellent effects achieving freedom from seizures in all our patients. Further randomized controlled studies are necessary to confirm this therapeutic effect.
Conflicts of interest None of the authors has any conflict of interest to disclose.
Acknowledgements We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References Barron, T.F., et al., 2000. Lamotrigine monotherapy in children. Pediatr. Neurol. 23 (2), 160—163. Bello-Espinosa, L.E., Roberts, S.L., 2003. Levetiracetam for benign epilepsy of childhood with centrotemporal spikes-three cases. Seizure 12 (3), 157—159. Covanis, A., 2006. Panayiotopoulos syndrome: a benign childhood autonomic epilepsy frequently imitating encephalitis, syncope, migraine, sleep disorder, or gastroenteritis. Pediatrics 118, 1237—1243. Engel Jr., J., 2001. International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 42, 796—803. Ferrie, C.D., et al., 2002. Atypical evolution of Panayiotopoulos syndrome: a case report. Epileptic Disord. 4, 35—42. Ferrie, C.D., et al., 2006. Panayiotopoulos syndrome: a consensus view. Dev. Med. Child Neurol. 48, 236—240. Kikumoto, K., et al., 2006. EEG and seizure exacerbation induced by carbamazepine in Panayiotopoulos syndrome. Epileptic Disord. 8, 53—56. Konishi, T., et al., 1993. Carbamazepine-induced skin rash in children with epilepsy. Eur. J. Pediatr. 152, 605—608. Leppik, I.E., 2001. The place of levetiracetam in the treatment of epilepsy. Epilepsia 42 (Suppl. 4), 44—45. Mula, M., et al., 2004. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure 13, 55—57. Panayiotopoulos, C.P., 2005. The Epilepsies: Seizures, Syndromes and Management. Panayiotopoulos Syndrome. Blandon Medical Publishing Chipping Norton, Oxfordshire, UK, pp. 235—248.
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
Efficacy and safety of levetiracetam in the treatment of Panayiotopoulos syndrome Carmen García ∗, Guillermo Rubio Neurology Service, Hospital Jerez, Cádiz, Spain Received 6 October 2008; received in revised form 22 March 2009; accepted 27 March 2009 Available online 6 May 2009
KEYWORDS Antiepileptic drugs; Levetiracetam; Panayiotopoulos syndrome; Epilepsy
Summary Panayiotopoulos syndrome (PS) represents the second commonest benign partial epilepsy of childhood. This study evaluated the effects of levetiracetam (LEV) in three children with this syndrome. All three children (aged 8, 12 and 10 years) had episodic autonomic symptoms for 4, 6 and 2 years, respectively. Symptoms duration varied between a few minutes and 5—7 days, reflecting an autonomic status epilepticus. Children previously controlled on valproate (VPA) but with recurring seizures, were given LEV (1000—2000 mg/day) initially as add-on therapy, and after as monotherapy. All three children received LEV monotherapy and remained seizure-free after 3, 3 and 2 years of treatment, respectively. One child, after 2 years seizure free, stopped LEV treatment. Now, he is asymptomatic for 2 years. LEV has shown efficacy on autonomic seizure control in three patients with PS where VPA was ineffective. © 2009 Elsevier B.V. All rights reserved.
PS is a common childhood-related idiopathic benign seizure disorder that has been officially recognised by the International League against Epilepsy (ILAE) (Engel, 2001). An expert consensus has defined it as a ‘‘benign age-related focal seizure disorder occurring in early and mid-childhood. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms, and by EEG that shows shifting and/or multiple foci, often with occipital predominance’’ (Ferrie et al., 2006). Prevalence of PS is high, around 6% of seizures in children 1—15 years old. In the general population 2—3/1000 children may be affected with a peak onset at 6—9 years.
∗ Corresponding author at: Avda Dr Mara˜ nón 8, 11500 El Puerto de Santa María, Cádiz, Spain. Tel.: +34 607256084; fax: +34 956851601. E-mail address: [email protected] (C. García).
The clinical features of this syndrome comprise a characteristic constellation of symptoms that start with autonomic symptoms, mainly emetic that can be followed by more conventional seizure-symptoms like impairment of consciousness, eyes deviation, hemiconvulsions or generalised convulsion, speech arrest or visual hallucinations. Patients begin with the full or partial emetic triad (nausea, retching and vomiting) and with consciousness preserved; they feel sick, look pale and mydriasis is sometimes very prominent. Nevertheless, pure autonomic seizures and pure autonomic status epilepticus (autonomic seizure that lasts for more than 30 min) occur in only about 10% of patients, because most patients develop behavioural changes (restlessness, agitation, quietness, terror) and impairment of consciousness. Two thirds of seizures occur during sleep. Fifty-four per cent of the seizures last from 1 to 30 min with a mean of 9 min and the rest last more than 30 min and can persist for hours or even days.
0920-1211/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2009.03.024
Safety of levetiracetam in children Despite similar clinical manifestations, there is significant EEG variability from normal to abnormal EEGs, with occipital or extraoccipital high or small amplitude spikes or multispikes or spike-wave complexes. PS is remarkably benign in terms of seizure frequency and evolution. Autonomic status epilepticus imparts no residual neurological deficit. The risk of developing epilepsy in adult life is probably no more than that in the general population. Nevertheless, cardio-respiratory arrest may exceptionally happen and is potentially fatal. The great majority of patients do not need treatment. However, prophylactic treatment may be desired if a child has multiple recurrences and in the event of parental insistence. We present the effect of LEV in three children with PS who needed treatment, and had received VPA for 6 months with recurrence of the seizures.
Case 1 An 8-year-old girl presented with episodes that began with nausea, retching and headache, tinnitus, felling sick and being unwell, sweating and looking pale. She vomited repeatedly and became unresponsive and confused for hours or even some days (until 7 days). The episodes started when the child was four and since then had occurred every 1—3 months. She had neither been diagnosed nor treated in that time. She was a 33-week gestation born. Developmental milestones where normal. She had no significant past medical or family history. Neurological exam and MRI were normal. The EEG revealed small, sparse spikes, and brief generalised discharges of small spikes. Treatment was started with VPA, increasing up to 1000 mg, with reduction in the duration (less than 24 h) and frequency (two in 6 months) of the attacks. She complained of important weight gain. Over the following 6 months, the frequency and initial duration of the attacks increased until the previous frequency. She was then started on LEV at 250 mg twice a day, increasing to 500 mg every 12 h after 2 weeks. After 3 months, she had an attack lasting 15 min, at which point the dose was increased to 1000 mg every 12 h. Three months later, the child was seizure free and the VPA was progressively reduced over 10 days and then stopped. She remains seizure free for 3 years and reports no side effects.
Case 2 A 12-year-old boy attended our clinic as a result of episodes involving sudden onset of headache, pallor, dizziness and the triad of emetic symptoms: retching, nausea and vomiting. These episodes began when the boy was 6 years old, and since then, he had been suffering an attack every 6 months, lasting between 10 and 15 min. Over the previous 6 months, the attacks had increased in frequency to two a month. Some of the attacks were taking longer to subside, with symptoms lasting for up to 5 days. In the last episode, before coming to the clinic, the vomiting had been so severe that it had caused bleeding in the digestive tract, as a result of Mallory Weiss Syndrome, diagnosed by endoscopy. The patient had not received any drug treatment until that time. His past medical history, family history, neurological exam and MRI
319 were negative. The EEG revealed repetitive spikes mainly from the frontal region while awake. The diagnosis was PS. He began VPA therapy (1000 mg) and was seizure free for 6 months, when he had two new episodes with VPA blood level of 96.5 g/ml. LEV was initiated at 250 mg twice a day increased to 1000 mg in a day, in 2 weeks. From the beginning of LEV therapy the boy was seizures free. One month later VPA was decreased until withdrawal. He has had no drug related adverse effects. He has been seizure free for 3 years.
Case 3 A 10-year-old boy complained of episodes of tinnitus, sweating, pallor, nausea, retching, vomiting and occipital headaches over the previous 2 years. The episodes happened mainly during sleep, and the duration was 3—6 min, and disappeared spontaneously. The frequency became once a day in the last months and happened at daytime as well. His medical history was positive only for allergic rhinitis and in the family history, his mother had migraine. His delivery and development were normal. Physical and neurological examinations were normal. Brain MRI was normal. EEG revealed multifocal spike and brief generalised discharges of multispikes and spike wave complexes. He had never been diagnosed or treated. He started on treatment with VPA (1000 mg) and was seizure free for 6 months, when the episodes returned and began to occur monthly over the next 9 months. At this point, he began taking LEV 250 mg twice in a day, increasing up to 1000 mg daily in 2 weeks, with complete control of seizures. One year later he was taller and had gained weight because he was 13 years old. He had two mild episodes. LEV dose was increased reaching 1000 mg twice a day, and he remained seizure-free again for 1 year with no drug related adverse effects. LEV was then withdrawal. Actually he is 16-year-old and he has had no further seizures. We present three patients with PS that had episodic autonomic symptoms for 4, 6, and 2 years, respectively. The most frequent manifestations were nausea, vomiting, headache, sickness, sweating and pallor. Symptom duration varied between a few minutes in 1 and 5 to 7 days in the other two, reflecting an autonomic status epilepticus. Episodes were daily in one child and one to three per month in the other two, significantly interfering with child’s life making necessary prophylactic treatment. EEG is the most useful diagnostic procedure in this syndrome even when clinical manifestations are more important. However, it should be emphasized that PS should not be equated with occipital spikes. Our patients showed small sparse spikes in one, and multi-focal spikes wave complexes with frontal predominance in the other two, with very brief bursts of generalised spike-wave discharges in two of them. All they showed abnormalities in wakefulness so they did not need sleep recording. These EEG findings reveal a big variability between different patients and in subsequent records of the same patient. They had ‘‘functional spikes’’ (Covanis, 2006), that refers to transient focal EEG abnormalities of sharp waves that occur in children with or without epileptic seizures and disappear in the late teenager years. They appear in many brain locations, often shifting from one to another region in series of EEGs. The frequency, location
320 and persistence of spikes do not determine clinical manifestation, duration, severity and frequency of seizures or prognosis. The same clinical symptoms with such different EEGs indicate that there is a diffuse cortical hyperexcitability which is maturation related. The preferential involvement of autonomic manifestation may be attributed to epileptic discharges triggering low-threshold emetic and hypothalamus centres of vulnerable children. A weak epileptic discharge irrespective of localization activates susceptible autonomic centres (Panayiotopoulos, 2005). Continuous anticonvulsant treatment is usually not recommended in PS because most children have only a single seizure or seizures are infrequent. The seizures are usually benign and focal, and the risks are small. The potential side effects of drugs appear to outweigh the benefits. However, 10—20% of patients may have frequent seizures or have persistent autonomic status epilepticus for up to some days or very intensive autonomic manifestations that need small doses of antiepileptic medication to prevent recurrences, such happened in our patients. There is no convincing evidence, that any therapy will be more effective than other to control seizures and it is reported that some patients are sometimes resistant to treatment. Most clinicians treat seizures with carbamazepine (CBZ) or VPA. However, there are two reports of atypical developments after introduction of CBZ. One with absence and myoclonic seizures that ceased immediately after discontinuation (Kikumoto et al., 2006), and the other, with absences and atonic seizures (drop attacks) that did not improve after the drug was stopped (Ferrie et al., 2002). In our patients, seizures disappeared under VPA therapy for 6 months, but all of them had new recurrences. It is likely that the efficacy of this drug decrease with time, with a ‘‘tolerance’’ effect, not described until now. Of the newer drugs, LEV has been reported as therapeutic in three cases of benign epilepsy of childhood with centrotemporal spikes (Bello-Espinosa and Roberts, 2003) but to our knowledge, it has never been reported in patients with PS. Potential advantages of LEV for the paediatric population include lack of non-linear elimination kinetics, autoinduction, drug interactions, significant protein binding or reactive metabolites such as epoxides -enes or oxides (Leppik, 2001). LEV does not cause the weight gain, polycystic ovarian syndrome and thinning of hair seen with VPA nor has the risk of rash of CBZ (10%) (Konishi et al., 1993) or lamotrigine (LMT) (6%) (Barron et al., 2000). LEV also takes a relatively short time to achieve therapeutic dose, unlike LMT that can take 5—6 weeks. All patients in our study became seizure free with LEV alone or as add-on therapy. There are some evidences of
C. García, G. Rubio behavioural adverse reactions in children treated with this drug (Mula et al., 2004). Therefore, we started with small doses (250 mg) and titration was slow (250 mg per week), with a maintenance dose of 1000—2000 mg in two divided doses daily and we did not find any adverse event. LEV had excellent effects achieving freedom from seizures in all our patients. Further randomized controlled studies are necessary to confirm this therapeutic effect.
Conflicts of interest None of the authors has any conflict of interest to disclose.
Acknowledgements We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References Barron, T.F., et al., 2000. Lamotrigine monotherapy in children. Pediatr. Neurol. 23 (2), 160—163. Bello-Espinosa, L.E., Roberts, S.L., 2003. Levetiracetam for benign epilepsy of childhood with centrotemporal spikes-three cases. Seizure 12 (3), 157—159. Covanis, A., 2006. Panayiotopoulos syndrome: a benign childhood autonomic epilepsy frequently imitating encephalitis, syncope, migraine, sleep disorder, or gastroenteritis. Pediatrics 118, 1237—1243. Engel Jr., J., 2001. International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 42, 796—803. Ferrie, C.D., et al., 2002. Atypical evolution of Panayiotopoulos syndrome: a case report. Epileptic Disord. 4, 35—42. Ferrie, C.D., et al., 2006. Panayiotopoulos syndrome: a consensus view. Dev. Med. Child Neurol. 48, 236—240. Kikumoto, K., et al., 2006. EEG and seizure exacerbation induced by carbamazepine in Panayiotopoulos syndrome. Epileptic Disord. 8, 53—56. Konishi, T., et al., 1993. Carbamazepine-induced skin rash in children with epilepsy. Eur. J. Pediatr. 152, 605—608. Leppik, I.E., 2001. The place of levetiracetam in the treatment of epilepsy. Epilepsia 42 (Suppl. 4), 44—45. Mula, M., et al., 2004. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure 13, 55—57. Panayiotopoulos, C.P., 2005. The Epilepsies: Seizures, Syndromes and Management. Panayiotopoulos Syndrome. Blandon Medical Publishing Chipping Norton, Oxfordshire, UK, pp. 235—248.