- Email: [email protected]
Magnetoencephalographic Findings of Panayiotopoulos Syndrome With Frontal Epileptic Discharges
Magnetoencephalographic Findings of Panayiotopoulos Syndrome With Frontal Epileptic Discharges Naka Saitoh, MD*, Osamu Kanazawa, MD, PhD†, Jun Tohyama, MD, PhD*, Noriyuki Akasaka, MD*, and Takanori Kamimura, MD* We previously reported the results of a magnetoencephalographic study in patients with Panayiotopoulos syndrome manifesting occipital epileptic discharges, in which the equivalent current dipoles of spike discharges were clustered alongside the major cortical sulci, such as parieto-occipital and calcarine. This report is the result of a magnetoencephalographic study of three patients with Panayiotopoulos syndrome exhibiting equivalent current dipoles clustering in the frontal area. Patient 1, a 13-year-old male, exhibited clustering equivalent current dipoles alongside right inferior frontal sulcus, but the orientations were irregular. Patient 2 is an 11-year-old younger brother of Patient 1, whose magnetoencephalograph revealed equivalent current dipoles clustering alongside right prefrontal sulcus and regular orientations. Patient 3 is a 10-year-old female who had equivalent current dipoles clustering alongside right superior frontal sulcus and extremely regular orientations. The locations of clustering equivalent current dipoles of frontal spike discharges were not restricted to one specific frontal sulcus but were present in various locations over the convexity of the prefrontal area. In conclusion, these
From *Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan; †Department of Psychiatry, Saitama Medical University, Saitama, Japan.
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findings suggest that it is inappropriate to classify Panayiotopoulos syndrome as occipital epilepsy. In addition, the result of this study, that frontal spike discharges seem to occur in relatively older patients, may suggest a correlation between brain maturation and spike occurrence. © 2007 by Elsevier Inc. All rights reserved. Saitoh N, Kanazawa O, Tohyama J, Akasaka N, Kamimura T. Magnetoencephalographic findings of Panayiotopoulos syndrome with frontal epileptic discharges. Pediatr Neurol 2007;36:190-194.
Introduction Panayiotopoulos syndrome is a recently recognized benign epileptic syndrome in childhood, characterized by complex partial seizures with vomiting and eye deviation [1-6]. Panayiotopoulos syndrome has now been incorporated into the proposed International Classification of Epileptic Syndromes as Panayiotopoulos-type early-onset benign childhood occipital epilepsy together with Gastauttype late-onset childhood occipital epilepsy. In Panayiotopoulos syndrome, two thirds of patients (68%) have at least one electroencephalogram with occipital paroxysms or, more commonly, occipital spikes, which are often (64%) concurrent with extraoccipital spikes in at least one electroencephalogram. They are often independent, and occur at various posterior or central locations and, less often at anterior locations [6]. We have already reported the results of a magnetoencephalographic study in patients with Panayiotopoulos syndrome and occipital epileptic discharges [7]. In that study, the equivalent current dipoles of spike discharges were clustered alongside the major cortical sulci, such as parieto-occipital, calcarine, and central sulci. In that previous series, we could not find frontal locations of equivalent current dipoles, despite the existence of spike-wave complexes with Fp-O synchronization in electroencephalography. The present study reports the results of a magnetoencephalographic investigation of three patients with Panayiotopoulos syndrome manifesting equivalent current dipoles clustering in the frontal areas. Because frontal spike discharges are less common [6], chances to capture the frontal spike discharges with a magnetoencephalo-
Communications should be addressed to: Dr. Kanazawa; Department of Psychiatry; Saitama Medical University; 38 Morohongo; Moroyama-Machi, Iruma-Gun; Saitama, 350-0495 Japan. E-mail: [email protected] Received March 24, 2006; accepted October 16, 2006.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.10.010 ● 0887-8994/07/$—see front matter
graphic investigation in Panayiotopoulos syndrome are rare. Therefore, this report is quite valuable concerning the pathophysiologic mechanism of interictal discharges in Panayiotopoulos syndrome. Patients and Methods From 18 patients who had undergone magnetoencephalographic examinations between August 2001 and September 2005 in our hospital, three patients with Panayiotopoulos syndrome who manifested spike equivalent current dipoles in the frontal area were retrospectively chosen. All three patients in this study, had undergone magnetoencephalographic examinations in August and September of 2005, had been diagnosed with Panayiotopoulos syndrome from their clinical symptoms, and fulfilled the following criteria: (a) normal development before the onset of epilepsy; (b) no organic brain lesions revealed by magnetic resonance imaging; (c) age of onset between 2 and 10 years; (d) the presence of brief or prolonged attacks characterized by initial vomiting and eye deviations with or without subsequent secondary generalized convulsions; and (e) confirmed excellent prognosis (in terms of seizures and cognitive functions after responding to medication during a follow-up period of over 1 year). An informed consent was obtained before the performance of this study, and the Ethics Committee in the hospital approved this research. Conventional 21-channel scalp electroencephalograms were recorded using a digital electroencephalographic data filing system, EEG-2100 Neurofax (Nihon Kohden Co.) by employing international 10-20 methods for each electrode position with a time constant of 0.1-0.3 and high-cut filter of 30-60 Hz along with monopolar and bipolar montages. Magnetoencephalography was measured using a helmet-shaped neuromagnetometer (Vectorview; Elekta-Neuromag, Oy, Finland) in a magnetically shielded room. This device uses 204 planar-type, first-ordered gradiometers. Before recording, the positions of three anatomic fiduciary points (nasion and bilateral preauricular) and four indicator coils on the scalp were digitized as reference points using a three-dimensional electromagnetic digitizer (Polhems, Colchester, VT). Magnetoencephalography and simultaneous scalp electroencephalographic data were continuously recorded over 30 minutes with the subjects in a drowsy to light-sleep state induced by sedatives (triclofos sodium). These data were sampled at 300 Hz using a bandpass filter of 0.03-160 Hz and analyzed offline using a bandpass filter of 3-45 Hz. In magnetoencephalographic analysis, an equivalent current dipole was calculated for the initial peak of each interictal spike discharge in a spherical model [8]. Acceptable equivalent current dipoles of spike sources had a goodness-of-fit ⬎80%. After this, the dipole moments, in terms of the strengths and orientation of the magnetoencephalographic spike sources, were evaluated and overlaid onto the spike sources with respect to the three anatomic fiduciary points on the magnetic resonance images of the patient’s head. For each patient, the dipole source was estimated for more than 10 interictal spikes. All patients underwent magnetic resonance imaging examination using a 1.5-Tesla system (MAGNEX Epios15; Shimazu, Kyoto, Japan) on the same day that the magnetoencephalographic data were collected to create a volumetric scan of the brain.
Case Reports Patient 1 Patient 1 is a 13-year-old male, whose younger brother has also had Panayiotopoulos syndrome and whose father’s elder sister suffered from residual epilepsy caused by head injury and died of status epilepticus at age 50. He was born uneventfully with no developmental delay or febrile convulsions before the onset of epilepsy at 3 years 6 months old. The first episode of epilepsy was characterized by sudden eye opening during night sleep and then tonic eye deviation to the left followed by nausea
and vomiting. During his seizure, his entire body was slightly hypertonic and loss of consciousness lasted for approximately 10 minutes. One month later, another seizure with the same pattern occurred, then medication with carbamazepine was initiated. Subsequently, his seizures reduced in frequency and duration, down to once per 4-6 months and for several minutes. At 4 years 9 months old, he was referred to our hospital. The dose of carbamazepine was increased up to a blood level 11.0 g/mL before his first visit to our hospital, which was effective. After having three complex partial seizures monthly, his epilepsy was completely controlled. Occipital spikes had been evident until age 6, and bilateral frontal independent but right-side-dominant spike discharges were observed on electroencephalograms at age 13. His magnetoencephalography at age 13 revealed clustering equivalent current dipoles of spike discharges alongside the right inferior frontal sulcus but the orientations were not so regular or well-ordered (Fig 1).
Patient 2 Patient 2, an 11-year-old male, is a younger brother of Patient 1. At 2 years 6 months old, he had his first epileptic episode with high fever, which was characterized by initial abdominal pain and nausea followed by loss of consciousness with perioral cyanosis for approximately 20 minutes; this was regarded as a febrile seizure because his electroencephalogram at that time was normal. The second episode occurred at 5 years 3 months old, and was characterized by sudden abdominal pain when sitting on a swing, and a feeling of thirst followed by loss of consciousness for several minutes with postictal headache. He was referred to our hospital. Since then, in spite of antiepileptic drug therapy, he had weekly complex partial seizures, characterized by eye deviation to the left or right side with occasional vomiting and hemifacial or hemibody convulsions. The maximum duration of unconsciousness was 20 minutes. Valproic acid, zonisamide, and ethosuximide induced adverse reactions such as drug eruption (drug allergy) or reduced white blood cell count. From 5 years 8 months old, when clobazam was administered, his seizures remitted for a period. However, at age 7, epilepsy relapsed with weekly sylvian seizures (see “Discussion”). Finally, he became seizure-free for over 13 months by additional medication with sultiame. His electroencephalogram previously documented frontopolar spike discharges or generalized spike-wave discharges. One electroencephalogram disclosed right occipital spike discharges, which was the last abnormal electroencephalogram revealing epileptic discharges at age 9. His recent electroencephalograms have displayed no epileptic discharges. Only magnetoencephalography at age 10 revealed equivalent current dipoles of spike discharges clustering alongside the right prefrontal sulcus with regular dipole orientations (Fig 2), whereas no spike discharges were observed in the simultaneous electroencephalographic recordings.
Patient 3 Patient 3 is a 10-year-old female with no family history of convulsion, who had febrile convulsions three times from age 8 months. At age 4 years, when she was diagnosed with Kawasaki disease (mucocutaneous lymph node syndrome), an episode of unconsciousness after vomiting lasted over 30 minutes. Since then, the same pattern of complex partial seizures, characterized by initial vomiting followed by tonic eye deviation and head version to the left side, has occurred yearly, evolving to occasional status epilepticus. At 8 years 11 months old, a complex partial seizure with high fever occurred during influenza type B infection. Since receiving additional medication with sultiame and carbamazepine, no seizures have occurred for over 12 months. Her electroencephalogram sometimes disclosed right frontal dominant spike-wave discharges with Fp-O synchronization. These epileptic discharges usually appeared as a spike-wave burst, which seemed to originate from a right frontopolar lesion, i.e., a spike wave on the Fp2 electrode preceded and dominated every burst. Magnetoencephalography at age 9 indicated equivalent
Saitoh et al: MEG Findings of Panayiotopoulos Syndrome 191
Figure 1. (A) Magnetoencephalographic wave forms at age 13 years in Patient 1 were observed. The reversed colored wave forms in white in the vertical dark zone were analyzed. (B) In Patient 1, magnetic source images at age 13 revealed clustering equivalent current dipoles of spike discharges alongside the right inferior frontal sulcus but the orientations were not so regular. All magnetic resonance images are T1-weighted. The pale-colored solid circles and tails represent the locations and orientations of equivalent current dipoles of the spike discharges. The early somatosensory evoked field was modeled using a single equivalent current dipole approach to estimate the spatial source of response, whereas the dark-colored solid circles and tails indicated by white arrows represent the locations and orientations of somatosensory evoked fields (N20).
current dipoles of spike discharge clustering alongside the right superior frontal sulcus and quite regular orientations.
Discussion There are few reports of magnetoencephalographic analysis in Panayiotopoulos syndrome patients [7,9,10], and these papers described occipital or central spike discharges analyzed by magnetoencephalography, i.e., equivalent current dipoles of spike discharges alongside calcarine sulcus only [9], or calcarine, parieto-occipital, or central sulci [7,10]. Sugita et al. [9] reported the result of magnetoencephalographic analysis of a patient with occasional seizure, which could not be precisely diagnosed as Panayiotopoulos syndrome. Because Panayiotopoulos syndrome exhibiting frontal spike discharges is less common [6], there has been no magnetoencephalographic study about frontal spikes in Panayiotopoulos syndrome. According to our magnetoencephalographic study of patients with Panayiotopoulos syndrome manifesting frontal spike discharges, the locations of clustering equivalent current dipoles were not restricted to one specific frontal sulcus but were present in several different sulci in the convexity of the prefrontal area, such as inferior frontal sulcus, prefrontal sulcus, and superior frontal sulcus.
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From August 2001 to September 2005, 18 patients with Panayiotopoulos syndrome underwent magnetoencephalographic examination in our hospital. Thirteen patients who underwent earlier examination in this series were reported in our previous paper [7]. The 13 patients produced focal epileptic discharges mainly in the occipital, parietal, or central areas. None of them manifested frontal spike discharges. Three patients with later examination in this series produced frontal spike discharges. The remaining two patients did not evince any spike discharges. The age range at examination in 13 patients with extrafrontal spike discharges was between 3 years 3 months and 11 years 11 months, and mean age was 7 years 8 months; whereas the age range at examination in three patients with frontal spike discharges was between 9 years 4 month and 13 years 3 months, and mean age was 11 years 0 months. Two patients who manifested no spike discharges were each 10 years old at the time of examination. Therefore frontal spike discharges or disappearance of spike discharges seem to occur in relatively older patients. The ages of seizure onset in the three groups of different spike foci were almost the same. In general, young children have occipital dominant brain and immature frontal lobes. Older children have mature frontal lobes.
Figure 2. In Patient 2, only the magnetoencephalography at age 10 revealed equivalent current dipoles of spike discharges clustering alongside the right prefrontal sulcus and regular orientations. The symbols in the picture are the same as those in Figure 1B.
The difference between age ranges in this study may suggest a correlation between brain maturation and spike occurrence. In this study, two younger patients had regular dipole orientations (Fig 2) but those of the oldest patient aged 13 years were irregular (Fig 1B). However, the oldest patient has been seizure-free for more than 3 years, whereas the two younger patients have only been seizure-free for over 5 months before the magnetoencephalographic examination. Therefore these findings are not inconsistent with our previous results in magnetoencephalographic findings of Panayiotopoulos syndrome: The orientations of equivalent current dipoles in Panayiotopoulos syndrome are mostly regular or well-ordered, except for Patient 8, aged 14 years [7]. This oldest female patient in our previous study manifested irregular and dispersed equivalent current dipoles alongside bilateral calcarine sulci. Her magnetoencephalographic findings suggest diminishing epileptic discharges associated with Panayiotopoulos syndrome. In the present study, Fp-O synchronization on electroencephalograms in Patient 3 revealed frontal clustering of equivalent current dipoles. This finding is inconsistent with our previous results and also those of Yoshinaga et al. and Ueno et al. [7,11,12]. However, in this case, there
seemed to be some reason why such a contradicting phenomenon occurred. Those epileptic discharges in her electroencephalogram usually appeared as a spike-wave burst, which seemed to originate from a right frontopolar region, i.e., the spike wave on the Fp2 electrode preceded and dominated every burst. In our study, we usually analyze the initial spike peak when the epileptic discharges appear in the burst formation. The pattern of the electroencephalogram in this case is quite different from spike waves with Fp-O synchronization in Patients 6 and 13 in our previous study [7]. Consequently, this phenomenon presented evidence that, in magnetoencephalographic analysis, Fp-O synchronization occasionally indicates the origin of equivalent current dipoles of spike discharges in the frontal region when appearing as a spike-wave burst pattern as in this case. Sylvian seizures occurred in Patient 2, who manifested no epileptic discharges on electroencephalogram. Sylvian seizure, which is also called rolandic seizure, is hemifacial, characterized by a clonic manifestation involving the hemiface, sometimes preceded by unilateral paresthesia (pins and needles, electricity, numbness) involving tongue, lips, gums, and cheek; the jerks can be associated with a lateral tonic deviation of the mouth involving lips and
Saitoh et al: MEG Findings of Panayiotopoulos Syndrome 193
tongue, as well as pharyngeal and laryngeal muscles, and result in anarthria or speech arrest and drooling due to sialorrhea and saliva pooling [13]. This seizure type is observed in the majority cases with benign epilepsy with rolandic or centro-temporal spikes. Rolandic spike discharges are often observed in patients with Panayiotopoulos syndrome, especially those who have sylvian seizures. Perhaps incidentally, none of the three patients exhibited rolandic spike discharges. Although Panayiotopoulos syndrome is closely related to benign epilepsy with rolandic or centro-temporal spikes, this result may suggest that rolandic spike discharges and frontal spike discharges cannot coexist in patients with Panayiotopoulos syndrome. In conclusion, the findings suggest that it is inappropriate to classify Panayiotopoulos syndrome as occipital epilepsy [5]. In addition, the result of this study, that frontal spike discharges seem to occur in relatively older patients, may suggest a correlation between brain maturation and spike occurrence. We thank Dr. Makoto Oishi and Kuniko Tsuchiya for their expert assistance during the magnetoencephalographic examinations and for their invaluable instruction and advice.
References [1] Panayiotopoulos CP. Vomiting as an ictal manifestation of epileptic seizures and syndromes. J Neurol Neurosurg Psychiatry 1988; 51:1448-51. [2] Panayiotopoulos CP. Benign childhood epilepsy with occipital paroxysms: A 15-year prospective study. Am Neurol 1989;26:51-6.
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[3] Panayiotopoulos CP. Benign childhood partial epilepsies: Benign childhood seizure susceptibility syndromes. J Neurol Neurosurg Psychiatry 1993;56:2-5. [4] Panayiotopoulos CP. Early onset benign childhood occipital seizures: Panayiotopoulos syndrome. In: Panayiotopoulos CP, ed. Benign childhood partial seizures and related epileptic syndromes. London: John Libbey, 1999:133-7. [5] Ferrie C, Caraballo R, Covanis A, et al. Panayiotopoulos syndrome: A consensus view. Dev Med Child Neurol 2006;48:702-3. [6] Panayiotopoulos CP. Benign childhood focal seizures and related epileptic syndromes. In: Panayiotopoulos CP, ed. The epilepsies. Seizures, syndromes and management. Oxfordshire: Blandon Medical Publishing, 2005:223-69. [7] Kanazawa O, Tohyama J, Akasaka N, Kamimura T. A magnetoencephalographic study of patients with Panayiotopoulos syndrome. Epilepsia 2005;46:1106-13. [8] Bath DS, Sutherling W, Engel J Jr., Beatty J. Neuromagnetic localization of epileptiform spike activity in the human brain. Science 1982;218:891-4. [9] Sugita K, Kato Y, Sugita K, Kato M, Tanaka Y. Magnetoencephalographic analysis in a case of early-onset benign childhood occipital seizures. J Child Neurol 2002;17:851-2. [10] Wolf M, Weiskopf N, Serra E, Preissl H, Birbaumer N, Kraegeloh-Mann I. Benign partial epilepsy in childhood: Selective cognitive deficits are related to the location of focal spikes determined by combined EEG/MEG. Epilepsia 2005;46:1661-7. [11] Yoshinaga H, Koutroumanidis M, Shirasawa A, Kikumoto K, Ohtuka Y, Oka E. Dipole analysis in Panayiotopoulos syndrome. Brain Dev 2005;27:46-52. [12] Ueno M, Oguni H, Yasuda K, Osawa M. Neurophysiological study of secondary synchronous occipito-frontopolar spikes in childhood. Clin Neurophysiol 2001;112:2106-12. [13] Dalla Bernardina B, Sgro V, Fejerman N. Epilepsy with centro-temporal spikes and related syndromes. In: Roger J, Bureau M, Dravet C, et al., eds. Epileptic syndromes in infancy, childhood and adolescence. Montrouge: John Libbey Eurotext, 2005:203-25.
From *Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan; †Department of Psychiatry, Saitama Medical University, Saitama, Japan.
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findings suggest that it is inappropriate to classify Panayiotopoulos syndrome as occipital epilepsy. In addition, the result of this study, that frontal spike discharges seem to occur in relatively older patients, may suggest a correlation between brain maturation and spike occurrence. © 2007 by Elsevier Inc. All rights reserved. Saitoh N, Kanazawa O, Tohyama J, Akasaka N, Kamimura T. Magnetoencephalographic findings of Panayiotopoulos syndrome with frontal epileptic discharges. Pediatr Neurol 2007;36:190-194.
Introduction Panayiotopoulos syndrome is a recently recognized benign epileptic syndrome in childhood, characterized by complex partial seizures with vomiting and eye deviation [1-6]. Panayiotopoulos syndrome has now been incorporated into the proposed International Classification of Epileptic Syndromes as Panayiotopoulos-type early-onset benign childhood occipital epilepsy together with Gastauttype late-onset childhood occipital epilepsy. In Panayiotopoulos syndrome, two thirds of patients (68%) have at least one electroencephalogram with occipital paroxysms or, more commonly, occipital spikes, which are often (64%) concurrent with extraoccipital spikes in at least one electroencephalogram. They are often independent, and occur at various posterior or central locations and, less often at anterior locations [6]. We have already reported the results of a magnetoencephalographic study in patients with Panayiotopoulos syndrome and occipital epileptic discharges [7]. In that study, the equivalent current dipoles of spike discharges were clustered alongside the major cortical sulci, such as parieto-occipital, calcarine, and central sulci. In that previous series, we could not find frontal locations of equivalent current dipoles, despite the existence of spike-wave complexes with Fp-O synchronization in electroencephalography. The present study reports the results of a magnetoencephalographic investigation of three patients with Panayiotopoulos syndrome manifesting equivalent current dipoles clustering in the frontal areas. Because frontal spike discharges are less common [6], chances to capture the frontal spike discharges with a magnetoencephalo-
Communications should be addressed to: Dr. Kanazawa; Department of Psychiatry; Saitama Medical University; 38 Morohongo; Moroyama-Machi, Iruma-Gun; Saitama, 350-0495 Japan. E-mail: [email protected] Received March 24, 2006; accepted October 16, 2006.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.10.010 ● 0887-8994/07/$—see front matter
graphic investigation in Panayiotopoulos syndrome are rare. Therefore, this report is quite valuable concerning the pathophysiologic mechanism of interictal discharges in Panayiotopoulos syndrome. Patients and Methods From 18 patients who had undergone magnetoencephalographic examinations between August 2001 and September 2005 in our hospital, three patients with Panayiotopoulos syndrome who manifested spike equivalent current dipoles in the frontal area were retrospectively chosen. All three patients in this study, had undergone magnetoencephalographic examinations in August and September of 2005, had been diagnosed with Panayiotopoulos syndrome from their clinical symptoms, and fulfilled the following criteria: (a) normal development before the onset of epilepsy; (b) no organic brain lesions revealed by magnetic resonance imaging; (c) age of onset between 2 and 10 years; (d) the presence of brief or prolonged attacks characterized by initial vomiting and eye deviations with or without subsequent secondary generalized convulsions; and (e) confirmed excellent prognosis (in terms of seizures and cognitive functions after responding to medication during a follow-up period of over 1 year). An informed consent was obtained before the performance of this study, and the Ethics Committee in the hospital approved this research. Conventional 21-channel scalp electroencephalograms were recorded using a digital electroencephalographic data filing system, EEG-2100 Neurofax (Nihon Kohden Co.) by employing international 10-20 methods for each electrode position with a time constant of 0.1-0.3 and high-cut filter of 30-60 Hz along with monopolar and bipolar montages. Magnetoencephalography was measured using a helmet-shaped neuromagnetometer (Vectorview; Elekta-Neuromag, Oy, Finland) in a magnetically shielded room. This device uses 204 planar-type, first-ordered gradiometers. Before recording, the positions of three anatomic fiduciary points (nasion and bilateral preauricular) and four indicator coils on the scalp were digitized as reference points using a three-dimensional electromagnetic digitizer (Polhems, Colchester, VT). Magnetoencephalography and simultaneous scalp electroencephalographic data were continuously recorded over 30 minutes with the subjects in a drowsy to light-sleep state induced by sedatives (triclofos sodium). These data were sampled at 300 Hz using a bandpass filter of 0.03-160 Hz and analyzed offline using a bandpass filter of 3-45 Hz. In magnetoencephalographic analysis, an equivalent current dipole was calculated for the initial peak of each interictal spike discharge in a spherical model [8]. Acceptable equivalent current dipoles of spike sources had a goodness-of-fit ⬎80%. After this, the dipole moments, in terms of the strengths and orientation of the magnetoencephalographic spike sources, were evaluated and overlaid onto the spike sources with respect to the three anatomic fiduciary points on the magnetic resonance images of the patient’s head. For each patient, the dipole source was estimated for more than 10 interictal spikes. All patients underwent magnetic resonance imaging examination using a 1.5-Tesla system (MAGNEX Epios15; Shimazu, Kyoto, Japan) on the same day that the magnetoencephalographic data were collected to create a volumetric scan of the brain.
Case Reports Patient 1 Patient 1 is a 13-year-old male, whose younger brother has also had Panayiotopoulos syndrome and whose father’s elder sister suffered from residual epilepsy caused by head injury and died of status epilepticus at age 50. He was born uneventfully with no developmental delay or febrile convulsions before the onset of epilepsy at 3 years 6 months old. The first episode of epilepsy was characterized by sudden eye opening during night sleep and then tonic eye deviation to the left followed by nausea
and vomiting. During his seizure, his entire body was slightly hypertonic and loss of consciousness lasted for approximately 10 minutes. One month later, another seizure with the same pattern occurred, then medication with carbamazepine was initiated. Subsequently, his seizures reduced in frequency and duration, down to once per 4-6 months and for several minutes. At 4 years 9 months old, he was referred to our hospital. The dose of carbamazepine was increased up to a blood level 11.0 g/mL before his first visit to our hospital, which was effective. After having three complex partial seizures monthly, his epilepsy was completely controlled. Occipital spikes had been evident until age 6, and bilateral frontal independent but right-side-dominant spike discharges were observed on electroencephalograms at age 13. His magnetoencephalography at age 13 revealed clustering equivalent current dipoles of spike discharges alongside the right inferior frontal sulcus but the orientations were not so regular or well-ordered (Fig 1).
Patient 2 Patient 2, an 11-year-old male, is a younger brother of Patient 1. At 2 years 6 months old, he had his first epileptic episode with high fever, which was characterized by initial abdominal pain and nausea followed by loss of consciousness with perioral cyanosis for approximately 20 minutes; this was regarded as a febrile seizure because his electroencephalogram at that time was normal. The second episode occurred at 5 years 3 months old, and was characterized by sudden abdominal pain when sitting on a swing, and a feeling of thirst followed by loss of consciousness for several minutes with postictal headache. He was referred to our hospital. Since then, in spite of antiepileptic drug therapy, he had weekly complex partial seizures, characterized by eye deviation to the left or right side with occasional vomiting and hemifacial or hemibody convulsions. The maximum duration of unconsciousness was 20 minutes. Valproic acid, zonisamide, and ethosuximide induced adverse reactions such as drug eruption (drug allergy) or reduced white blood cell count. From 5 years 8 months old, when clobazam was administered, his seizures remitted for a period. However, at age 7, epilepsy relapsed with weekly sylvian seizures (see “Discussion”). Finally, he became seizure-free for over 13 months by additional medication with sultiame. His electroencephalogram previously documented frontopolar spike discharges or generalized spike-wave discharges. One electroencephalogram disclosed right occipital spike discharges, which was the last abnormal electroencephalogram revealing epileptic discharges at age 9. His recent electroencephalograms have displayed no epileptic discharges. Only magnetoencephalography at age 10 revealed equivalent current dipoles of spike discharges clustering alongside the right prefrontal sulcus with regular dipole orientations (Fig 2), whereas no spike discharges were observed in the simultaneous electroencephalographic recordings.
Patient 3 Patient 3 is a 10-year-old female with no family history of convulsion, who had febrile convulsions three times from age 8 months. At age 4 years, when she was diagnosed with Kawasaki disease (mucocutaneous lymph node syndrome), an episode of unconsciousness after vomiting lasted over 30 minutes. Since then, the same pattern of complex partial seizures, characterized by initial vomiting followed by tonic eye deviation and head version to the left side, has occurred yearly, evolving to occasional status epilepticus. At 8 years 11 months old, a complex partial seizure with high fever occurred during influenza type B infection. Since receiving additional medication with sultiame and carbamazepine, no seizures have occurred for over 12 months. Her electroencephalogram sometimes disclosed right frontal dominant spike-wave discharges with Fp-O synchronization. These epileptic discharges usually appeared as a spike-wave burst, which seemed to originate from a right frontopolar lesion, i.e., a spike wave on the Fp2 electrode preceded and dominated every burst. Magnetoencephalography at age 9 indicated equivalent
Saitoh et al: MEG Findings of Panayiotopoulos Syndrome 191
Figure 1. (A) Magnetoencephalographic wave forms at age 13 years in Patient 1 were observed. The reversed colored wave forms in white in the vertical dark zone were analyzed. (B) In Patient 1, magnetic source images at age 13 revealed clustering equivalent current dipoles of spike discharges alongside the right inferior frontal sulcus but the orientations were not so regular. All magnetic resonance images are T1-weighted. The pale-colored solid circles and tails represent the locations and orientations of equivalent current dipoles of the spike discharges. The early somatosensory evoked field was modeled using a single equivalent current dipole approach to estimate the spatial source of response, whereas the dark-colored solid circles and tails indicated by white arrows represent the locations and orientations of somatosensory evoked fields (N20).
current dipoles of spike discharge clustering alongside the right superior frontal sulcus and quite regular orientations.
Discussion There are few reports of magnetoencephalographic analysis in Panayiotopoulos syndrome patients [7,9,10], and these papers described occipital or central spike discharges analyzed by magnetoencephalography, i.e., equivalent current dipoles of spike discharges alongside calcarine sulcus only [9], or calcarine, parieto-occipital, or central sulci [7,10]. Sugita et al. [9] reported the result of magnetoencephalographic analysis of a patient with occasional seizure, which could not be precisely diagnosed as Panayiotopoulos syndrome. Because Panayiotopoulos syndrome exhibiting frontal spike discharges is less common [6], there has been no magnetoencephalographic study about frontal spikes in Panayiotopoulos syndrome. According to our magnetoencephalographic study of patients with Panayiotopoulos syndrome manifesting frontal spike discharges, the locations of clustering equivalent current dipoles were not restricted to one specific frontal sulcus but were present in several different sulci in the convexity of the prefrontal area, such as inferior frontal sulcus, prefrontal sulcus, and superior frontal sulcus.
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From August 2001 to September 2005, 18 patients with Panayiotopoulos syndrome underwent magnetoencephalographic examination in our hospital. Thirteen patients who underwent earlier examination in this series were reported in our previous paper [7]. The 13 patients produced focal epileptic discharges mainly in the occipital, parietal, or central areas. None of them manifested frontal spike discharges. Three patients with later examination in this series produced frontal spike discharges. The remaining two patients did not evince any spike discharges. The age range at examination in 13 patients with extrafrontal spike discharges was between 3 years 3 months and 11 years 11 months, and mean age was 7 years 8 months; whereas the age range at examination in three patients with frontal spike discharges was between 9 years 4 month and 13 years 3 months, and mean age was 11 years 0 months. Two patients who manifested no spike discharges were each 10 years old at the time of examination. Therefore frontal spike discharges or disappearance of spike discharges seem to occur in relatively older patients. The ages of seizure onset in the three groups of different spike foci were almost the same. In general, young children have occipital dominant brain and immature frontal lobes. Older children have mature frontal lobes.
Figure 2. In Patient 2, only the magnetoencephalography at age 10 revealed equivalent current dipoles of spike discharges clustering alongside the right prefrontal sulcus and regular orientations. The symbols in the picture are the same as those in Figure 1B.
The difference between age ranges in this study may suggest a correlation between brain maturation and spike occurrence. In this study, two younger patients had regular dipole orientations (Fig 2) but those of the oldest patient aged 13 years were irregular (Fig 1B). However, the oldest patient has been seizure-free for more than 3 years, whereas the two younger patients have only been seizure-free for over 5 months before the magnetoencephalographic examination. Therefore these findings are not inconsistent with our previous results in magnetoencephalographic findings of Panayiotopoulos syndrome: The orientations of equivalent current dipoles in Panayiotopoulos syndrome are mostly regular or well-ordered, except for Patient 8, aged 14 years [7]. This oldest female patient in our previous study manifested irregular and dispersed equivalent current dipoles alongside bilateral calcarine sulci. Her magnetoencephalographic findings suggest diminishing epileptic discharges associated with Panayiotopoulos syndrome. In the present study, Fp-O synchronization on electroencephalograms in Patient 3 revealed frontal clustering of equivalent current dipoles. This finding is inconsistent with our previous results and also those of Yoshinaga et al. and Ueno et al. [7,11,12]. However, in this case, there
seemed to be some reason why such a contradicting phenomenon occurred. Those epileptic discharges in her electroencephalogram usually appeared as a spike-wave burst, which seemed to originate from a right frontopolar region, i.e., the spike wave on the Fp2 electrode preceded and dominated every burst. In our study, we usually analyze the initial spike peak when the epileptic discharges appear in the burst formation. The pattern of the electroencephalogram in this case is quite different from spike waves with Fp-O synchronization in Patients 6 and 13 in our previous study [7]. Consequently, this phenomenon presented evidence that, in magnetoencephalographic analysis, Fp-O synchronization occasionally indicates the origin of equivalent current dipoles of spike discharges in the frontal region when appearing as a spike-wave burst pattern as in this case. Sylvian seizures occurred in Patient 2, who manifested no epileptic discharges on electroencephalogram. Sylvian seizure, which is also called rolandic seizure, is hemifacial, characterized by a clonic manifestation involving the hemiface, sometimes preceded by unilateral paresthesia (pins and needles, electricity, numbness) involving tongue, lips, gums, and cheek; the jerks can be associated with a lateral tonic deviation of the mouth involving lips and
Saitoh et al: MEG Findings of Panayiotopoulos Syndrome 193
tongue, as well as pharyngeal and laryngeal muscles, and result in anarthria or speech arrest and drooling due to sialorrhea and saliva pooling [13]. This seizure type is observed in the majority cases with benign epilepsy with rolandic or centro-temporal spikes. Rolandic spike discharges are often observed in patients with Panayiotopoulos syndrome, especially those who have sylvian seizures. Perhaps incidentally, none of the three patients exhibited rolandic spike discharges. Although Panayiotopoulos syndrome is closely related to benign epilepsy with rolandic or centro-temporal spikes, this result may suggest that rolandic spike discharges and frontal spike discharges cannot coexist in patients with Panayiotopoulos syndrome. In conclusion, the findings suggest that it is inappropriate to classify Panayiotopoulos syndrome as occipital epilepsy [5]. In addition, the result of this study, that frontal spike discharges seem to occur in relatively older patients, may suggest a correlation between brain maturation and spike occurrence. We thank Dr. Makoto Oishi and Kuniko Tsuchiya for their expert assistance during the magnetoencephalographic examinations and for their invaluable instruction and advice.
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