Letter to the Editor

Epileptic Disord 2010; 12 (1): 91-4 Panayiotopoulos syndrome: a debate

To the editor superbly illustrated by the syndrome of benign partial Yalcin et al. (2009) describe three patients with neuro- with centro-temporal spikes, a syndrome that radiological abnormalities identifi ed on magnetic has robustly defi ed eponymous adoption for many resonance imaging (MRI), which they consider to be decades. “coincidental” and un-related to an underlying electro- clinical diagnosis of Panayiotopoulos syndrome Richard E. Appleton, Brian Tedman, (PS). While they propose that the MRI abnormalities Teresa Preston, Tam Foy demonstrated are coincidental and do not preclude The Roald Dahl EEG Department, the diagnosis of PS, there may be another explana- Paediatric Neurosciences Foundation Trust, tion. It could reasonably be argued that the radiolog- Alder Hey Children’s NHS Foundation Trust, ical abnormalities seen in their patients (particularly Liverpool L12 2AP, UK patients 2 and 3) are not coincidental and that these patients have a symptomatic focal or multifocal epilepsy and not Panayiotopoulos syndrome. Response to the letter of R. Appleton, et al. Although an “expert consensus” has attempted to To the editor defi ne and classify the existence of PS (Ferrie et al., 2006), it does not necessarily follow that their opinion We welcome the comments of Appleton and his is correct. There appear to be ever-increasing reports colleagues regarding issues raised for a better under- of “atypical” cases of PS. On scientifi c grounds this standing of Panayiotopoulos syndrome (PS). must surely raise the question as to whether this does The authors argue that the 3 children we described represent a true “syndrome” as defi ned in both the had symptomatic focal or multifocal epilepsy not PS. English language and by the ILAE. This issue has been However, our fi ndings showed that the clinical and EEG recently addressed (Capovilla et al., 2009) and has raised manifestations of the 3 patients were not associated concerns over both the nosology and existence of the with a particular focus expected from their MRI abnor- syndrome, concerns shared by ourselves. Capovilla malities and prognosis was excellent with just a few and colleagues (2009) appropriately concluded that, autonomic typical of PS. Similar cases have “Many theoretical and practical points, including also been described in as we detail diagnostic, genetic, and pathophysiologic issues (still) in our report. remain unresolved for PS”. The most worrying aspect of this letter is that the authors In this EEG department, we have identifi ed only doubt even the existence of PS. Numerous indepen- three children over the past 12 months who would dent and prospective studies, including more than “fulfi ll” the electro-clinical criteria for PS; we are fully 500 children provided the evidence of this syndrome aware of the reported electro-clinical features of this (Michael et al., 2010). The ILAE commission recognizes syndrome. This is from a cohort of approximately the syndrome with the highest score of confi dence in 1,100 paediatric EEGs each year and with one of us a scale of 1-3 (Engel, 2006). The few atypical cases that (RA) directly involved with the management of over the authors refer to are those that may have more than 120 children presenting during the same year with de 10 seizures in their life but also with fi nal remission and novo epilepsy Over the same period, and using both more severe autonomic seizures that may be related to the accepted 1989 and proposed 2001 ILAE Classifi - contributing SCN1A mutations (Panayiotopoulos et al., cation, we have identifi ed 15 children with benign 2008). On the other hand, the authors contradict them- partial epilepsy with centro-temporal spikes (BECTS) selves by doubting the existence of PS as they are iden- and 11 patients with childhood-onset absence tifying PS in their practice at a prevalence of one out of epilepsy (CAE). 5 patients with rolandic epilepsy. We would suggest that, in the context of the proposed The relatively low prevalence of PS in their cohorts revised classifi cation of the and epilepsy may be explained as follows: a signifi cant number syndromes and the absence of any genetic or of patients in their area may not be referred to them biochemical marker, great caution should be exercised because of misdiagnosis as , or before accepting and certainly over-expanding a new other non-epileptic paroxysmal disorders. Addition- and eponymous entity such as PS. It would also seem ally, their practice not to recommend an EEG after a entirely appropriate to simply describe the seizures fi rst may result in missing one third of patients

doi : 10.1684/epd.2010.0299 on the basis of the electro-clinical features; this is with PS manifesting with a single seizure.

Epileptic Disord Vol. 12, No. 1, March 2010 91

jleepd00416_cor3.indd 91 3/11/2010 12:54:45 PM Letter to the Editor

In regard to nomenclature proposed by the ILAE, like epilepsy with occipital paroxysms” of Gastaut many others, we follow the eponymic term (Panayio- (ICOE-G); multifocal spikes suggested symptomatic topoulos syndrome) rather than “early onset benign epilepsies with poor prognosis. childhood occipital epilepsy” because the latter may be misleading as one third of children with PS do The veracity of Panayiotopoulos’s initial descriptions not have occipital epileptogenicity in semiological has, over the last two decades, been confi rmed in clinical seizure onsets, ictal and interictal EEG or large and long term studies from Europe, Japan and magnetoencephalography. South America. The published database on which our knowledge of PS is now based includes over 500 cases Destina Yalçin, Hülya Ertasoglu Toydemir, (Michael et al., 2010); there are few Lale Gündogdu Çelebi, Hulki Forta which are better characterised. What emerges are a Neurology Clinic, remarkably uniform clinical picture and a diagnosis Sisli Etfal Education and Research Hospital, which is strikingly useful in helping predict prognosis Sisli-Istanbul, Turkey and dictate management. These independent researchers have joined together to produce consensus statements on PS (Ferrie et al., 2006) and autonomic (Ferrie Invited editorial comment et al., 2007). PS is a model of autonomic seizures and autonomic status epilepticus specifi c to childhood (Ferrie et al., 2006, 2007; Koutroumanidis et al., 2007; Panayiotopoulos syndrome: learning Panayiotopoulos et al., 2008; Michael et al., 2010). lessons from atypical cases Affected children are otherwise normal and the EEG and magnetoencephalogram are the only tests expected to be abnormal, usually showing multifocal Panayiotopoulos with his original report of ictal epileptogenic abnormalities. Ictal EEG recordings both (Panayiotopoulos, 1988) and his related studies confi rm the clinical manifestations of autonomic status (Panayiotopoulos, 1989, 1999) opened new chapters epilepticus and that it is associated with epileptiform in paediatric epileptology. He described autonomic discharges arising from various cortical areas (Iannetti seizures and autonomic status epilepticus specifi c to et al., 2009). PS is a common childhood epilepsy, childhood. These were common and mainly occurred probably affecting one child for every 2-3 with rolandic in otherwise normal children whose prognosis in epilepsy. Moreover, it is the most common cause of terms of seizure remission and development was non-febrile, non-convulsive status epilepticus in excellent. Their EEG was characterised by spikes and childhood (Okanishi et al., 2008). Prognosis is usually sharp waves occurring in variable localisations. These excellent; around two third of children have less than children are now classifi ed as having Panayiotopoulos 5 seizures. Prophylactic antiepileptic drug medication syndrome (PS) (Ferrie et al., 2006; Koutroumanidis is often not needed. et al., 2007). However, there was initial scepticism and There are some “atypical cases” of PS. These include resistance to these fi ndings, including from infl uential children who have frequent, but otherwise typical because: seizures of PS and whose EEGs are typical. Their ultimate – ictal vomiting had been considered as extremely prognosis, in terms of eventual seizure remission, is rare and hitherto had been mainly described in the same as that of “typical cases”. In statistical terms neurosurgical series of adult patients. In children it was when considering seizure frequency, they lie within generally not considered as having an epileptic origin; the “expected distribution” but relatively distant from the median. Other “atypical cases” include – autonomic status epilepticus was not recognised around 5 reported children who developed other as a diagnostic entity; the proposition that it might be and unexpected reversible cognitive a common occurrence in a benign seizure disorder and behavioural problems, sometimes associated challenged orthodox concepts of status epilepticus; with continuous spike- and- slow wave during sleep. – it implied that paediatricians had been failing Similar cases are well recognised and are probably to diagnose signifi cant numbers of children with more common in benign rolandic epilepsy. This, and epilepsy, instead erroneously labelling then as having other shared features between these two common diverse non-epileptic disorders such as encephalitis, childhood epilepsy syndromes and probably also , migraine, cyclic vomiting syndrome and ICOE-G have prompted the suggestion that for some gastroenteritis; purposes it can be useful to recognize a broader – the characteristic EEG fi ndings suggested alternative category of benign childhood seizure susceptibility diagnoses. Occipital spikes suggested “childhood syndrome (Panayiotopoulos et al., 2008).

92 Epileptic Disord Vol. 12, No. 1, March 2010

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Atypical cases are not unique in PS. They occur in all seizure manifestations, such as visual hallucinations; epilepsy syndromes and indeed all diseases. They absent in well over 80% of cases), and researchers of should (and this is why they tend to be reported) the autonomic nervous system (who might be puzzled stimulate further enquiry into questions such as the as to why autonomic manifestations should be linked interaction between genetic and acquired causes with the occipital lobes, despite no autonomic and the role of “epilepsy genes” in causing markedly centres having been identifi ed in the occipital lobes) different phenotypes. The last of these has helped (Martinovic, 2007). Also, PS is now the preferred name demonstrate that SCN1A mutations contribute to in all recent reports. a more severe phenotype of PS (Grosso et al., 2007; Undoubtedly, children with autonomic seizures and Livingston et al., 2009). When the genetic basis for a autonomic status epilepticus were misdiagnosed disease is identifi ed it is almost invariable that the for generations. For some, perhaps many, this will originally described phenotype is broadened as have had deleterious effects probably persisting well “atypical” cases carrying the mutation are reported. after their tendency to have epileptic seizures. Most In the september 2009 issue of this journal, Yalçin et al. clinicians now fi nd PS an easy condition to recognise. (2009) reported three children with a few autonomic We should be pleased that we can now diagnose such seizures and EEG features strongly suggestive of PS children correctly, reassure their families that they but with abnormal MRI. The authors considered that have a good prognosis and hopefully avoid detrimental MRI fi ndings were likely to be coincidental on the treatments. However, there are still many issues basis of the electro-clinical features and the excellent which require further research and enquiry including long term prognosis of these children. This is also not genetic, pathophysiological, epidemiological, social, unique to PS. As was discussed by Yalçin et al., similar and management issues. case series have been reported in benign rolandic epilepsy. Colin D. Ferrie, John H. Livingston In this issue of the journal, Appleton et al. (2010), Department of Paediatric Neurology, apparently prompted by the cases reported by Leeds General Infi rmary, Leeds, UK Yalçin et al. (2009), suggest that all the independent researchers already cited in this editorial and the ILAE Commission (Engel, 2001, 2006) have been References wrong in their studies and assessments of PS. They do not offer any evidence to support this view other Appleton RE, Tedman B, Preston T, Foy T. Panayiotopoulos than that they found only 3 cases of PS compared to syndrome : a debate. Epileptic Disord 2010; 1: 91. 15 with rolandic epilepsy over a one year period. Why Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and this casts doubt on the existence of PS is unclear. In concepts for organization of seizures and epilepsies: Report fact, their “evidence” appears to contradict their own of the ILAE Commission on Classifi cation and Terminology, argument. 2005-2009. Epilepsia 2010; 51 (in press). The ILAE Classifi cation Task Force has formally Capovilla G, Striano P, Beccaria F. Changes in Panayiotopoulos recognised PS (Engel, 2001) and stated that it is syndrome over time. Epilepsia 2009; 50 (Suppl. 5): 45-8. amongst the most “clearly and reproducibly defi ned” Engel J Jr. A proposed diagnostic scheme for people with epilepsy syndromes with regards the certainty with epileptic seizures and with epilepsy: Report of the ILAE which it represents a “unique diagnostic entity”. The Task Force on Classifi cation and Terminology. Epilepsia 2001; 42:796-803. new report of the ILAE Commission on classifi cation and terminology has now discarded the descriptive Engel J Jr. Report of the ILAE Classifi cation Core Group. Epilepsia 2006; 47: 1558-68. name of “early onset benign childhood occipital epilepsy” in favour of the eponymous name for the Ferrie C, Caraballo R, Covanis A, et al. Panayiotopoulos syndrome only (Berg et al., 2010). There is strong syndrome: a consensus view. Dev Med Child Neurol 2006; 48: 236-40. precedent for doing so: (rather than severe in infancy), Landau-Kleffner Ferrie CD, Caraballo R, Covanis A, et al. Autonomic status epilepticus in Panayiotopoulos syndrome and other syndrome (rather than acquired epileptic aphasia), childhood and adult epilepsies: a consensus view. Epilepsia (rather than early infantile 2007; 48: 1165-72. epileptic encephalopathy with suppression-burst), Grosso S, Orrico A, Galli L, Di BR, Sorrentino V, Balestri P. Rasmussen syndrome (rather than chronic epileptic SCN1A mutation associated with atypical Panayiotopoulos encephalitis). This convention is particularly useful for syndrome. Neurology 2007; 69: 609-11. PS because of the potential for the term “occipital” to Iannetti P, Spalice A, Rocchi V, Verrotti A. Diffuse onset of ictal mislead electroencephalographers (who might expect in a typical case of panayiotopoulos occipital spikes, absent in around a third of cases), syndrome and review of the literature. J Child Neurol 2009; clinicians (who might expect conventional occipital 24: 472-6.

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Koutroumanidis M. Panayiotopoulos Syndrome: An Panayiotopoulos CP. Vomiting as an ictal manifestation Important Electroclinical Example of Benign Childhood of epileptic seizures and syndromes. J Neurol Neurosurg System Epilepsy. Epilepsia 2007; 48: 1044-53. Psychiatr 1988; 51: 1448-51. Livingston JH, Cross JH, McLellan A, Birch R, Zuberi SM. A Panayiotopoulos CP. Benign childhood epilepsy with Novel Inherited Mutation in the Voltage Sensor Region of occipital paroxysms: a 15-year prospective study. Ann Neurol SCN1A Is Associated With Panayiotopoulos Syndrome in 1989; 26: 51-6. Siblings and With Febrile Seizures Plus. Panayiotopoulos CP. Extraoccipital benign childhood partial J Child Neurol 2009; 24: 503-8. seizures with ictal vomiting and excellent prognosis. J Neurol Martinovic Z. The new ILAE Report on Classifi cation and Neurosurg Psychiatry 1999; 66: 82-5. Evidence-Based Commentary on Panayiotopoulos Syndrome Panayiotopoulos CP, Michael M, Sanders S, Valeta T, and Autonomic Status Epilepticus. Epilepsia 2007; 48: 1215-6. Koutroumanidis M. Benign childhood focal epilepsies: Michael M, Tsatsou K, Ferrie CD. Panayiotopoulos assessment of established and newly recognized syndromes. syndrome: An important childhood autonomic epilepsy to Brain 2008; 131: 2264-86. be differentiated from occipital epilepsy and acute non- Yalcin AD, Toydemir HE, Celebi LG, Forta H. Panayiotopoulos epileptic disorders. Brain Dev 2010; 32: 4-9. syndrome with coincidental brain lesions. Epileptic Disord Okanishi T, Maegaki Y, Ohno K, Togari H. Underlying 2009; 11: 270-6. neurologic disorders and recurrence rates of status epilepticus in childhood. Brain Dev 2008; 30: 624-8.

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