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ARTICLES: S. Shinnar, D. C. Hesdorffer, D. R. Nordli, Jr, J. M. Pellock, C. O’Dell, D. V. Lewis, L. M. Frank, S. L. Moshé, L. G. Epstein, A. Marmarou, E. Bagiella, and The FEBSTAT Study Team Phenomenology of prolonged febrile seizures: Results of the FEBSTAT study Neurology 2008; 71: 170-176 [Abstract] [Full text] [PDF]

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Phenomenology of prolonged febrile seizures: Results of the FEBSTAT study

Rod C. Scott, Brian G Neville   (22 September 2008)

Reply from the author

Shlomo Shinnar   (22 September 2008)

Phenomenology of prolonged febrile seizures. Results of the FEBSTAT study

Edgar Avalos Herrera, Silvia Yamanic Alvarez, Oliver Cobox, Teresa Villeda   (26 August 2008)

Reply from the authors

Shlomo Shinnar, MD, PhD, 111 E 210th St, Bronx, NY 10467   (26 August 2008)

Phenomenology of prolonged febrile seizures: Results of the FEBSTAT study 22 September 2008
Rod C. Scott, UCL-Institute of Child Health 30 Guilford Street, London, WC1N 1EH, UK, Brian G Neville Send Correspondence to journal: Re: Phenomenology of prolonged febrile seizures: Results of the FEBSTAT study rscott{at}ich.ucl.ac.uk Rod C. Scott, et al.	Shinnar et al. recently described the phenomenology of febrile status epilepticus (FSE) [1] which is important given the relationship between FSE and later mesial temporal sclerosis (MTS). It may be even more important than Shinnar et al. suggest as this relationship is not a binary phenomenon but rather MTS is likely to be the most severe end of the spectrum of brain injury associated with FSE. We studied children with FSE who had evidence of hippocampal edema soon after an episode. We observed subsequent increases in asymmetry in hippocampal volume consistent with permanent hippocampal injury that does not meet the criteria for MTS. [2,3] The negative impact of such injury remains unclear. Assuming it is the prolonged nature of the seizure that is largely responsible for the injury then early diagnosis of FSE—and other types of convulsive status epilepticus—is critical. Shinnar et al.’s finding that children with non-continuous seizures are less likely to be recognized than those with continuous status epilepticus replicates the data from our epidemiological study on childhood convulsive status epilepticus. [4] In that study, the phenomenon applied to all types of CSE and not only FSE. [4] These children are less likely to be treated early and are more likely to have seizures lasting longer than 60 minutes. [5] As these previous studies have shown, the under-recognition of status epilepticus in children extends beyond teaching hospitals in the US and is likely to be a worldwide problem. References 1. Shinnar S, Hesdorffer DC, Nordli DR et al. Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2008;71:170-176. 2. Scott RC, Gadian DG, King MD et al. Magnetic resonance imaging findings within 5 days of status epilepticus in childhood. Brain 2002;125(Pt 9):1951-1959. 3. Scott RC, King MD, Gadian DG, Neville BG, Connelly A. Hippocampal abnormalities after prolonged febrile convulsion: a longitudinal MRI study. Brain 2006;126:2551-2557 4. Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006; 368(9531):222-229. 5. Chin RF, Neville BG, Peckham C, Wade A, Bedford H, Scott RC. Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7:696-703. Disclosure: The authors report no disclosures.
Reply from the author 22 September 2008
Shlomo Shinnar, Comprehensive Epilepsy Management Center Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467 Send Correspondence to journal: Re: Reply from the author sshinnar{at}aol.com Shlomo Shinnar	Drs. Scott and Neville point out that MTS is likely to be the most severe end of the spectrum of injury associate with prolonged febrile seizures and cite their studies to confirm this statement. [2,3]. We agree. [6,7] The goal of the FEBSTAT study is to prospectively study hippocampal injury following prolonged febrile seizures. We described the baseline phenomenology of the seizures in this study. [1] We are currently analyzing the data from the follow-up MRI studies and examining the spectrum of consequences. While it is premature to discuss the results, our findings are consistent with the scenario proposed by Scott and Neville: MTS may be the most severe end of a spectrum of injury. The FEBSTAT study will hopefully elucidate the spectrum of this injury and its clinical correlate in terms of developing epilepsy. We agree with Drs. Scott and Neville that the under-recognition of febrile status epilepticus is not limited to teaching hospitals in the US but is likely to be even more of a problem elsewhere. We thank them for providing supporting data on the importance of the issue. The assumption made by Drs. Scott and Neville that it is the prolonged nature of the seizure that is largely responsible for injury—regardless of whether it is febrile status or other forms of status—is less clear. Duration is important as brief febrile seizures are benign. However, the pattern of injury we observed appears to be specific to prolonged febrile seizures, at least in children. In children with a first unprovoked seizure, seizure duration has no impact on outcome. [8.9] Animal studies also showed that the injury appears to be peculiar to febrile seizures and is not seen in many other models of prolonged seizures in the immature brain. [10] While there is some disagreement on how unique prolonged febrile seizures are, the importance of early recognition and prompt treatment of prolonged seizures is clear. References 6. Lewis DV, Barboriak DP, MacFall JR, Provenzale JM, Mitchell TV, Vanlandingham KE. Do prolonged febrile seizures produce medial temporal sclerosis? Hypotheses, MRI evidence and unanswered questions. Prog Brain Res 2002;135:263-278. 7. Lewis DV, Shinnar S. Febrile status epilepticus. In Engel J Jr, Pedley TA eds. Epilepsy: A Comprehensive Textbook , Second Edition. Philadelphia, Lippincott-Raven. 2008;731-736. 8. Shinnar S, Berg AT, Moshe SL, et al. The risk of seizure recurrence following a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216-225. 9. Shinnar S, Berg AT, Moshe SL, Shinnar R. How long do new-onset seizures in children last? Ann Neurol 2001;49:659-664. 10. Dube CM, Brewster AL, Richichi C, Zha Q, Baram TZ. Fever, febrile seizures and epilepsy. Trends Neurosci 2007;30:490-496. Disclosure: The author reports no disclosures.
Phenomenology of prolonged febrile seizures. Results of the FEBSTAT study 26 August 2008
Edgar Avalos Herrera, Guatemala 5ta Calle 0-72 zona 1, Guatemala, Silvia Yamanic Alvarez, Oliver Cobox, Teresa Villeda Send Correspondence to journal: Re: Phenomenology of prolonged febrile seizures. Results of the FEBSTAT study eavalosh{at}yahoo.com Edgar Avalos Herrera, et al.	We read the article by Shinnar et al. with interest. [1] They described the semiology of febrile status epilepticus in 119 children aged between 1 month to 5 years old. They found 67% with partial seizures, 86% with normal development, and 25% with a family history of febrile seizures. Twenty-six percent of their patients were diagnosed in the first year of life. The Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study will recruit 200 children to assess the development of mesial temporal lobe epilepsy and mesial temporal sclerosis in follow-up. It is interesting that Dravet syndrome is usually diagnosed in children between 2 and 4 years old yet seizures present in the first year of life. These seizures are frequently partial and febrile and then become afebrile. Prolonged seizures often lead to status epilepticus but children develop normally. [2,3] The characteristics of Dravet syndrome in its variant without myoclonias resemble almost 26% of the patients enrolled in the FEBSTAT study although this is not addressed by the authors. Recently a clinical-genetic score for predicting the risk of development of Dravet syndrome has been published. [3] According to this criteria, almost a quarter of the FEBSTAT study participants could score 5 or more points which indicates a high risk for Dravet syndrome. This requires genetic analysis of SCN1A mutations for the patient and parents because the absence of SCN1A mutations does not preclude the diagnosis. [2] Mutations have been reported from 33% to as high as 100% in the report by Claes et al. [4] Shinnar et al. mention in the online Data Supplement that participation in genetic analysis is "optional" and it is not clear if SCN1A testing is planned. [1] The early diagnosis of Dravet syndrome and genetic analysis for SCN1A in FEBSTAT study participants is relevant not only for long term management [2] but particularly in the management and prophylaxis against status epilepticus as reported recently by Tanabe et al. [5] References 1. Shinnar S, Hesdorffer DC, Nordli Jr DR, et al. Phenomenology of prolonged febrile seizures. Results of the FEBSTAT study. Neurology 2008;71:170-176 2. Dravet C, Bureau M. Severe myoclonic epilepsy in infancy (Dravet syndrome) In In Engel J Jr, Pedley TA eds. Epilepsy: A Comprehensive Textbook Second Edition. Philadelphia, Lippincott-Raven. 2008;2343-2348. 3. Hattori J, Ouchida M, Ono J, et al. A Screening test for the prediction of Dravet syndrome before one year of age Epilepsia 2008;49:626-633. 4. Claes L, Ceulemans B, Audenaert D, et al. De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum Mutat. 2003;21:615-621. 5. Tanabe T, Awaya Y, Matsuishi T, et al. Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome) - A nationwide questionnaire survey in Japan. Brain Dev. 2008 Apr 16. [Epub ahead of print] Disclosures: The authors report no disclosures.
Reply from the authors 26 August 2008
Shlomo Shinnar, MD, PhD, Montefiore Medical Center, Albert EInstein College of Medicine Epilepsy Management Center, Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467 Send Correspondence to journal: Re: Reply from the authors sshinnar{at}aol.com Shlomo Shinnar, MD, PhD, et al.	Avalos et al. were interested in the proportion of children in our FEBSTAT study [1] who presented with febrile status epilepticus (SE) as the initial presentation of Dravet syndrome—also known as severe myoclonic epilepsy. [2] They applied a recently published algorithm for predicting the risk of Dravet syndrome to our data and conclude that many of our children were high risk for this syndrome. [3] The Hattori study cited by Avalos et al. examined all children with febrile seizures and found that a seizure lasting >10min was a risk factor for eventually developing Dravet syndrome. [3] As all children in FEBSTAT had seizures >30min, they by definition met the at-risk criteria in the Hattori study. Focality is known to be associated with duration which explains the proportion of children in FEBSTAT with focal febrile SE. [1,6] We are aware that in addition to prolonged febrile seizures causing temporal lobe epilepsy, the focus of FEBSTAT, they can also be the initial presentations of several syndromes including Dravet. It is also clear that genetics play an important role in febrile seizures. As part of FEBSTAT, we have banked serum for future genetic analysis at the NINDS-sponsored epilepsy genetics repository at Coriell Cell Repositories. A genetic analysis of these samples is planned once recruitment is completed in the next year. The SCNA1 gene—where the mutation for Dravet occurs [2]—and the SCNA1B gene—which has been associated with temporal lobe epilepsy [7]— are two of the loci which will be analyzed. Currently, Dravet syndrome is rare in the setting of febrile SE. Among more than 150 cases enrolled in FEBSTAT, only two developed clinical Dravet syndrome, one of whom has the mutation confirmed. Unlike temporal lobe epilepsy where the latency between febrile SE and later seizures can be very long, the latency to develop the typical other seizures of Dravet syndrome is short. [2] So while many children with Dravet syndrome present with prolonged and focal febrile seizures, only a small number of children who present with prolonged febrile seizures--whether focal or not--will turn out to have this syndrome. The frequency of the mutation, however, may turn out to be higher. Avalos et al.'s correspondence emphasizes the importance of including genetics in studies of well-defined cohorts to increase our understanding of these disorders. References 6. Berg AT, Shinnar S. Complex febrile seizures. Epilepsia 1996;37:126-133. 7. Scheffer IE, Harkin LA, Grinton BE, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain 2007;130(Pt 1):100-109. Disclosures: The authors report no disclosures.