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ARTICLES: R. Tarkka, E. Pääkkö, J. Pyhtinen, M. Uhari, and H. Rantala Febrile seizures and mesial temporal sclerosis: No association in a long-term follow-up study Neurology 2003; 60: 215-218 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

Heikki Rantala, Matti Uhari   (7 March 2003)

Febrile seizures and mesial temporal sclerosis: No association in a long-term follow-up study

Rod Scott   (7 March 2003)

Reply to Letter to the Editor 7 March 2003
Heikki Rantala University of Oulu Finland, Matti Uhari Send Correspondence to journal: Re: Reply to Letter to the Editor heikki.rantala{at}oulu.fi Heikki Rantala, et al.	No epidemiological data of the occurrence of MTS in children with febrile seizures is available, but in children with newly diagnosed epilepsy it is found in only about 1% of children, [2,3] and would therefore be much lower in children with febrile seizures. If we assume an exceptionally high occurrence of 0,1% of MTS in children with febrile seizures, and use the rule of thumb of three-fold amount of patients to be examined to find out a significant difference, we should have to perform MRI volumetric study in 3000 children with febrile seizures. Even having this kind of patient series it would be hard to avoid type II error, i.e. being wrong when claiming that there is no association between febrile seizures and MTS. However, if MTS is so rare it would not be clinically relevant. Thus, the only way to produce evidence about the association of febrile seizures and MTS is to little by little publish unpowered studies and then later if it is still relevant, to combine them in a meta- analysis. We are fully aware of the large amount of the animal model studies, but in all these studies the seizures have been provoked in a manner that is not comparable to human febrile seizures and febrile seizures per se do not occur in any animal. We think that it is unfortunate to use the evidence from these highly experimental studies to make clinicians uncertain about the good prognosis of febrile seizures. What they definitely indicate is only follow-up surveys of the patients having had febrile seizures. Only if there would be clinical evidence of the occurrence of MTS in unselected patient series we should change our understanding about the prognosis of febrile seizures. As we have stated in our article, it has earlier been shown that the right-left hippocampal volume difference is independent of total intracranial volume.[4] We have discussed the significance of this finding as well as the hippocampal edema shown in the study of Van Landingham et al.[1] Since we have studied children at the highest risk for MTS, i.e. children with prolonged febrile seizures and those who developed epilepsy during a follow-up time of over 12 years and found no case of MTS, we think that it is correct to conclude that the occurrence of MTS after febrile seizures is an uncommon event. References: 1) VanLandingham KE, Heinz ER, Cavazos JE, Lewis DV. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Neurology 1998;43:413-426. 2) King MA, Newton MR, Jackson GD et al. Epileptology of the first- seizure presentation: A clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet 1998;352:1007- 1011. 3) Berg AT, Testa FM, Levy SR, Shinnar S. Neuroimaging in children with newly diagnosed epilepsy: A community-based study. Pediatrics 2000;106:527-532. 4) Jack CR Jr, Sharbrough FW, Cascino GD, Hirschorn KA, O'Brien PC, Marsh WR. Magnetic resonance image-based hippocampal volumetry: Correlation with outcome after temporal lobectomy. Ann Neurol 1992;31:138- 146.
Febrile seizures and mesial temporal sclerosis: No association in a long-term follow-up study 7 March 2003
Rod Scott Great Ormond Street Hospital United Kingdom Send Correspondence to journal: Re: Febrile seizures and mesial temporal sclerosis: No association in a long-term follow-up study r.scott{at}ich.ucl.ac.uk Rod Scott	In a recent paper, it was concluded that prolonged febrile convulsion (PFC) does not cause either neurologic sequelae or brain damage [1], particularly mesial temporal sclerosis (MTS). This is an extremely strong epidemiological statement that has been made on the basis of follow-up of only 24 patients who had a PFC. Although that study confirms that MTS is not inevitable following PFC, in order to define the prevalence of MTS in a population that has had PFC, a much larger dataset would be required. In addition, the authors have not discussed their results in the context of the large animal model literature supporting the view that prolonged seizures can cause hippocampal injury consistent with MTS. The hippocampal injury associated with PFC may encompass a spectrum from subtle neuronal injury to MTS. Studies that have reported hippocampal abnormalities, consistent with hippocampal edema, within a few days of PFC have concluded that PFC could result in hippocampal injury that does not necessarily meet the criteria for MTS. [2, 3] The authors have not attempted to address this extremely important issue. In addition, there is a methodological flaw that makes such a discussion difficult. The authors have used a right minus left hippocampal volume difference as a measure of side to side asymmetry. They suggest that this is independent of total intracranial volume, which is incorrect. A similar absolute right - left difference could occur in hippocampi that are large and reasonably symmetrical, or small and markedly asymmetrical. As hippocampal volume is dependent upon intracranial volume, right-left difference is also dependent upon intracranial volume. Even given this flaw, the authors do not discuss the biological relevance of the difference in asymmetry when their patients with a history of PFC compared to the other groups. A difference in symmetry could be interpreted as evidence of neuronal injury especially in the three individuals who had a unilateral small hippocampal volume. There is also doubt about whether patients with simple first febrile seizures are an adequate control group given that families of patients with mesial temporal sclerosis associated with a prolonged febrile convulsion have hippocampal asymmetry even if the family member has not had a prolonged febrile convulsion. [4] This study in no way provides strong evidence that prolonged febrile convulsion does not cause mesial temporal sclerosis or more subtle hippocampal injury, and therefore the results must be interpreted with caution. References 1. Tarkka R, Paakko E, Pyhtinen J, Uhari M, Rantala H. Febrile seizures and mesial temporal sclerosis. No association in a long-term follow-up study. Neurology 2003; 60:215-218. 2. Scott RC, Gadian DG, King MD, Chong WK, Cox TC, Neville BG et al. Magnetic resonance imaging findings within 5 days of status epilepticus in childhood. Brain 2002;125(Pt 9):1951-1959. 3. VanLandingham KE, Heinz ER, Cavazos JE, Lewis DV. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Annals of Neurology 1998;43:413-426. 4. Fernandez G, Effenberger O, Vinz B, Steinlein O, Elger CE, Dohring W et al. Hippocampal malformation as a cause of familial febrile convulsions and subsequent hippocampal sclerosis. Neurology 1998;50:909- 917.