with refractory tonic–clonic SE (Shiloh-Malawsky et al., 2011), although the use in tonic SE is not reported. Our experience suggests that LCM is a treatment option in tonic SE. The emergence of side effects with prolonged IV use may require switching to oral formulation in lower doses or restricting use to acute management only. DISCLOSURE None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical pub- lication and affirm that this report is consistent with those guidelines. Vivek Jain A. Simon Harvey simon.harvey@rch.org.au Children’s Neurosciences Centre, The Royal Children Hospital, Melbourne, Victoria, Australia REFERENCES Goraya JS, Khurana DS, Valenceia I, Melvin JJ, Cruz M, Legido A, Kot- hare SV. (2008) Intravenous levetiracetam in children with epilepsy. Paediatr Neurol 38:177–180. Hçfler J, Unterberger I, Dobesberger J, Kuchukhidze G, Walser G, Trinka E. (2011) Intravenous lacosamide in status epilepticus and seizure clusters. Epilepsia 50:e148–e152. Mehta V, Singhi P, Singhi S. (2007) Intravenous sodium valproate versus diazepam infusion for the control of refractory status epilepticus in children: a randomized controlled trial. J Child Neurol 22:1191– 1197. Shiloh-Malawsky Y, Fan Z, Greenwood R, Tennison M. (2011) Success- ful treatment of childhood prolonged refractory status epilepticus with lacosamide. Seizure 20:586–588. Tassinari CAI, Dravet C, Rojer J, Cano JP, Gastaut H. (1972) Tonic status epilepticus precipitated by intravenous benzodiazepine in five patients with Lennox–Gastaut syndrome. Epilepsia 13:421–435. Causal or casual association between lamotrigine and sudden unexpected death in females with epilepsy? To the Editors: Aurlien et al. (2012) reported a higher proportion of female patients using lamotrigine (LTG) among cases with sudden unexpected death in epilepsy (SUDEP). This observation is an important contribution, which will be useful in future studies, and we want to acknowledge the authors for their efforts. However, several issues raise con- cerns regarding the suggestion of ‘‘genuine adverse effect’’ of LTG. Assessing causal connections between agents and event is fundamental to the practice of medicine and to the understanding of adverse drug reactions. The likeli- hood of a causal relation between a drug and an adverse event should be accessed on a case-by-case basis and graded according to certainty levels (Edwards & Aron- son, 2000). Detailed analysis of available clinical data could indicate that some of the seven definite/probable SUDEP cases in female patients taking LTG happened in close temporal relation with (1) fast LTG discontinuation (case 16), (2) no adequate LTG dose escalation after valproate discontinua- tion (case 1) (Aurlien et al., 2009), or (3) absent/subthera- peutic LTG levels (cases 2, 4, 8, and 16). This could favor the hypothesis of an insufficient effect of LTG in these patients leading to fatal seizures rather than the ‘‘genuine adverse effect’’ suggestion. Moreover, the nested case–con- trol study design (cases selected from national registry and controls selected from university hospital registry) deserves further analysis of potentially diverse patterns of LTG man- agement strategies (e.g., dosing, titration schedules, initial or maintaining doses) at different health care levels. In addition, the study did not use strict exclusion criteria. Namely, the study included patients with some concurrent disease, which could be competing causes for the SUDEP on an individual basis, regardless of group comparison. For example, conditions such as congenital long-QT syn- drome (case 1) or long-lasting insulin-dependent diabetes mellitus (case 4) carry the high risk for sudden death (Bergner & Goldberger, 2010; van Noord et al., 2010) and, therefore, may be important confounding variables. Finally, and most importantly, the analysis is not adjusting for frequency of generalized tonic–clonic seizures (GTCS). All female patients taking LTG from the definite/probable SUDEP group had pharmacoresistant epilepsy; they all used to have GTCS and all except one had generalized/bilateral EEG activity. Because none of the deaths were observed, GTCS may be a major contribution variable, and association with LTG therapy could simply reflect the severity of epi- lepsy. Indeed, the recent community-based long-term pro- spective study of children with epilepsy (Sillanpää & Shinnar, 2010) as well as meta-analysis of add-on drug trials (Ryvlin et al., 2011) found bad seizure control as the most important variable to be associated with risk of SUDEP. Hence, we were unable to consider whether the increased risk for SUDEP was associated with LTG therapy without matching on GTCS frequency. Overall, observed association can be graded only as ‘‘possible’’ on causality assessment and we highly support efforts for future studies in this field. However, adequate rigor of the scientific methods must take place before any judgment of causality is made. DISCLOSURE None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical pub- lication and affirm that this report is consistent with those guidelines. Stevo Lukic ´ 1,2 slukic@medfak.ni.ac.rs Bojko Bjelakovic ´ 2,3 Mirjana Spasic ´ 1,2 Epilepsia, 53(4):761–764, 2012 762 GRAY MATTERS