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Aurlien D, Taubøll E, and Gjerstad L (2007) Lamotrigine in idiopathic epilepsy – Increased risk of cardiac death? Acta Neurol Scand 115:3 199–203

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Abstract: OBJECTIVES: Lamotrigine (LTG) has recently been shown to inhibit the cardiac rapid delayed rectifier potassium ion current (Ikr). Ikr-blocking drugs may increase the risk of cardiac arrhythmia and sudden unexpected death. With this background, it may be of importance that in our outpatient clinic between August 1, 1995 and August 1, 2005 we registered four consecutive cases of sudden unexpected death in epilepsy (SUDEP) in non-hospitalized patients that were all being treated with LTG in monotherapy. Here we describe and discuss these cases, the relevant literature, and the reasons to question whether these events were as a result of coincidence alone. METHODS:'' All the cases were collected consecutively at the outpatient clinic, Department of Neurology, Stavanger University Hospital, Norway. Clinical and pathological data were obtained and the relevant literature reviewed. RESULTS: All were females with idiopathic epilepsy. CONCLUSIONS: A systematic study is needed to reveal whether LTG may increase the risk of SUDEP in certain groups of patients.

Keywords: female, idiopathic epilepsy, lamotrigine, SUDEP

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Review of 4 cases of SUDEP in outpatients over 10 year span in this Norwegian study. All 4 patients were females being treated with lamotrigine monotherapy. During the period the deaths occurred, LTG had an average market share of 6.7% in the county housing the clinic. Of the 4 patients one had no detectable LTG in her serum after death, and for another the serum level was not measured; the authors point to Tomson et al. showing the unreliability of postmortem serum levels. Lamotrigine’s effect as an antagonist of the rapid delayed rectifier potassium ion current (Danielsson et al.) and possible tendency to cause arrhythmias is raised by the authors. e group followed up with Aurlien et al. and touched on the issue again in Aurlien et al.

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 ''Aurlien D, Taubøll E, and Gjerstad L (2007) Lamotrigine in idiopathic epilepsy – Increased risk of cardiac death? Acta Neurol Scand 115:3 199–203''
-'''Abstract:''' ''OBJECTIVES:'' Lamotrigine (LTG) has recently been shown to inhibit the cardiac rapid delayed rectifier potassium ion current (Ikr). Ikr-blocking drugs may increase the risk of cardiac arrhythmia and sudden unexpected death. With this background, it may be of importance that in our outpatient clinic between August 1, 1995 and August 1, 2005 we registered four consecutive cases of sudden unexpected death in epilepsy (SUDEP) in non-hospitalized patients that were all being treated with LTG in monotherapy. Here we describe and discuss these cases, the relevant literature, and the reasons to question whether these events were as a result of coincidence alone. ''METHODS:'' All the cases were collected consecutively at the outpatient clinic, Department of Neurology, Stavanger University Hospital, Norway. Clinical and pathological data were obtained and the relevant literature reviewed. ''RESULTS:'' All were females with idiopathic epilepsy. ''CONCLUSIONS: ''A systematic study is needed to reveal whether LTG may increase the risk of SUDEP in certain groups of patients.
+'''[http://onlinelibrary.wiley.com.ezp.welch.jhmi.edu/doi/10.1111/j.1600-0404.2006.00730.x/epdf Link to Article]'''
-=Article=
+'''Abstract:''' <u>''OBJECTIVES:''</u> Lamotrigine (LTG) has recently been shown to inhibit the cardiac rapid delayed rectifier potassium ion current (Ikr). Ikr-blocking drugs may increase the risk of cardiac arrhythmia and sudden unexpected death. With this background, it may be of importance that in our outpatient clinic between August 1, 1995 and August 1, 2005 we registered four consecutive cases of sudden unexpected death in epilepsy (SUDEP) in non-hospitalized patients that were all being treated with LTG in monotherapy. Here we describe and discuss these cases, the relevant literature, and the reasons to question whether these events were as a result of coincidence alone. <u>''METHODS:'</u>' All the cases were collected consecutively at the outpatient clinic, Department of Neurology, Stavanger University Hospital, Norway. Clinical and pathological data were obtained and the relevant literature reviewed. <u>''RESULTS:''</u> All were females with idiopathic epilepsy. <u>''CONCLUSIONS:''</u> A systematic study is needed to reveal whether LTG may increase the risk of SUDEP in certain groups of patients.
-==Introduction==
+'''Keywords:''' female, idiopathic epilepsy, lamotrigine, SUDEP
-Sudden unexpected death in epilepsy (SUDEP) has been defined by Nashef and Brown as the ‘sudden unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without evidence for a seizure, and excluding documented status epilepticus, in which post-mortem examination does not reveal toxicologic or anatomic cause of death’.
+=Comments and Context=
-The risk is approximately 1:200 per year in severe epilepsy and less than 1:1000 per year in mild idiopathic epilepsy. Most cases of SUDEP seem to be seizure related, and in the majority of witnessed cases generalized tonic-clonic seizures (GTCS) have been reported. Central or obstructive apnea and cardiac arrhythmia are the most probable pathophysiological mechanisms, but no definite mechanism has yet been ascertained.
+*Review of 4 cases of SUDEP in outpatients over 10 year span in this Norwegian study. All 4 patients were females being treated with lamotrigine monotherapy. During the period the deaths occurred, LTG had an average market share of 6.7% in the county housing the clinic. Of the 4 patients one had no detectable LTG in her serum after death, and for another the serum level was not measured; the authors point to Tomson et al. showing the unreliability of postmortem serum levels. Lamotrigine’s effect as an antagonist of the rapid delayed rectifier potassium ion current (Danielsson et al.) and possible tendency to cause arrhythmias is raised by the authors. e group followed up with Aurlien et al. and touched on the issue again in Aurlien et al.
-Recently, Danielsson et al. showed that lamotrigine (LTG) possesses the potential to inhibit the cardiac rapid delayed rectifier potassium ion current (Ikr). Ikr-blocking drugs are generally considered to be associated with an increased risk of cardiac arrhythmia and sudden unexpected death. With this background it may be of importance that between August 1, 1995 and August 1, 2005, four consecutive cases of SUDEP in non-hospitalized patients were registered among our outpatients at the Department of Neurology, Stavanger University Hospital, Norway. All were young women on LTG monotherapy.
-The aim of the present paper is to describe and discuss these cases, the relevant literature and the reasons to question whether these events were a result of coincidence alone.
-==Materials and Methods==
-Information on the cases was collected as they appeared in the clinical setting. Although we have not systematically registered all the cases of SUDEP in our catchment area, these four cases represent all the patients with SUDEP reported by the pathologist to the Department of Neurology at Stavanger University Hospital within the past 10 years (August 1, 1995–August 1, 2005). During this period we have not been aware of other cases among our outpatients.
-The first case occurred in 1995. The second occurred in 2002, and as the same drug, LTG, was involved, this gave rise to some concern. We were, however, aware that SUDEP may occur during treatment with various antiepileptic drugs (AEDs), and therefore this was considered a coincidence. However, when the third and fourth SUDEP cases with LTG monotherapy occurred in 2004 and 2005, we considered it pertinent to review all four cases and the available relevant literature.
-Stavanger University Hospital serves a population of about 300,000 in the southern part of Rogaland County, Norway; 58% of the population are below 40 years of age, and the genders are equally distributed (Statistics Norway: http://ssb.no).
-In 1995 LTG had a market share in defined daily doses of 0.8% in Rogaland County. In the following years the market share of LTG gradually increased to 8.7% in 2002, 11.4% in 2003 and 14.7% in 2004 (Farmastat AS: http://farmastat.no). The mean market share of LTG over the 10-year period was 6.7%.
-==Results==
-===Case 1 – SUDEP at the age of 25 years===
-The patient had previously been healthy when she had her first seizure at the age of 17 years. The seizures started with a feeling of déjà vu, followed by a feeling of fear and a sensation down her chest which she described as being similar to an electrical current. She also felt flushed and had palpitations. The seizures lasted only a few seconds. Sometimes the patient's consciousness was reduced during these episodes.
-Before treatment was started, the electroencephalogram (EEG) showed numerous bursts of bilateral synchronous epileptogenic activity lasting up to 2–3 s. The classification of the seizures was uncertain, but most probably localization-related idiopathic or cryptogenic (Table 1).
-The last blood samples that were analysed, 4 months before death, showed normal electrolytes, liver enzymes, creatinine and hematology. At autopsy there were no signs of tongue or lip bite, but some blood was found in her nostrils. The weight of the lungs was higher than expected which may indicate congestion of blood and fluid. No evidence of drugs, ethanol and narcotics was detected at an extensive screening conducted at the Norwegian Institute of Public Health.
-===Case 2 – SUDEP at the age of 16 years===
-The patient first experienced signs of photosensitivity at the age of 13 years. Exposure to flickering light at a discotheque induced myoclonias throughout her body, and on one occasion she lost consciousness in relation to the myoclonias. The patient also experienced myoclonias in her arms and upper part of the body throughout the day. Episodes lasting less than 2 s in which she felt dizzy, but without any feeling of reduced consciousness, occurred many times each week. The patient was 14 years old when she experienced her first generalized convulsive seizure, with tongue bite and foam from her mouth. Two months later she had her second generalized seizure.
-The EEG showed bursts of bilateral sharp potentials (Table 1). The epilepsy was considered to be idiopathic generalized, possibly juvenile myoclonic epilepsy. On her last hospital consultation, 6 weeks before her death, the patient had been completely free from seizures for 6 months and reported no side effects from her medication. The last blood samples 6 months before death showed normal electrolytes, liver enzymes, creatinine and hematology. She was found dead in the morning, lying on her stomach in bed, with abundant foam and some blood from her mouth. At midnight everything had been observed to be normal. At autopsy the lungs showed significant congestion of blood and fluid. No evidence of drugs, ethanol and narcotics was detected at an extensive screening conducted at the Norwegian Institute of Public Health.
-===Case 3 – SUDEP at the age of 37 years===
-The patient first consulted her physician at the age of 29 years, after she had awoken in the morning with a tongue bite and bruising around the eye. Six years earlier she had experienced a similar incident when a friend had observed what she had considered was an epileptic seizure during the night, and the patient had awoken with tongue bite. At the age of 31 years she awoke one morning with a severe tongue bite, her chin was bruised and she felt slightly confused. Her fourth and last documented seizure occurred in the morning 18 months before her death with convulsions, loss of consciousness and foam from her mouth. The EEG on five occasions showed bilateral synchronous epileptic activity, and on one occasion, sporadic epileptic activity, with a maximum over the right frontal region (Table 1). The epilepsy was considered to be idiopathic generalized.
-The last blood samples analysed, 11 months before death, showed normal electrolytes, liver enzymes, creatinine and hematology. She was found dead in the shower less than 2 h after a telephone contact. At autopsy she had hematomas which were considered to be some days old around one eye and in the forehead, and she had foam in the mouth, nose and airways as well as in the lungs. No evidence of drugs, ethanol and narcotics was detected at an extensive screening conducted at the Norwegian Institute of Public Health.
-===Case 4 – SUDEP at the age of 24 years===
-The patient had insulin-dependent diabetes mellitus from the age of 6 years. From the age of 17 years she started having frequent episodes with loss of consciousness, sometimes with generalized convulsions and urination, and often with tongue bite. Initially the episodes were related to low blood sugar levels, but eventually it was apparent that the episodes occurred independently from the hypoglycemias (Table 1).
-The epilepsy was considered to be idiopathic generalized. The last blood samples analysed, 5 months before death, showed normal electrolytes, liver enzymes, creatinine and hematology. Two days before her death she was examined by a cardiologist because of episodes with palpitations and a cardiac murmur. The murmur was found to be physiologic, the ECG was normal and no sign of heart disease was found, although sinus tachycardia was noted. The patient was found at noon, dead in her bed, by her boyfriend upon his return from a short errand. At autopsy the lungs showed significant congestion of blood. The heart showed normal valves and no sign of coronary heart disease except from some fatty streaks. The glucose level in the vitreous humor was 5.3 mmol/l. No evidence of drugs, ethanol and narcotics was detected at an extensive screening conducted at the Norwegian Institute of Public Health.
-==Discussion==
-Our patients all fit the definition of SUDEP. The common denominators are LTG monotherapy, female gender, idiopathic epilepsy and young age (Table 1). The apparent accumulation of LTG-related SUDEP cannot be explained simply by the market share, which had a mean value of 6.7% over the 10-year period, 1995–2005 (Farmastat AS: http://www.farmastat.no). There are four possible explanations: (i) an insufficient effect of LTG in these patients leading to fatal seizures; (ii) a direct effect of LTG on vital functions, such as cardiac rhythmicity; (iii) a combination of drug-induced effects and seizures; and (iv) coincidence, as these cases have not emerged through a systematic study of SUDEP.
-As none of the deaths described were observed, it is uncertain whether or not a seizure was involved. However, as most cases of SUDEP seem to be seizure-related and pulmonary edema is almost a sine qua non of SUDEP, the pulmonary changes that were found at autopsy in these cases may indicate that a terminal seizure had occurred, although such changes are non-specific.
-Case 2 did not have a detectable blood concentration of LTG post mortem and case four had a low post-mortem s-LTG (3.2 μmol/l) compared with the last antemortem level (27.5 μmol/l) when the patient was on combination therapy with carbamazepine. Similar observations of low blood concentrations of AEDs in cases of SUDEP have led to the suspicion that non-compliance may play a role in SUDEP, but the reliability of post-mortem drug levels has been questioned. Tomson et al. found that post-mortem blood levels of PHT in rabbits were 35% of antemortem serum concentrations, and the fate of the blood concentrations of LTG post mortem is unknown. It should also be remembered that at least one case (case 3) had therapeutic LTG concentrations even on post mortem. Therefore, in our opinion, although the possibility of non-compliance clearly exists, this factor alone cannot explain these instances of SUDEP.
-Case 4 also had insulin-dependent diabetes mellitus, and it is possible that her death may have been caused by hypoglycemia. However, the glucose level in her vitreous humor was found to be 5.3 mmol/l, and the autopsy concluded that there was neither biochemical nor clinical evidence that could indicate hypoglycemia or severe hyperglycemia.
-It may also be relevant that all our cases seem to have had idiopathic epilepsy. All had GTCS, and cases 1, 3 and 4 had bilateral synchronous epileptogenic activity in their EEGs. Case 2 had myoclonic and GTC seizures, and an EEG showing bilateral sharp potentials. This concurs with the findings of Nilsson et al. who demonstrated a higher relative risk of SUDEP among patients with idiopathic epilepsy. It may also be of interest that an increasing number of idiopathic epilepsies have been shown to be associated with channelopathies, and it has been postulated that the same channelopathy may cause both familial long QT syndromes and epilepsy.
-A number of class I and class III anti-arrhythmics and non-cardiac drugs like antihistamines, psychotropics and antimicrobial agents with the potential to inhibit the Ikr, have been associated with prolonged QT intervals and risk of arrhythmia (including the potentially life-threatening ventricular tachyarrhythmia torsade de pointes), and many drugs have been withdrawn or suspended from the market because the risk has been found to be unacceptably high. Danielsson et al. have assessed the possible arrhythmogenic properties of AEDs using the whole cell patch-clamp recording technique to study the effects on Ikr channels. The IC50 ratio in vitro (the concentration when 50% inhibition is obtained compared with control values)/therapeutic free plasma concentration is considered potentially relevant for values of approximately 30 and below, and for LTG it was found to be less than 10, indicating a significant and clinically relevant Ikr inhibition. In comparison, a previous study by Danielsson et al. found the ratio to be 30 for phenobarbital and 25 for phenytoin. In our patients, seizure-induced acidosis may have contributed to a further increase in the Ikr inhibition, as in cardiac myocytes a decrease in the external pH in the interval 7.4–6.5 is associated with inhibition of Ikr and a marked prolongation of the action potential. However, to our knowledge, an influence of LTG on cardiac function has not been shown in a clinical setting, and we are not aware of any previous studies that have shown elevated SUDEP in patients treated with LTG. In a large clinical development program for LTG, the rate of SUDEP was calculated to be 3.5 in 1000 patient-years of exposure to LTG. This was found to be comparable to the rate that would be expected in young adults with severe epilepsy, and was interpreted as unrelated to drug treatment. However, the inclusion criterion for entry into the evaluation studies was an established diagnosis of refractory epilepsy with any type of partial seizures, including secondary generalized seizures. Consequently, the risk for SUDEP for patients with idiopathic generalized epilepsy on LTG cannot be assessed from this study.
-In a later study, the standardized mortality ratio of LTG-treated patients was slightly higher than expected, but the difference was not statistically significant when compared with the other drugs studied, which were gabapentin (GBP) and vigabatrin (VGB). There were 18 cases of sudden death among the 1050 patients treated with LTG (1.7%), when compared with 4 of 361 treated with GBP (1.1%) and 9 of 713 with VGB (1.2%). It may be relevant that a much higher percentage of patients in the LTG group had generalized epilepsy (26%) compared with the GBP (9%) or VGB (12%) groups. In our opinion, these data do not exclude the possibility that there may be subgroups of patients with idiopathic epilepsy and GTCS treated with LTG that are at an increased risk of SUDEP.
-The fact that all our patients were females may not be due solely to coincidence, as the risk of drug-induced torsade is increased by up to threefold in females. Women also have an increased prevalence of symptoms of congenital long QT syndrome and there is an increase in episodes of supraventricular tachycardia in the perimenstrual period in susceptible patients.

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