The influence of circadian rhythms on sudden unexpected death in epilepsy

Influência do ritmo circadiano na morte súbita inesperada em epilepsia

CLINICAL/SCIENTIFIC NOTES

The influence of circadian rhythms on sudden unexpected death in epilepsy

Influência do ritmo circadiano na morte súbita inesperada em epilepsia

Vera C. Terra^I; Hélio R. Machado^I; Américo C. Sakamoto^I; Ricardo M. Arida^II; Carla A. Scorza^III; Marly de Albuquerque^III; Esper A. Cavalheiro^III; Fulvio A. Scorza^III

^IDepartamento de Neurologia, Psiquiatria e Psicologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto SP, Brazil

^IIDepartamento de Fisiologia, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), São Paulo SP, Brazil

^IIIDisciplina de Neurologia Experimental, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), São Paulo SP, Brasil

Patients with epilepsy are at two- to three-fold higher risk of dying prematurely compared with healthy individuals, being the most frequent epilepsy-related cause of death the sudden unexpected death in epilepsy (SUDEP)¹. SUDEP is defined as sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death in patients with epilepsy. Documented status epilepticus (SE) is excluded in SUDEP, and post mortem examination does not reveal any cause of death². Risk factors for SUDEP include epilepsy refractoriness, presence of generalized tonic-clonic seizures, polytherapy with antiepileptic drugs, young age, duration of the seizure disorder ranging from 15 to 20 years, and early epilepsy onset^1,3. The pathophysiological causes of SUDEP are unknown, but it is very probable that cardiac abnormalities during and between seizures might play a potential role in the event^1,3. In recent years, some studies have indicated that sudden cardiac death might follow circadian distribution⁴; however, to our knowledge, there is no data describing a possible relationship between daily, weekly or seasonal variation and SUDEP.

The present report shows a SUDEP case that could be associated with circadian distribution.

CASE

A 15 year-old boy with poorly controlled epilepsy, no perinatal neurological problems, and normal neurological and cognitive development presented with seizures since the age of three. Between three and ten years of age, seizures occurred sporadically, but they became clinically refractory to treatment thereafter. Patient described daily complex motor seizures, which occurred almost only during sleep. Seizures frequently evolved to tonic and tonic-clonic generalization. Clinical and neurological examinations were normal. Brain MRI scan gave evidence of volumetric reduction in the left temporal pole. Video-EEG revealed rare interictal frontal and rolandic spikes and complex partial seizures with bilateral frontal and temporal theta activity. Recent blood serum chemistry was normal for glucose, renal, hepatic and hematological functions. Levels of serum antiepileptic drugs were not available. Although he had been on polytherapy (oxcarbazepine, lamotrigine and topiramate), he experienced two to three seizures per night and took no other medications.

He was last seen alive at 7 AM of a July Monday morning and continued sleeping. At 11 AM, he was found dead in bed, lying prone, with conjunctiva hyperemia. No post mortem examination was done. No signs of an infectious process or any other concomitant disease were noted, either. The patient was considered to have died of SUDEP.

DISCUSSION

This report describes circadian distribution (i.e. hours of the day, seasonal variation and days of the week) that could be involved in a SUDEP case. Recognition of these patterns could help develop the concept of cardiovascular events "triggering". As research in this field must focus on the potential prevention of SUDEP, a number of arguments might be put forward.

Firstly, colder temperatures might explain the SUDEP case described here because patient died during winter and it is possible that this factor contributed to a SUDEP event. Exposure to low temperatures is well-established as one of the risk factors in cardiac mortality⁴, and our group reported that winter temperatures may lead to some cardiovascular abnormalities and hence SUDEP⁵. This hypothesis has been experimentally evaluated and we demonstrated that low temperatures clearly increase the heart rate of rats with epilepsy, suggesting that cold weather could be considered an important risk factor in cardiovascular abnormalities and therefore sudden cardiac death in epilepsy⁶. Following this reasoning, colder temperatures have been associated with an increase in vascular resistance, coronary vasospasm, blood pressure, and hemostasis⁴.

A second argument in favour of SUDEP in the case reported here is the fact that our patient died on a Monday. This finding is in agreement with available evidence that suggests a peak in the incidence of cardiovascular events on Mondays compared with others days⁷. Peckova and colleagues⁷ explored weekly variation in 6603 out-of-hospital cardiac arrests during an 8-year period and observed a higher incidence of sudden death on Monday compared with the other days. Arntz and co-workers⁴ analyzed the emergency medical system data of Berlin (West) from 1987-1991 with respect to all consecutive sudden deaths in subjects older than 18 years and found that a maximum of events occurred on Mondays (n=3721). This corresponded to a relative increase of 18.3%, which was more pronounced in young patients and men compared with older patients and women, respectively.

The time of day when sudden cardiac deaths occur is another important issue. In the present case, the patient was last seen alive at 7 AM and was found dead around 11 AM. This observation is in agreement with Muller and colleagues⁸, who analyzed the time of day of sudden cardiac death as indicated by death certificates of 2203 individuals dying out of the hospital. Their data revealed a prominent circadian variation of sudden cardiac death, with a low incidence during the night and an increased incidence from 7 to 11 A.M. Willich and colleagues⁹ analyzed the time of day when sudden cardiac deaths occurred and there was higher incidence of cardiac deaths between 7 and 9 AM, and the risk of such event was at least 70% higher during this peak period compared with the average risk during other periods of the day. More recently, a large study showed that the time of day with higher incidence of sudden deaths was between 6 and 10 AM⁴.

Although the patient described here presented some risk factors that might have made him a potential candidate for SUDEP, our study shows that a possible role of circadian variation in the occurrence of this event should not be neglected. The present data could be sustained by Tomson's group, who demonstrated a circadian variation in heart-rate variability in localization-related epilepsy¹⁰. To sum up, we would like to raise the possibility that circadian variation could underlie some processes that culminate in SUDEP and that heart failure could have a significant role in this mechanism. However, a clear relationship between epilepsy, cyclic patterns, and SUDEP still needs to be demonstrated in both experimental and human conditions.

Received 31 October 2008. Accepted 25 February 2009.

Financial Support: FAPESP, CInAPCe-FAPESP and CNPq.

Dra. Vera C. Terra - Departamento de Neurologia/CIREP/Hospital das Clínicas de Ribeirão Preto - Avenida Bandeirantes SN - 14048-900 Ribeirão Preto SP - Brasil. E-mail: [e-mail]

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Publication Dates

• Publication in this collection
  22 June 2009
• Date of issue
  June 2009