Print version ISSN 0004-282X
Arq. Neuro-Psiquiatr. vol.63 no.3b São Paulo Sept. 2005
Menstrual cycle worsening of epileptic seizures in women with symptomatic focal epilepsy
Piora de crises epilépticas durante o período menstrual em mulheres com epilepsia focal sintomática
Ana Carolina Belini Bazán; Maria Augusta Montenegro; Fernando Cendes; Li Li Min; Carlos A.M. Guerreiro
Department of Neurology - University of Campinas (FCM/UNICAMP), Campinas SP, Brazil
INTRODUCTION: Hormonal fluctuation is responsible for worsening of epileptic seizures during the menstrual cycle.
OBJETIVE: To identify irregularities in the menstrual cycles of women with mesial temporal lobe epilepsy (MTLE) and extratemporal focal epilepsy (ETFE) and correlate the frequency of seizures during the menstrual cycles.
METHOD: We evaluated prospectively women in the menacme with MTLE and ETFE. Calendars were provided for these patients, and they were asked to mark their seizure frequency according to the menses. Calendars were reviewed in each routine medical appointment.
RESULTS: Thirty-nine patients with MTLE and 14 with ETFE were evaluated. We registered 211 cycles in the patients with MTLE and 49 in those with ETFE. Irregular menstrual cycles were found in 28 (28/39, 71.7%) patients with MTLE and 6 (6/14, 42.8%) with ETFE (p=0.052). Premenstrual seizure worsening was observed in 46 (21.8%) patients with MTLE and 9 (18.3%) with ETFE (p=0.596). Menstrual worsening was observed in 47 (22.2%) patients with MTLE and 15 (30.6%) with ETFE (p=0. 217). Ovulatory worsening was observed in 36 (17%) patients with MTLE and 13 (26.5%) with ETFE (p=0,126). Catamenial worsening was observed in 58 (27.4%) of the patients with MTLE and in 17 (34.7%) of the patients with ETFE (p=0.315).
CONCLUSION: There was no difference between the group of patients with MTLE and ETFE regarding the frequency of irregular cycles and seizure worsening during the premenstrual, menstrual, catamenial or ovulatory periods.
Key words: epilepsy, catamenial, temporal lobe epilepsy, extra-temporal epilepsy, menstrual cycle.
INTRODUÇÃO: Admite-se que a flutuação hormonal seja a responsável para a piora de crises epilépticas no período catamenial.
OBJETIVO: Identificar irregularidades nos ciclos menstruais de mulheres com epilepsia de lobo temporal mesial (ELTM) e epilepsia focal extratemporal (EFET); e relacionar a frequencia de crises durante o ciclo menstrual.
MÉTODO: Avaliamos mulheres na menacme, que apresentem quadro clínico laboratorial compatível com ELTM e EFET. Foram fornecidos calendários para estas pacientes e instruídas para preenchimento correto da menstruação e das crises epilépticas e serão revistos em cada consulta médica rotineira.
RESULTADOS: Foram avaliadas 39 pacientes com ELTM e 14 com EFET. Registramos 211 ciclos nas pacientes com ELTM e 49 nas com EFET. Ciclos menstruais irregulares foram apresentados por 28 (71,7%) pacientes com ELTM e 14 (42,8%) com EFEP (p=0,052). Piora pré-menstrual foi observada em 46 (21,8%) pacientes com ELTM e 9 (18,3%) com EFET (p=0,596). Piora menstrual foi observada em 47 (22,2%) pacientes com ELTM e 15 (30,6%) com EFET (p=0,217). Piora ovulatória foi observada em 36 (17%) pacientes com ELTM e 13 (26,5%) com EFET (p=0,126). Piora catamenial foi observada em 58 (27,4%) das pacientes com ELTM e em 17 (34,7%) das pacientes com EFET (p=0,315).
CONCLUSÃO: Não houve diferença entre os grupos de pacientes com ELTM e EFET quanto à freqüência de ciclos irregulares e piora das crises nos períodos pré-menstrual, menstrual, catamenial ou ovulatório.
Palavras-chave: epilepsia, catamenial, epilepsia de lobo temporal, epilepsia extratemporal, ciclo menstrual.
Epilepsy has an estimated prevalence between 1 and 1.8%1-3. The incidence of epilepsy in women is similar to that in men. Anovulatory cycles are more frequent in women with epilepsy. In addition, it seems that epileptic seizures are more frequent in anovulatory cycles than in normal cycles4. There are reports that up to 50% of women with epilepsy in the menacme present worsening of seizures through the menstrual cycle5.
Herzog et al.6 described three standards of seizure worsening related to different periods of the menstrual cycle: a) seizures that occur during the three days before menses and on the first three days of menses; b) seizures that occur close to the middle of the cycle, before the ovulation between the 8th and 14th days; c) seizures that are frequent between the 8th day of a cycle and the 2nd day of the next; these cycles are anovulatory. This last standard is more difficult to identify, comparing to those that occur in normal menstrual cycles. Experimental studies showed that estrogen is epileptogenic and progesterone protects against seizures7. Epileptiform activity is observed during menses, on the days that precede it and in the middle of the menstrual cycle. Patients with both partial and generalized epilepsies present catamenial seizure worsening8.
The objective of this study was to identify irregularities in the menstrual cycles of women with mesial temporal lobe epilepsy (MTLE) and extra-temporal focal epilepsy (ETFE), and correlate the frequency of seizures during menstrual cycle.
Women in fertile age were evaluated. Patients were seen at the epilepsy clinic of our University Hospital.
MTLE was characterized according to clinical end electroencephalographic criteria established by the ILAE9. Patients presented seizures with epigastric sensation, nausea, autonomic signs, eructation, pallor, facial flush, activity break, pupillary dilatation, fear, panic and olfactory and gustative hallucination9. Neuroimaging evaluation by high resolution showed hippocampal atrophy and hyperintense T2 signal indicating mesial temporal sclerosis.
ETFE was based on clinical, EEG and neuroimaging findings of frontal, parietal and occipital epilepsy10,11.
Every patient was submitted to a questionnaire concerning gynecological and obstetrical antecedents and detailed menstrual history. In addition they were asked to fill out of the calendar regarding the menstrual period.
We considered as irregular cycles the ones shorter than 26 days and longer than 32 days of duration.
Inclusion criteria a) Women in the menacme with MTLE and ETFE diagnosis according to the criteria of the ILAE for at least one year9 ;b) MRI and EEG investigation performed at our institution; c) Good compliance to the treatment and available telephone for contact if needed; d) Attendance to clinical follow-ups regularly; e) Fill out the calendar properly; f) Absence of hormonal therapy or the use of valproate; g) Signature of informed consent submitted and approved by the Research Ethics Committee of the institution.
Analysis of the data The analysis of the data was based on the different periods of the menstrual cycle. The average of crises per day was calculated for each period and compared to other days of the cycle. We estimated worsening when the average of seizure/day in a determined period of the cycle was higher than the either average of the other days or twice or three times the average.
Premenstrual period: three days before the first day of the cycle (the menstruation first day).
Menstrual period: period when there was bleeding until the fifth day.
Ovulatory period: period of 5 days, 14 days before the menstruation ± 2 days.
Catamenial period: premenstrual period + menstrual period.
Catamenial worsening: three-fold increase in seizure frequency in relation to the other days of the cycle.
Statistical analysis was performed using the Chi-Square test.
Irregular menstrual cycles were presented by 28 (28/39, 71.7%) patients with MTLE and 6 (6/14, 42.8%) with ETFE (p= 0.052). Information related to seizure counting and regular and irregular menstrual cycles are in Table 3 and 4. Menstrual worsening was observed in 46 cycles (21.8%) of patients with MTLE and 9 cycles (18.3%) of patients with ETFE (p= 0.596). Menstrual worsening was observed in 47 cycles (22.2%) of patients with MTLE and 15 cycles (30.6%) of patients with ETFE (p= 0.217). Ovulatory worsening was observed in 36 cycles (17%) of patients with MTLE and 13 cycles (26.5%) of patients with ETFE (p= 0.126).
Catamenial increasing of seizures (seizures predominantly on the pre and menstrual cycles) was observed in 58 cycles (27.4%) of patients with MTLE and in 17 cycles (34.7%) of patients with ETFE (p=0.315). Catamenial worsening (according to our definition of three-fold increase in seizure frequency in relation to the other days of the cycle) was present in 29 (13.7%) of the patients with MTLE and 4 (8.1%) of the patients with ETFE (p= 0.290)
Catamenial epilepsy refers to seizures related to menstrual cycle and affects approximately m 10-70% of women with epilepsy, depending on the definition of worsening6. Experimental studies demonstrated that the ovarian steroid hormones affect the neuronal excitability, that way they give support to a biologic base for these fluctuations in epilepsy that occur in association with the menstruation, from the menarche to the menopause12-19. The low levels of progesterone in the menses, the rising of estrogen level in the ovulation and low levels of progesterone during the luteal phase of anovulatory cycles are among the several factors that precipitate the catamenial epilepsy. These factors result in the elevation of the estrogen/progesterone ratio20. A decrease on serum levels of the antiepileptic drugs on the days that precede the menstruation, can also contribute for the premenstrual exacerbation of the seizures. It is supposed that the lower serum levels of antiepileptic drugs is due to an increase in their metabolism by the hepatic microsomal enzyme system that involves the gonadal steroid metabolism19.
Mattson et al.4 reported an increase in seizure frequency during the anovulatory cycle, mainly during the estrogen peak. Jansen and Vaernet21 related larger incidence of amenorrhea in women with MTLE than in the general population of women. Our data showed that one third of patients evaluated presented catamenial seizure worsening; if we accept the definition proposed by Herzog et al.6 - higher frequency of seizure on the catamenial (pre + menstrual) period than that of the rest of the cycle.
We evaluated the menstrual disorders in patients with MTLE and ETFE because of the fact that these conditions are well-defined electro-clinic syndromes10,11,22,23. These two forms of lesional epilepsies, frequently refractory to the antiepileptic drug (AED) treatment, were evaluated in women who did not use hormone therapy or sodium valproate. It is confirmed that the use of valproate increases the occurrence of anovulatory cycles, mainly in women with generalized idiopathic epilepsy24,25. Theoretically, the group of patients with limbic lesions (MTLE) would be more inclined to hormonal dysfunctions originated from the influence of limbic structures on the hypothalamus and hypophysis and the consequent hormonal disorder and possible influence on the menstrual cycle.
Anovulatory cycles occur in 14 to 39% on the diverse forms of epilepsy in women26,27. According to the methodology utilized, we did not evaluate the patients under the endocrinologic point of view (if the irregular cycles observed were anovulatory or not). Nevertheless, it is known that 11% of women with epilepsy have cycles with intervals out of the period of 21-35 days, which is larger than what is expected on the general population, about 2%26,28,29. We adopted the period of 26-32 days for the definition of regular cycles based on the Herzog and Friedmans findings26, who found significant increase of anovulatory cycles out of this period. It is known that the irregular cycles have higher probability of being anovulatory26. The irregular cycle finding has clinic importance because the frequency of epileptic seizures is higher in these cycles6,20. In addition, the incidence of reproductive endocrine disorders is higher in these women30-32, particularly the polycystic ovary syndrome32-34. These disturbances are associated with an increase of the infertility rate, migraine, emotional disturbances, resistance to insulin, cardiovascular disease and cancer35. The real role of the irregular or anovulatory cycles in these patients and their medical dimension need complementary investigations.
A recent study about long-term reproductive endocrine health in young women with epilepsy during puberty have shown that 56% patients taking antiepileptic medication, 32% of patients without drugs and 38% normal control presented irregular menstrual cycles. They defined irregular cycle if the intermenstrual variation was > 7 days or the cycle duration was >35 days or <21 days, at least once during the preceding 6 months. In the same study, Mikkonen et al.36 found that polycystic ovary syndrome was more common in patients on medication (38%, mainly valproate) than in patients without medication (6%) or in controls (11%). These authors36 proposed that irregular menses may be considered an adverse event of antiepileptic drug treatment, particularly in puberty.
There was no seizure worsening difference on the premenstrual, menstrual, catamenial or ovulatory periods in the two groups of patients we studied. This is a preliminary study and a larger sample should be evaluated in order to confirm our findings.
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Received 16 November 2004, received in final form 21 March 2005. Accepted 9 May 2005.
Supported by FAPESP.
Dr. Carlos A.M. Guerreiro - Department of Neurology, FCM/UNICAMP, Caixa Postal 6111 - 13083-970 Campinas SP - Brasil. E-mail: email@example.com