Seizure course during pregnancy in catamenial epilepsy

Claudia Cagnetti, MD Simona Lattanzi, MD Nicoletta Foschi, MD Leandro Provinciali, MD Mauro Silvestrini, MD

Correspondence to Dr. Cagnetti: [email protected]

ABSTRACT

Objective: Our aim was to evaluate seizure course in catamenial epilepsy (CE) and noncatamenial epilepsy (NCE) during pregnancy.

Methods: We prospectively followed women referred to our Epilepsy Center for pregnancy planning to the end of the pregnancy. According to their seizure frequency variations across the menstrual cycle, all patients were divided into either the CE or the NCE group. Data on seizure frequency during pregnancy were collected for each patient and compared with seizure frequency during the pregestational 9 months. Results: Fifty-nine women with CE and 215 with NCE were included. Forty-seven subjects (79.7%) with CE and 48 subjects (22.3%) with NCE remained seizure-free throughout pregnancy (odds ratio [OR] 5 2.612, 95% confidence interval [CI] 1.901–3.323, p , 0.001), whereas 30 (50.8%) in the CE group and 18 (8.4%) in the NCE group had reduced seizure frequency during pregnancy (OR 5 2.427, 95% CI 1.724–3.129, p , 0.001). Decreases in seizures $50% occurred in 26 women (44.1%) with CE and 14 women (6.5%) with NCE (OR 5 2.426, 95% CI 1.679–3.173, p , 0.001). Multiple logistic regression models confirmed the significant role of catamenial pattern as predictor for better outcomes. Conclusions: Better seizure control during pregnancy in the catamenial group may be attributable to the absence of cyclical hormone variations and the increase in circulating progesterone levels. These data may have practical implications for therapeutic management of patients with CE during pregnancy. Neurology® 2014;83:339–344 GLOSSARY AED 5 antiepileptic drug; CE 5 catamenial epilepsy; CI 5 confidence interval; NCE 5 noncatamenial epilepsy; OR 5 odds ratio.

Epilepsy is one of the most common neurologic disorders that require ongoing treatment during pregnancy; antiepileptic drug (AED) types as well as dose and frequency of exposure to drugs are important teratogenic risk factors, especially during organogenesis.1 It is therefore not surprising that the influence of pregnancy and related changes on the course of epilepsy, which are predictive for or known to modify seizure occurrence, have been debated in terms of therapeutic optimization. Several hypotheses exist regarding the role of such factors, but none has been clearly correlated to the course of seizures. The aim of this study was to determine the occurrence of seizures and investigate changes in seizure frequency during pregnancy in women with catamenial epilepsy (CE) compared to those with noncatamenial epilepsy (NCE).

Supplemental data at Neurology.org

METHODS Participants. We selected study participants from consecutive women with epilepsy referred for pregnancy planning to the Epilepsy Center of the Ospedali Riuniti of Ancona from January 1999 to June 2011 and prospectively followed these patients until the end of pregnancy. Information obtained for all subjects included data regarding demographics, clinical history, medications, types of seizures and epilepsy,2,3 and neurologic evaluation. We categorized subjects with perimenstrual CE as group 1 and those with NCE as group 2. CE was defined according to Herzog et al.4 as a 2-fold or greater increase in seizure frequency during perimenstrual (days 23 to 3) and periovulatory periods (days 10 to 213) in normal cycles, and luteal phase (days 10 to 3) in inadequate luteal phase cycles, with day 1 as the first day of menstrual flow and day 214 as the day of presumed ovulation. We considered within the CE group only women with a perimenstrual catamenial pattern because it was the only one demonstrable by charting menses and seizures without obtaining a midluteal-phase serum progesterone level. We included only patients whom we observed for at least 24 months before From the Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology

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pregnancy and only patients with pregnancies registered within 8 weeks of the start of gestation. Women were excluded from the study if they had a total of less than 3 verified epileptic seizures or if data on seizure frequency were incomplete. For women with multiple pregnancies, only the first one was used for group analysis.

Follow-up and seizure frequency. Every 3 months from enrollment until end of pregnancy, each subject underwent a clinical evaluation including data collection on drug toxicity, treatment compliance, and seizure occurrence. We prescribed folate prophylaxis (5 mg/d) for all patients from enrollment to the end of the first trimester of pregnancy. Data on seizure frequency during pregnancy were collected for each patient and compared with seizure frequency during the 9 months before pregnancy. For purposes of this study, reduction and increase in seizure frequency is defined as at least one seizure less or more during pregnancy than in the prior 9 months. Because this definition may be overly sensitive to small changes in frequency, which are not significant, we used a cutoff of 50% as an adjunct criterion. Statistical analysis. Values are presented as mean 6 SD or median (interquartile range) for continuous variables and as the number (percent) of subjects for categorical variables. We compared baseline characteristics between groups using the Student t test, Mann-Whitney test, or x2 test. Study outcomes were the absence of seizures during pregnancy (independently from pregestational seizure frequency), and the reduction in seizure frequency and the reduction in seizure frequency $50% during pregnancy in comparison to the 9 prior months. Differences in these endpoints for CE and NCE were analyzed with x2 test and then confirmed with logistic regression modeling. For multivariate analysis, variables with p values ,0.02 from comparisons of baseline characteristics and associations with outcome that were biologically plausible were identified as potential confounders for statistical adjustment. Selected variables were type of epilepsy (idiopathic, symptomatic, cryptogenic), type of seizures (focal, generalized, undetermined), AED treatment, and the occurrence of seizures in the pregestational 9 months (expressed as present or absent), and seizure frequency (expressed as number of seizures). The AED treatment variable consisted of one class for every monotherapy treatment, accounting in each group for more than 2% of the total subjects enrolled, and of the following categories: “no therapy,” “polytherapy,” and “other monotherapy” for monotherapy treatments accounting for less than 2% of total subjects in every group. Results are reported as odds ratio (OR) with associated 95% confidence interval (CI). Logistic regression analysis was then applied to also identify potential positive predicting factors within the catamenial group. Dependent variables were the absence of seizures during pregnancy, the reduction in seizure frequency, and the reduction in seizure frequency $50% during pregnancy compared with the 9 prior months, and selected independent variables were type of epilepsy, type of seizures, AED treatment, and the 9-month pregestational occurrence of seizures and seizure frequency. Variations in seizure course in women with multiple pregnancies were analyzed through repeated-measure statistics (Friedman test) to assess their consistency in each subject. All statistical analyses were performed using the SPSS version 19 software package (IBM Corp., Armonk, NY) for Windows systems. Results were considered significant for p values ,0.05 (2-sided). Standard protocol approvals, registrations, and patient consents. The local ethical committee approved this study, and all study participants provided written informed consent. 340

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RESULTS Demographic data. Three hundred thirtysix women with epilepsy were enrolled in the study and 18 patients were lost to follow-up; 44 pregnancies ended prematurely due to induced (n 5 2) or spontaneous (n 5 42) abortions and were thus excluded. Prospective information on seizure control throughout pregnancy was thus available for 274 women, distributed as follows: 59 as CE and 215 as NCE. Forty-five women presented more than one pregnancy for a total of 52 additional pregnancies. Baseline characteristics are summarized in table 1. Smoking habits, alcohol consumption, and history of febrile convulsion did not differ among groups.

Overall seizure control and changes in seizure frequency.

Of all patients, 95 (34.7%) were seizure-free throughout the pregnancy. Frequency of seizures decreased in 48 subjects (17.5%), decreased $50% in 40 subjects (14.6%), and increased in 64 (23.4%) and $50% in 25 subjects (9.1%). The median number of seizures during pregnancy was 1 (0–2). Of 110 pregnancies with generalized epilepsy, 34 (30.9%) were completely controlled during pregnancy compared with 55 of 152 (36.2%) with localization-related epilepsy (p 5 0.374); 14 patients (12.7%) with generalized epilepsy had reduced seizure frequency compared with 31 of 152 (20.4%) with localization-related epilepsy (p 5 0.104). Among 87 subjects with idiopathic epilepsy, 29 (33.3%) remained seizure-free compared with 14 of 57 patients (24.6%) with symptomatic epilepsy and 52 of 130 patients (40.0%) with cryptogenic epilepsy. The reduction in seizure frequency occurred in 16 (18.4%), 11 (19.3%), and 21 (16.2%) of the patients affected by idiopathic, symptomatic, and cryptogenic epilepsy, respectively. Group-wise, 47 patients (79.7%) in the CE group and 48 (22.3%) in the NCE group remained seizurefree throughout pregnancy (OR 5 2.612, 95% CI 1.901–3.323, p , 0.001); among subjects with NCE who experienced seizures, the median number was 2 (0–3) (p , 0.001). Reduction of seizure frequency occurred in 30 women (50.8%) in the CE group and 18 (8.4%) in the NCE group (OR 5 2.427, 95% CI 1.724–3.129, p , 0.001), and the decrease in seizures was $50% in 26 subjects (44.1%) with CE and 14 (6.5%) with NCE (OR 5 2.426, 95% CI 1.679– 3.173, p , 0.001) (figure). Seizure frequency increased in 10 (16.9%) and 54 (25.1%) of the patients in the CE and NCE groups, respectively (p 5 0.189), with an increase of $50% in 3 subjects (5.1%) with CE and 22 (10.2%) with NCE (p 5 0.224). The AED load was modified during pregnancy in 7 patients (11.9%) with CE and 23 (10.7%) with NCE (p 5 0.799). Multiple logistic regression models confirmed the predictive role of CE for better outcomes after

Table 1

Baseline characteristics Full cohort (N 5 274)

Catamenial epilepsy (n 5 59)

Noncatamenial epilepsy (n 5 215)

p Value

Age at onset of epilepsy, y, mean (SD)

15.78 (7.19)

16.66 (3.12)

15.54 (7.94)

0.291a

Age at pregnancy, y, mean (SD)

30.57 (4.96)

30.31 (4.87)

30.65 (4.99)

0.640a

Idiopathic

87 (31.8)

20 (33.9)

67 (31.2)

0.689b

Symptomatic

57 (20.8)

12 (20.3)

45 (20.9)

0.921b

Cryptogenic

130 (47.4)

27 (45.8)

103 (47.9)

0.770b

Focal

152 (55.5)

37 (62.7)

115 (53.5)

0.207b

Generalized

110 (40.1)

20 (33.9)

90 (41.9)

0.269b

Undetermined

12 (4.4)

2 (3.4)

10 (4.7)

0.675b

None

25 (9.1)

2 (3.4)

23 (10.7)

0.084b

CBZ

43 (15.7)

10 (16.9)

33 (15.3)

0.765b

LEV

14 (5.1)

2 (3.4)

12 (5.6)

0.498b

LMT

9 (3.3)

2 (3.4)

7 (3.3)

0.959b

OXC

10 (3.6)

2 (3.4)

8 (3.7)

0.904b

PB

74 (27.0)

19 (32.2)

55 (25.6)

0.310b

VPA

21 (7.7)

2 (3.4)

19 (8.8)

0.164b

Other monotherapy

10 (3.6)

2 (3.4)

8 (3.7)

0.904b

Polytherapy

68 (24.8)

18 (30.5)

50 (23.3)

0.253b

Occurrence

146 (53.3)

36 (61.0)

110 (51.2)

0.179b

No.

1 (0–3)

2 (0–3)

1 (0–3)

0.018c

Type of epilepsy, n (%)

Type of seizure, n (%)

AED treatment, n (%)

Pregestational seizures

Abbreviations: AED 5 antiepileptic drug; CBZ 5 carbamazepine; LEV 5 levetiracetam; LMT 5 lamotrigine; OXC 5 oxcarbazepine; PB 5 phenobarbital; VPA 5 valproic acid. a Two-sample t test. b Chi-square test. c Mann-Whitney test.

adjustment for confounding variables (absence of seizures: OR 5 27.077, 95% CI 10.872–67.438, p , 0.001; reduced seizure frequency: OR 5 32.260, 95% CI 9.579–108.647, p , 0.001; and reduced seizure frequency $50%: OR 5 19.650, 95% CI 6.658–57.989, p , 0.001). No positive predicting factors were found when regression analysis was applied within the catamenial group (tables e-1 to e-3 on the Neurology® Web site at Neurology.org). The gestational variations in seizure course in the subjects with multiple pregnancies were consistent in each woman (Friedman test: p 5 0.102 and 0.135, respectively, for subjects who experienced 2 and 3 pregnancies). DISCUSSION Treatment of epilepsy during pregnancy represents a major clinical challenge because the potential adverse effects and teratogenic risks of AEDs must be balanced with both maternal and fetal

risks of poor seizure control. Wide ranges in seizure frequency variation have been reported with increases occurring in approximately 15% to 32%, decreases in 3% to 25%, and no significant changes in 50% to 83% of pregnant women.5 Investigators hypothesized that several factors potentially influence seizure control; these include hormonal changes, variations in the pharmacokinetics of AEDs, sleep deprivation, poor pharmacotherapeutic compliance, physiologic and psychosocial adjustments, or physical and mental stress during labor, but none clearly predicts the course of seizures.6,7 Furthermore, seizures during pregnancy in those with CE is not well studied despite the fact that, according to the most accepted definition, approximately one-third of women with epilepsy have CE.8 In our cohort, we found a similar rate of improvement in seizure control during pregnancy to that reported in the literature5,9,10; meaningful differences Neurology 83

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Figure

Study outcomes in catamenial and noncatamenial epilepsy

Course of seizures during pregnancy. In the catamenial group, 79.7% of subjects remained seizure-free compared with 22.3% in the noncatamenial group. Decreased frequency of seizures occurred in 50.8% of women with catamenial epilepsy and in 8.4% of those without catamenial epilepsy. Decreases in seizures $50% were observed in 44.1% and 6.5% of patients in the catamenial and noncatamenial groups, respectively. *p , 0.001.

emerged between catamenial and noncatamenial patterns, suggesting the former as a predictor of favorable outcomes. In fact, patients with perimenstrual CE were more than twice as likely to be seizure-free or have reduced seizure frequency throughout the pregnancy. Furthermore, the higher rate observed for both reduction of seizure frequency and absence of seizures confirmed that the perimenstrual catamenial pattern may truly represent a favorable prognostic factor for seizure control in pregnancy, even considering the notorious and well-established poor seizure control known to exist in CE in nonpregnant patients. It is an accepted fact that hormones are involved in the manifestations of epilepsy and its treatment,11 and their role may be even more important in CE. Various mechanisms have been proposed to explain enhanced catamenial seizure susceptibility; this includes fluctuations in AED serum levels and variations in fluid and electrolyte balance, but the most accepted explanation concerns the cyclical changes in circulating levels of ovarian hormones.12–15 It is widely known that steroid hormones have a key role in the control of neuronal excitability and brain function through both shortlatency neuronal membrane-mediated effects and long-latency genomic effects.16–19 Although their effects might be more complex and dependent on multiple factors such as dose and temporal pattern of exposure, we know that estrogens are proconvulsant20–22; estrogens exert excitatory effects at the neuronal membrane, enhance the resting discharge rates of neurons, potentiate neuronal plasticity and excitability, 342

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and decrease inhibitory neurotransmission.23–28 In contrast, progesterone and its neuroactive metabolites, primarily allopregnanolone, promote neuroinhibition and have anxiolytic, sedative-hypnotic and antiseizure properties, and act as positive allosteric modulators of all g-aminobutyric acid type A receptor isoforms.29–32 Lower serum progesterone levels and higher estrogen/progesterone ratios are reported in women with CE compared with control subjects33; above all, the perimenstrual pattern of seizure exacerbations correlates to progesterone withdrawal at menstruation and partly to the increase in estrogen/progesterone ratio in the perimenstrual period.34 We hypothesize that changes in sex hormone levels occurring during pregnancy may at least partially explain the reduced seizure rates and improved seizure control observed in perimenstrual-catamenial epileptic pregnant women. The absence of cyclical hormone variations and the increase in circulating progesterone levels accompanying pregnancy35 may be involved in the underlying mechanism for this change. This hypothesis is in accordance with evidence that progestogen replacement therapy is useful for prevention of catamenial seizure exacerbations and has greater efficacy when administered continuously instead of intermittently.34,36–39 Our study has limitations that should be considered when interpreting the results. The small number of patients involved does not allow for definitive conclusions. Moreover, the observational design may be only considered reliable for development of preliminary insights, and to suggest working hypotheses. Indeed, plasma levels of AEDs and sex hormones were not collected during the pregnancies. Because within the CE group we considered only the women presenting with a perimenstrual seizure pattern, presumably the most strictly connected to progesterone levels and its withdrawal, we cannot exclude the possibility that other patterns of catamenial seizure exacerbations may respond differently to pregnancy and to its hormone variations. Strengths of the study include the prolonged observation time before pregnancy, the prospective assessment of both pregestational and gestational seizure frequency, and the limited variations in AED load during pregnancy. There remains a large gap in our knowledge about functional changes occurring in the brain in relation to hormonal fluctuations and pregnancy and how these changes modify cerebral excitability. Because pharmacologic treatment during pregnancy entails a precarious equilibrium between seizure management and teratogenic hazard, identification of clinical factors that may influence and predict the course of seizures holds important practical implications for care of women with epilepsy and in complicated therapeutic choices.

AUTHOR CONTRIBUTIONS Claudia Cagnetti, Simona Lattanzi, Nicoletta Foschi, and Leandro Provinciali: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and will give final approval. Mauro Silvestrini: drafting/revising the manuscript, analysis or interpretation of data, accepts responsibility for conduct of research and will give final approval, study supervision.

17.

18.

19.

STUDY FUNDING No targeted funding reported.

20. DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Received November 7, 2013. Accepted in final form April 16, 2014. REFERENCES 1. Tomson T, Battino D, Bonizzoni E, et al; EURAP Study Group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP Epilepsy and Pregnancy Registry. Lancet Neurol 2011;10:609–617. 2. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. 3. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–399. 4. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38:1082–1088. 5. EURAP Study Group. Seizure control and treatment in pregnancy: observations from the EURAP Epilepsy Pregnancy Registry. Neurology 2006;66:354–360. 6. Pennell PB. Pregnancy, epilepsy, and women’s issues. Continuum 2013;19:697–714. 7. Tomson T, Hiilesmaa V. Epilepsy in pregnancy. BMJ 2007;335:769–773. 8. Harden CL, Pennell PB. Neuroendocrine considerations in the treatment of men and women with epilepsy. Lancet Neurol 2013;12:72–83. 9. Tomson T, Lindbom U, Ekqvist B, Sundqvist A. Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin. Epilepsia 1994;35:122–130. 10. Gjerde IO, Strandjord RE, Ulstein M. The course of epilepsy during pregnancy: a study of 78 cases. Acta Neurol Scand 1988;78:198–205. 11. Rho JM, Sankar R, Cavazos JE. Epilepsy: Scientific Foundations of Clinical Practice. New York: Marcel Dekker; 2004:319–355. 12. Reddy DS. Role of neurosteroids in catamenial epilepsy. Epilepsy Res 2004;62:99–118. 13. Reddy DS. Perimenstrual catamenial epilepsy. Womens Health 2007;3:195–206. 14. Bonuccelli U, Melis GB, Paoletti AM, Fioretti P, Murri L, Muratorio A. Unbalanced progesterone and estradiol secretion in catamenial epilepsy. Epilepsy Res 1989;3:100–106. 15. Scharfman HE, MacLusky NJ. The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female. Epilepsia 2006;47:1423–1440. 16. Finocchi C, Ferrari M. Female reproductive steroids and neuronal excitability. Neurol Sci 2011;32(suppl 1): S31–S35.

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Seizure course during pregnancy in catamenial epilepsy Claudia Cagnetti, Simona Lattanzi, Nicoletta Foschi, et al. Neurology 2014;83;339-344 Published Online before print June 18, 2014 DOI 10.1212/WNL.0000000000000619 This information is current as of June 18, 2014 Updated Information & Services

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Seizure course during pregnancy in catamenial epilepsy.

Our aim was to evaluate seizure course in catamenial epilepsy (CE) and noncatamenial epilepsy (NCE) during pregnancy...
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