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The XXIV-th National Conference of The Romanian Society Against Epilepsy. Catamenial epilepsy. Alina Blesneag M.D. PhD. Fior Dafin Mureșanu M.D. PhD. UMF “ Iuliu Hatieganu ” Cluj-Napoca. www.ilae-romania.ro Bucuresti, 17-19 Noiembrie 2016.
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The XXIV-th National Conference of The Romanian Society Against Epilepsy Catamenial epilepsy AlinaBlesneagM.D.PhD. Fior Dafin Mureșanu M.D. PhD. UMF “IuliuHatieganu” Cluj-Napoca www.ilae-romania.roBucuresti, 17-19 Noiembrie 2016
a XXIV-a Conferinta Nationala de EpileptologieFormular pentru declararea conflictelor de interese BUCURESTI, 17-19 Noiembrie 2016
Catamenial epilepsy • katomenios-greek word meaning “monthly” • Newmark ME, Penry KJ, 1980 -> defined as the occurrence of seizures exclusively or significantly more often in the 7-day period of the menstrual cycle -3 days < menstruation < +4 • Duncan S, Read CL, 1993 -> defined as the occurrence of at least 75% of seizures each month in the 10-day time frame -4< menstruation < +6 Reddy DS, Neuroendocrine aspects of catamenial epilepsy. HormBehav. 2013 February; 63(2): 254-266. VerrottiA, D’Egidio C, Agostinelli S et al. Diagnosis and management of catamenial seizures: a review. International Journal of Women’s Health, 27 sep 2012.
Herzog AG, Klein P, 1997 -> proposed an extension of the definition of catamenial epilepsy to include threepatterns: perimenstrual (C1) periovulatory (C2) inadequate luteal phase (C3) Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy.Epilepsia.1997 Oct;38(10):1082-8.
multifaceted neuroendocrine condition with seizures that cluster around specific points in the menstrual cycle • diagnosis- seizure diaries + menstrual diaries cycle type and duration • affect10%-70% of fertile women with epilepsy (inaccurate records, multiple studies) Duncan S, Read CL, Brodie MJ. How common is catamenial epilepsy? Epilepsia, 34(5): 827-831, 1993, Raven Press, New York.
Seizure frequency • significantcorrelation with the serumestradiol/progesterone ratio • days prior to ovulation and menstruation • during the early and mid luteal phase Herzog AG, Haden CL, Liporace J. Frequency of catamenial seizure exacerbation in women with localization-related epilepsy. Ann Neurol 2004; 56:431-434. Verrotti A, D’Egidio C, Agostinelli S et al. Diagnosis and management of catamenial seizures: a review. International Journal of Women’s Health, 27 sep 2012.
Estradiol • inhibits GABA • potentiates glutamatergic transmission • increases neuronal metabolism and discharge rates • in low doses estradiol can produce neuroprotective effects Allopregnanolone • endogenous GABA-A receptor agonists • a potent barbiturate-like ligand • reduces neuronal metabolism and discharge rates • pregnant women tend to have a better seizure control during pregnancy combined oral contraceptives have not been associated with an increase in seizures Reddy DS.Neuroendocrine aspects of catamenialepilepsy.Horm Behav.2013 Feb;63(2):254-66. D. Craiu.Implications of sex hormones in the treatment of women with epilepsy: catamenialepilepsy Velisek L, Veliskova J. New avenue of research: antiepileptic drug and estradiolneuroprotection in epilepsy. Recent Patents CNS Drug Discov. 2008; 3: 128-37.
High incidence associations: • Menstrual dysfunctions anovulatory cycles amenorrhea • Polycystic ovarian syndrome More common among women with left temporal foci. Taking into consideration that premenstrual syndrome is associated with estrogen and progesterone, could it anticipate seizure exacerbation? Or could dysmenorrhea be a significant trigger?
Treatment Reddy DS.Neuroendocrine aspects of catamenial epilepsy.Horm Behav.2013 Feb;63(2):254-66.
Antiepileptic drugs that induce CYP34A: • Phenitoin • Phenobarbital • Carbamazepine • Felbamate • Topiramate • Oxcarbazepine • Primidone Antiepileptic drugs that don’t induce CYP34A: • Gabapentin • Levetiracetam • Tiagabine • Zonisamide • Pregabalin • Lamotrigine
Acetazolamide • potent inhibitors of carbonic anhydrase • produces an accumulation of CO2 in the brain • inhibits the spread of neuronal activity and stabilizes the axonal membrane by reducing extracellular calcium • the anticonvulsant properties - may be due to its diuretic effect • tolerance- dose escalation/ alternate-day or cyclical dosing to maintain the anticonvulsant effect • significant in seizure frequency (40% of subjects) seizure severity (30% of cases) • the small sample size and retrospective study Lim LL, Foldvary N, Mascha E, Lee J. Acetazolamide in Women with Catamenial Epilepsy. Epilepsia. 2001 Jun;42(6):746-9
BenzodiazepinesClobazam • Potent allosteric modulators of GABA-A receptors and broad spectrum antiseizure agents • 20 to 30 mg/day intermittently: from 2 to 4 days before menses • Administration was intermittently to avoid tolerance • adverse reaction: sedation, depression 11. Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow up. Neurology. 1999; 52:1917-1918.
Lamotrigine • not involved in the dynamic equilibrium changes between estrogen and progesterone during menses • 75 pacients: newly diagnosed + intractable seizures under a first line anti-epileptic drug - included in the study • MRI examination + EEG • monotherapy: started with 25 mg/day- gradually increased up to 100mg • 66% beneficial effect • a possibility: increased progesterone level production 22% seizure-free 44% had a 50% reduction in number of seizures Gilad R, Sadeh M, Rapoport A, Dabby R, Lampl Y.Lamotrigine and catamenial epilepsy.Seizure. 2008 Sep;17(6):531-4.
C1pattern:hormonal therapy: intermittent progesterone • C2+ C3: usually non-responsive to hormonal therapy acetazolamide cyclical use of benzodiazepines conventional antiepileptic drugs patterns good results D. Craiu.Implications of sex hormones in the treatment of women with epilepsy: catamenial epilepsy.
Take home messages • Catamenial epilepsy is a specific form of pharmacoresistant epilepsy that impacts a substantial number of women • Synthetic neurosteroids may be useful for pharmacotherapy of catamenial epilepsy especially because they avoid the hormonal side-effects of progesterone therapy • It is important to also consider the comorbidities of these patients and adapt therapy accordingly