1. Catamenial epilepsy Alina Blesneag M.D. PhD.
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
Bucuresti, Noiembrie 2016

2. a XXIV-a Conferinta Nationala de Epileptologie Formular pentru declararea conflictelor de interese
Numele companiei
Natura sponsorizarii
Nimic de declarat
Folosire off-label de produse
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BUCURESTI, Noiembrie 2016

3. Catamenial epilepsy katomenios- greek word meaning “monthly”
Newmark ME, Penry KJ, > 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, > 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. Horm Behav February; 63(2):
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.

4. Herzog AG, Klein P, > proposed an extension of the definition of catamenial epilepsy to include three patterns:
perimenstrual (C1)
periovulatory (C2)
inadequate luteal phase (C3)
Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy.Epilepsia.1997 Oct;38(10):

5. diagnosis- seizure diaries + menstrual diaries cycle type and duration
multifaceted neuroendocrine condition with seizures that cluster around specific points in the menstrual cycle
diagnosis- seizure diaries + menstrual diaries
cycle type and duration
affect 10%-70% of fertile women with epilepsy (inaccurate records, multiple studies)
Duncan S, Read CL, Brodie MJ. How common is catamenial epilepsy? Epilepsia, 34(5): , 1993, Raven Press, New York.

6. Seizure frequency
significant correlation with the serum estradiol/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:
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.

7. potentiates glutamatergic transmission
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 catamenial epilepsy.Horm Behav.2013 Feb;63(2):
D. Craiu.Implications of sex hormones in the treatment of women with epilepsy: catamenial epilepsy
Velisek L, Veliskova J. New avenue of research: antiepileptic drug and estradiol neuroprotection in epilepsy. Recent Patents CNS Drug Discov. 2008; 3:

9. 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?

10. Treatment
Reddy DS.Neuroendocrine aspects of catamenial epilepsy.Horm Behav.2013 Feb;63(2):

11. Antiepileptic drugs that induce CYP34A: Phenitoin Phenobarbital
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

12. 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 Jun;42(6):746-9

13. Benzodiazepines Clobazam
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:

15. Lamotrigine MRI examination + EEG
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 Sep;17(6):531-4.

16. C1 pattern: 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.

17. 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