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Catamenial epilepsy: current concepts of definition, prevalence, pathophysiology and treatment

Katameniale Epilepsie: aktuelle Konzepte zu Definition, Verbreitung, Pathophysiologie und Behandlung

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Abstract

Seizures do not occur randomly. They tend to cluster in the majority of men and women with epilepsy. Seizure clusters, in turn, often show a periodicity. When the periodicity of seizure exacerbation aligns itself with that of the menstrual cycle, it is designated as catamenial epilepsy. The neuroactive properties of reproductive steroids and the cyclic variation in their serum concentrations are important pathophysiologic factors. There is evidence for the existence of at least three patterns of catamenial seizure exacerbation: perimenstrual and periovulatory in ovulatory cycles and entire luteal phase in anovulatory cycles. A rational mathematical basis for this categorization of catamenial epilepsy has been developed. It identifies approximately 1/3 of women as having catamenial epilepsy. If seizures show hormonal sensitivity in their occurrence, they may also respond to hormonal treatment. The randomized, double-blind, placebo-controlled NIH Progesterone Trial found that cyclic progesterone supplement is no better than placebo overall but did reduce seizure frequency significantly in the subset of women with perimenstrual seizure exacerbation. There have also been successful open label trials using depomedroxyprogesterone and gonadotropin-releasing hormone analogues.

Zusammenfassung

Anfälle treten nicht zufällig auf, sondern meist gehäuft bei Frauen und Männern mit Epilepsie. Anfallshäufungen wiederum zeigen oft Periodizität und werden als katameniale Epilepsie bezeichnet, wenn sie mit dem Menstruationszyklus zusammentreffen. Als wichtige pathophysiologische Faktoren gelten die neuroaktiven Anteile reproduktiver Steroide und die zyklische Schwankung in ihren Serumkonzentrationen. Mindestens 3 Formen von katamenialer Anfallsverstärkung konnten nachgewiesen werden: perimenstruell und periovulatorisch im ovulatorischen Zyklusteil und in der gesamten Lutealphase im anovulatorischen Zyklusteil. Für diese Kategorisierung wurde eine rationale mathematische Grundlage entwickelt. Sie identifiziert etwa ein Drittel der Frauen als Betroffene von katamenialer Epilepsie. Treten die Anfälle in hormoneller Abhängigkeit auf, könnten sie auf Hormonbehandlung ansprechen. Die randomisierte, doppelblinde, placebokontrollierte Progesteron-Studie des National Institute of Health (NIH) ergab, dass ein periodisch verabreichtes Progesteronpräparat gegenüber Placebo bezüglich der gesamten Studiengruppe keine bessere Wirkung erzielt, jedoch die Anfallshäufigkeit in der Untergruppe der Frauen mit perimenstrueller Anfallsverstärkung signifikant reduziert. Es gab darüber hinaus erfolgreiche markenunabhängige Tests mit depomedroxyprogesteron- und gonadotropin-freisetzenden Hormonanaloga.

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Abbreviations

C1:

perimenstrual (Day −3 to +3)

C2:

periovulatory (Day 10 to −13)

C3:

luteal in anovulatory cycles (Day 10 to 3)

Prog:

progesterone

Plac:

placebo

C1:

perimenstrual seizure exacerbation

References

  1. Tauboll E, Lundervold A, Gjerstad L (1991) Temporal distribution of seizures in epilepsy. Epilep Res 8:153–165

    Article  CAS  Google Scholar 

  2. Herzog AG, Fowler KM, Sperling MR, Massaro JM, the Progesterone Trial Study Group (2015) Distribution of Seizures Across the Menstrual Cycle. Epilepsia 56(5):e58–e62

    Article  PubMed  Google Scholar 

  3. Almqvist R (1955) The rhythm of epileptic attacks and its relationship to the menstrual cycle. Acta Psychiatr Neurol Scand 30(suppl 105):1–116

    Google Scholar 

  4. Herzog AG, Klein P, Ransil BJ (1997) Three patterns of catamenial epilepsy. Epilepsia 38:1082–1088

    Article  CAS  PubMed  Google Scholar 

  5. Backstrom T (1976) Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand 54:321–347

    Article  CAS  PubMed  Google Scholar 

  6. Laidlaw J (1956) Catamenial epilepsy. Lancet 271:1235–1237

    Article  CAS  PubMed  Google Scholar 

  7. Herzog AG et al (2004) Frequency of catamenial seizure exacerbation in women with localization-related epilepsy. Annals of Neurology 56:431–434

    Article  PubMed  Google Scholar 

  8. McEwen BS (1994) How do sex and stress hormones affect nerve cells? Annals N Y Acad Sci 743:1–16

    Article  CAS  Google Scholar 

  9. Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB Journal 6:2311–2322

    CAS  PubMed  Google Scholar 

  10. Klein P, Herzog AG (1997) Endocrine aspects of epilepsy. In: Pretel S, Knigge KM, Prasad A (Hrsg) Neuroendocrine and neuromolecular aspects of epilepsy and brain disorders. Research Signpost, Trivandrum, India, S 111–140

    Google Scholar 

  11. Hojo Y, Hattori TA, Enami T, Furukawa A, Suzuki K, Ishii H, Mukai H, Morrison JH, Janssen WGM, Kominami S et al (2004) Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017a and P450 aromatase localized in neurons. Proc Natl Acad Sci USA 101:865–870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Hojo Y, Higo S, Ishii H, Ooishi Y, Mukai H, Murakami G, Kominami T, Kimoto T, Honma S, Poirier D, Kawato S (2013) Comparison between hippocampus-synthesized and circulation-derived sex steroids in the hippocampus. Endocrinology 150:5106–5112

    Article  Google Scholar 

  13. Marcus EM, Watson CW, Goodman PL (1966) Effects of steroids on cerebral electrical activity. Arch Neurol 15:521–532

    Article  CAS  PubMed  Google Scholar 

  14. Velíšková J, De Jesus G, Kaur R, Velíšek L (2010) Females, their estrogens and seizures. Epilepsia 51(Suppl 3):141–144

    Article  PubMed Central  PubMed  Google Scholar 

  15. Teresawa E, Timiras P (1968) Electrical activity during the estrous cycle of the rat; cyclic changes in limbic structures. Endocrinology 83:207–216

    Article  Google Scholar 

  16. Wong M, Moss R (1992) Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons. J Neurosci 12:3217–3225

    CAS  PubMed  Google Scholar 

  17. Kawakami M, Teresawa E, Ibuki T (1970) Changes in multiple unit activity in the brain during the estrous cycle. Neuroendocrinology 6:30–48

    Article  CAS  PubMed  Google Scholar 

  18. Logothetis J, Harner R (1960) Electrocortical activation by estrogens. Arch Neurol 3:290–297

    Article  CAS  PubMed  Google Scholar 

  19. Hom AC, Buterbaugh GG (1986) Estrogen alters the acquisition of seizures kindled by repeated amygdala stimulation or pentylenetetrazol administration in ovariectomized female rats. Epilepsia 27:103–108

    Article  CAS  PubMed  Google Scholar 

  20. Nicoletti F et al (1985) Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats. Epilepsia 26:252–257

    Article  CAS  PubMed  Google Scholar 

  21. Spiegel E, Wycis H (1945) Anticonvulsant effects of steroids. J Lab Clin Med 30:947–953

    CAS  Google Scholar 

  22. Woolley DE, Timiras PS (1962) The gonad-brain relationship: effects of female sex hormones on electroshock convulsions in the rat. Endocrinology 70:196–209

    Article  CAS  PubMed  Google Scholar 

  23. Woolley CS, McEwen BS (1993) Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 336:293–306

    Article  CAS  PubMed  Google Scholar 

  24. Woolley CS, McEwen BS (1994) Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J Neurosci 14:7680–7687

    CAS  PubMed  Google Scholar 

  25. Schumacher M, Coirini H, McEwen BS (1989) Regulation of high affinity GABA, receptors in the dorsal hippocampus by estradiol and progesterone. Brain Res 487:178–183

    Article  CAS  PubMed  Google Scholar 

  26. Smejkalova T, Woolley CS (2010) Estradiol acutely potentiates hippocampal excitatory synaptic transmission through a presynaptic mechanism. J Neurosci 30:16137–16148

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Huang GZ, Woolley CS (2012) Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism. Neuron 74:801–808

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Luine VN, Renner KJ, McEwen BS (1986) Sex-dependent differences in estrogen regulation of choline acetyltransferase are altered by neonatal treatments. Endocrinology 119:874–878

    Article  CAS  PubMed  Google Scholar 

  29. Harte-Hardgrove L, MacLuskey NL, Scharfman H (2013) Brain-derived neurotrophic factor-estragon interactions in the hippocampal mossy fiber pathway: implications for normal brain function and disease. Neuroscience 239:46–66

    Article  Google Scholar 

  30. Logothetis J, Harner R, Morrell F, Torres F (1959) The role of estrogens in catamenial exacerbation of epilepsy. Neurol (Minneap) 9:352–360

    Article  CAS  Google Scholar 

  31. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986) Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232:1004–1007

    Article  CAS  PubMed  Google Scholar 

  32. Gee KW, McCauley LD, Lan NC (1995) A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons. Crit Rev Neurobiol 9:207–227

    CAS  PubMed  Google Scholar 

  33. Phyllis JW (1986) Potentiation of the depression by adenosine of rat cerebral cortex neurones by progestational agents. Brit J Pharmacol 89:693–702

    Article  Google Scholar 

  34. Valera S, Ballivet M, Bertrand D (1992) Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc Nat Acad Sci USA 89:9949–9953

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Hsueh AJW, Peck EJ, Clark JH (1976) Control of uterine estrogen receptor levels by progesterone. Endocrinology 98:438–444

    Article  CAS  PubMed  Google Scholar 

  36. Frye CA (1995) The neurosteroid 3a-5a-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy. Brain Res 696:113–120

    Article  CAS  PubMed  Google Scholar 

  37. Smith SS, Waterhouse BD, Woodward DJ (1987) Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters. Brain Res 422:52–62

    Article  CAS  PubMed  Google Scholar 

  38. Landgren S, Backstrom T, Kalistratov G (1978) The effect of progesterone on the spontaneous interictal spike evoked by the application of penicillin to the cat’s cerebral cortex. J Neurol Sci 36:119–133

    Article  CAS  PubMed  Google Scholar 

  39. Backstrom T, Zetterlund B, Blom S, Romano M (1984) Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol Scand 69:240–248

    Article  CAS  PubMed  Google Scholar 

  40. Maguire JL, Stell BM, Rafizadeh M, Mody I (2005) Ovarian cycle-linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 8:797–804

    Article  CAS  PubMed  Google Scholar 

  41. Wu FS, Gibbs TT, Farb DH (1990) Inverse modulation of g-aminobutyric acid- and glycine-induced currents by progesterone. Mol Pharmacol 37:597–602

    CAS  PubMed  Google Scholar 

  42. Cheney DL, Uzunov D, Costa E, Guidotti A (1995) Gas chromatographic-mass fragmentographic quantitation of 3a-hydroxy-5a-pragnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats. J Neurosci 15:4641–4650

    CAS  PubMed  Google Scholar 

  43. Belleli D, Bolger MB, Gee KW (1989) Anticonvulsant profile of the progesterone metabolite 5a-pregnan-3a-ol-20-one. Eur J Pharmacol 166:325–329

    Article  Google Scholar 

  44. Kokate TG, Svensson BE, Rogawski MA (1994) Anticonvulsant activity of neurosteroids: correlation with g-aminobutyric acid-evoked chloride current potentiation. J Pharmacol ExpTher 270:1223–1229

    CAS  Google Scholar 

  45. Kokate TG, Cohen AL, Karp E, Rogawski MA (1996) Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice. Neuropharmacology 35:1049–1056

    Article  CAS  PubMed  Google Scholar 

  46. Smith SS, Gong QH, Hau F-C, Markowitz RS, ffrench-Mullen JMH, Li X (1998) GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392:926–930

    Article  CAS  PubMed  Google Scholar 

  47. Irwin RP, Maragakis NJ, Rogawski MA, Purdy RH, Farb DH, Paul SM (1992) Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons. Neurosci Lett 141:30–34

    Article  CAS  PubMed  Google Scholar 

  48. Heuser G, Ling GM, Buchwald NA (1965) Sedation or seizures as dose-dependent effects of steroids. Arch Neurol 13:195–203

    Article  CAS  PubMed  Google Scholar 

  49. Levesque LA, Herzog AG, Seibel MM (1986) The effect of phenytoin and carbamazepine on dehydroepiandrosterone sulfate in men and women who have partial seizures with temporal lobe involvement. J Clin Endocrinol Metab 63:243–245

    Article  CAS  PubMed  Google Scholar 

  50. Herzog AG et al (2004) Differential effects of antiepileptic drugs on serum neuroactive steroid concentrations in men with localization-related epilepsy. Epilepsia 45:122–123

    Article  Google Scholar 

  51. Dana Haeri J, Richens A (1983) Effect of norethistrone on seizures associated with menstruation. Epilepsia 24:377–381

    Article  CAS  PubMed  Google Scholar 

  52. Mattson RH, Cramer JA, Caldwell BV, Siconolfi BC (1984) Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurol (Clevel) 34:1255–1258

    Article  CAS  Google Scholar 

  53. Herzog AG (1986) Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders. Neurology 36:1607–1610

    Article  CAS  PubMed  Google Scholar 

  54. Herzog AG (1995) Progesterone therapy in complex partial and secondary generalized seizures. Neurology 45:1660–1662

    Article  CAS  PubMed  Google Scholar 

  55. Herzog AG (1999) Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 52:1917–1918

    Article  CAS  PubMed  Google Scholar 

  56. Herzog AG, Fowler KM, Smithson SD, Kalayjian LA, Heck CN, Sperling MR, Liporace JD, Harden CL, Dworetzky BA, Pennell PB, Massaro JM, Progesterone Trial Study Group (2012) Progesterone versus placebo therapy for women with epilepsy: a randomized clinical trial. Neurology 78:1959–1966

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Duncan S, Read CL, Brodie MJ (1993) How common is catamenial epilepsy? Epilepsia 34:827–831

    Article  CAS  PubMed  Google Scholar 

  58. Herzog AG, Frye CA, Progesterone Trial Study Group (2014) Allopregnanolone levels and seizure frequency in progesterone treated women with epilepsy. Neurology 83:345–348

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Herzog AG (2008) Catamenial Epilepsy: definition, prevalence, pathophysiology and treatment. Seizure 17(2):151–159

    Article  PubMed  Google Scholar 

  60. Zimmerman AW, Holden KR, Reiter EO, Dekaban AS (1973) Medroxyprogesterone acetate in the treatment of seizures associated with menstruation. J Pediatr 83:959–963

    Article  CAS  PubMed  Google Scholar 

  61. Hall SM (1977) Treatment of menstrual epilepsy with a progesterone-only oral contraceptive. Epilepsia 18:235–236

    Article  CAS  PubMed  Google Scholar 

  62. Bauer J, Wildt L, Flugel D, Stefan H (1992) The effect of a synthetic GnRH analogue on catamenial epilepsy: a study in ten patients. J Neurol 239:284–286

    Article  CAS  PubMed  Google Scholar 

  63. Haider Y, Barnett DB (1991) Catamenial epilepsy and goserelin. Lancet 338:1530

    Article  CAS  PubMed  Google Scholar 

  64. Reid B, Gangar KF (1992) Catamenial epilepsy and goserelin. Lancet 339:253

    Article  CAS  PubMed  Google Scholar 

  65. Finkelstein JS, Klibenski A, Schaefer EH, Hornstein MD, Schiff I, Neer RM (1994) Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. New Engl J Med 331:1618–1623

    Article  CAS  PubMed  Google Scholar 

  66. Herzog AG (1991) Reproductive endocrine considerations and hormonal therapy for women with epilepsy. Epilepsia 32:S27–S33

    Article  PubMed  Google Scholar 

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Acknowledgement

The NIH Progesterone Trial was supported by a grant from the National Institute of Neurological Disorders and Stroke (NIH R01 NS39466).

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Authors and Affiliations

  1. Harvard Medical School, Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center, 422 Worcester Street, Suite 303, 02481, Wellesley, MA, USA

    A. G. Herzog M.D., M.Sc.

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  1. A. G. Herzog M.D., M.Sc.
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Correspondence to A. G. Herzog M.D., M.Sc..

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Andrew G. Herzog states that there are no conflicts of interest.

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

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Herzog, A.G. Catamenial epilepsy: current concepts of definition, prevalence, pathophysiology and treatment. Z. Epileptol. 28, 295–303 (2015). https://doi.org/10.1007/s10309-015-0005-6

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