Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial

Herzog, Andrew G.

doi:10.1016/j.seizure.2015.02.024

Cited by 112 publications

(122 citation statements)

References 42 publications

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“…Thus, the failure of the primary outcome measure may have stemmed from the fact that subtypes of catamenial epilepsy as defined by exacerbation periodicity have distinct pathophysiologic mechanisms, demanding unique therapeutic approaches. Furthermore, marked elevation in AP levels over baseline was observed in progesterone but not placebo-treated women, with a striking inverse correlation between AP level and seizure frequency in responsive women (in the perimenstrual exacerbation category) [72, 73]. Thus, these data suggest a mechanistic role for AP in mediating the ameliorative effects of progesterone therapy in this subset of catamenial epilepsy patients.…”

Section: Catamenial Epilepsymentioning

confidence: 92%

Clinical Potential of Neurosteroids for CNS Disorders

Reddy

Estes

2016

Trends in Pharmacological Sciences

153

164

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Summary Neurosteroids are key endogenous molecules in the brain that affect many neural functions. Here, we describe recent advances in NIH-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus, brain injury, Fragile X syndrome, and chemical neurotoxicity. The neurosteroid field has entered a new era, as many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends.

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Section: Catamenial Epilepsymentioning

confidence: 92%

Clinical Potential of Neurosteroids for CNS Disorders

Reddy

Estes

2016

Trends in Pharmacological Sciences

153

164

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“…In spite of the many beneficial properties of progesterone administration found in preclinical studies based on models of epilepsy (Herzog ) or nerve tissue injury (Stein ), Phase III clinical trials have been largely discouraging, as in the case of traumatic brain injury (Skolnick et al . ; Wright et al .…”

Section: Discussionmentioning

confidence: 99%

Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus

Meletti

Lucchi

Monti³

et al. 2018

Journal of Neurochemistry

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Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by γ-aminobutyric acid type A (GABA ) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem-mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007-2017 period. Seventy-three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work-up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5α-dihydroprogesterone, pregnanolone and allopregnanolone were, respectively, 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearman's ρ = 0.4335, p < 0.01), allopregnanolone (ρ = 0.4121, p < 0.05) and pregnanolone (ρ = 0.592, p < 0.001) levels significantly increased by aging in controls. We conclude that neurosteroidogenesis is defective in patients with SE.

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“…Significance of treatment for the C1 pattern was only achieved when there was at least a three-fold increase in seizure frequency during C1 days. Notably, there was no response for subjects with catamenial patterns type 2 or 3 or for the enrolled subjects without a catamenial pattern, who comprised slightly more than 50 % of the study population [20].…”

Section: Treatment-hormonalmentioning

confidence: 92%

A Treatment Approach to Catamenial Epilepsy

Navis

Harden

2016

Curr Treat Options Neurol

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The cyclic hormonal underpinnings of catamenial seizure exacerbations are consistent with the neurophysiologic activity of estrogen and progesterone. For women with catamenial epilepsy who have regular menses, intermittent treatment approaches may be utilized. These interventions are targeted at adding or increasing anti-seizure treatments during established vulnerable days of the menstrual cycle, such as perimenstrually (C1 pattern), at ovulation (C2 pattern), and during the luteal phase (C3 pattern). The single large study of natural progesterone treatment showed benefit for women with clear perimenstrual seizure exacerbations (C1 pattern), but not for subjects with other catamenial patterns or for randomized women with epilepsy of reproductive age who did not have catamenial seizure exacerbations. In this protocol, natural progesterone was given at a high dose during the luteal phase and was generally well tolerated. Other intermittent cyclic treatments include benzodiazepine use, increasing the dose of an anti-seizure drug already in use, or acetazolamide. For women with irregular menses, or those in which the intermittent cyclic treatments are not effective, pharmacologically stopping the menstrual cycle altogether by using synthetic hormones such as medroxyprogesterone (Depo-Provera) or sustained oral contraceptives may be considered.

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Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial

Abstract: There is sound evidence for the existence of catamenial epilepsy and class 3 evidence for adjunctive progesterone treatment of the perimenstrually exacerbated subtype.

Cited by 112 publications

References 42 publications

Clinical Potential of Neurosteroids for CNS Disorders

Clinical Potential of Neurosteroids for CNS Disorders

Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus

A Treatment Approach to Catamenial Epilepsy

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