How Neurosteroids Modulate Seizures in Children and Adults November 30, 2012

Transcription

1 How Neurosteroids Modulate Seizures in Children and Adults November 30, 2012 Page B. Pennell, MD Brigham and Women s Hospital Harvard Medical School Boston, MA American Epilepsy Society Annual Meeting 1

2 Disclosure Name of Commercial Interest None Type of Financial Relationship None American Epilepsy Society Annual Meeting

3 Learning Objectives Increase knowledge base of the existing clinical data that support an important role of neurosteroids in the phenotypic expression of epilepsy To understand how we can use this background information to guide therapeutic options for patients with epilepsy Learn how to implement specific therapies that can positively influence the neurosteroid environment to decrease seizure activity American Epilepsy Society Annual Meeting

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5 Clinical evidence of the influence of neurosteroids on the expression of epilepsy ACTH treatment for infantile spasms Common onset of epilepsy during puberty Role of stress in provoking seizures EST and PROG fluctuate, and therefore, have the most obvious influence on seizure frequency Patterns of catamenial epilepsy in 1/3 of women with focal epilepsy Change in seizure frequency during menopausal transition Effect of hormone therapies on seizure frequency American Epilepsy Society Annual Meeting

6 Hypothalamic-Pituitary-Ovarian Axis Harden CL, Pennell PB. Lancet Neurol, in press. 6

7 Biosynthesis Pathways for Neuroactive Steroids Pennell PB. Unpublished. Green = Proconvulsant Pink = Anticonvulsant 7

8 Adapted from Herzog, et al. Epilepsia

9 Adapted from Herzog, et al. Epilepsia

10 Hypothalamic-Pituitary-Testes Axis Harden CL, Pennell PB. Lancet Neurol, in press. 10

11 Androgens in Men Testosterone and metabolites are neurosteroids Testosterone: 2 major classes of metabolites Estrogens, through the P450 enzyme CYP19 5-alpha reduced androgens (androstanediol) Enzymes are expressed in many organs (prostate, liver, skin) but also de novo in brain, especially glial cells Androsterone/etiocholanolone may also be anticonvulsants Lack of fluctuating levels may obscure clinical importance American Epilepsy Society Annual Meeting

12 Progesterone & Allo concentrations (nmol/l) in Pregnant Women with Epilepsy (n=84) Slide Unavailable Pennell, PB, Frye CA, Pennell KD, unpublished. Supported by RO3NS

13 Estradiol concentrations (nmol/l) in Pregnant Women with Epilepsy (n=84) Slide Unavailable Which NAS is the driving force behind seizure worsening during pregnancy? Pennell, PB, Frye CA, Pennell KD, unpublished. Supported by RO3NS

14 Perimenopause and Menopause Perimenopause transition EST levels may rise steadily or are erratic with surges in response to the elevated FSH, until menopause is complete Increased anovulatory cycles, and less cyclic progesterone No prospective, observational data; cross-sectional evaluation, using mailed questionnaires Two-thirds reported an increase in seizures during perimenopause H/o catamenial pattern was associated with an increase in seizures Decrease in seizures after menopause was more likely with h/o C1 pattern HRT was associated with an increase in seizures Harden CL, et al. Epilepsia

15 Menopause and Treatment Double-blind, randomized, placebo-controlled trial of HRT in postmenopausal women with epilepsy mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate (CEE/MPA) single dose and double dose study halted early due to findings from Women s Health Initiative study Possibly consider a natural progesterone supplement rather than Prempro Seizure Frequency Increases with Hormone Replacement Dose (N=21) HRT Group Simple Partial Complex Partial * 2 Gen Any Sz Type* Total # Sz Most severe Sz Type* n (%) n (%) n (%) n (%) n (%) n (%) Placebo (n=6) Single CEE/MPA (n=8) Double CEE/MPA (n=7) * p< 0.05 by chi-square test for trend. Harden CL,et al. Epilepsia Treatment of Women 15

16 Role of Hormones in Epileptogenesis? Onset of many common epilepsy syndromes during puberty Nurses Health Study (n=114,847) Validated seizure questionnaires & medical records to confirm cases Increased risk of epilepsy in women h/o menstrual irregularity in early adulthood (RR 1.67 [ ]) Increased risk of isolated seizure in women with menstrual irregularity (RR 2.21 [ ]) with early age of menarche (RR 1.76 [ ]) Dworetzky BA, et al. Epilepsia

17 Therapeutic options based on Neurosteroid theories Can therapies be used differently during various life stages? Cyclic and continuous treatments for catamenial epilepsy Development of AEDs based on mechanisms of action, but without direct effects on reproductive function Greater potential for use across ages and genders Greater potential for continuous use Greater potential for monotherapy use 17

18 Progesterone Treatment Trial Randomized, double-blind, placebo-controlled, Phase III, multicenter clinical trial (n=294) Stratified by catamenial and non-catamenial status Treatment: progesterone or placebo (2:1) Progesterone oral lozenges 200 mg TID Days14-25, 100 mg TID D26-27, 50 mg TID D28, then stop 3 baseline months and 3 treatment menstrual-cycles No difference in Responder Rates (both groups) Secondary analysis C1 exacerbation level was a predictor of response to Progesterone Herzog A et al. Neurology 2012;78:

19 Adapted from Herzog, et al. Epilepsia

20 Responder rates with progesterone and placebo treatment vs perimenstrual (C1) catamenial level of seizure exacerbation Herzog A et al. Neurology 2012;78:

21 Case Report of Sz Frequency increase with Finasteride use for 3 months, in a woman on cyclic progesterone Herzog A, Frye CA, Ann Neurol

22 Other Treatment Trials in Catamenial Epilepsy Clobazam Double-blind, placebo-cross-over study (n=18) mg over 10-day periods (beginning D-11 to D-4) Superior to placebo in 14 of 18 women, with complete seizure control in 12 during the 10-day treatment phase Medroxyprogesterone acetate (open-label, pilot studies) 7 of 14 WWE had fewer seizures, w/30% reduction in Sz Frequency 14 WWE on oral or IM; 39% fewer seizures Limitations: side effects including spotting, prolonged return to normal hormonal cycles and fertility Acetazolamide: Case reports or small open-label series only mg/day for 3-7 days perimenstrual Feely M, et al. Lancet 1982; Mattson RH, et al. Neurology 1984; ; Ansell B, Clarke E BMJ

23 C1 Level > 3 C1 Level < 3 Progesterone lozenges 200 mg, Days (Consider taper beginning Day 26) Clobazam, mg/day x 10 days Begin 2 days prior to phase of increased seizures based on individual diary review Acetazolamide, mg/day, beginning Day -7 to -3 until Day 1^ Continuous oral contraceptive pills without placebo phase or Implanon^ Increase daily dosage of AEDs (other than PHT) during days of seizure worsening^ Medroxyprogesterone acetate 150mg IM q weeks# Most treatments are for focal-onset seizures in women with regular menses. ^ no randomized trials # higher risk of osteoporosis and prolonged return to normal fertility Harden CL & Pennell PB, Lancet Neurol, in press.

24 Ganaxolone as an AED GNX is a beta methylated synthetic analog of ALLO Lacks any detectable classic nuclear hormone activity Beta methylation inhibits its enzymatic back conversion to a progestin Human trials Open-label, dose-escalating add-on trial in 5-15yo pts w/daily seizures (n=15) ITT analysis: RR 25% (>50% reduction in SzF): moderate response 13% ; 1 seizure free Randomized, placebo-controlled, DB study in EMU, added after off AEDs (n=52) 8 Day study using Survival Analysis, with exit criteria (4 sz s of any type, 3 GTCSz; SE) ITT analysis not sig. by survival curves, but completers were different (50% vs. 25%) Open-label, add on trial in pediatric Infantile Spasms (n=20; 16 completed) 1/3 had > 50% reduction; 1/3 had 25-50% reduction; 1/3 no change Adverse effects mild to moderate, with somnolence most common One limitation is oral bioavailability in a solid formulation Pieribone VA, et al, Epilepsia 2007; Laxer et al. Epilepsia 2000; Kerrigan et al., Epilepsy Res 2000.

25 Allopregnanolone Courtesy of Michael Rogawski, MD, PhD 25

26 Limitations of Human Studies Plasma measurements don t necessarily reflect local brain concentrations Metabolic pathways are active and can convert to other NAS compounds Local synthesis and conversion Effects of steroid hormones include both short-latency effects (neuronal membrane-mediated) long-latency effects (binds to receptors on DNA with genomic effects, and prolonged exposure can change expression of GABAA receptor subunits) NAS other than estradiol, progesterone, and testosterone are very difficult to separate and measure, and assays are very expensive More difficult to detect effects of androgens and other metabolites without cyclic fluctuations that occur with female sex steroid hormones American Epilepsy Society Annual Meeting

27 Impact on Clinical Care and Practice Basic understanding of how neurosteroids/hormones can influence the phenotypic expression of epilepsy Acknowledging the pattern can be reassuring to patients Consider how existing treatments can be modified, or consider adjunctive therapies Ultimate goals Improve our understanding of neurosteroid influence on epilepsy in humans across genders and age spectrum Deliver personalized medicine, by providing alternative treatment options to supplement standard treatments Use this knowledge to develop new & refine old therapeutic targets 27

28 Hot Topics Symposium: Modulators of Epilepsy: The Influence of Lifestyle and Environmental Factors 11/30/2012 R. Edward Hogan, M.D. Director, Adult Epilepsy Center Associate Professor, Department of Neurology Washington University in St. Louis American Epilepsy Society Annual Meeting

29 Name of Commercial Interest Disclosure Type of Financial Relationship Eisai Pharmaceuticals Ortho-McNeil Pharmaceuticals Institutional sponsorship of clinical pharmaceutical studies NIH Washington University ICTS Grant Number UL1 RR American Epilepsy Society Annual Meeting 2012

30 Conclusions Epileptic seizures include complex underlying pathophysiology, with associated modulating factors including: Exercise Stressors/environmental enhancement Neurosteroids Investigation of associated modulating factors in epilepsy allows potential new therapeutic avenues for the treatment of epileptic seizures American Epilepsy Society Annual Meeting 2012