Review
Precision medicine in women with epilepsy: The challenge, systematic review, and future direction

https://doi.org/10.1016/j.yebeh.2021.107928Get rights and content

Highlights

  • Women with epilepsy (WWE) face specific challenges throughout their lifespan.

  • With the advance of genetic sequencing, precision medicine approach has been advocated in WWE.

  • Review of current pharmacogenomic research in WWE highlights the need for further investigations.

Abstract

Epilepsy is one of the most prevalent neurologic conditions, affecting almost 70 million people worldwide. In the United States, 1.3 million women with epilepsy (WWE) are in their active reproductive years. Women with epilepsy (WWE) face gender-specific challenges such as pregnancy, seizure exacerbation with hormonal pattern fluctuations, contraception, fertility, and menopause. Precision medicine, which applies state-of-the art molecular profiling to diagnostic, prognostic, and therapeutic problems, has the potential to advance the care of WWE by precisely tailoring individualized management to each patient’s needs. For example, antiseizure medications (ASMs) are among the most common teratogens prescribed to women of childbearing potential. Teratogens act in a dose-dependent manner on a susceptible genotype. However, the genotypes at risk for ASM-induced teratogenic deficits are unknown. Here we summarize current challenging issues for WWE, review the state-of-art tools for clinical precision medicine approaches, perform a systematic review of pharmacogenomic approaches in management for WWE, and discuss potential future directions in this field. We envision a future in which precision medicine enables a new practice style that puts focus on early detection, prediction, and targeted therapies for WWE.

Section snippets

Introduction:

Epilepsy is one of the most prevalent neurologic conditions and an important cause of disability. It has been estimated to affect almost 70 million people worldwide. In the United States, 1.2% of the population has epilepsy as an active diagnosis, including over one million women of childbearing age [1]. Women with epilepsy (WWE) face specific challenges throughout their lifespan, such as special reproductive and general health concerns.

Recent biotechnological advances have led to a rapid

Women with epilepsy (WWE) and pregnancy outcomes

Over 90% of pregnancies in WWE proceed without any apparent complications [3]. However, WWE are considered at high risk in pregnancy due to increased maternal and fetal risks. They face particular challenges during their pregnancy, such as spontaneous abortion, antepartum hemorrhage, gestational hypertension, pre-eclampsia, breech position, induction of labor, cesarean section, and preterm birth [4]. Further, increased clearance of several anti-seizure medications (ASMs) during pregnancy can

Precision medicine approaches

This review section is tailored to neurologists and other clinicians who are less familiar with rapid developments in genomic medicine. From discovery of the double helix to the assembly of the human genome’s 3 billion nucleotides over the past decades, genomic medicine has undergone persistent rapid development. Recent advancements with next generation sequencing technique have improved the quality of sequencing while tremendously reducing the cost as well. Clinical practitioners have started

Systematic review of current pharmacogenomic approaches in treatment for WWE

Personalized treatment for WWE has long been advocated; it is complex and challenging, but the pharmacogenetic approach could be an important instrument. Here we provide an updated systematic review of studies that utilize pharmacogenetics to inform the management for WWE.

Biomarker identification for personalized treatment regimen

Prevalence of ASM use for pregnant women has increased from 15.7 per 1000 deliveries in 2001 to 21.9 per 1000 deliveries in 2007 in the United States, primarily driven by a 5-fold increase in the use of newer ASMs. This increase includes women beyond WWE, as ASMs are also commonly used in patients with psychiatric or pain disorders [34]. The general rule in clinical practice is to use an ASM with the least severe side-effect profile such as lamotrigine or levetiracetam, and to avoid valproate

Ethics of genetic testing

Precision medicine offers hope for patients, and in particular it has been applied fairly routinely in the field of oncology [76]. Hopefully, we will also expand the approach of precision medicine to our patients with epilepsy including WWE. Emerging genetic information and the availability of genetic testing in current clinical neurology practice, which even in the absence of active genetic modifications, can raise important ethical concerns [77]. A previous study has shown in apparently

Conclusion

In summary, in this era of medicine where epileptologists provide care using trial and failure to reduce the seizure burden, often at significant expense from continued seizures and from medication-related adverse effects and comorbidities of epilepsy such as adverse pregnancy and fetal outcomes, suboptimal bone health, as well as decreased quality of life; we envision a future in which precision medicine enables the emergence of new practice style shifting toward early detection, prediction,

Declaration of interest

Dr. Li reports no disclosures.

Dr. Zhang reports no disclosures.

Dr. Michael Snyder receives research support from National Institutes of Health (5UM1HG00944203, 5U24DK11234803, 5U54HG01042602, 5R01AT01023202, 1U2CCA233311-01, 1R25HG01085701).

Dr. Meador receives research support from the NIH NINDS, Sunovion Pharmaceuticals and Medtronic Navigation Inc, serves on the editorial boards of Neurology, Epilepsy & Behavior, Epilepsy & Behavior Case Reports, and Genes & Diseases, travel support from Eisai

Funding

Study supported by NIH NINDS, NICHD #2U01-NS038455 (Li, Meador).

Competing interests

The authors declare no competing interests.

Contributions

Yi Li: Study concept and design, literature review, data analysis, drafting and revising the manuscript.

Sai Zhang: Literature review, critical revision of manuscript for intellectual content.

Michael Snyder: Study concept and design, critical revision of manuscript for intellectual content.

Kimford Meador: Study concept and design, critical revision of manuscript for intellectual content.

References (80)

  • D.I. Walker et al.

    Metabolome-wide association study of anti-epileptic drug treatment during pregnancy

    Toxicol Appl Pharmacol

    (2019)
  • E.F.G. Naninck et al.

    The importance of maternal folate status for brain development and function of offspring

    Adv Nutr

    (2019)
  • E.H. Reynolds

    Antiepileptic drugs, folate and one carbon metabolism revisited

    Epilepsy Behav

    (2020)
  • N.M. Jadavji et al.

    MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring

    Neuroscience

    (2015)
  • K.J. Meador et al.

    Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study

    Lancet Neurol

    (2013)
  • J. Robitaille et al.

    Prevalence, family history, and prevention of reported osteoporosis in U.S. women

    Am J Prev Med

    (2008)
  • K. Trajanoska et al.

    The genetic architecture of osteoporosis and fracture risk

    Bone

    (2019)
  • S. Drury et al.

    Cell-free fetal DNA testing for prenatal diagnosis

    Adv Clin Chem

    (2016)
  • J. Hayward et al.

    Beyond screening for chromosomal abnormalities: advances in non-invasive diagnosis of single gene disorders and fetal exome sequencing

    Semin Fetal Neonatal Med

    (2018)
  • C. Maggioni et al.

    Circadian rhythm of maternal blood pressure and fetal growth

    Biomed Pharmacother

    (2005)
  • M.M. Zack et al.

    National and State Estimates of the Numbers of Adults and Children with Active Epilepsy - United States, 2015

    MMWR Morb Mortal Wkly Rep

    (2017)
  • R. Mirnezami et al.

    Preparing for precision medicine

    N Engl J Med

    (2012)
  • T. Tomson et al.

    Executive summary: management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy

    Epilepsia

    (2019)
  • N. Oyen et al.

    Maternal epilepsy and offsprings' adult intelligence: a population-based study from Norway

    Epilepsia

    (2007)
  • J. Christensen et al.

    Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism

    JAMA

    (2013)
  • K.J. Meador et al.

    Developmental effects of antiepileptic drugs and the need for improved regulations

    Neurology

    (2016)
  • S. Bangar et al.

    Women with epilepsy: clinically relevant issues

    Funct Neurol

    (2016)
  • P.C. Souverein et al.

    Use of antiepileptic drugs and risk of fractures: case-control study among patients with epilepsy

    Neurology

    (2006)
  • L.D. Carbone et al.

    Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: findings from the women's health initiative (WHI)

    J Bone Miner Res

    (2010)
  • L. Sagi-Dain et al.

    Chromosomal microarray analysis results from pregnancies with various ultrasonographic anomalies

    Obstet Gynecol

    (2018)
  • M.E. Talkowski et al.

    Clinical diagnosis by whole-genome sequencing of a prenatal sample

    N Engl J Med

    (2012)
  • RK CY, Merico D, Bookman M, J LH, Thiruvahindrapuram B, Patel RV, Whitney J, Deflaux N, et al, Whole genome sequencing...
  • S. Jessberger et al.

    Epigenetic modulation of seizure-induced neurogenesis and cognitive decline

    J Neurosci

    (2007)
  • J. Godovac-Zimmermann et al.

    Perspectives for mass spectrometry and functional proteomics

    Mass Spectrom Rev

    (2001)
  • C.L. Harden et al.

    Practice parameter update: management issues for women with epilepsy–focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society

    Neurology

    (2009)
  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Ann Intern Med

    (2009)
  • M. Maleki et al.

    Association between ABCB1-T1236C polymorphism and drug-resistant epilepsy in Iranian female patients

    Iran Biomed J

    (2010)
  • M. Sayyah et al.

    Association analysis of intractable epilepsy with C3435T and G2677T/A ABCB1 gene polymorphisms in Iranian patients

    Epileptic Disord

    (2011)
  • S. Grover et al.

    Genetic association analysis of transporters identifies ABCC2 loci for seizure control in women with epilepsy on first-line antiepileptic drugs

    Pharmacogenet Genomics

    (2012)
  • S. Grover et al.

    Genetic polymorphisms in sex hormone metabolizing genes and drug response in women with epilepsy

    Pharmacogenomics

    (2010)
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      There has been no impact on the congenital anomaly prevalence with ‘high dose’ FA supplementation in epileptic pregnancy care (Harden, 2014; Keni et al., 2020; Baishya et al., 2020; Kashif et al., 2019; Harden et al., 2009; Harden et al., 2009; Morrow et al., 2009; Kjaer et al., 2008; Tomson et al., 2015; Herzog et al., 2017; Mahdavi et al., 2019) as the AEDs teratogenic mechanism may have no FA component or association (Harden et al., 2009; Harden et al., 2009; Morrow et al., 2009). High dose FA should no longer be recommended for congenital anomaly reduction for pregnant women with epilepsy (Stephen et al., 2019; Tomson et al., 2020; Li et al., 2021). Benefit from FA supplementation use in epileptic pregnancy cohorts has been associated with neonatal neurodevelopmental benefits (Meador et al., 2020).

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