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Biology Matters: Women often experience neurologic diseases differently than men. That reality has contributed to sex-specific approaches to diagnosis, treatment, and management.

Colino, Stacey

doi: 10.1097/01.NNN.0000520751.14042.c4
Features: Sex-Specific Medicine

Women often experience neurologic diseases differently than men. That reality has contributed to sex-specific approaches to diagnosis, treatment, and management.

Illustrations by Maria Hergueta

WEB EXTRA: For advice on how to stay positive after a diagnosis, go to http://bit.ly/NN-3WaystoStayPositive.

Women comprise more than half the population in the United States, but until somewhat recently, they weren't routinely included in clinical trials or other medical research. That changed in 1994, when Congress mandated that scientists begin including women in their studies as a matter of course, says Marianne J. Legato, MD, PhD, founder and director of the Foundation for Gender-Specific Medicine (http://gendermed.org) and emerita professor of clinical medicine at Columbia University in New York. Historically, scientists believed that studying male subjects served just as well as including both sexes, says Dr. Legato, “but that isn't always true.”

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A DIFFERENT LENS

The idea of studying biological sex as it relates to various diseases has gained recognition in the last two decades, thanks to several trends. In 2001, for example, in a report from the Institute of Medicine titled Exploring the Biological Contributions of Human Health: Does Sex Matter? researchers noted that every cell has a sex, and that sex differences start in the womb and continue throughout life. In 2006, two gender-specific organizations were established—Dr. Legato's foundation and the International Society for Gender Medicine—to promote collaboration among scientists throughout the world to study the ways in which sex affects normal function as well as various diseases. Then in 2016 the National Institutes of Health introduced a policy requiring all scientists requesting funding for research to consider the role of sex as a variable in studies involving cells, animals, and humans.

Noteworthy differences in risk factors, symptoms, and disease progression exist between women and men with many conditions, including cardiovascular disease, type 2 diabetes, and neurologic disorders, says Dr. Legato. “Many diseases are multifactorial at the genetic level, and how genes are expressed is profoundly influenced by sex,” she explains. Scientists continue to gain a better understanding of the anatomical, neurologic, chemical, and functional differences in how various medical conditions affect women versus men, which will lead to improved diagnosis and treatment.

We look at how six neurologic conditions—Alzheimer's disease, epilepsy, migraine, multiple sclerosis (MS), Parkinson's disease, and stroke—manifest in women, and how that influences their diagnosis, symptoms, medication, and prognosis.

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PARKINSON'S DISEASE

STATISTICS: Men are one and a half times more likely to be diagnosed with Parkinson's disease than women, according to the Parkinson's Foundation. Women also tend to be diagnosed much later, long after symptoms are present.

DIAGNOSIS: Because more men than women are diagnosed with Parkinson's disease, primary care doctors are less likely to consider it in women who have the symptoms, says Maria De Leon, MD, a neurologist and movement disorders specialist in Nacogdoches, TX, who has Parkinson's disease herself. She's also a research advocate for the Parkinson's Foundation. In 2010, Robin Morgan, an award-winning feminist writer and activist in New York City, was diagnosed with Parkinson's disease after being misdiagnosed for a year and a half. She was quite sure the tremor in her hands was a sign of Parkinson's, given that her mother had the disease, but her doctor dismissed the possibility. Still, she considers herself fortunate because, she says, “I know women who've waited seven years for a diagnosis.” To raise awareness of sex and gender differences in Parkinson's disease and to encourage research into women-specific issues, the Parkinson's Disease Foundation—a forerunner to the Parkinson's Foundation—launched the Women and PD Initiative in 2015.

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SYMPTOMS: “Women present more with affective disorders [such as depression], cognitive changes, fatigue, and stiffness—not the tremors people recognize [as a hallmark of Parkinson's disease],” Dr. De Leon says. “Women have better survival rates, but they turn out to be more disabled and have a lower quality of life,” says Allison Willis, MD, assistant professor of neurology and biostatistics and epidemiology at the University of Pennsylvania School of Medicine in Philadelphia.

MEDICATIONS: Some drugs prescribed for Parkinson's disease can cause bones to thin, which may heighten the chance of developing osteoporosis, especially for women who are already at risk for it. Women may also be more vulnerable to side effects—such as nausea, sleepiness, dizziness, and headaches—than men, Dr. De Leon says. As a result, women may need lower doses or more time to adjust to the drugs.

HORMONES: Estrogen, a predominantly female hormone, has a somewhat protective effect. Researchers believe it may inhibit inflammation, which is common in Parkinson's disease. Or the hormone may increase the release and expression of growth factors in the cells surrounding neurons that are responsible for ensuring and maintaining the survival of those neurons, Dr. De Leon says. Either theory may explain why the risk of developing Parkinson's disease increases after menopause when estrogen levels drop significantly. It may also explain why “women who have induced menopause—their ovaries are removed early—have the same incidence of Parkinson's disease as men,” Dr. Willis says.

MENSTRUAL CYCLE: Younger women who have Parkinson's disease face a vicious cycle when it comes to menstruation. “Parkinson's disease makes periods worse—longer, heavier, and sometimes more painful—and periods can make Parkinson's symptoms worse,” says Dr. De Leon. “Parkinson's medications can also influence the menstrual cycle, making periods irregular.”

BIRTH CONTROL PILLS: The effects of birth control pills aren't well established, but since hormonal fluctuations affect symptoms, using birth control pills to shorten the length and lessen the severity of periods might help manage symptoms, Dr. De Leon says.

PREGNANCY: Several reports of successful pregnancies in women with Parkinson's disease have been published, but medications need to be chosen carefully during pregnancy. Levodopa has been shown to be safe, but some medications for Parkinson's disease can cause birth defects if they're taken during pregnancy.

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MIGRAINE

STATISTICS: Migraines are three times as common in women as in men, according to the Migraine Research Foundation.

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DIAGNOSIS: Women tend to be diagnosed with migraine earlier than men, says Teshamae Monteith, MD, professor of clinical neurology and chief of the headache division at the University of Miami Miller School of Medicine.

SYMPTOMS: Migraine symptoms are generally worse for women, but women are also more likely to get treated for them, Dr. Monteith says. “However, men have fewer headache days per month, less disability, and less skin sensitivity than women with migraine.”

MEDICATIONS: A study from Italy published in the journal Neurological Sciences in 2014 found that triptans, a class of drugs that constrict blood vessels in the brain, were equally effective for treating migraines in women and men with similar rates of adverse reactions.

HORMONES: During perimenopause, migraines may worsen. After menopause, when hormone levels stabilize, most women get better, Dr. Monteith says.

MENSTRUAL CYCLE: Migraines can be “more severe, longer lasting, and less responsive to treatment [around menstruation],” says Dr. Monteith. For migraines that are exacerbated by menstruation, women might take an additional medicine or higher doses of the usual drug. To blunt the cyclical hormonal fluctuations, “long-acting triptans are often used, but some patients are also placed on hormonal therapy,” she says. In a study published in the July 2016 issue of Neurology, researchers from the Albert Einstein College of Medicine/Montefiore Medical Center in the Bronx, NY, found that women with migraine experience a greater and faster decline in estrogen over the two days following ovulation than women without migraine—a factor that may indicate “neuro-endocrine vulnerability in women with migraine,” according to the researchers. If your regular doctor can't help you address your menstrual migraines, ask for a referral to a physician who specializes in migraine.

BIRTH CONTROL PILLS: Taking an oral contraceptive can make migraines better or worse, depending on the individual's response and the type of hormones in the pill, says Dr. Monteith. Birth control pills can also decrease the effectiveness of migraine medications, or vice versa, which can increase the chances of an unplanned pregnancy. For example, topiramate (Topamax) can make birth control pills less effective, requiring women to take higher doses to ensure they're effective, Dr. Meador says.

PREGNANCY: Sometimes, migraines get better during pregnancy, although this is less likely for those who have migraine with aura (vision changes such as seeing zigzag or squiggly lines). And some migraine drugs, including divalproex sodium, topiramate, and nonsteroidal anti-inflammatory drugs, may increase the risk of birth defects during pregnancy. (For more information about migraine, listen to our podcast with Dr. Monteith at http://bit.ly/NN-MigrainePodcast.)

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ALZHEIMER'S DISEASE

Statistics: Women make up nearly two-thirds of those who have Alzheimer's disease, according to the Alzheimer's Association.

DIAGNOSIS: After age 70, women with Alzheimer's disease are diagnosed sooner than men. Because many women continue to manage the household, including doing the cooking and grocery shopping, and stay involved in community-related activities such as volunteering, their declines in functionality may be more noticeable, says Douglas W. Scharre, MD, director of the division of cognitive neurology at Ohio State University. By contrast, “after they retire, some men don't stay as active [in different areas of their lives], so we can't tell as readily if their functional status is affected.”

SYMPTOMS: Symptoms are similar in both sexes and typically include short-term memory loss, forgetfulness, repeating questions, misplacing items, and forgetting conversations.

MEDICATIONS: Some women may experience more gastro-intestinal side effects from certain medications for Alzheimer's disease, such as donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), Dr. Scharre notes. After being diagnosed with early-stage Alzheimer's disease in 2013, Carol Poole, of Rockledge, FL, had trouble adjusting to her medication and had to increase her dosage gradually. “I'd get side effects like dizziness, an upset stomach, or fatigue, and sometimes I'd forget to take it,” she admits, which meant the adjustment process would start over again.

HORMONES: Estrogen may have a protective effect against Alzheimer's disease. As in Parkinson's, estrogen may inhibit inflammation, which is also common in Alzheimer's disease. Or the hormone may “increase the release and expression of growth factors in glial cells [which surround neurons] that are responsible for ensuring and maintaining the survival of neurons,” says Dr. De Leon. Either theory may explain why the risk of developing Alzheimer's disease increases after menopause when estrogen levels drop significantly. However, the effectiveness of estrogen therapy for minimizing the risk of Alzheimer's disease after menopause has shown mixed results, says Jennifer Rose Molano, MD, FAAN, associate professor of neurology at the University of Cincinnati Academic Health Center.

MENSTRUAL CYCLE/BIRTH CONTROL PILLS/PREGNANCY: “Less than 3 percent of patients develop Alzheimer's disease before age 65,” so little is known about the effects of the menstrual cycle, birth control pills, or pregnancy on early-onset Alzheimer's, Dr. Scharre says.

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EPILEPSY

STATISTICS: While the prevalence of epilepsy is slightly lower in women than in men, the risk of recurrent seizures is similar for both, according to the Epilepsy Foundation.

DIAGNOSIS: No scientific data suggest a difference in diagnosis between the sexes. Even so, “I have had some women tell me that when they initially reported seizure symptoms, particularly when they were perimenopausal, they were told by their doctor that ‘it was just hormones,’” says Jacqueline A. French, MD, FAAN, co-director of research and clinical trials at NYU's Comprehensive Epilepsy Center.

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SYMPTOMS: Women report slightly more autonomic sensations (such as nausea, heart palpitations, chest pain, or butterflies in the stomach), visual distortions (such as auras, which include seeing zigzag lines or slowly spreading spots), and psychic symptoms (such as feelings of déjà vu) than men do, according to a 2014 study in Epilepsy & Behavior. Depression is common among men and women who have epilepsy but it's even more common in women with epilepsy, just as it is in the general population, says Kimford J. Meador, MD, FAAN, professor of neurology and neurologic sciences at the Stanford University School of Medicine in Palo Alto, CA. There are no sex-specific differences in cognitive function related to epilepsy.

MEDICATIONS: Some antiseizure medications can have an adverse effect on bone health, causing bones to thin, which increases the risk of osteoporosis, especially in women who are already vulnerable to it.

HORMONES: “Estrogen lowers the seizure threshold [the tipping point at which the brain produces a seizure] while progesterone raises it,” explains Dr. Meador. So “right before a woman's period and right around ovulation, seizures tend to occur in clusters,” a pattern that's known as catamenial epilepsy. Similarly, changes in seizure susceptibility and frequency can appear during puberty, pregnancy, and menopause.

MENSTRUAL CYCLE: In catamenial epilepsy, when estrogen levels rise during menstruation, levels of lamotrigine (Lamictal), an anticonvulsant used to control seizures, drop, which can lead to a seizure, Dr. French explains. Since increasing the dosage of lamotrigine increases the risk of side effects, doctors may prescribe another drug or recommend rescue medications for times when patients are most susceptible to seizures.

BIRTH CONTROL PILLS: Oral contraceptives containing estrogen can worsen seizures, Dr. Meador says. They can also decrease the effectiveness of epilepsy medications, or vice versa, which increases the risk of an unplanned pregnancy. For example, carbamazepine (Tegretol) can make birth control pills less effective, requiring women to take higher doses to ensure they prevent pregnancy, Dr. Meador says.

PREGNANCY: Hormonal changes during pregnancy can either increase or decrease seizure frequency. Mariellen Ghavami, 34, of Riverside, CA, who developed epilepsy as a complication of brain inflammation she experienced after being infected with the West Nile virus in 2012, went seven months without a seizure during pregnancy, a record for her. However, the seizures came back after her son was born in June 2015. “At the end of pregnancy, the body returns to its pre-pregnancy state, and all the changes that occurred during pregnancy are reversed. Sometimes this happens very quickly,” Dr. French explains, which means that a woman's medication dosage may need to be adjusted within a week of delivery. Some antiepileptic drugs, such as divalproex sodium (Depakote), can harm a developing baby, increasing the risk of birth defects, cognitive impairment, and autism. The risk is so great that “in Europe, doctors are not allowed to prescribe divalproex to women of childbearing age,” notes Dr. French. “This is a big deal because the seizure type that is often the hardest to control—grand mal seizures—can be controlled with divalproex.” Women should have a detailed discussion with their doctors about which drugs are safe during pregnancy before they get pregnant, Dr. Meador says. Doctors and patients have to walk a fine line between controlling the seizures and mitigating medication-related risks. “You need to be sure you're protecting the baby and the mother,” Dr. French says. (For more information about neurologic diseases and pregnancy, visit http://bit.ly/NN-Pregnancy.)

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MULTIPLE SCLEROSIS

STATISTICS: Relapsing-remitting multiple sclerosis, a form of the disease characterized by temporary periods of flare-ups or exacerbations when new symptoms appear, is three times more prevalent among women, particularly during their childbearing years, says Tanuja Chitnis, MD, associate professor of neurology at Harvard Medical School/Brigham and Women's Hospital. However, primary progressive MS is equally common among men and women.

DIAGNOSIS: “Women are diagnosed at a younger age, partly because they typically present with symptoms five years earlier than men do,” Dr. Chitnis says. Because the disease affects more women than men, “MS in men may go unrecognized until the symptoms are progressive,” Dr. Chitnis says.

SYMPTOMS: Women tend to recover from exacerbations or flare-ups more quickly, their disease progresses at a slower pace, and they are likely to accrue disability more slowly than men, Dr. Chitnis says.

MEDICATIONS: High doses of steroids used to treat MS relapses can cause bones to thin, which raises the risk of osteoporosis, especially in women who are already susceptible to it.

HORMONES: Women with MS often experience a slight increase in their level of disability right after menopause, says Dr. Chitnis. This makes sense, she says, because estrogen can modulate the immune system and provide a somewhat protective effect on MS. It also increases production of anti-inflammatory cytokines, decreases damage to the protective myelin sheath that surrounds nerve fibers in the brain and spinal cord, and enhances energy-producing processes in the central nervous system, according to a review published in the February 2015 issue of the journal Maturitas.

MENSTRUAL CYCLE: Symptoms such as fatigue, mood changes, and spasticity often increase at certain times during the menstrual cycle, Dr. Chitnis notes, but symptom flare-ups can vary from one woman to another.

BIRTH CONTROL PILLS: Data on the effects of birth control pills on MS are mixed, Dr. Chitnis says. A study in a 2015 issue of the journal Neurology: Neuroimmunology & Neuroinflammation found that oral contraceptives taken in conjunction with interferon reduced disease activity in women with relapsing-remitting MS. By contrast, a study by Dr. Chitnis and her colleagues published in a 2017 issue of the Multiple Sclerosis Journal found that women with MS who had previously taken oral contraceptives but no longer did had significantly lower relapse rates than those who'd never used oral contraceptives.

PREGNANCY: None of the disease-modifying drugs used to treat MS are considered 100 percent safe during pregnancy, Dr. Chitnis says, “so women often have to stop taking them two to three months before conceiving.” Pregnancy may have a biologically protective effect against MS due to elevated estrogen levels: pregnant women often experience fewer MS relapses, especially in the second and third trimesters, says Dr. Chitnis. “But the protective effects stop shortly after delivery, and there can be increased relapses during the three months after delivery. So, women should consider restarting medication after delivery.” (For more about MS, listen to a podcast with Barbara S. Giesser, MD, FAAN, clinical director of the Multiple Sclerosis Program at UCLA, at http://bit.ly/NN-MSPodcast.)

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STROKE

STATISTICS: More women experience strokes each year, partly because women live longer than men. Research also shows that after age 75 women have more severe strokes and worse outcomes than men, says Sarah Song, MD, MPH, assistant professor of neurology at Rush University Medical Center in Chicago.

DIAGNOSIS: The American Heart Association's Go Red for Women program to boost awareness of heart disease in women now also addresses stroke risk. (Many women still believe that heart disease and strokes affect men primarily.)

SYMPTOMS: Women have the same stroke symptoms as men, but when older women have strokes, they experience more disability, says Dr. Song. This may be partly because of their age, but also because women are more likely to experience depression after stroke, which can impair recovery, according to a 2010 review in Current Cardiology Reports.

MEDICATIONS: There aren't any sex-based differences related to medication for stroke, Dr. Song says.

HORMONES: After menopause, “women are more susceptible to putting on weight around the abdomen—what's called central obesity—and that increases the risk for stroke,” notes Dr. Song. Similarly, atrial fibrillation, a type of heart arrhythmia that is more common among women, is a major risk factor for stroke, she says. And depression, which is twice as common in women as in men, increases the risk of stroke.

BIRTH CONTROL PILLS: Oral contraceptives can increase the risk of ischemic stroke, which is caused by blood clots disrupting blood flow to the brain, especially if women smoke or have migraines with aura. “Hormone treatment in general can increase the risk of blood clots,” says Dr. Song, whether it's for contraception, fertility treatments, or menopause.

PREGNANCY: Pregnancy is a high-risk period for strokes, Dr. Song notes, largely because pregnant women are more prone to blood clots and high blood pressure.

© 2017 American Academy of Neurology