653

Movement Disorders in Women

Jessica M. Baker, MD1 Albert Y. Hung, MD, PhD1

1 Division of Movement Disorders, Department of Neurology, Address for correspondence Albert Y. Hung, MD, PhD, Division of
Massachusetts General Hospital, Boston, Massachusetts Movement Disorders, Department of Neurology, Massachusetts
General Hospital, 55 Fruit Street, Boston, MA 02114
Semin Neurol 2017;37:653–660. (e-mail: ahung@mgh.harvard.edu).

Abstract
Keywords
► Parkinson’s disease
► restless legs
syndrome
► Tourette syndrome
► chorea gravidarum
► essential tremor
Movement disorders such as Parkinson’s disease (PD), restless legs syndrome (RLS), chorea,
essential tremor, and Tourette syndrome, occur in men and women of all ages. Yet,
considerable sex differences in epidemiology, clinical features, and treatment exist in these
disorders. In this review, we highlight key differences in the evaluation and management of
women with movement disorders, addressing sex-specific complications of treatment and
unique challenges surrounding the management of movement disorders during preg-
nancy. We review the complex relationship between estrogen and movement disorders,
including the putative neuroprotective effects of estrogen in PD and the modulatory effects

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► estrogen on RLS and chorea associated with autoimmune disease. Further understanding of sex-
► sex differences specific and hormonal effects on clinical features will be important to optimize the
► pregnancy management of women with movement disorders in the future.

Movement disorders are found in women of all ages, from young
adulthood to older age. Substantial differences in presentation
and management exist between men and women for a variety
of movement disorders. Many of these conditions reflect under-
lying dysfunction of the basal ganglia and their connections. In
particular, changes in activity of the mesostriatal dopamine
system are expressed as either an excess (hyperkinetic) or
paucity (hypokinetic) of movement. Within the striatal dopa-
minergic system, estrogen may exert both symptomatic and
neuroprotective effects.1
In this review, we describe phenotypic differences between
men and women in Parkinson’s disease (PD), essential tremor,
and Tourette syndrome (TS). We discuss two conditions unique
to women: restless legs syndrome (RLS) in pregnancy and
chorea gravidarum (CG), highlighting the association of chorea
in women with underlying autoimmune disease. We aim to
provide clinicians with a framework for the treatment of
movement disorders in women, including unique considera-
tions arising during pregnancy.
Parkinson’s Disease
PD is a progressive neurodegenerative disorder characterized
by bradykinesia, rigidity, resting tremor, and, later in the
disease course, postural instability.2 It is common in the
elderly, affecting 1 in 100 individuals over the age of 65,
with even higher prevalence in individuals over age 80.3
Prodromal non-motor symptoms, such as rapid eye movement
(REM) sleep behavior disorder, loss of olfaction, depression,
and autonomic dysfunction including constipation, precede
motor symptoms by at least a decade.4 Here, we review the
epidemiology and sex-specific clinical features of PD and
highlight treatment considerations that are unique to women.
Epidemiology: Multiple individual cohort studies report a
decreased risk of PD in women. Based on two meta-analyses,
the age-adjusted incidence of PD is 1.5-fold greater in men
than that in women,5,6 with an individual’s risk representing
a complex interaction between genetic and environmental
factors. Pesticide exposure7 and traumatic brain injury8 are
associated with an increased risk of developing PD, whereas
cigarette exposure9,10 and caffeine use11,12 are associated
with decreased risk. One might speculate that differential
exposure to these environmental factors may contribute to
the observed disparity in PD risk between men and women.
Neuroprotection: Current treatments for PD are sympto-
matic and do not slow progression of disease. Drawing from
epidemiological data showing a lower incidence of PD in
women, estrogen has been investigated as a potential neuro-
protective therapy, with most supporting evidence derived
from preclinical models.13 Multiple studies demonstrate most

Issue Theme Women’s Issues in Copyright © 2017 by Thieme Medical DOI https://doi.org/
Neurology; Guest Editor, Steven K. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0037-1608845.
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Tel: +1(212) 584-4662.
654 Movement Disorders in Women Baker et al.
consistently that 17β-estradiol protects against 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydo-
pamine-mediated toxicity in rodent models; similar effects
have been reported with the selective estrogen receptor
modulator raloxifene, although results with the related com-
pound tamoxifen have been more variable.13 The precise
mechanism through which estrogen exerts its neuroprotective
effects in these animal models is unknown, but reduction in
oxidative stress, decreased mitochondrial dysfunction, anti-
inflammatory effects, and downstream effects on pathways
mediating cell death are postulated to contribute.13
The clinical evidence supporting a neuroprotective role
for estrogen in PD is less convincing than the pre-clinical
data. Though case-control studies demonstrate an increased
risk of PD in women who have undergone surgical meno-
pause,14,15 presumably due to premature estrogen defi-
ciency, these findings contrast with larger epidemiological
studies. Multiple cohort studies demonstrate that post-me-
nopausal hormone use either increases or has no significant
effect on PD risk,16–18 while attenuating the potentially
beneficial effects of caffeine and tobacco.19–22 No convincing
association exists between PD risk and other reproductive
factors, including parity, age at menarche or menopause, or
number of reproductive years.16,17,22 The few clinical trials
investigating estrogen replacement in women with PD are
limited by small sample sizes and short durations of treat-
ment (<12 weeks); progression of disease was not specifi-
cally assessed.23–26 Though no significant adverse events
were recorded during these studies, concerns about the
long-term safety of estrogen supplementation in women
over the age of 60 (specifically venous thromboembolism,
coronary artery disease, and cancer risk27) limit hormone
use in a typical PD population. Given the complex and often
contradicting relationship between PD risk and estrogen
exposure, hormone replacement therapy currently has no
role in the treatment of women with PD.
Urate, a potent anti-oxidant, has a putative neuroprotec-
tive effect based on epidemiological studies associating
elevated serum urate levels with decreased risk of PD.28–31
Notably, however, several prospective cohort studies suggest
that these findings are less robust in women than in
men.32–34 Based on these observations, urate elevation is
under investigation as a potential disease-modifying therapy
for PD. A phase II trial (hence, not powered to assess efficacy)
demonstrated primarily that oral inosine is safe and effective
in raising serum and cerebrospinal fluid (CSF) urate levels in
participants diagnosed with early PD and also demonstrated
modest trends toward slower disease progression.35 Post-
hoc analysis suggested that this trend was significant in
women, but not in men, perhaps because women had lower
pre-treatment uric acid levels and, therefore, a lower anti-
oxidant capacity at baseline.36 A disease-modifying role for
uric acid elevation is under investigation in a phase III clinical
trial (SURE-PD3, NCT02642393); it will be interesting to see
whether there is a differential effect on progression of PD in
men versus women.
Clinical Features: Subtle differences exist in the clinical
features of PD in women and those in men. Women are older
Seminars in Neurology Vol. 37 No. 6/2017
at presentation and more likely to have relatively mild,
tremor-predominant disease.37,38 Non-motor symptoms
(NMS) are common in patients with PD, significantly impact
quality of life, and rarely improve solely with dopamine
replacement. Common NMS include daytime fatigue, con-
stipation, pain, sleep disorders, mood disorders, and urinary
symptoms. Women are more likely than are men to report
fatigue, depression, and anxiety, but less likely to report
hyposmia or sexual dysfunction.39–44 Feelings of worthless-
ness, irritability, agitation, self-punishment, loss of pleasure,
and self-dislike may differentiate women with PD and
depression from those without depression.39 Women also
have a lower risk of developing cognitive impairment.45,46
Nonetheless, women with PD are more likely than men to
utilize long-term care facilities.47
Treatment: Common PD medications used for sympto-
matic treatment include levodopa, dopamine agonists, and
MAO-B inhibitors. Choice of therapy is driven primarily by
severity of symptoms and degree of motor disability rather
than by sex.48 However, certain complications of dopami-
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nergic therapy, namely levodopa-induced dyskinesias,
impulse control disorders (ICDs), and dopamine dysregula-
tion syndrome (DDS), differ between women and men and
merit further discussion.
Treatment with levodopa is associated with the development
of motor complications, including levodopa-induced dyskine-
sias, with a frequency ranging from 30 to 80%.49 Multiple studies
have identified female sex as a risk factor for levodopa-induced
dyskinesias, with other predictors including young age at PD
onset, higher levodopa dose, and low bodyweight (irrespective
of sex).50–52 The pathophysiology of levodopa-induced dyski-
nesias is complex and is beyond the scope of this review, but no
clear explanation exists for the disparity between men and
women. Nonetheless, sex and the subsequent risk of levodopa-
induced dyskinesias remain a consideration in choosing the
initial therapy for patients with PD. Though deep brain stimula-
tion is effective in treating the motor fluctuations of advanced
PD, women are less likely than men to receive this therapy;
whether this reflects true underutilization or a more benign
course of disease in women is uncertain.53,54 Non-motor fluc-
tuations also occur more commonly in women than in men.55
Non-motor complications of dopaminergic therapy also
differ in their expression between men and women. ICDs,
such as pathological gambling, compulsive sexual behavior,
compulsive buying, and binge-eating disorder, occur in over
13% of patients with PD and are more common in those
treated with dopamine agonists and levodopa as opposed to
levodopa alone (17.7% versus 7.2%). Though the overall risk of
developing ICDs is similar in men and women, women are
more likely to report compulsive buying and binge-eating
disorder and are less likely to report compulsive sexual
activity.56 DDS is characterized by the compulsive use of
dopaminergic medications in excess of the dose necessary to
control motor symptoms of parkinsonism, often resulting in
disabling dyskinesias, accompanied by an affective syndrome
of depression, anxiety, and irritability upon attempted with-
drawal of the offending medication.57,58 Women appear less
likely than men to develop DDS,59 although it is important to

recognize this syndrome regardless of sex. Both ICDs and
DDS appear to be associated with younger disease onset and
a personal or family history of substance abuse, ICDs, or
mood disorders.56,58 Careful screening for signs of an ICD or
DDS, and particularly for compulsive buying or binge eating
in women, is imperative, because patients may not report
symptoms unless directly asked.
Restless Legs Syndrome
Patients with RLS describe an uncomfortable or unpleasant
sensation in the legs causing an urge to move the legs.
Symptoms worsen during inactivity and in the evening or
night and are relieved by movement such as walking or
stretching.60 Though classically divided into primary (familial)
and secondary (symptomatic) forms, it is increasingly clear
that RLS results from the interaction of genetic and metabolic
factors, including iron deficiency and chronic kidney disease.61
RLS and Pregnancy: RLS is a common movement disorder;
prevalence estimates vary with study methodology, but range
from 2 to 15% in the general population.62 RLS is even more
common during pregnancy, occurring in 10 to 34% of pregnant
women,63 often as a transient phenomenon limited to preg-
nancy and the immediate post-partum period. The strongest
risk factors for RLS in pregnancy are a family history of RLS,
history of RLS in a previous pregnancy, and a history of RLS
while not pregnant.64 Iron deficiency, vitamin D deficiency,
hormonal changes, and altered hemodynamics may further
contribute to this increased risk, but the mechanisms by which
they influence RLS are largely speculative.63 RLS symptoms
peak during the third trimester (though earlier onset is not
uncommon65) and resolve dramatically within about 1 month
of delivery.65,66 For women with a history of RLS independent
of previous pregnancies, 60% experience worsening symp-
toms, mostly during the third trimester, while the remaining
40% report improvement or no change.66
The association between pregnancy and RLS extends well
beyond the immediate post-partum period. Despite resolution
of transient RLS post-partum, symptoms recur in 60% of the
subsequent pregnancies and confer a four-fold increased risk
of developing chronic RLS later in life, independent of preg-
nancy.67 RLS occurs almost twice as frequently in women
versus men across all age groups,68,69 but when women with
past pregnancies are excluded, the prevalence of RLS in
nulliparous women is actually similar to that of men. Parous
women have a significantly higher risk of developing RLS than
nulliparous women,70 and this risk may correlate positively
with the number of past pregnancies.69 Thus, a history of
pregnancy can be considered a risk factor for the development
of RLS later in life.
Treatment: Women with RLS during pregnancy report
decreased sleep time, high rates of insomnia, and excessive
daytime sleepiness.66 Evidence-based guidelines for the treat-
ment of RLS71 do not consider issues unique to pregnancy, such
as teratogenesis and the often transient nature of symptoms.
Moreover, limited safety data are available for commonly
prescribed medications, including the α2δ ligands pregabalin
and gabapentin enacarbil (a prodrug of gabapentin), and
Movement Disorders in Women Baker et al. 655
dopamine agonists (pramipexole, ropinirole, rotigotine), and
thus their use is not recommended during pregnancy.72 In
2015, a multidisciplinary team, which included specialists in
sleep and maternal-fetal medicine, created clinical guidelines
for the treatment of RLS during pregnancy and lactation from
published evidence and expert opinion.72 A recommended
algorithm is presented in ►Fig. 1. To summarize, once the
diagnosis of RLS is established, non-pharmacological therapies
and iron supplementation may be sufficient to treat mild
symptoms. For RLS symptoms refractory to conservative mea-
sures, carbidopa/levodopa given in the evening is safe and
effective in treating RLS during pregnancy. However, levodopa
is not considered the first-line therapy in non-pregnant
patients, given the significant risk of augmentation. A compli-
cation of chronic dopaminergic therapy, RLS symptoms in
patients with augmentation are more severe, begin earlier in
the evening, occur more quickly after rest, and may spread to
involve other body parts, including the arms.73 The risk of
augmentation ranges from 0 to 33% with dopamine agonists,
and 14 to 73% with levodopa, increasing with duration of
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treatment.73 Therefore, if used only transiently during the
third trimester, the risk of augmentation is theoretically lower.
Clonazepam (after the first trimester) or oxycodone given in
the evening may also be considered during pregnancy. Gaba-
pentin is only minimally excreted in breast milk and is safe and
effective during lactation. Medications should be limited to the
lowest dose for the shortest amount of time, reassessing need
after delivery, when symptoms typically resolve. Risks and
benefits of each specific medication should be discussed in
detail with the patient.72
Movement Disorders Associated with
Autoimmune Disease
Systemic Lupus Erythematosus (SLE) and Antiphospholipid
Syndrome (APS): SLE is an autoimmune disorder with pro-
tean clinical manifestations and a strong female predomi-
nance, typically affecting women and men in a ratio of
9:1.74 The APS may be primary or secondary to the under-
lying SLE. It manifests as vascular thrombosis and pregnancy
morbidity in the presence of antibodies against phospholi-
pids.75 Chorea, defined as involuntary, rapid movements that
seemingly flow from one part of the body to another, is a
well-established but rare manifestation of SLE and APS,
occurring in 1 to 2% of patients.76,77
Chorea in SLE and APS typically presents in childhood or
early adulthood; onset after age 60 is rare, and the majority of
cases occur in women. Chorea develops subacutely, often
preceding diagnosis of the associated autoimmune disease,
and it may be unilateral or bilateral. The average duration of
symptoms is 2 months, though they rarely may last for years.
A majority of patients have a monophasic course, but relapse
occurs in up to one third of patients, often several years later.
Concurrent thrombosis and fetal loss are common.78–80
Though stroke is a well-established complication of APS, the
subacute onset of chorea and lack of explanatory imaging
findings argue against ischemia as a precipitant of chorea.76,79
It is postulated that antiphospholipid antibodies cross a
Seminars in Neurology Vol. 37 No. 6/2017
656 Movement Disorders in Women Baker et al.
Fig. 1 Algorithm for the diagnosis and management of restless legs syndrome during pregnancy and lactation. (Reproduced with permission
from Picchietti et al.72) RLS, restless legs syndrome.
disrupted blood–brain barrier and interact with as yet uniden-
tified neuronal antigens in the basal ganglia.81 Fluorodeoxyglu-
cose positron emission tomography (FDG-PET) in patients with
SLE chorea demonstrates contralateral striatal hypermetabo-
lism, similar to findings in other autoimmune causes of chorea.
By comparison, hypometabolism is observed in the striatum of
Huntington’s disease, stroke, and other neurodegenerative
causes of chorea, further supporting an autoimmune mechan-
ism for chorea in SLE and APS.81
Treatment with antiplatelet agents and anticoagulation is
recommended in patients with SLE- or APS-associated chorea
and thrombotic manifestations, but antithrombotic agents are
unlikely to play a direct role in the treatment of chorea.
Symptomatic management of chorea with dopamine antago-
nists or dopamine-depleting agents, such as tetrabenazine,
effects substantial improvement within weeks in 75% of
patients.79 Drawing on the possible autoimmune mechanism
Seminars in Neurology Vol. 37 No. 6/2017
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of APS-associated chorea, steroids and other immunosuppres-
sive treatments such as cyclophosphamide, azathioprine, in-
travenous immunoglobulin and plasma exchange are often
utilized in severe cases, but whether these more aggressive
treatments provide incremental benefit over symptomatic
therapies has not been established.78,79,82
Chorea Gravidarum: Chorea associated with SLE or APS
may be triggered by exposure to estrogen, as with oral contra-
ceptives (OCPs) or pregnancy.78 In the latter case, this is termed
chorea gravidarum. CG refers not to a specific disease, but to
the syndrome of chorea with onset during pregnancy. Histori-
cally, CG was estimated to occur in 1 in 2,000 pregnancies,
most commonly associated with rheumatic fever or Syden-
ham’s chorea.83 With the increasingly routine use of antibio-
tics to treat group A streptococcal infections, CG is now rare
and most commonly caused by SLE and APS.83 Onset of chorea
is typically during the first or second trimester, with resolution

in the third trimester or within weeks after delivery. Seventy-
five percent of women with a history of Sydenham’s chorea
develop chorea during pregnancy; the risk of spontaneous
abortion is elevated in these cases.84 Treatment should address
the underlying disease. Symptomatic treatment with dopa-
mine antagonists may be considered if severity warrants. In
the case of chorea induced by OCPs, symptoms typically
resolve with the discontinuation of OCPs, and only if that fails,
dopamine antagonists are given.78,79 The evaluation of CG
must also consider causes of chorea not unique to pregnancy,
including cerebrovascular disease, thyrotoxicosis, Wilson’s
disease, drug-induced chorea (cocaine, morphine, methadone,
and amphetamines), Huntington’s disease, and neuroacantho-
cytosis.83,85 The emergence of chorea with rising estrogen
levels suggests a link between estrogen and dopaminergic
pathways of the striatum. In preclinical models, estrogen may
increase dopamine synthesis and release, decrease dopamine
reuptake, and act as a direct agonist at striatal D2 receptors.83
Two cases of torticollis with onset during pregnancy and
spontaneous resolution either before or shortly after delivery
have been termed dystonia gravidarum and may share a
similar pathophysiology with CG.86,87
Essential Tremor
Essential tremor (ET) is characterized primarily by an action
tremor of the hands with kinetic and postural components.
A positive family history and improvement with alcohol
further support the diagnosis. Embarrassment is a signifi-
cant cause of disability in ET and is reported twice as
frequently in women as in men.88 ET involves the upper
extremities in 95% of patients and progresses to include the
head and neck (34%), jaw (5%), and voice (12%) in a subset of
patients.89 Female sex is associated with a four-fold increase
in the risk of head tremor, suggesting that sex hormones may
influence the expression of ET.90 Isolated head tremor,
however, is a rare manifestation of ET, and its presence
should prompt consideration of alternative diagnoses, par-
ticularly in women. Cervical dystonia, an adult-onset focal
dystonia affecting muscles of the neck, may present as a
dystonic head tremor. It occurs more frequently in females91
and may mimic the head tremor of ET. Isolated vocal tremor
is an equally rare presentation of ET, occurring more fre-
quently in women than in men.92 ET is treated with medica-
tions, typically primidone or propranolol, or, for more
refractory cases, deep brain stimulation or focused ultra-
sound thalamotomy.
Tourette Syndrome
Gilles de la Tourette Syndrome (TS) presents in childhood with
persistent motor and vocal tics. Up to 90% of affected children
have comorbid obsessive-compulsive disorder (OCD) or atten-
tion-deficit/hyperactivity disorder (ADHD). Tics first occur
around ages 5 to 7, reach peak severity at ages 10 to 12, and
remit before adulthood in most cases. Treatment is with a
combination of behavioral therapy, α2-adrenergic agonists,
and neuroleptics.93
Movement Disorders in Women Baker et al. 657
TS is about five times more common in boys than in girls,
but this ratio attenuates in adulthood, when TS is only about
two- to three-fold more common in men versus women. There
is as yet no convincing explanation for this narrowing gender
gap, and bias introduced by differences in treatment-seeking
behavior in men versus women may in part explain this
disparity.94,95 Limited evidence suggests that the course of
TS diverges between men and women in adulthood. After
adolescence, tic severity tends to improve in males, but may
worsen in females. Adult women are also more likely than are
men to experience an expansion of the number of body regions
affected by tics.96 The TS phenotype may be more severe in
women with respect to functional impairment, particularly in
social domains, such as avoidance of events, public places, and
group activities.96,97 OCD, ADHD, anxiety, and mood disorders
remain common in adult women with TS, affecting upward of
two thirds of patients.96,97 There is neither consistent associa-
tion between tic severity and estrogen levels during the
menstrual cycle or pregnancy, nor does TS itself appear to
have adverse effects on pregnancy.98–100 In cases of pregnancy
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in women with TS where medication cannot be withdrawn
prior to pregnancy, limited safety data necessitate an indivi-
dualized discussion of risks and benefits.
Conclusions
Movement disorders are common in women of all age groups
and present unique challenges for clinicians, both diagnosti-
cally and therapeutically. The clinical presentation of certain
movement disorders differs between men and women. In PD,
women tend to have milder, tremor-predominant disease and
may be less likely than men to develop cognitive impairment.
Therapeutically, women with PD are more likely to develop
levodopa-induced dyskinesias and certain ICDs, differences
that must be considered while choosing a treatment strategy.
Head involvement in EToccurs more commonly in women and
must be differentiated from cervical dystonia if presenting as
an isolated feature. Functional impairment, particularly in
social domains, appears more common in women with TS.
Pregnancy highlights several unique features of movement
disorders in women. RLS is particularly prevalent during the
third trimester of pregnancy and confers a higher risk of devel-
oping RLS later in life. Pregnancy presents a unique management
challenge, as the safety of the most first-line medications for RLS
is not established during pregnancy. CG is a syndrome unique to
pregnancy and is most commonly a manifestation of underlying
autoimmune disease, particularly SLE and APS.
The relationship between female sex hormones and specific
movement disorders remains complex. RLS and chorea related
to underlying autoimmune disease are clearly exacerbated by
high estrogen states and pregnancy. Though preclinical models
of PD suggest that estrogen is neuroprotective, conclusions
from epidemiological studies are conflicting. There is currently
no role for estrogen in the treatment of movement disorders.
Research exploring genetic, epigenetic, and hormonal effects
on sex differences in brain development and neurodegenera-
tion may provide more insight and may optimize treatment of
movement disorders in women in the future.
Seminars in Neurology Vol. 37 No. 6/2017
658 Movement Disorders in Women Baker et al.
Conflict of Interest
None.
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