Most sleep alterations are not gender specific, but some sleep disorders occur in women with idiosyncratic variations that are worth considering. Restless legs syndrome appears with relative frequency during pregnancy and is more common in older women than in older men. Also, insomnia and parasomnias like sleep-related eating disorder are more prevalent in women. I will cover these subheadings independently. Nightmares and post-traumatic stress disorder are also more common and intense in women,1 probably because women suffer a high level of distress when experiencing negative dreams, particularly in adolescence and early adulthood. The latter two conditions are best addressed in the context of their behavioral and psychiatric co-morbidities.

Restless Legs Syndrome
Restless legs syndrome (RLS) is a common, frequently undiagnosed sensorimotor disorder that impairs sleep and reduces the quality of life. It is characterized by an urge to move the legs, usually with uncomfortable leg sensations, a worsening of symptoms at rest or inactivity, an aggravation of symptoms in the evening and at night, and relief with movement, walking, or stretching. RLS affects five to 10 percent of the general population, increases with age, and is more prevalent in women.2,3 RLS is a dysfunction of the dopamine system. Primary RLS is idiopathic and may be familial with a genetic background, 4 whereas secondary RLS occurs with iron deficiency, renal failure, pregnancy, and advanced peripheral neuropathy of any etiology. Iron is a cofactor necessary for the production of dopamine, and its deficiency is indicated by ferritin levels in blood of less than 50ng/ml.

The presence of periodic limb movements (PLMS) in the polysomnogram (Fig. 1) supports the diagnosis of RLS. PLMS are repetitive movements of the legs, sometimes of the arms, occurring at five to 90 second intervals, often associated with arousals that reduce the quality of nocturnal sleep. Blood pressure and heart rate rise with PLMS, increasing the risk of hypertension and cardiovascular disease.5

Non-pharmacologic therapy of RLS and PLMS rests on abstention from nicotine, caffeine, and alcohol, as well as discontinuation of medications that exacerbate RLS (sedating antihistamines, dopamine-receptor antagonists and antidepressants, except bupropion; See sidebar). Leg massages, hot baths, stretching, and walking alleviate the symptoms. Iron replacement should be added when appropriate. The goal of therapy is to maintain ferritin levels above 50ng/ml. Treatment consists of ferrous sulfate 325mg plus 100mg Vitamin C one hour before or up to two hours after a meal, three times daily. In severe iron deficiency expressed by a ferritin level in blood under 10ng/ml, consideration should be given to administration of iron via intravenous infusions of 100-125mg at least two days apart.6 Pharmacologic options are dopamine agonists such as pramipexole7 and ropinirole, as drugs of choice, followed by gabapentin and low potency opioids.8 Levodopa preparations are also effective but with continued use may cause augmentation, a peculiar worsening of symptoms earlier in the day. In consequence, levodopa preparations should be limited to transient situations such as long flights, car drives and shows with forced confinement to a seat. Dopamine agonists are safe but some individuals develop excessive somnolence and compulsive behaviors including hypersexuality and pathologic gambling.9

Twenty to 25 percent of women experience RLS during pregnancy, generally in the second half.10 Symptoms stop soon after delivery, but the occurrence of RLS may herald a recurrence later in life. Opiates are the safest pharmacologic choice for treatment of RLS during pregnancy.

Insomnia
Insomnia is defined as the repeated difficulty initiating and maintaining sleep. The difficulty sets in despite adequate opportunity to sleep and results in daytime impairment.11 Insomnia in women shows some variations mostly related to biologic life-cycles. The menstrual phase worsens sleep quality in 31 percent of menstruating women.12 Pregnant women frequently describe difficulty sleeping as noted in Part I of this series. Thirty percent of pregnant women rarely or never get a good night's sleep and 84 percent experience a sleep problem a few nights per week.13 In the third trimester of pregnancy there is typically decreased total sleep time, increased number of nocturnal awakenings, and increased daytime sleepiness. Sleep is disrupted by general physical discomfort, frequent urination, back and neck pains, vivid dreams, nasal congestion, leg cramps, fetal movements, and uterine contractions. The most dramatic correlate is that women with severely disrupted sleep have longer labors and are 5.2 times more likely to have C-sections.14 Medications to treat insomnia are generally unsafe during pregnancy. In the classification developed by the US Food and Drug Administration15 drugs are classified according to their known adverse effect on the fetus both in animals and humans (Table 1). Common hypnotics such as eszopiclone, zaleplon, and zolpidem are classified as class C drugs; benzodiazepines are classified as D; and diphenhydramine—occasionally used to induce sleep—is classified as B. Pregnant women who develop severe insomnia should resort to non-pharmacologic measures such as improving sleep hygiene, exercising as recommended by the obstetrician, and avoiding the supine position in sleep. The snore shirt may be of help. It consists of a T-shirt with three soft cylinders or tennis balls sewed to the back. The discomfort produced when turning on the back forces the individual to sleep on her side. Naps during the day are acceptable if short and not too close to bedtime.

Insomnia complaints increase in menopause, an epoch in the life-cycle that is associated with sleep complaints in 35-60 percent of women.16 Commonly associated disorders are pain syndromes, fibromyalgia, depression, RLS and nocturnal sleep-related eating disorder. Insomnia in menopause should be considered a multifactorial alteration in which aging plays an important role. Psychiatric disorders and chronic medical conditions are important risk factors. Hormone replacement therapy (HRT) users report improvement in the quality of nocturnal sleep in menopause,17 a phenomenon that suggests a strong influence of hormones in sleep duration, depth and continuity. Similarly, hot flashes are commonly associated with insomnia in 80 percent of women18 and also respond favorably to HRT. Unfortunately there are significant risk factors associated with HRT, including breast cancer, stroke, heart disease, vascular dementia, and other forms of dementia.

For non-pregnant women, the general approach to the treatment of insomnia starts with the investigation of possible physical factors affecting the quality of sleep including sleep apnea, RLS and PLMS. Suspicion of these conditions indicates the need to refer to a sleep specialist and perform a polysomnography. Cognitive behavioral therapy alone or in combination with pharmacologic treatment with antidepressants, anxiolytics, or hypnotics is effective and most often should be preceded by a consultation with a sleep specialist.

Sleep-Related Eating Disorder
Sleep-related eating disorder (SRED) refers to recurrent episodes of involuntary eating and drinking during partial arousals from sleep with adverse consequences. Episodes occur without control by the individual. There is generally no recall but a small number of patients have some awareness and retain fragmented memory of the episode. The diagnostic criteria set forth by ICSD-211 include consumption of peculiar foods in bizarre combinations at times with inedible substances, like frozen pizza, buttered cigarettes, raw bacon, cat food, coffee grounds, and cleaning solutions. In addition, there is sleep disruption with complaints of non-restorative sleep, daytime fatigue and somnolence. Sleep-related injuries may occur; Examples are burns, lacerations, poisoning, and injuries from inappropriate use of kitchen utensils or internal lesions from eating inedible substances. Patients may gain weight—mean weight gain 12.6 kg19—and become depressed. Sweets, pasta, peanut butter, milk and dairy products are preferred items. Sixty to 83 percent of SRED patients are women depending on the series reported.20 SRED is more common between the ages of 22 and 40 years. Episodes may occur nightly, sometimes several times per night. Triggering factors are hypoglycemic states, Kleine-Levin syndrome, reflux esophagitis, peptic ulcer disease, and zolpidem administration.21 Cessation of smoking or drinking alcohol has also been reported as triggering events.19 SRED should be considered a final common pathway emerging from a broad range of clinical disorders. The episodes appear in all stages of sleep and therefore may occur at any time during the night. The differential diagnosis should be made with the night-eating syndrome that refers to eating during nocturnal awakenings with total recall and control of the events. The treatment of SRED includes elimination of triggering factors and treatment of underlying disorders such as sleep apnea. Topiramate is effective in doses of 100- 200mg at bedtime. Alternative therapies are dopamine agonists, opiates, clonazepam, bupropion, trazodone and levodopa.

Summary
Several sleep-related disorders including RLS, insomnia, and sleep-related eating disorder are more prevalent and intense in women. The presenting complaint may be fatigue, non-restorative sleep or insomnia. It is important to reach a correct diagnosis because specific treatment is possible in most cases. Referral to a sleep disorders center and in many instances overnight polysomnography are recommended, not only to reach a correct diagnosis, but also to identify co-morbid sleep-related conditions that may act as precipitating factors.

Dr. Culebras is Professor of Neurology, Upstate Medical University and Consultant, The Sleep Center at Community General Hospital in Syracuse, New York.