confirmed by a Doppler

ultrasound at 5 weeks’ gestation. She has a significant history of having multiple DVTs in her prior pregnancies, and

her thrombophilia workup was negative. During her pregnancy, she was on therapeutic low-molecular-weight heparin (LMWH) 80 mg (weight, 76 kg) SC every 12 hours. Her

dosage was increased to 100 mg SC every 12 hours after

subsequent anti-factor Xa levels were subtherapeutic. Her

LMWH was discontinued 24 hours before she received an

epidural for labor pain. After delivery, H.P. is restarted on

LMWH and then changed to warfarin on day 5. H.P. also is

breast-feeding. Do either of these drugs present a risk to

the nursing infant?

Heparin does not cross into breast milk (see Drug Excretion

in Human Milk section) because of its high molecular weight

(∼12,000) and is therefore safe in breast-feeding. Warfarin is a

weakly acidic drug (pKa 5.05) that is highly ionized at physiologic pH (>99%) in maternal serum.246 It also is highly protein

bound (97%).43 These pharmacokinetic parameters make warfarin very unlikely to transfer into breast milk. Case reports in

lactating mothers confirm that warfarin is not detected in breast

milk or infant plasma.43 The American Academy of Pediatrics

(AAP) considers warfarin compatible with breast-feeding,101 and

it is widely considered to be safe in breast-feeding.249 There are

no studies to guide duration of anticoagulation in women who

have had a DVT associated with pregnancy. However, most recommend anticoagulation for at least 6 weeks post partum, with

total duration of anticoagulation of a minimum of 6 months

after the thromboembolic event.249 H.P. can safely breast-feed

her infant while she is on LMWH and warfarin.

Estimating Infant Exposure

The actual amount an infant will ingest is difficult to determine

owing to varying maternal, drug, and infant parameters. Available data generally are from single or small numbers of case

reports or pharmacokinetic studies involving few mother–infant

pairs. An M/P ratio is sometimes used alone as the basis for a

recommendation, but this should be avoided because its accuracy can be affected by many factors such as the time of sampling

after maternal ingestion (peak versus steady state), dose, length

of therapy, route of administration, and milk composition.250 A

relative infant dose (RID) is sometimes reported in resources or

literature, which is expressed as a percentage of the maternal

dose.251 Generally, an RID of less than 10% is interpreted as an

acceptable level. This must be interpreted with caution, however, taking into account other variables such as the age and

health of the infant and the safety profile of the drug. It is also

important to note that these are estimated values, often based

on data collected from one or only a few individuals. Applying

these equations using measurements specific to a woman and

her infant is not clinically practical, however. Compared with the

M/P ratio, experts believe that the RID is a better estimate of

infant exposure.

Sampling during maternal peak drug concentration attempts

to approximate the highest amount of drug that can reach the

infant. This assumption is inherently flawed because peak drug

concentration in the mother does not necessarily equate with

peak drug concentration in milk at that same point in time.245,250

The amount of drug an infant actually receives also depends

on the volume of milk ingested. Even if a drug has a high M/P

ratio, the actual amount received by the infant could be low

if only a small volume of milk was consumed. Therefore, an

M/P ratio describes the likelihood of drug excretion into breast

milk, but it does not indicate the level of infant exposure. In

general, drugs with lower M/P ratios (<1) are preferred over

RLS, restless legs syndrome.

1381Parkinson Disease and Other Movement Disorders Chapter 57

with uncomfortable paresthesias or dysesthesias felt deep inside

the limbs. Patients describe the sensation as “creepy-crawly” or

“like soda water in the veins.”147 The symptoms may occur unilaterally or bilaterally, affecting the ankle, knee, or entire lower

limb. With progressive disease, symptoms can begin earlier in

the day, and progressive involvement of the arms or trunk may

occur. Temporary or partial relief of symptoms can be achieved

with movement. If patients attempt to ignore the urge to move

the legs, akathisia will progressively intensify until they either

move their legs or the legs jerk involuntarily.147 Symptoms usually manifest in a circadian pattern with onset or worsening during nighttime hours (usually between 6 pm and 4 am, with peak

symptoms between midnight and 4 am). The circadian pattern

persists even in patients with inverted sleep–wake cycles. As a

result of their symptoms, patients with RLS become “nightwalkers,” spending significant time walking, stretching, or bending

the legs in an effort to relieve symptoms.

J.J.’s case is an example of a classic presentation of RLS. The

prevalence of RLS increases with age and appears to be slightly

more common in women.148 She describes “creepy-crawly” sensations that are relieved partially with walking, a core feature

of RLS. Her symptoms are worse during the evening hours. J.J.

reports her mother suffered from similar symptoms. The observation of a familial tendency suggests a genetic component, and

several chromosomal loci have been linked to the disease.149

A strong family history of RLS appears to correlate with an

early age of onset (<45 years), whereas presentation at a later

age is associated with more neuropathy and accelerated disease

progression.147

Most cases of RLS are considered primary or idiopathic; therefore, the diagnosis does not require elaborate laboratory tests

or diagnostic procedures. Several conditions are associated with

RLS, and include iron deficiency, pregnancy, and end-stage renal

disease. A thorough medical history should be taken in J.J. to

rule out reversible causes of RLS or other conditions with similar characteristics. Several medications and substances are known

aggravators of RLS, including medications with antidopaminergic properties, such as metoclopramide and prochlorperazine.

Nicotine, caffeine, and alcohol can aggravate RLS through their

own ability to interfere with quality of sleep. Additionally, SSRIs,

tricyclic antidepressants, and commonly used over-the-counter

antihistamines, such as diphenhydramine, can trigger or worsen

RLS symptoms.149 Hypotensive akathisia, leg cramps, and other

conditions such as arthritis, which can cause positional discomfort with extended periods of sitting in one position, can mimic

RLS. These conditions are easily distinguished from RLS because

they are usually localized to certain joints or muscles, do not have

a circadian pattern, and are not associated with an uncontrollable

urge to move.

With an otherwise unremarkable physical examination and

medical history, specific laboratory tests that should be performed in J.J. are limited to serum ferritin and percent transferrin saturation (total iron-binding capacity) to rule out iron

deficiency anemia. It is important to note that ferritin is an

acute-phase reactant and may be artificially elevated if there is

an underlying inflammatory or infectious condition. Therefore,

the ferritin level should always be accompanied by the percent transferrin saturation. Several studies have documented a

relationship between low ferritin concentrations and increased

symptom severity.150,151 J.J. is postmenopausal, so a pregnancy

test is not necessary. Polysomnography is not usually indicated

unless there is clinical suspicion for sleep apnea or if sleep remains

disrupted despite treatment of RLS. When clinical suspicion from

the physical examination or medical history suggests a possible

peripheral nerve or radiculopathy cause, a routine neurologic

panel, including thyroid function tests, fasting glucose, vitamins

B6 and B12, and folate, should be obtained.149 Renal function tests

(serum creatinine and blood urea nitrogen) can be obtained to

screen for uremia, although RLS does not usually occur in this

situation until the patient has reached end-stage renal failure.

CASE 57-5, QUESTION 2: What is the difference between

RLS and periodic limb movements of sleep (PLMS)?

In addition to the presence of RLS, J.J.’s spouse has

noticed what are likely PLMS. PLMS, also known as nocturnal myoclonus, are best described as involuntary clonic-type

movements of the lower extremities while sleeping that usually

involve bilateral ankle dorsiflexion, knee flexion and hip flexion.

Approximately 80% of patients with RLS will also have PLMS,

but PLMS can occur by itself and is also associated with significant sleep dysfunction. The diagnosis of PLMS usually requires

a polysomnogram; the universally accepted criteria for diagnosis

are that there should be at least four periodic leg movements

(PLMs) in a 90-second period, with contractions typically lasting

0.5 to 5 seconds and recurring every 5 to 90 seconds.152 A PLM

index (PLMI) is calculated by dividing the total number of PLMs

by sleep time in hours; an index of more than 5 but less than

25 is considered mild, a PMLI of more than 25 and less than 50

is moderate, and a PLMI of more than 50 is severe. The diagnosis of PLM disorder can be made when patients present with

insomnia, tiredness, and daytime sleepiness in the presence of a

high PLMI.153 There is considerable overlap in the treatments of

PLMS and RLS. Because J.J. clearly has RLS there is no need to

perform a polysomnogram. The diagnosis of PLMS in her case

is incidental and would not alter the clinical management. An

exception to this would be if J.J.’s medical history revealed the

possibility of sleep apnea, as there is a high association between

PLMS and upper airway resistance154; a polysomnogram would

then be indicated.

Treatment

CASE 57-5, QUESTION 3: The decision is made to treat

J.J.’s symptoms with medication. What pharmacologic therapy should be selected? What nonpharmacologic therapies

should be recommended?

Figure 57-6 presents an approach to the treatment of RLS.

Iron supplements can potentially cure RLS symptoms in patients

found to be iron deficient.155 If J.J. is iron deficient, she should

be prescribed 50 to 65 mg of elemental iron one to three times

daily on an empty stomach with 200 mg of vitamin C to enhance

absorption. After ruling out possible reversible causes of RLS,

it is important to establish the frequency of J.J.’s symptoms and

whether or not they are associated with pain. This information

will help determine appropriate therapy.

Several classes of medications are effective for treating RLS.156

Dopaminergic therapies are most consistently effective in relieving RLS symptoms, improving sleep, and reducing leg movements. The available dopaminergic therapies that have been

evaluated in RLS include carbidopa/levodopa, pramipexole,

ropinirole, bromocriptine, and rotigotine (not currently available in the United States).156,157 Dopamine agonists are now the

preferred dopaminergic class to treat RLS because they are longer

acting than levodopa, which allows for more sustained efficacy

and control of symptoms throughout the entire night. J.J. should

be started on either ropinirole (0.25 mg initially, up to 0.5–8.0 mg/

day) or pramipexole (0.125 mg initially, up to 0.5–1.5 mg/day),

as both are both Food and Drug Administration–approved for

treating RLS. Several randomized, controlled clinical trials have

1382Section 13 Neurologic Disorders

Bothersome leg symptoms at night

Meets criteria for

diagnosis of RLS

Discontinue aggravators Replace iron if deficient

Rule out reversible causes

Nonpainful symptoms Painful symptoms

Gabapentin

Opiate

Dopamine agonist

Pregabalin

Dopamine agonist

Benzodiazepine

Carbidopa/levodopa

Benzodiazepine

Opiate

Gabapentin

Pregabalin

Clonidine

Carbamazepine

Valproic Acid

Topiramate

Combination

therapy if symptoms

not relieved

Try behavioral therapies

Initial

choice

First-tier

alternatives

Second-tier

alternatives

FIGURE 57-6 Approach to the treatment of restless legs syndrome.

documented efficacy of these agents in both objective and subjective ratings of improvement by patients and clinicians with

either short- or long-term use.158–162 Ropinirole and pramipexole do not appear to differ with regard to efficacy or adverse

effects. When used for RLS, ropinirole and pramipexole should

be administered 2 hours before bedtime. Adverse effects are similar to those seen with the use of these agents in PD, and patients

should be counseled accordingly.

Other medications may also provide modest benefit in

RLS, including benzodiazepines, opiates, anticonvulsants, and

clonidine.156 With the exception of gabapentin or opiates,163,164

which could be considered initially if J.J.’s discomfort was primarily caused by pain, all are considered to be alternatives to the

dopaminergics. The dosing and adverse effects of the benzodiazepines used in RLS are similar to their use in the general population. No evidence suggests that one benzodiazepine is more

effective than another for RLS, and selection should be based on

the patient’s primary sleep disorder complaint. For example, a

newer short-acting benzodiazepine with quick onset of action

may be preferred in a patient whose primary problem is getting

to sleep. Older anticonvulsants such as carbamazepine and valproic acid may be efficacious, but lack substantial study in RLS

patients.156 Newer agents such as pregabalin and topiramate have

also been studied with favorable preliminary results.156,165

In addition to a dopamine agonist, nonpharmacologic therapies and behavioral techniques should also be recommended for

J.J. Most important among these include discontinuing all RLS

aggravators and practicing good sleep hygiene. Physical and mental activity (e.g., reading, playing card games, or working on the

computer) if patients are unable to sleep can reduce symptoms.149

Counter stimuli such as massage or hot baths may be helpful.149

CASE 57-5, QUESTION 4: After carefully considering the

costs of therapy, J.J. and her physician choose levodopa

to treat her RLS. She initially responds well to the therapy. One year later, J.J. returns for follow-up. Her dose of

carbidopa/levodopa has progressively increased to three

25/100 mg tablets at bedtime. She describes continued

worsening of her symptoms, and they do not seem to be

relieved with increasing doses of carbidopa/levodopa. Her

symptoms are now starting earlier in the evening, occur

almost every night, and are now painful. How should J.J.’s

therapy be further adjusted?

J.J. is likely experiencing augmentation, a common problem with long-term use of dopaminergic drugs, particularly

levodopa.166 Augmentation is described as a progressive worsening of RLS symptoms after an initial improvement, and is

1383Parkinson Disease and Other Movement Disorders Chapter 57

manifested by gradually intensified symptoms that occur earlier in the evening and spread to other parts of the body.167 It

is the most common side effect occurring with long-term use

(>3 months) of dopaminergic agents, and usually occurs 6 to

18 months after therapy is initiated.149 Doses of dopaminergic

agents are often increased in response; however, with each incremental dose increase symptoms progress more rapidly until they

may occur continuously throughout the day.149 Although augmentation has been clinically recognized for many years, it has

not been systematically studied. The exact etiology is uncertain,

but it likely relates to the finding that RLS, unlike PD, is actually

a hyperdopaminergic condition with an apparent postsynaptic

desensitization that overcompensates during the circadian low

point of dopaminergic activity in the evening and night. Adding

dopamine in the evening initially corrects the symptoms, but

ultimately leads to increasing postsynaptic desensitization.

The highest risk for augmentation is with levodopa. An estimated 50% to 85% of patients on levodopa will develop augmentation, compared with only 20% to 30% with dopamine

agonists.156 The primary treatment strategy in dealing with augmentation is to withdraw the dopaminergic agent and substitute other nondopaminergic agents. Given her presentation, J.J.

should have her carbidopa/levodopa discontinued. She should