In end-stage renal failure, screening for uremia should
be considered because this can trigger symptoms.
CASE 59-4, QUESTION 2: What is the difference between RLS and PLMS?
In addition to the presence of RLS, the symptoms reported by the spouse of J.J. are
likely related to PLMS. These are also known as nocturnal myoclonus and 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.
154 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
155 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 whether her medical history
revealed the possibility of sleep apnea, because there is a high association between
PLMS and upper airway resistance.
symptoms. What pharmacologic therapy should be selected? What nonpharmacologic therapies should be
It is important to rule out possible reversible causes before treating RLS. Iron
supplements can potentially cure RLS symptoms in patients found to be iron
If J.J. is iron deficient, she should be prescribed 50 to 65 mg of
elemental iron 1 to 3 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 her symptoms and to select appropriate
Several classes of medications are effective for treating RLS.
Dopaminergic therapies are most consistently effective in relieving RLS symptoms,
improving sleep, and reducing leg movements. High-quality evidence has found that
levodopa/carbidopa improves RLS symptoms.
preferred dopaminergic class to treat RLS because they are longer acting than
levodopa, which allows for more sustained efficacy and control of symptoms
158 J.J. should be started on either ropinirole (0.25
mg initially, up to 0.5–4 mg/day) or pramipexole (0.125 mg initially, up to 0.5
mg/day), because both are FDA-approved for treating RLS. Although rotigotine is
approved and supported by guidelines, the transdermal formulation may limit use in
the early titration phases of RLS management.
50 Several randomized, controlled
clinical trials have documented efficacy of these agents in both objective and
subjective ratings of improvement by patients and clinicians with either short- or
158 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
Other medications may also provide benefit in RLS. Guidelines recommend the
use of pregabalin and gabapentin enacarbil.
158 As a result of their mechanisms
of action, these agents may be helpful if JJ had RLS involving neuropathic pain or if
she could not tolerate dopaminergic therapy. Though studied, there are inconclusive
data to support the use of benzodiazepines, opiates, anticonvulsants, and
158 Opiates may be helpful in patients who experience significant pain
related to RLS, but these agents have not proven to conclusively treat RLS
158 Risks associated with the use of opiates, including respiratory
depression and addiction, should be reviewed with the patient prior to initiation.
Benzodiazepines and opiates should be avoided in concomitant sleep apnea due to
their ability to suppress respiratory drive.
In addition to pharmacologic therapy, 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.
152 Counter stimuli such as massage
or hot baths may also be helpful.
every night, and are now painful. How should her therapy be further adjusted?
J.J. is likely experiencing augmentation, a common problem with long-term use of
dopaminergic drugs, particularly levodopa.
159 Augmentation is described as a
progressive worsening of RLS symptoms after an initial improvement and is
manifested by gradually intensified symptoms that occur earlier in the evening and
spread to other parts of the body.
It is the most common side effect occurring with
long-term use (>3 months) of dopaminergic agents, and usually occurs 6 to 18 months
152 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.
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
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%
161 The primary treatment strategy for the management of
augmentation is to withdraw the dopaminergic agent and substitute this with
nondopaminergic agents. Given her presentation, J.J. should have her
carbidopa/levodopa discontinued. She should be counseled that her symptoms will
likely rebound severely for 48 to 72 hours, but approximately 4 to 7 days later her
symptoms should gradually return to baseline or pretreatment state.
With the discontinuation of carbidopa/levodopa in J.J., an alternative therapy
should be selected. The selection of an alternative agent in cases in which the initial
therapy failed or augmentation occurs must be approached on an individual basis.
Although a number of agents are available to choose from, clinical experience
generally guides the decision because lack of comparative trials precludes
development of any formal recommendations. Because J.J. describes increasing pain
with her RLS, it would be appropriate to initiate a trial of gabapentin encarbil or
pregabalin. If ineffective or not tolerated, J.J. could be prescribed an opiate to
manage her pain. Hydrocodone, oxycodone, methadone, codeine, and tramadol have
152 Risks associated with opiate use, including respiratory
depression and addiction, should be discussed in detail with J.J. prior to initiation.
Augmentation does not prevent a future reintroduction of dopaminergic therapy; in the
case of J.J., a dopamine agonist could be added after an extended dopaminergic free
period if her symptoms are not completely controlled with nondopaminergic agents
or if her symptoms were not painful.
QUESTION 1: K.H. is a 52-year-old white female office manager who was referred to a neurologist for
Beginning in the mid-20th century, the term essential tremor (ET) has been
consistently used to describe a kinetic tremor for which no definite cause has been
established. ET is a common neurologic disorder with an estimated incidence of 616
cases/100,000 person-years, and a prevalence of about 0.9% to 4.6%.
its prevalence, it is underrecognized and undertreated, likely because it has been
traditionally viewed as a monosymptomatic disorder of little consequence. More
recently, it is recognized to be complex and progressive, resulting in significant
disability in ADLs and job performance, and social embarrassment.
incidence and prevalence of ET increase with age. In addition, ethnicity and family
history of ET are consistently identified risk factors; it is approximately 5 times more
common in whites than in blacks, and approximately 50% of patients report a
positive family history. The latter finding suggests that genetic predisposition may
play a role in ET; however, differences in intrafamilial onset and severity suggest
environmental factors may also influence underlying susceptibility to the disease.
found in elevated concentrations in patients with ET compared with normal control
Because parkinsonian tremor and ET are the most common forms of tremor
observed in practice, it is important to distinguish between the two because the
treatments differ substantially. Tremor should first be identified as either an action
(kinetic, postural, and isometric) or resting tremor. The defining feature of ET is a
bilateral, largely symmetrical, 5- to 10-Hz kinetic and postural tremor of the arms.
The tremor can also affect the head or voice. The symptoms must be present for
greater than 5 years and must not be attributable to other causes such as tremorogenic
165 Although both kinetic and postural action tremors can be present in ET and
PD, the presence of resting tremor is much more common in PD. Lack of resting
tremor and absence of bradykinesia or rigidity in K.H. suggest the tremor is not
parkinsonian. She describes interference of her tremor occurring with voluntary
movement, such as in her ADLs and drinking from a cup. Other signs and symptoms
that support a diagnosis of ET include her age, family history, large and tremulous
handwriting (as opposed to micrographia in PD), and improvement in tremor with
alcohol consumption. Table 59-7 summarizes the similarities and differences of ET
Differentiation of Essential Tremor and Parkinson’s Disease (PD)
Characteristic Essential Tremor Parkinson’s Disease
Kinetic tremor in arms, hands, or head ++ ++
Hemibody (arm and leg) tremor 0 ++
Kinetic tremor > resting tremor ++ +
Resting tremor > kinetic tremor 0 ++
Usual age of onset (years) 15–25, 45–55 55–65
Symmetry Bilateral Unilateral > bilateral
Family history of tremor +++ +
Response to anticholinergics 0 ++
Handwriting analysis Large, tremulous script Micrographia
0, not observed; +, rarely observed; ++, sometimes observed; +++, often observed.
Several medications and substances are known to cause tremor, and all patients
should have thorough medication history to rule out these causes. Medications
commonly implicated include corticosteroids, metoclopramide, valproate,
sympathomimetics (e.g., albuterol, amphetamines, pseudoephedrine), SSRIs, tricyclic
antidepressants, theophylline, and thyroid preparations.
tobacco, and chronic alcohol use can cause tremor that resembles ET. K.H. does not
report taking any regularly prescribed medications; however, she should be
questioned regarding any over-the-counter medication use as well as her alcohol use
and caffeine and smoking habits.
The diagnosis of ET is based solely on clinical examination and neurologic
history. Neuroimaging is not useful, and there are no available biologic markers or
diagnostic tests that are specific to ET. The evaluation of the tremor that K.H. is
experiencing should include laboratory analysis to rule out possible medical
conditions associated with tremor. Such conditions may include the presence of
hyperthyroidism or Wilson disease (particularly in patients younger than 40 years of
CASE 59-5, QUESTION 2: What therapies are effective in treating ET? How should K.H. be treated?
Patients with ET who have mild disability that does not cause functional
impairment or social embarrassment can go without treatment. Because K.H. is
experiencing tremor that is interfering with her occupation and causing social
embarrassment, she should be considered for pharmacotherapy (Table 59-8). It is
important to note that although effective treatments exist, tremor is rarely eliminated
completely. Factors predicting lack of response have not been readily identified.
Propranolol, a nonselective β-adrenergic receptor blocker, or primidone, an
anticonvulsant, is recommended as first-line agent to treat ET.
typically effective in doses of at least 120 mg/day, with about 50% of patients having
171 Long-acting propranolol is as effective as the regularrelease formulation. Other beta-1 (β1
)-selective blockers such as atenolol and
metoprolol have also been studied, but with mixed findings.
demonstrated greater efficacy than these β1
-selective agents, suggesting that blockade
receptors is of importance. β-adrenergic receptor blockers with intrinsic
sympathomimetic activity, such as pindolol, appear ineffective in ET.
should be exercised with propranolol in patients with asthma, congestive heart
failure, diabetes mellitus, and atrioventricular block.
Pharmacotherapy for Essential Tremor
Propranolol 10 mg every day to BID 120–320 mg divided every
Atenolol 12.5–25 mg every day 50–150 mg every day Bradycardia, fatigue,
Nadolol 40 mg every day 120–240 mg every day Bradycardia, fatigue,
Primidone 12.5 mg every day at
Gabapentin 300 mg every day in
Topiramate 25 mg every day 200–400 mg divided BID Appetite suppression,
Pregabalin 75 mg BID 75–300 mg divided BID Weight gain, dizziness,
Alprazolam 0.125 mg every day 0.75–3 mg divided TID Sedation, fatigue, ataxia,
Clonazepam 0.25 mg every day 0.5–6 mg divided every
Botulinum toxin A Varies by injection site: 50–100 units/arm for hand
tremor; 40–400 units/neck for head tremor; 0.6–15
units/vocal cords for voice tremor; repeat no sooner
than every 3 months (extend as long as possible)
BID, 2 times daily; TID, 3 times daily.
Several studies have compared propranolol and primidone in ET, and they are
considered to have similar efficacy.
169–171 Primidone is metabolized to a
phenobarbital-based metabolite; however, phenobarbital is inferior to primidone in
171 Acute adverse effects of primidone include nausea, vomiting, and
ataxia, which can occur in up to one-fourth of patients, often limiting its use.
Primidone should be initiated at 12.5 mg/day and administered at bedtime to reduce
the occurrence of acute side effects. It can be titrated gradually as tolerated up to 750
mg/day in divided doses, although side effects become more common at doses
Other agents that have demonstrated variable efficacy in ET include gabapentin,
pregabalin, topiramate, and benzodiazepines (specifically, alprazolam and
170 They are generally considered to be less-proven, second-line
therapies. Adverse effects and potential for abuse should be considered when an
If oral pharmacotherapy options for ET are not beneficial, intramuscular injections
of botulinum toxin A or surgical treatments can be used in selected patients.
Targeted botulinum toxin A injections can reduce hand, head, and voice tremor;
however, they are associated with focal weakness of the adjacent areas.
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