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subjects failed to find a significant difference, 73 , 74 whereas
one study (the only one performed in early evening)
reported less binding to D 2 receptors for the patients
with RLS. 75 These studies also looked at binding for
the dopamine transporter and failed to find any significant
difference between patients with RLS and control
subjects. In contrast, two 6-[ 18 F] luoro-L-dopa PET
studies reported small decreases in binding for patients
with RLS. 71 , 76
There have been two cerebrospinal fluid (CSF) studies
on series of patients with RLS compared with control
subjects; both failed to find any significant difference for
either homovanillic acid or biopterin that was unrelated to
age. 77 , 78 A more-recent report, however, notes that in two
different studies with CSF obtained at different times
of the day (10 PM and 10 AM), there were significant
increases in 3-ortho-methyldopa that in one of the samples
correlated with increased CSF homovanillic acid. 79 This
suggests a possible increase in dopaminergic activity.
Overall, aside from the remarkable pharmacologic response
to dopaminergic medications and the one CSF finding
regarding 3-ortho-methyldopa increases, there is scant
consistent evidence supporting any significant dopaminer-
gic abnormality in RLS.
The positive pharmacologic response to opioid treat-
ment in RLS and the reversal of that treatment with the
opiate receptor blocker naloxone has also been used as an
argument in favor of the hypothesis of an endogenous
opiate system dysfunction in RLS and PLMS. 80 However,
pharmacologic data suggest that the effect of L-dopa is not
secondary to the action of dopamine on the opioid system,
but rather the reverse. An opiate receptor PET scan study
showed no difference in postsynaptic opiate receptor
binding between RLS patients and controls, but there was
an inverse correlation between the degree of opiate recep-
tor binding and the severity of RLS. 81 A preliminary
autopsy study showed decreased levels of the endogenous
opioids beta endorphin and met-enkephalin in RLS
patients compared to controls. 82
Hypocretin (orexin) has been reported to be increased
in the CSF of early-onset RLS patients. 83 Hypocretin
arousal is largely mediated by histamine, and it was found
that RLS symptoms can be severely exacerbated by anti-
histamines, 84 suggesting a histaminergic abnormality that
might be related to increased hypocretin.
compared with age-matched control subjects. 90-92 Autopsy
analyses of substantia nigra tissue from patients with RLS
compared with age-matched control subjects have revealed
a complex pattern of iron-related abnormalities. 93 These
data suggest that RLS involves an iron deficiency in the
substantia nigra that may be associated with an abnormal-
ity in the regulation of the transferrin receptor.
These findings, combined with the success of intrave-
nous iron treatments, support the putative concept that a
brain iron deficiency causes RLS in many patients. Of
interest is the role of iron in dopaminergic transmission in
the CNS. Iron deficiency is associated with increased
extracellular dopamine, decreased dopamine transporter,
and decreased D 2 and D 1 receptors in the striatum of rats.
Thus abnormalities in iron metabolism or environmental
factors producing brain iron deficiency may be a primary
cause of RLS symptoms or they may be factors contribut-
ing to the development of RLS.
It is important to inform patients to maintain good sleep
hygiene to prevent the development of psychophysiologic
insomnia, which is frequently encountered in RLS . Patients
should also refrain from drinking alcohol in the evening
because it aggravates symptoms in most patients. Some
patients report that they alter their sleep patterns to
accommodate their RLS. 94
Four categories of medications are commonly prescribed
to treat RLS: dopaminergic agents, opioids, anticonvul-
sants, and benzodiazepines.
Several open-label and placebo-controlled studies docu-
mented the short-term efficacy and long-term benefit of
levodopa, given with a dopa-decarboxylase inhibitor, either
benserazide or carbidopa, in idiopathic RLS and RLS asso-
ciated with uremia. Several adverse effects were reported
in patients treated with levodopa, including nausea, vomit-
ing, tachycardia, orthostatic hypotension, hallucinations,
insomnia, daytime fatigue, and daytime sleepiness.
Two adverse effects were more specifically studied in
RLS patients treated with levodopa: morning rebound and
RLS augmentation. Morning rebound is characterized by
the presence of RLS symptoms occurring de novo as a
consequence of evening or nighttime treatment. Augmen-
tation 95 is characterized by an earlier onset of symptoms
by at least 4 hours or by an earlier onset between 2 and 4
hours plus at least one of the following compared to
symptom status before treatment: shorter latency to symp-
toms when at rest, extension of symptoms to other body
parts, greater intensity of symptoms, and shorter duration
of relief from treatment. One group 96 found augmentation
in 29 of 36 (81%) patients treated with levodopa. Increased
severity of RLS and higher dosage of levodopa were associ-
ated with higher risk of developing augmentation. Another
recent study 97 showed augmentation in 36 of 60 (60%)
Ekbom was among the first to note that RLS commonly
occurs with iron-deficiency anemia. 85 In addition to iron-
deficiency anemia, end-stage renal disease, pregnancy,
low-density lipoprotein apheresis, and gastric surgery have
been clearly established as causes of secondary RLS. All of
these conditions involve iron deficiency. Treatment of
iron-deficiency anemia can completely resolve all RLS
symptoms for some patients. 86-88
One study showed no significant differences in serum
ferritin or iron, but the CSF ferritin was reduced and
transferrin was increased, consistent with a CNS iron defi-
ciency occurring despite apparently normal peripheral iron
status. 89 MRI and ultrasound studies of regional brain iron
content have consistently shown reduced brain iron,
particularly in the substantia nigra for subjects with RLS
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