CASE
A 52-year-old female presented to the clinic with symptoms of daytime somnolence and nocturnal leg discomfort. She described the leg discomfort as an “urge to move” and “tingly.” The sensation disappeared with walking or activity. The patient also reported that she had leg symptoms in the daytime. The results of a physical examination, including neurologic and musculoskeletal assessments, were unremarkable. Results were normal on the CBC, the basic metabolic panel, and the test for thyroid stimulating hormone.
On nocturnal polysomnography, decreased sleep efficiency (67%) was noted as calculated by the ratio of time spent asleep to time spent in bed. An arousal awakening index of 17.3 per hour suggested significant sleep fragmentation. The patient's sleep architecture demonstrated a predominance of stage II sleep, comprising 58.3% of the sleep; and deep delta wave sleep comprising stages III and IV was decreased to 7.9%. Sleep latency was 27 minutes. Rapid eye movement (REM) latency was 219.5 minutes, which is significantly prolonged. The patient had an increased apnea/hypopnea index of 8.5 per hour (normal, <5/hour). There were significant periodic limb movements present, with 355 total count noted during the study and an index of 70.1 per hour. Seven out of the 355 were associated with arousals. The patient was titrated on 8 cm of nasal continuous positive airway pressure (CPAP) with a C-flex of 3 for treatment of apnea/hypopneas.
At the 1-month follow-up visit, the patient reported that her daytime somnolence had diminished and she had increased energy. She was using the CPAP device and tolerating it well. Eighteen months later, however, she returned to the clinic reporting a nocturnal “urge to move” and restless sensations in her legs that were not relieved with the use of CPAP. Eventually, the leg symptoms progressed to the level where the patient took several hours to fall asleep. She stopped using the CPAP because she needed to get out of bed often to walk to relieve her symptoms. The daytime somnolence returned. The patient was then started on pramipexole, 0.125 mg orally at bedtime titrated up to 0.5 mg. The medication and the CPAP produced only partial relief, and the patient continued to have delayed sleep onset due to the restless legs syndrome (RLS).
A physician who specializes in sleep disorders was consulted and recommended obtaining an iron and ferritin level to determine if iron deficiency was present. The patient's iron level was 16 µg/dL (normal value 26-170 µg/dL), and her ferritin was 6 ng/mL (normal value, 10-200 ng/mL). The specialist recommends treating patients with a ferritin level less than 50 ng/mL with iron infusion therapy.
The patient was started on iron sucrose infusion therapy (Venofer). She received three treatments at 2-week intervals for 6 weeks. The first treatment was 500 mg IV infused over 2 hours. The patient experienced burning and paresthesias of the feet following infusion, resulting in the dose being decreased to 250 mg IV for the 2 remaining treatments. She received a total of 1,000 mg of Venofer and was weaned off the pramipexole between the first and second doses of Venofer.
Two weeks after the last Venofer infusion, the patient reported complete resolution of the symptoms of restless legs. She had a sleep latency of only 5 to 10 minutes and now was able to sleep through the night using her CPAP. On followup testing, her iron level was 104 µg/dL and the ferritin level was 176 ng/mL.
DISCUSSION
Although the pathophysiology of RLS is unknown, CNS dysregulation,1 neurotransmitter systems (dopaminergic), and abnormal iron metabolism2 have all been considered to play a role. RLS may be associated with decreased dopaminergic neurotransmission; RLS symptoms have been observed to increase at night, when dopamine levels fall.3 Allen pointed out that “RLS improved with use of dopaminergic medications and is exacerbated with use of dopamine blockers.”2 Earley and Allen have looked at the pathophysiology of RLS in relation to CNS iron homeostatic dysregulation using MRI studies that showed reduced iron stores in the striatum and red nucleus.2,4 They also found reduced iron echogenicity in the substantial nigra on CNS ultrasound in patients with RLS.2,4
Primary RLS is considered an autosomal-dominant disorder, and clinicians should ask affected patients about a family history of the condition. A significant number (up to 50%) report that other family members describe symptoms of RLS.5 People who develop RLS at a young age (less than 45 years) are likely to have a genetic form.3 As was true in this case, the primary etiology of RLS may include iron deficiency in as high as 25% to 30% of patients.3