Sleep Medicine 15 (2014) 1473–1476
`
`Contents lists available at ScienceDirect
`
`Sleep Medicine
`
`journal homepage: www.elsevier.com/locate/sleep
`
`Original Article
`Response to intravenous iron in patients with iron deficiency anemia
`(IDA) and restless leg syndrome (Willis–Ekbom disease)
`Tahir Mehmood a, Michael Auerbach b,c, Christopher J. Earley d, Richard P. Allen d,*
`a Division of Transfusion Medicine, Department Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
`b Department of Medicine, Georgetown University, Washington DC, USA
`c Private Practice, Baltimore, MD, USA
`d Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
`
`A R T I C L E
`
`I N F O
`
`A B S T R A C T
`
`Article history:
`Received 23 December 2013
`Received in revised form 24 August 2014
`Accepted 28 August 2014
`Available online 10 September 2014
`
`Keywords:
`Restless legs syndrome (RLS)
`Iron deficiency anemia
`Willis–Ekbom disease (WED)
`Sleep
`IV iron
`Low-molecular-weight dextran
`INFeD
`
`Objectives: Iron deficiency anemia (IDA) engenders restless legs syndrome (RLS, aka Willis–Ekbom disease).
`Intravenous (IV) iron can rapidly reverse IDA and would be expected to similarly reverse RLS caused by
`IDA. This is the first consecutive case series evaluating the effects of IV iron therapy on RLS occurring
`with IDA (RLS–IDA).
`Methods: RLS–IDA patients were evaluated before and 7–12 months after a 1000-mg IV infusion of low-
`molecular-weight iron dextran (INFeD@) using validated questionnaires and standardized telephone
`interview. Patients were classified as respondent versus nonrespondent for RLS improvement.
`Results: Follow-up data were obtained on 42 (70%) of 60 consecutive RLS–IDA patients. The symptoms
`of RLS were reduced in 76% (32/42) with 47% (20/42) showing an extended response lasting >6 months.
`The response did not relate to age or gender, but tended to be less among African–Americans than Whites
`(40% (2/5) vs. 81% (30/37), p = 0.078). White respondents versus nonrespondents had higher hemoglo-
`bin levels after treatment (12.1 vs. 11.3 g/dl, p = 0.03).
`Conclusions: RLS–IDA is reduced after administration of IV iron in most cases, but the 24% failing to respond
`was higher than expected. The nonrespondents all showed below-normal hemoglobin levels (<12.5 g/
`dl) suggesting a failure of adequate treatment of the iron deficiency. IV iron treatment of the RLS with
`IDA likely requires ensuring more than minimally adequate body iron stores to support iron delivery to
`the brain. For some, this may require a dose higher than the customary 1000-mg IV iron used for the
`treatment of either IDA or RLS alone.
`
`© 2014 Elsevier B.V. All rights reserved.
`
`1. Introduction
`
`Restless legs syndrome (RLS) is a well-known neurological disease
`whose underlying pathology is associated with compromised brain
`iron status. Peripheral iron deficiency (ID) with or without anemia
`appears to be an important environmental trigger of RLS symp-
`toms [1,2]. Studies carried out in populations with iron deficiency
`anemia (IDA) report approximately 35% with RLS symptoms (RLS–
`IDA) [3,4] compared to the general US population prevalence of 5%
`[5]. It might be expected that if IDA is a primary cause or precipi-
`tant of the RLS symptoms then the treatment of IDA should largely,
`if not completely remove, the symptoms. In particular, the treat-
`ment of IDA with intravenous (IV) iron rapidly reverses IDA and
`would therefore be expected to similarly reverse RLS produced by
`
`* Corresponding author. Department of Neurology, 5501 Hopkins Bayview Circle,
`Baltimore, MD 21224, USA. Tel.: +1 410 550 2609; fax: +1 410 550 2647.
`E-mail address: richardjhu@mac.com (R.P. Allen).
`
`http://dx.doi.org/10.1016/j.sleep.2014.08.012
`1389-9457/© 2014 Elsevier B.V. All rights reserved.
`
`the IDA for most if not all patients. This would contrast with the
`IV iron treatment of RLS without IDA that reduces RLS symptoms
`in about 50% of the patients only [6,7]. Despite this obvious ex-
`pected response, there has been no prior systematic evaluation of
`the effects of IV iron on RLS–IDA. A small number of sporadic clin-
`ical cases reported that IV iron improved or eliminated RLS
`symptoms occurring with ID [2,4,8]. However, no prior study pro-
`vides the basic information about the percentage of those with RLS–
`IDA improving with this treatment, the nature of the improvement,
`the duration of the improvement, and the relation between im-
`provement and hemoglobin concentration or iron status. Gender
`and race (African–American vs. Caucasian) are known to affect iron
`status [9] and might also affect RLS–IDA response to IV iron, but this
`has also not been previously studied. This retrospective study of con-
`secutive RLS–IDA cases was designed to provide a preliminary
`exploration of RLS clinical response after a single 1000-mg infu-
`sion of low-molecular-weight iron dextran (LMW ID, INFeD@) given
`as a standard IDA treatment practice in a community-based hema-
`tology practice. Both the rate of response and factors related to
`response were determined.
`
`Pharmacosmos, Exh. 1064, p. 1
`
`

`
`1474
`
`2. Methods
`
`T. Mehmood et al./Sleep Medicine 15 (2014) 1473–1476
`
`All patients seen at one community hematology practice, as part
`of a clinical evaluation for IDA, completed a questionnaire that in-
`cluded the validated 13-item Cambridge-Hopkins RLS diagnostic
`questionnaire (CH-RLSq). The CH-RLSq sensitivity and specificity of
`87.2% and 94.4% [10], respectively, give a positive predictive value
`of 89% for an IDA population with the expected 35% prevalence of
`RLS. The treatment consisted of a single infusion of LMW ID (INFeD®)
`administered as 1000 mg/250 ml normal saline over 1 h. Subjects
`were followed up in the hematology clinic at an average of two
`months after the initial treatment. A consecutive series of 60 pa-
`tients with RLS–IDA who were treated with IV iron were contacted
`by a physician in the clinical practice approximately 12 months after
`the IV iron treatment (average 13, range 7–20 months) to deter-
`mine the response of the RLS symptoms and changes in sleep after
`the treatment. We excluded patients who had received more than
`one infusion in that interim. The standard questionnaire used for
`the patient contact included four questions: two covered patient-
`reported global impression of improvement (PGI) on a Likert scale
`(−3 much worse to +3 much better) [11] for RLS symptoms and for
`sleep quality, and two additional items covered the duration
`(months) of any improvement in the RLS symptoms and sleep quality.
`The charts were then retrospectively reviewed for pre- and post-
`iron infusion serum ferritin, total iron-binding capacity (TIBC), and
`hemoglobin levels. Serum iron and percent transferrin saturation
`can be significantly altered by recent food intake and oral iron. These
`factors were not closely monitored or controlled at the time of the
`blood sample collection and thus serum iron and percent transfer-
`rin saturation were not analyzed. De-identified data were provided
`for analyses. As this was a part of the clinical practice conducted
`by physicians in the practice evaluating treatment response for their
`patients and all data analyses were based on de-identified data, this
`was judged to be exempt from human subjects review.
`Patients were classified by their reported change in RLS symp-
`toms after treatment as nonrespondent (very much worse to no
`change, −3 to 0) or respondent (some to very much better, 1–3). As
`the minimum period between treatment and reporting on treat-
`ment outcomes was seven months after treatment, the respondents
`were further divided into limited respondents (response lasting no
`more than 6 months) and extended respondents (response lasting
`>6 months).
`
`2.1. Statistical analyses
`
`Fisher’s exact tests were used to evaluate the relation of gender and
`race to response. Unequal variance t-tests were used to evaluate
`
`Table 1
`Demographics and response to 1000 mg IV iron for IDA with RLS/WED.
`
`differences in response groups for follow-up time (months since IV iron);
`PGI; age; and for the before, after, and change in iron status. The PGI
`and both after and change in iron status were each tested for the hy-
`pothesis that improved iron status related to the response and to the
`duration of response using one-tailed t-tests. Age, follow-up time, and
`iron status before treatment were evaluated using two-tailed tests given
`no reason to assume directional hypotheses. Both the duration and
`degree of response were evaluated for linear correlation with each of
`the iron measures. For this preliminary study, the significance level was
`set at 0.05 for all analyses.
`
`3. Results
`
`3.1. Patients
`
`From the 60 patients with RLS–IDA selected for this review, six
`declined to respond to the questions, 12 could not be reached, and
`42 (70%) provided follow-up data. These 42 had a mean (±stan-
`dard deviation (sd)) age of 53.6 (±18.1) years with 14% male (6/
`42), 12% African–American (5/42), and 88% White (36/42).
`The time interval (months after IV iron) between the IV iron in-
`fusion and the phone evaluation did not differ significantly between
`respondent and nonrespondent groups (mean ± sd: 13.25 ± 4.33 vs.
`12.30 ± 4.69, respectively, p = 0.29) nor between limited- and
`extended-respondent groups (mean ± sd: 12.75 ± 4.05 vs. 13.55 ± 4.57,
`respectively, p = 0.31).
`
`3.2. RLS treatment response
`
`Seventy-six percent (32/42) reported a reduction in RLS symp-
`toms after IV iron and were considered respondents. The response
`duration lasted on average (±sd) 9.2 (±5.5) months. The degree of
`response was “very much” improved for 72% of the respondents (55%
`of total sample) and was “much” or “very much” improved for 84%
`of the respondents (64% of total sample). There were no signifi-
`cant differences between the respondent and nonrespondent groups
`for age (54.2 ± 17.8 vs. 51.7 ± 20.0, p = 0.37) or gender (percent male
`and female responding: 83% and 75%, respectively, Fisher’s exact
`>0.50). African–Americans showed a nonsignificant tendency to
`respond less than Whites (percent African–American and Whites
`responding: 40% and 81%, respectively, Fisher’s exact = 0.078) (see
`Table 1).
`The degree of response was significantly less for the African–
`Americans than the Whites. “Much” or “very much” improved
`was reported for neither (0%) of the two African–American
`
`Total sample
`Age (years)
`Avr ± sd
`Gender:
`n (% of males)
`n (% of females)
`Race:
`n (% of Blacks)
`n (% of Whites)
`
`n
`
`42
`
`6
`36
`
`5
`37
`
`Nonrespondents
`
`Limited respondents
`(response for ≤6 months)
`
`Extended Respondents
`(response for >6 months)
`
`10 (24%)
`
`51.7 ± 20.0
`
`1 (17%)
`9 (25%)
`
`3 (60%)
`7 (19%)
`
`12 (29%)
`
`56.6 ± 17.4
`
`2 (33%)
`10 (28%)
`
`1 (20%)
`11 (30%)
`
`20 (47%)
`
`52.7 ± 18.4
`
`3 (50%)
`17 (47%)
`
`1 (20%)
`19 (51%)
`
`Test for nonrespondents
`versus any response
`p < 0.0004*
`
`p > 0.50**
`
`p > 0.50***
`
`p = 0.078***
`
`Respondent defined by report of reduced RLS symptoms after treatment.
`Lasting respondent: Reported response lasting to month 6 or longer.
`Partial respondent: Reported response was lost before month 6.
`* Binomial test for 50% chance of either alternative.
`** t-test for unequal variance.
`*** Fisher’s exact for 2 × 2 contingency table with two-sided probability.
`
`Pharmacosmos, Exh. 1064, p. 2
`
`

`
`T. Mehmood et al./Sleep Medicine 15 (2014) 1473–1476
`
`1475
`
`Table 2
`Number and percentage response to 1000 mg IV iron for IDA with RLS/WED by di-
`agnosis for cause of IDA.
`
`Dx
`
`N
`
`Nonrespondent
`
`N (% sample)
`
`n
`GI bleed
`Menorrhagia
`Pregnancy
`Unknown
`Gastric Bypass
`Malabsorption
`Crohn’s
`
`42
`12
`9
`7
`7
`5
`1
`1
`
`10 (23%)
`4 (33%)
`2 (22%)
`2 (29%)
`1 (14%)
`1 (20%)
`0 (0%)
`0 (0%)
`
`Limited
`respondents
`≤6 months
`N (% any
`response)
`
`Extended
`Respondents
`>6 months
`N (% any
`response)
`
`12 (28%)
`4 (33%)
`2 (22%)
`2 (29%)
`2 (29%)
`2 (40%)
`0 (0%)
`0 (0%)
`
`20 (48%)
`4 (33%)
`5 (56%)
`3 (43%)
`4 (57%)
`2 (40%)
`1 (100%)
`1 (100%)
`
`respondents compared to 90% of the 30 White respondents (Fis-
`her’s exact, p = 0.03). The degree of response (“much” or “very much”
`vs. “some”) was not significantly related to age, gender, or the
`laboratory tests.
`The duration of response showed no indications of relation to
`age or gender and only a nonsignificant difference favoring a longer
`duration for White than African–American respondents (see Table 1).
`Sixty-five percent of all respondents had a response lasting >6
`months. The medical condition producing IDA did not appear to sig-
`nificantly affect the response rate. The percentage of respondents
`ranged from 67% to 86% across the medical conditions present in
`five or more patients (see Table 2).
`Subjective sleep quality after treatment was reported as im-
`proved in 57.1% of all patients with improvement lasting on average
`10.4 months (sd = 5.0). The nonrespondent group reported no sig-
`nificant improvement in sleep while 67% of the limited-respondent
`group and 80% of the extended-respondent group reported
`improved sleep.
`
`3.3. Iron status relation to RLS treatment response
`
`As the response to treatment showed a race-related difference
`and there were only five non-Whites, the relationship between lab-
`oratory tests and RLS response were evaluated for only the White
`patients. The only significant (p < 0.05) difference between
`
`respondents and nonrespondents was a higher hemoglobin level
`after treatment for respondents (p = 0.03). The treatment of anemia
`commonly seeks to increase the hemoglobin level to ≥12.5 g/dl. None
`of the nonrespondents versus 13 (41%) of the respondents reached
`this goal after IV iron treatment (Fisher’s exact p = 0.04). The re-
`spondents had a nonsignificantly (p = 0.08) higher serum ferritin
`before treatment than the nonrespondent group (see Table 3). The
`extended-respondent group after treatment had significantly lower
`TIBC (p = 0.02) and trend for higher ferritin (p = 0.10) compared to
`the limited-respondent group (see Table 3).
`The linear regressions of iron measures for White respondents
`versus PGI (degree of response) and duration of response (months)
`were significant only for TIBC after treatment versus the duration
`of response (r = −0.40, p < 0.05). The PGI correlated significantly with
`the duration of response (r = 0.54, p < 0.01).
`Adverse effects: No clinically relevant toxicity or persisting adverse
`effects were observed.
`
`4. Discussion
`
`There are two primary findings from this study. First, a single,
`1000-mg IV dose of LMW dextran was effective for reducing RLS
`symptoms in 76% of the patients with ID. Thus, this dose of IV iron
`should be considered as a possibly effective treatment for RLS oc-
`curring with IDA. This needs to be confirmed in larger controlled
`studies.
`The second primary finding was the lower-than-expected rate
`of response to the IV iron treatment of RLS–IDA. It was assumed
`that as the RLS occurred with IDA the IV iron should reduce the RLS
`symptoms in almost all patients. Contrary to our expectations, 24%
`of the RLS–IDA did not respond to treatment despite the large dose
`of 1000 mg of IV iron. There are three likely explanations for this
`lower-than-expected response rate: 1) some had primary RLS in-
`dependent of IDA, 2) the dose used is not adequate for this
`population, and 3) RLS induced by IDA may not be reversible in all
`cases.
`First, there was no effort to assess primary RLS independent of
`IDA. This was partly because of difficulties ascertaining the onset
`of IDA needed to determine if RLS occurred before or after the IDA.
`Some of the nonrespondents may, therefore, represent primary RLS
`occurring before developing IDA rather than IDA-induced RLS. The
`prevalence of RLS in the general US population is about 5% [5], while
`
`Table 3
`Age, iron status, and response to 1000 mg IV iron for IDA with RLS/WED (means ± sd) (Caucasian sample only).
`
`Nonrespondents
`
`All respondents
`
`n
`
`7
`7
`–
`–
`7
`6
`5
`5
`6
`5
`5
`7
`6
`6
`
`Avr ± sd
`55.0 ± 21.0
`0.0
`–
`–
`55.0 ± 21.0
`7.0 ± 4.0
`142 ± 98
`135.1 ± 93.8
`440.2 ± 68.7
`294.0 ± 26.0
`120.0 ± 39.4
`10.0 ± 1.47
`11.28 ± 0.73
`1.43 ± 1.33
`
`n
`
`30
`30
`
`30
`28
`19
`18
`30
`19
`19
`30
`27
`26
`
`Avr ± sd
`54.9 ± 18.1
`2.67 ± 0.66
`23 (77%)
`27 (90%)
`54.9 ± 18.1
`14.1 ± 19.3
`93 ± 82
`80 ± 86.4
`455.9 ± 71.1
`339.0 ± 48.5
`98.7 ± 48.5
`10.3 ± 1.1
`12.1 ± 1.3
`1.77 ± 1.20
`
`t, p values
`non versus
`respondents**
`
`0.02, ns
`–
`–
`–
`0.02, ns
`1.8, p = 0.08***
`0.96, ns
`1.10, ns
`0.15, ns***
`2.2, ns
`0.49, ns
`0.43, ns**
`1.99, p = 0.03
`0.54, ns
`
`Limited respondents
`
`Extended respondents
`
`n
`
`11
`11
`
`11
`9
`6
`5
`11
`7
`7
`11
`9
`9
`
`Avr ± sd
`57.6 ± 17.9
`2.18 ± 0.87
`5 (45%)
`8 (72%)
`57.6 ± 17.9
`9.7 ± 8.03
`62 ± 54
`61 ± 56.9
`454.5 ± 79.7
`369.1 ± 43.0
`88.7 ± 44.6
`10.6 ± 0.96
`12.3 ± 0.86
`1.67 ± 1.1
`
`n
`
`19
`19
`
`19
`19
`13
`13
`19
`12
`12
`18
`18
`17
`
`Avr ± sd
`53.4 ± 18.6
`2.95 ± 0.23
`18 (95%)
`19 (100%)
`53.4 ± 18.6
`16.2 ± 22.7
`107 ± 90
`88 ± 96.3
`454.5 ± 79.7
`341.4 ± 43.9
`104.5 ± 50.2
`10.1 ± 1.21
`12.0 ± 1.41
`1.82 ± 1.28
`
`t, p value limited
`versus extended
`respondents
`
`0.60, ns
`2.98, p = 0.01
`
`0.60, ns
`1.12, ns***
`1.33, p = 0.10
`0.73, ns
`0.15, ns***
`2.3, p = 0.02
`0.69, ns
`1.05, ns
`0.68, ns
`0.31, ns
`
`Age
`PGI score
`
`Age
`Ferritin
`mcg/l
`
`TIBC
`mcg/dl
`
`Hgb
`g/dl
`
`score n (%)
`score = 3*
`score = 3.2*
`
`Before
`After
`Increase**
`Before
`After
`Decrease**
`Before
`After
`Increase**
`
`ns = p > 0.15.
`* PGI 3 = “very much” and PGI 2 = “much” PGI1 = “some” improved. PGI 0 = “no change”.
`** Increase is after–before, Decrease is before–after IV iron.
`*** Two-tailed t-test with unequal variance; all other t-tests are one-tailed unequal variance testing directional hypotheses.
`
`Pharmacosmos, Exh. 1064, p. 3
`
`

`
`1476
`
`T. Mehmood et al./Sleep Medicine 15 (2014) 1473–1476
`
`the prevalence of RLS in this IDA population is 33% [3]. Assuming
`5% of the total sample has primary RLS, then about 15% (5/33) of
`the RLS–IDA population reflect background population risk for
`primary RLS. A prior study of primary RLS without anemia found
`that 52% of the patients did not respond well to 1000 mg of IV iron
`[7]. We might, therefore, have expected to see no response for half
`of the primary RLS in our RLS–IDA sample or about three (8%) of
`our RLS–IDA. This amounts to only about one-third of the
`nonrespondents in this study and alone fails to explain the unex-
`pectedly low response rate.
`Second, regarding the adequacy of the dose used, the 1000-mg
`dose used in this study appeared to produce maximum benefit for
`RLS without IDA. Subsequent extra IV iron doses after an initial
`1000 mg given in one study did not improve the response in RLS
`without IDA [7]. IDA changes the situation. It alters iron manage-
`ment to favor distribution of iron to the periphery for erythropoiesis
`rather than to the central nervous system (CNS) to reduce RLS
`symptoms. The lower hemoglobin level in nonrespondents indi-
`cate persisting demand for iron distribution to peripheral tissue
`for treating IDA with less distributed to the CNS for treating RLS.
`The usual goal for managing anemia is hemoglobin >12.5 g/dl.
`None of the nonrespondents versus 41% of the RLS respondents
`achieved that goal. Even a hemoglobin level of 12.5 g/dl should be
`considered marginally adequate for RLS treatment as it occurs with
`only minimally adequate peripheral stores (serum ferritin <20
`mcg/l) in a majority of patients [12]. Thus, the dose of IV iron
`needed for RLS–IDA needs to be adequate to both completely correct
`the IDA and provide additional iron for distribution to the CNS
`to treat the RLS. The IV iron dose for RLS–IDA may therefore
`need to be higher than that required to treat either only IDA or
`RLS without IDA.
`The third possible explanation for the low response rate is some-
`what disturbing as it raises the possibility that for some patients
`IDA produces a currently unrecognized but significant long-
`lasting health consequence, that is, RLS, that is not responsive to
`iron treatment. This may seem unlikely but not impossible given
`the tissue and epigenetic changes that might occur with IDA. This
`needs to be evaluated in future studies.
`The secondary findings in this study indicate possible signifi-
`cant racial differences in response to IV iron treatment. However,
`the very small sample of only five African–Americans hardly suf-
`fices to be considered any more than indicating the need for further
`evaluation. The multiple evaluations of TIBC and ferritin showed no
`consistent pattern that would indicate possible factors related to
`treatment response. The TIBC after treatment was significantly lower
`for extended than limited respondents, but nonrespondents had the
`lowest TIBC. There were no other significant differences between
`any of the groups (see Table 3).
`It deserves mention that the sleep disturbance with IDA–RLS in
`this sample improved only when the RLS improved. Treating the
`anemia does not suffice to treat the sleep disturbance unless the
`RLS is also treated. This is consistent with a prior study indicating
`that the sleep disturbance with anemia is closely associated
`with RLS [3].
`This study has major strengths in the use of a validated ques-
`tionnaire for ascertainment of RLS, the use of standard accepted
`Likert scales for evaluating clinical outcome, and the inclusion of
`all consecutive patients in one major clinical practice. There are also
`weaknesses. First, this is a pilot study. The sample sizes are small
`and there is no statistical correction for multiple comparisons.
`Second, data are taken from clinical evaluations of patients in a he-
`matology practice. This was not a prospective planned follow-up,
`but rather a review of clinical records. Records were often missing
`or incomplete as shown by the numbers in Table 3. Third, neither
`standard measures of RLS severity nor objective measures of leg
`movements were used.
`
`5. Conclusion
`
`About a third of patients with IDA have RLS symptoms; more
`concerning is that 75% of those with RLS–IDA have moderate to
`severe disease [3]. Patients with moderate to severe RLS have sig-
`nificant problems with sleep loss, poor job performance, diminished
`cognition, and poor quality of life [13]. Thus, it is important to rec-
`ognize this comorbid condition and consider more appropriate
`management than that usual for IDA without RLS. An oral iron treat-
`ment produces marginal response for RLS–IDA [14] and has a high
`frequency of gastrointestinal adverse events and nonadherence to
`therapy. IV iron therapy is therefore preferable as it offers a more
`rapid solution to replenishing body iron stores and thus more quickly
`diminishes or eliminates RLS symptoms in those with comorbid IDA.
`The data in this paper indicate that 1000 mg LMW ID reduces
`RLS symptoms for most patients with RLS–IDA but doses >1000 mg
`may be required for a more effective RLS treatment. Larger and
`blinded studies are needed to confirm these results and to better
`evaluate clinical or serum factors that might indicate optimal IV iron
`dose for better and longer-lasting treatment response for RLS
`with IDA.
`
`IRB exemption
`
`As this was a part of the clinical practice conducted by physi-
`cians in the practice evaluating the treatment response for their
`patients and all data analyses were based on de-identified data, this
`was judged to be exempt from human subjects review.
`
`Conflict of interest
`
`The ICMJE Uniform Disclosure Form for Potential Conflicts of In-
`terest associated with this article can be viewed by clicking on the
`following link: http://dx.doi.org/10.1016/j.sleep.2014.08.012.
`
`References
`
`[1] Nordlander NB. Therapy in restless legs. Acta Med Scand 1953;145:453–7.
`[2] Ask-Upmark E. Contribution to the pathogenesis of the syndrome of restless
`legs. Acta Med Scand 1959;164:231.
`[3] Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ. The prevalence and
`impact of restless legs syndrome on patients with iron deficiency anemia. Am
`J Hematol 2013;88(4):261–4.
`[4] Akyol A, Kiylioglu N, Kadikoylu G, Bolaman AZ, Ozgel N. Iron deficiency anemia
`and restless legs syndrome: is there an electrophysiological abnormality? Clin
`Neurol Neurosurg 2003;106(1):23–7.
`[5] Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless
`legs syndrome prevalence and impact: REST general population study. Arch
`Intern Med 2005;165(11):1286–92.
`[6] Earley CJ, Heckler D, Horská A, Barker PB, Allen RP. The treatment of restless
`legs syndrome with intravenous iron dextran. Sleep Med 2004;5(3):231–5.
`[7] Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ. Clinical efficacy
`and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred,
`placebo-controlled preliminary clinical trial. Sleep Med 2011;12(9):906–13.
`[8] Ekbom KA. Restless legs syndrome. Neurology 1960;10:868–73.
`[9] Zacharski LR, Ornstein DL, Woloshin S, Schwartz LM. Association of age, sex,
`and race with body iron stores in adults: analysis of NHANES III data. Am Heart
`J 2000;140(1):98–104.
`[10] Allen RP, Burchell BJ, Macdonald B, Hening WA, Earley CJ. Validation of the
`self-completed Cambridge-Hopkins questionnaire (CH-RLSq) for ascertainment
`of restless legs syndrome (RLS) in a population survey. Sleep Med 2009;
`10(10):1097–100.
`[11] National Insitute of Mental Health CGI. Clinical global impressions. In: Guy W,
`editor. ECDEU assessment manual for psychopharmacology. Rockville, MD:
`National Institute of Mental Health; 1976. p. 217–22.
`[12] Waterbury L. Anemia. In: Fiebach N, Kern D, Thomas C, Ziegelstein R, editors.
`Principles of ambulatory medicine. Baltimore: Lippincott, Williams & Williams;
`2007. p. 817–36.
`[13] Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences
`and the need for better treatment. Sleep Med 2010;11(9):807–15.
`[14] Bryant BJ, Yau YY, Arceo SM, Hopkins JA, Leitman SF. Ascertainment of iron
`deficiency and depletion in blood donors through screening questions for pica
`and restless legs syndrome. Transfusion 2013;53(8):1637–44.
`
`Pharmacosmos, Exh. 1064, p. 4