1. Iron as a Treatment: Successes and Failures. What next? Christopher J Earley MB, BCh, PhD, FRCP(I) Professor Department of Neurology Johns Hopkins School of Medicine

2. If Low Brain Causes RLS Then Can Iron Therapy Be Used To Treat It?

3. How Iron Gets to the Brain StomachBlood/ body Brain/ CSF Gut-Blood Barrier Blood-Brain Barrier

4. Oral Iron Treatment in RLS O’Keeffe 1994 –Open label trial; 120 mg iron for 12 wks; mean ferritin 32 mcg/l. –The lower the ferritin the better the improvement (< 45 mcg/l). Davis 2000 –R/DB/Pc trial; 130 mg iron for 14 wks; mean ferritin at start = 134 mcg/l. –No significant treatment effect but also no significant change in serum ferritin. O’Keeffe 1994 –Open label trial; 120 mg iron for 12 wks; mean ferritin 32 mcg/l. –The lower the ferritin the better the improvement (< 45 mcg/l). Davis 2000 –R/DB/Pc trial; 130 mg iron for 14 wks; mean ferritin at start = 134 mcg/l. –No significant treatment effect but also no significant change in serum ferritin.

5. Intravenous Iron Therapy in RLS Nordlander 1953 –Open label 200-300 mg iron dextran –21/22 complete improvement for mean of 4.6 months Parrow 1966 –55/64 complete improvement –Open-label, multiple doses iron dextran Nordlander 1953 –Open label 200-300 mg iron dextran –21/22 complete improvement for mean of 4.6 months Parrow 1966 –55/64 complete improvement –Open-label, multiple doses iron dextran

6. Intravenous Iron Therapy in RLS Earley 2004 –Open-label, single 1000 mg iron dextran –Subject (GRS) and objective (PLMS) improvement (7/10) for a mean duration of 6 mo (range 3 –36 mo) Earley 2004 –Open-label, single 1000 mg iron dextran –Subject (GRS) and objective (PLMS) improvement (7/10) for a mean duration of 6 mo (range 3 –36 mo)

7. Hours of Symptoms - Post IV Iron Dextran

8. Sleep Efficiency - Post IV Iron Dextran

9. PLMS - Post IV Iron Dextran

10. The Unexpected Rate of Decline in Serum Ferritin Following IV Iron Treatment

11. The serum ferritin after a single 1000 mg doses of iron dextran dropped by 2.3 –11.6 mcg/l/week faster than the predicted rate

12. Supplemental IV Iron Treatment in RLS Earley 2005  5 Subjects: initial response to 1000 mg IV iron dextran and a return of symptoms.  Treatment: 150 mg iron glucose (Ferrlecit) IV X 3 doses (450 mg)  Outcomes: GRS and serum ferritin monthly over 2 years (104 weeks). Earley 2005  5 Subjects: initial response to 1000 mg IV iron dextran and a return of symptoms.  Treatment: 150 mg iron glucose (Ferrlecit) IV X 3 doses (450 mg)  Outcomes: GRS and serum ferritin monthly over 2 years (104 weeks).

13. Outcomes in 5 subjects with repeated IV iron (450 mg Ferrlecit) over 2 years

14. Subject 7 Changes in serum ferritin per weeks after initial 1000mg (Dextran) IV iron and 2 repeated 450 mg (Ferrlecit) IV doses. Weeks after IV Iron

15. 0 50 100 150 200 250 300 350 400 -20020406080100120140 weeks 100 200 300 400 500 600 700 0 20406080100 Weeks 0 50 100 150 200 250 300 01020304050 50 100 150 200 250 300 350 400 -20020406080100120140 weeks ferritin (mcg/l) Changes in Serum Ferritin Post 1000 mg and Following 500 mg Supplemental Treatments Changes in Serum Ferritin Post 1000 mg and Following 500 mg Supplemental Treatments Subject 1 Subject 3 Subject 4 Subject 6

16. Duration of Symptom relief vs. rate of ferritin loss 2.4 2.6 2.8 3 3.2 3.4 3.6 3.8 4 4.2 4.4 4.6 024681012141618 Ferritin decrease (mcg/l per week) ln(weeks of Sx relief duration) r= 0.67 normal rate

17. Implications  The rate of decline in ferritin may explains why high iron doses do not have sustained benefits.  The rate of decline in ferritin may be slowed with repetitive infusions.  The rate of ferritin decline may reflect problems with retention of iron in RLS patients  The rate of decline in ferritin may explains why high iron doses do not have sustained benefits.  The rate of decline in ferritin may be slowed with repetitive infusions.  The rate of ferritin decline may reflect problems with retention of iron in RLS patients

18. Iron Sucrose (Venofer) Earley etal 2008 –IV iron (Venofer) 500mg x2 within 36 hr –Baseline and 2-week follow up evaluation –Subjects: Iron (11) placebo (7) –Ran(2:1), D-B, Placebo-Controlled Earley etal 2008 –IV iron (Venofer) 500mg x2 within 36 hr –Baseline and 2-week follow up evaluation –Subjects: Iron (11) placebo (7) –Ran(2:1), D-B, Placebo-Controlled

19. The Changes in Primary and Secondary Outcome Measures at 2-Weeks Post-treatment

20. 1000 mg Venofer 500 mg Venofer Serum Ferritin

21. Ulfberg 2007  R,DB, PC trial of Venofer 200mg x 5  N =60; ferritin < 50 mcg/l  IRLSSS –@ 7 weeks: 12 (Iron ) vs 20 (Plac) p =0.017 –@ 12 weeks: 7 (iron) vs 17 (plac) p = 0.123  R,DB, PC trial of Venofer 200mg x 5  N =60; ferritin < 50 mcg/l  IRLSSS –@ 7 weeks: 12 (Iron ) vs 20 (Plac) p =0.017 –@ 12 weeks: 7 (iron) vs 17 (plac) p = 0.123

22. To Treat or Not to Treat with Iron Iron status –Iron deficient vs non-deficient –Serum (ferritin?) vs CSF ferritin –Lymphocyte; MRI determined Type iron treatment –Oral: heme iron, iron salts –Intravenous: Iron Dextran (INFeD), sucrose (Venofer), gluconate (Ferrlicit) Dosing schedule –multiple small vs single large –Time of day Iron status –Iron deficient vs non-deficient –Serum (ferritin?) vs CSF ferritin –Lymphocyte; MRI determined Type iron treatment –Oral: heme iron, iron salts –Intravenous: Iron Dextran (INFeD), sucrose (Venofer), gluconate (Ferrlicit) Dosing schedule –multiple small vs single large –Time of day