Transcript PLEASE SET YOUR CELL PHONES AND PAGERS TO VIBRATE …

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
If Low Brain Causes RLS
Then Can Iron Therapy Be Used
To Treat It?
How Iron Gets to the
Brain
Stomach
Brain/
CSF
Blood/
body
Gut-Blood
Barrier
Blood-Brain
Barrier
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.
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
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)
Hours of Symptoms - Post IV Iron Dextran
16
14
Average Daily Hours with RLS
12
pt01
pt02
pt03
pt04
pt05
pt06
pt07
pt08
pt09
pt10
10
8
6
4
2
0
-2
-2
0
2
4
6
8
Months post IV Iron
10
12
14
Sleep Efficiency - Post IV Iron Dextran
1.1
1
.9
pt01
pt02
pt03
pt04
pt05
pt06
pt07
pt08
pt09
pt10
Sleep Efficiency
.8
.7
.6
.5
.4
.3
.2
.1
-2
0
2
4
6
8
Months post IV Iron
10
12
14
PLMS - Post IV Iron Dextran
200
180
160
PLMS/hr 1st 3hrs
140
pt01
pt02
pt03
pt04
pt05
pt06
pt07
pt08
pt09
pt10
120
100
80
60
40
20
0
-20
-2
0
2
4
6
8
Months post IV Iron
10
12
14
The Unexpected Rate of Decline in
Serum Ferritin Following IV Iron
Treatment
Serum Ferritin decrease after IV treatment
vs. expected normal
for the patient with the slowest rate of decrease
Serum ferritin (mcg/L)
250
200
150
ferritin
100
Normal
50
0
0
5
10
15
20
weeks after IV treatment
25
30
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
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).
Outcomes in 5 subjects with repeated
IV iron (450 mg Ferrlecit) over 2 years
Table 3. Patient characteristics and response to supplemental IV iron
therapy
Pt
Age
Gender
Duration
Supplemental
Global**
Serum Ferritin
effective
treatments
RLS Rating
(g/L)
treatment
Give n at
initial, Best,
(weeks)
Number week*
last month
Initial Final
#1
51
F
120
4
26, 32, 56, 85
0, 10, 5
26
291
#3
68
M
100
1
25
0, 10, 4.5
188
514
#4
51
F
50
3
12, 25, 37
0, 10, 5
9
140
#6
54
M
128***
2
20, 48
0, 10, 10
84
296
#7
58
F
127***
2
52, 103
0, 10, 10
9
145
* weeks after initial IV iron treatment.
** Global rating 0 – 10: 0 = seve re , 10 = no RLS.
*** Patients remain symptom-free at time of last evaluation at about 2.5 years after the initial treatment.
Serum %Sat
Initial
26.7
41.9
36.9
30.1
22.0
Final
23.4
24.0
59.3
16.3
16.6
Changes in serum ferritin per weeks after initial
1000mg (Dextran) IV iron and 2 repeated 450 mg
(Ferrlecit) IV doses.
Subject 7
450
400
350
300
250
200
150
100
50
0
-20
0
20
40
60
80
100
Weeks after IV Iron
weeks after start of IV iron treatment
120
140
Weeks
400
350
300
250
200
150
Subject 1
100
50
weeks
0
-20
0
20
40
60
80
100
120
140
700
600
500
Changes in Serum
Ferritin Post 1000 mg
and Following 500 mg
Supplemental
Treatments
400
300
Subject 3
200
W eek s
100
20
0
40
60
80
100
3 00
250
2 00
1 50
1 00
50
Subject 4
0
0
10
20
30
40
50
400
350
ferritin (mcg/l)
300
250
200
Subject 6
150
100
50
-20
0
20
40
60
80
100
120
weeks
140
Duration of Symptom relief vs. rate of
ferritin loss
4.6
4.4
ln(weeks of Sx relief duration)
4.2
r= 0.67
4
3.8
3.6
3.4
3.2
3
2.8
2.6
2.4
0
2
4
6
8
10
12
14
normal rate
Ferritin decrease (mcg/l per week)
16
18
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
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
The Changes in Primary and Secondary
Outcome Measures at
2-Weeks Post-treatment
1000 mg
Venofer
500 mg
Venofer
500 mg
Venofer
500 mg
Venofer
180.00
160.00
Serum Ferritin
140.00
120.00
100.00
80.00
60.00
40.00
20.00
0.00
0
5
10
15
20
Weeks
25
30
35
40
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
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