correspondence

High-Sensitivity CRP

No. of
Participants

No. of
Events

<1.0
1.01.9
2.02.9
3.03.9
4.04.9
5.0

8,931
12,822
4,563
2,254
1,525
2,347

530
817
392
221
170
288

mg/liter

Risk of Ischemic Heart Disease

P Value for Trend

<0.001

0.8

1.0

2.0

3.0

Odds Ratio (95% CI)

Figure 1. Risk of Ischemic Heart Disease as a Function of Plasma Levels of High-Sensitivity C-Reactive Protein
in the General Population.
1st Population Study; 2418 of
RETAKE General
Harbord
(Nordestgaard)
AUTHOR:
Plasma levels of CRP were measured
persons
from
the Copenhagen
ICMin 34,860
2nd
2
of
2
FIGURE:
these persons had ischemic heart REG
disease.
Odds
ratios
were
adjusted
for
age,
sex,
and
the use or nonuse of statins
F
3rd
as in Figure 5 of our article.
CASE
Revised

Line
4-C
SIZE
H/T
H/T
33p9
Enon
Combo
1. Ridker PM, Cook N. Clinical usefulness of very high and very
plasma measurement will be sufficient to
iden- PLEASE
AUTHOR,
NOTE:
low levels
of C-reactive protein across the full range of FramingFigure
has
been
redrawn
and type has been reset.
tify persons who are at increased risk for ische- ham
Risk Scores. Circulation 2004;109:1955-9.
Please check carefully.
2. Freiberg JJ, Tybjrg-Hansen A, Jensen JS, Nordestgaard BG.
mic vascular disease.
EMail

Jeppe Zacho, M.D.

ARTIST: ts

JOB: 36009

Copenhagen University Hospital Herlev

DK-2730 Herlev, Denmark

Anne Tybjrg-Hansen, M.D.

Copenhagen University Hospital Rigshospitalet
DK-2100 Copenhagen, Denmark

Nonfasting triglycerides and risk of ischemic stroke in the genISSUE: 02-26-09

eral population. JAMA 2008;300:2142-52.
3. Frikke-Schmidt R, Nordestgaard BG, Agerholm-Larsen B,
Schnohr P, Tybjaerg-Hansen A. Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype. J Lipid Res 2000;41:
1812-22.

Brge G. Nordestgaard, M.D.

Copenhagen University Hospital Herlev
DK-2730 Herlev, Denmark
brno@heh.regionh.dk

Levodopa for Parkinsons Disease

To the Editor: In his Clinical Therapeutics article, LeWitt (Dec. 4 issue)1 emphasizes that levodopa is still the pivotal treatment in Parkinsons
disease, despite the disabling motor complications
caused by the intermittent, pulsatile supply of
levodopa.2-4 Since these complications can be
mitigated by strategies that extend levodopas
pharmacokinetic profile, we wish to draw attention to the clinical application of the concept of
continuous dopaminergic stimulation. The aim
is to reverse the priming process.2-4 Continuous
intravenous infusion of levodopa produces a prolonged, stable clinical response.4 Continuous intraduodenal infusion of carbidopalevodopa
through a gastrostomy port reduced motor complications more effectively than all oral regimens5
and was an effective, long-term treatment for severe motor complications in 91 patients with ad-

vanced disease.6 In Europe, more than 500 patients

are currently being treated with this approach. We
recently initiated a direct jejunostomy strategy, in
order to decrease technical complications and increase the patients comfort. Given the uncertainty surrounding future therapeutic approaches, we
believe that the concept of continuous dopami
nergic stimulation is of clinical importance.
David Devos, M.D., Ph.D.
Caroline Moreau, M.D., Ph.D.
Alain Deste, M.D.
Centre Hospitalier Universitaire
F-59037 Lille, France
d-devos@chru-lille.fr
1. LeWitt PA. Levodopa for the treatment of Parkinsons dis-

ease. N Engl J Med 2008;359:2468-76.

2. Carlsson T, Winkler C, Burger C, et al. Reversal of dyskinesias in an animal model of Parkinsons disease by continuous
L-DOPA delivery using rAAV vectors. Brain 2005;128:559-69.

n engl j med 360;9 nejm.org february 26, 2009

The New England Journal of Medicine

Downloaded from nejm.org on September 29, 2015. For personal use only. No other uses without permission.
Copyright 2009 Massachusetts Medical Society. All rights reserved.

935

The

n e w e ng l a n d j o u r na l

3. Jenner P. The MPTP-treated primate as a model of motor com-

plications in PD: primate model of motor complications. Neurology 2003;61:Suppl 3:S4-S11.

4. Quinn N, Marsden CD, Parkes JD. Complicated response
fluctuations in Parkinsons disease: response to intravenous infusion of levodopa. Lancet 1982;2:412-5.
5. Nyholm D, Nilsson Remahl AIM, Dizdar N, et al. Duodenal
levodopa infusion monotherapy vs oral polypharmacy in advanced
Parkinson disease. Neurology 2005;64:216-23.
6. Devos D. Patient profile, indications, efficacy and safety of
duodenal levodopa infusion in advanced Parkinsons disease. Mov
Disord (in press).

To the Editor: In the review article by LeWitt,

Figure 1 suggests that exogenous levodopa can be
effective by acting directly on the caudate and putamen. To the best of our knowledge, exogenous
levodopa administered for the treatment of Parkinsons disease is taken up by the terminals of
dopaminergic neurons, where conversion to do
pamine takes place. There are some interstitial
dopaminergic neurons in the striatum that increase in number in response to dopaminergic depletion,1 but their importance is highly controversial. The efficacy of exogenous levodopa depends
on the residual presence of pigmented midbrain
neurons in the substantia nigra pars compacta. In
contrast, dopaminergic agonists are effective without the presence of these pigmented neurons.
Jean Marie Grard, M.D.
Jos-Antonio Elosegi, M.D.
Hpital A. Par
7000 Mons, Belgium
1. Cossette M, Parent A, Lvesque D. Tyrosine hydroxylase-posi-

tive neurons intrinsic to the human striatum express the transcription factor Nurr 1. Eur J Neurosci 2004;20:2089-95.

The author replies: Although intermittent dopaminergic stimulation contributes to the initiation of dyskinesias and motor fluctuations with
long-term use of levodopa, other factors besides
its short plasma clearance half-life also may be
responsible.1 Devos and colleagues mention another formulation of levodopa that offers an improvement over oral levodopa tablets in controlling the variability of dopaminergic effects. This
treatment option, a microsuspension of carbidopalevodopa (Duodopa) continuously infused at
an optimized rate into the duodenum or jejunum,2 provides a lasting remedy for patients with
Parkinsons disease whose only alternative might
be the neurosurgical intervention of deep-brain
stimulation. However, this treatment is available
only in Europe, is quite expensive, and requires surgical access to the gastrointestinal tract to insert
936

of

m e dic i n e

a catheter connected with a portable pump. There

is no evidence that continuous dopaminergic stimulation in this manner reverses the underlying
mechanisms of levodopa complications once dyskinesias and motor fluctuations have been initiated. Over the four decades that levodopa has been
in use for Parkinsons disease, several alternative
therapeutic strategies for extending its effect have
undergone extensive testing,3 and others continue
to be sought.4
An illustration can convey only so much, and
Grard and Elosegi correctly note that levodopa
is taken up and converted in dopaminergic nerve
terminals which are situated in the caudate
nucleus and putamen (striatum), as shown in Figure 1 of my article. How dopamine continues to
be generated from levodopa even in advanced Parkinsons disease has been a puzzle for many years.
Given the extensive loss of dopaminergic neuronal
projections to the striatum, it might seem that the
brain in Parkinsons disease would lack adequate
nerve terminals for taking up and decarboxylating
levodopa so that the neurotransmitter could be
released. However, for most patients with advanced
disease, levodopa continues to exert some antiparkinsonian effect. Even after experimental destruction of dopaminergic neurons arising from
the substantia nigra, as occurs in Parkinsons
disease, levodopa can be metabolized to do
pamine by decarboxylase activity that persists
in the striatum.5
Peter A. LeWitt, M.D.
Henry Ford Hospital
Detroit, MI 48302
palewitt@ameritech.net
Dr. LeWitt reports having received fees from NeoPharma for
consultation associated with the development of its intraduodenal levodopa product (Duodopa). No further potential conflict
of interest relevant to this letter was reported.
1. Maratos EC, Jackson MJ, Pearce RK, Cannizzaro C, Jenner P.
Both short- and long-acting D-1/D-2 dopamine agonists induce
less dyskinesia than L-DOPA in the MPTP-lesioned common
marmoset (Callithrix jacchus). Exp Neurol 2003;179:90-102.
2. Nyholm D, Lewander T, Johansson A, LeWitt P, Lundqvist C,
Aquilonius S-M. Enteral levodopa/carbidopa infusion in advanced
Parkinsons disease: long-term exposure. Clin Neuropharmacol
2008;31:63-73.
3. LeWitt PA. The pharmacology of levodopa in treatment of
Parkinsons disease: an update. In: Calne DB, ed. Drugs for the
treatment of Parkinsons disease. Vol. 88 of Handbook of experimental pharmacology. Berlin: Springer-Verlag, 1989:325-84.
4. Idem. Levodopa therapeutics for Parkinsons disease: new
developments. Parkinsonism Relat Disord 2009;15:Suppl 1:
S31-S34.
5. Lopez-Real A, Rodriguez-Pallares J, Guerra MJ, LabandeiraGarcia JL. Localization and functional significance of striatal
neurons immunoreactive to aromatic L-amino acid decarboxylase or tyrosine hydroxylase in rat Parkinsonian models. Brain
Res 2003;969:135-46.

n engl j med 360;9 nejm.org february 26, 2009

The New England Journal of Medicine

Downloaded from nejm.org on September 29, 2015. For personal use only. No other uses without permission.
Copyright 2009 Massachusetts Medical Society. All rights reserved.