Correspondence

Levodopa for Parkinson's Disease

N Engl J Med 2009; 360:935-936February 26, 2009

Article

To the Editor:

In his Clinical Therapeutics article, LeWitt (Dec. 4 issue)1 emphasizes that levodopa is still the pivotal treatment in Parkinson's 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 levodopa's 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 carbidopa–levodopa 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 advanced 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 patient's comfort. Given the uncertainty surrounding future therapeutic approaches, we believe that the concept of continuous dopaminergic stimulation is of clinical importance.

David Devos, M.D., Ph.D.
Caroline Moreau, M.D., Ph.D.
Alain Destée, M.D.
Centre Hospitalier Universitaire, F-59037 Lille, France
d-devos@chru-lille.fr

6 References

1. 1

   LeWitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med 2008;359:2468-2476
   Full Text | Web of Science | Medline

2. 2

   Carlsson T, Winkler C, Burger C, et al. Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors. Brain 2005;128:559-569
   CrossRef | Web of Science | Medline

3. 3

   Jenner P. The MPTP-treated primate as a model of motor complications in PD: primate model of motor complications. Neurology 2003;61:Suppl 3:S4-S11
   Web of Science | Medline

4. 4

   Quinn N, Marsden CD, Parkes JD. Complicated response fluctuations in Parkinson's disease: response to intravenous infusion of levodopa. Lancet 1982;2:412-415
   CrossRef | Web of Science | Medline

5. 5

   Nyholm D, Nilsson Remahl AIM, Dizdar N, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005;64:216-223
   CrossRef | Web of Science | Medline

6. 6

   Devos D. Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson's 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 Parkinson's disease is taken up by the terminals of dopaminergic neurons, where conversion to dopamine 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 Gérard, M.D.
José-Antonio Elosegi, M.D.
Hôpital A. Paré, 7000 Mons, Belgium

1 References

1. 1

   Cossette M, Parent A, Levesque D. Tyrosine hydroxylase-positive neurons intrinsic to the human striatum express the transcription factor Nurr 1. Eur J Neurosci 2004;20:2089-2095
   CrossRef | Web of Science | Medline

Author/Editor Response

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 carbidopa–levodopa (Duodopa) continuously infused at an optimized rate into the duodenum or jejunum,2 provides a lasting remedy for patients with Parkinson's 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 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 Parkinson's 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 Gérard 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 Parkinson's 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 Parkinson's 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 anti-parkinsonian effect. Even after experimental destruction of dopaminergic neurons arising from the substantia nigra, as occurs in Parkinson's disease, levodopa can be metabolized to dopamine 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.

5 References

1. 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
   CrossRef | Web of Science | Medline

2. 2

   Nyholm D, Lewander T, Johansson A, LeWitt P, Lundqvist C, Aquilonius S-M. Enteral levodopa/carbidopa infusion in advanced Parkinson's disease: long-term exposure. Clin Neuropharmacol 2008;31:63-73
   CrossRef | Web of Science | Medline

3. 3

   LeWitt PA. The pharmacology of levodopa in treatment of Parkinson's disease: an update. In: Calne DB, ed. Drugs for the treatment of Parkinson's disease. Vol. 88 of Handbook of experimental pharmacology. Berlin: Springer-Verlag, 1989:325-84.
   

4. 4

   Levodopa therapeutics for Parkinson's disease: new developments. Parkinsonism Relat Disord 2009;15:Suppl 1:S31-S34
   Web of Science | Medline

5. 5

   Lopez-Real A, Rodriguez-Pallares J, Guerra MJ, Labandeira-Garcia 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;969:135-146
   CrossRef | Web of Science | Medline