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ARTICLES: F. J.G. Vingerhoets, J.-G. Villemure, P. Temperli, C. Pollo, E. Pralong, and J. Ghika Subthalamic DBS replaces levodopa in Parkinson’s disease: Two-year follow-up Neurology 2002; 58: 396-401 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

FJG Vingerhoets, A Berney, J Ghika, and JG Villemure   (11 September 2002)

Subthalamic DBS replaces levodopa in Parkinson’s disease: Two-year follow-up

JL Houeto, V Mesnage, ML Welter, BP Bejjani, L Mallet, and Y Agid   (11 September 2002)

Reply to Letter to the Editor

FJG Vingerhoets, JG Villemure and J Ghika   (7 May 2002)

Subthalamic DBS replaces levodopa in Parkinson’s disease: Two-year follow-up

Anthony E Lang, G Kleiner-Fisman, JA Saint-Cyr, J Miyasaki, and A Lozano   (7 May 2002)

Reply to Letter to the Editor 11 September 2002
FJG Vingerhoets Service de Neurologie Lausanne Switzerland, A Berney, J Ghika, and JG Villemure Send Correspondence to journal: Re: Reply to Letter to the Editor francois.vingerhoets{at}chuv.hospvd.ch FJG Vingerhoets, et al.	We also thank Houeto et al. for their interest in our paper [1], and agree that mood and behavioral modifications may occur following STN-DBS neurosurgery, independently of motor improvement. In particular, mood deterioration is a frequent problem, an observation that we report in a forthcoming paper in Neurology. [3] However, we think that the statement where these kinds of complications occur "probably as a result of the dramatic reduction in levodopa treatment" remains hypothetical and warrants further specific investigations. For instance, in our prospective study [3], neither the rate of reduction of L-dopa equivalent, nor the average daily dose of L-Dopa post-operatively, differed between post- operatively depressed and non-depressed PD patients. This observation does not support levodopa reduction as the major actor for mood disorders, as suspected on restrospective data [2]. Moreover, the relation between behavioral complications and and STN-DBS is certainly of a complex nature, and not uniquely related to dopaminergic neurotransmission since growing evidences in the literature point to a link between behavioral symptoms in PD and serotoninergic neurotransmission [2, 4]. In addition behavioral modifications may be induced by therapy and a majority of depression usually fail to respond to antiparkinsonian treatment [5]. There is no doubt that for some patients, there is a benefit to reintroduce L-dopa and we have done so in 50% of our patients when clinically needed [1]. However we think that controlled prospective studies are needed to better delineate patients at risks and treatment strategies to prevent or treat behavioral complications following STN-DBS and improve quality of life in PD. Keeping or reintroducing systematically dopaminergic therapy as suggested by Houeto et al. will not do the job. References: 1. Vingerhoets FJG, Villemure J-G, Temperli P, Pollo C, Pralong E, Ghika J. Subthalamic DBS replaces levodopa in Parkinson's disease. Two year follow-up. Neurology 2002;58:396-401. 2. Houeto JL, Mesnage V, Mallet L, et al. Behavioral disorders, Parkinson's disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry 2002;72:701-707. 3. Berney A, Vingerhoets F, Perrin A, Guex P, Villemure JG, Burkhardt P, Benkelfat C, Ghika J. Effect on mood of chronic subthalamic DBS for Parkinson's Disease: a consecutive series of 24 patients Neurology (in press) 4. Murai T, Muller U, Werheid K, et al. In vivo evidence for differential association of striatal dopamine and midbrain serotonin systems with neuropsychiatric symptoms in Parkinson's disease. J Neuropsychiatry Clin Neurosciences 2001, 13:222-228. 5. Okun MS, Watts RL, Depression associated with Parkinson's disease: Clinical features and treatment. Neurology 2002;58:S63-S70.
Subthalamic DBS replaces levodopa in Parkinson’s disease: Two-year follow-up 11 September 2002
JL Houeto Centre d'Investigation Clinique Paris France, V Mesnage, ML Welter, BP Bejjani, L Mallet, and Y Agid Send Correspondence to journal: Re: Subthalamic DBS replaces levodopa in Parkinson’s disease: Two-year follow-up jean-luc.houeto{at}psl.ap-hop-paris.fr JL Houeto, et al.	We read with interest the report of Vingerhoets et al. [1] showing, as others, [2] that long-term subthalamic (STN) stimulation monotherapy can be achieved in up to 50% of patients with Parkinson's disease (PD), thereby allowing similar motor improvement as that provided by levodopa treatment before the operation. Authors suggest that STN stimulation can replace levodopa treatment, which should therefore be routinely withdrawn in patients treated neurosurgically. We believe that this statement warrants a prerequisite and deserves a comment. In their study, parkinsonian motor disability was ameliorated by only 45%. [1] This response to levodopa is lower than that described in other report, [3] and is very likely explained by the characteristics of patients included. The residual motor score, which was unresponsive to levodopa, was not improved by STN stimulation since, as stated by the authors themselves, STN-stimulation "replaces levodopa", but no more. An almost complete disappearance of parkinsonian symptoms postoperatively implies to select PD patients who dramatically respond to levodopa treatment preoperatively, in particular in the absence of axial motor symptoms such as freezing, hypophonia and postural instability. [3] Despite satisfactory postoperative motor results, social adjustment disorders and behavioral complications such as anxiety, apathy and depression can emerge, which may limit the quality of life of several patients. [4, 5] probably as a result of the dramatic reduction in levodopa treatment. [4] In support of the latter hypothesis, we observed among 82 PD patients operated between 1997 and 2001 that 17% (postoperative follow-up= 18 ± 10 months; improvement in parkinsonian score "on" stimulation "off" drug = 77± 16%) no longer needed dopaminergic therapy postoperatively. However, dopamine agonists or levodopa were reintroduced in all 14 patients 16 ± 14 weeks after surgery (levodopa-equivalent dosage = 250 ± 134 mg/day) to improve affective blunting, in the absence of significant additional parkinsonian motor improvement. Since the administration of levodopa is known to reestablish a normal dopaminergic transmission within both the nigrostriatal and the meso-cortico-limbic pathways (implicated in the modulation of psychic and cognitive functions), it may be postulated that STN stimulation improved motor symptoms, thereby compensating for the decreased dopaminergic nigrostriatal transmission, without compensating for the decreased extrastriatal dopaminergic systems. We postulate that the still present dopaminergic denervation in cortical associative and limbic territories needed to be compensated for using small doses of dopamine agonists to avoid persistence or reactivation of behavioral symptoms such as apathy and anxiety. [4, 5] A direct deleterious effect of neurosurgery cannot be ruled out. [4] However in contrast to the report by Vingerhoets et al., [1] we suggest that systematic withdrawal of dopaminergic therapy postoperatively may negatively impact the quality of life in some patients and should not be advocated systematically. References: 1. Vingerhoets FJG, Villemure J-G, Temperli P, et al. Subthalamic DBS replaces levodopa in Parkinson's disease, two years follow-up. Neurology 2002;58:396-401. 2. Valledeoriola F, Pilleri M, Tolosa E, et al. Bilateral subthalamic stimulation monotherapy in advanced Parkinson's disease: long-term follow- up. Movement Disorders 2002;17(1):121-132. 3. Welter ML, Houeto JL, Tezenas du Montcel S, et al. Subthalamic stimulation in Parkinson's disease: clinical predictive factors. Brain 2002;25:575-583. 4. Volkmann J, Allert N, Voges J, et al. Safety and efficacy of pallidal or subthalamic stimulation in advanced PD. Neurology 2001;56:548- 551. 5. Houeto JL, Mesnage V, Mallet L, et al. Behavioural disorders, Parkinson's disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry 2002;72:701-707.
Reply to Letter to the Editor 7 May 2002
FJG Vingerhoets Service de Neurologie BH13 CHUV Lausanne Switzerland, JG Villemure and J Ghika Send Correspondence to journal: Re: Reply to Letter to the Editor sandi_moriarity{at}urmc.rochester.edu FJG Vingerhoets, et al.	We thank Kleiner-Fisman et al. for comments on our paper [1]. Without entering into an ongoing controversy [5, 6, 7] we never considered eliminating medication as a specific objective in the treatment of PD but it is good practice to keep treatment at the lowest dosage needed, and the aim of neurosurgical approach of PD is to reduce complications of drug treatment. We found that with frequent postoperative adjustments of STN DBS, the reintroduction of medication was only transiently necessary for 50% of the patients. We discussed already malignant syndrome (MS) in our paper and have currently operated 58 patients with this protocol and never observed any signs of MS, suggesting that STN DBS might prevent MS. However, we would not advocate yet to use our approach without careful monitoring, particularly regarding the efficacy of DBS. We would therefore agree with Kleiner-Fisman et al., who delay DBS programming by three weeks, that their approach does not permit to keep patients off medication. Postoperative confusion is multifactorial and seems less frequent in our study than in those where medications were kept [2, 8]. Treated symptomatically agitated confusion resolved in few days. The only patient with a longer episode was not improved by reintroduction of the antiparkinsonian medication at 66% of its initial dosage: making a direct relationship with the withdrawal unlikely [4]. Effects of STN DBS on voice [9] and mood [10] are complex, involving combination of effects of DBS, medication and disease. In our patients, worsening of dysarthria was twice less frequent in patients without medication, and only one patient starting antidepressant was on STN DBS alone: these results do not support drug withdrawal as major cause for these evolutions. We disagree that STN DBS programming should be delayed by 3 weeks after surgery. Effectiveness of DBS is immediately observable and used preoperatively to ascertain the correct localization of the electrodes [3, 8, 10]. We are well aware of the challenges of early programming, and agree that it may be frustrating especially when the fluctuating effect of medication is maintained postoperatively with a reduced therapeutic window [2]. However, initiating programming in the immediate postoperative period, when inpatient clinical observation is easy, reliable, and safely possible without antiparkinsonian treatment, is preferable to multiple outpatients {practically off} assessments, where long term effects of antiparkinsonian drugs confuse the assessments. The cost effectiveness and scientific reliability of adding multiple {practically off} outpatient assessments, instead of a careful postoperative follow-up, seems questionable. While not aimed to stop medication, early STN DBS programming helped keeping patients off medication. It had "the virtue" to improve PD patients so efficiently that medication was no longer needed in fifty per cent. These patients had better outcome than those still on medication, supporting our approach. References: 1. Vingerhoets FJG, Villemure J-G, Temperli P, Pollo C, Pralong E, Ghika J. Subthalamic DBS replaces levodopa in Parkinson's disease. Two year follow-up. Neurology 2002;58:396-401. 2. Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V. Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 2001;56:548-551. 3. Moro E. Scerrati M, Romito LM, Roselli R, Tonali P, Albanese A. Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson's disease. Neurology 1999;53:85-90. 4. Lang AE. Sudden Confusion with Levodopa Withdrawal. Mov Disord 1987;2(3):223. 5. Montastrue JL, Rascol O, Senard JM. Treatment of Parkinson's disease should begin with a dopamine agonist. Mov Disord 1999;14:725-730. 6. Weiner WJ. The initial treatment of Parkinson's disease should begin with levodopa. Mov Disord 1999;14:716-724. 7. Agid Y. Levodopa: is toxicity a myth? Neurology 1998;50:858-863. 8. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. New England Journal of Medicine 1998;339:1105-1111. 9. Gentil M, Chauvin P, Pinto S, Pollak P, Benabid A. Effect of bilateral stimulation of the subthalamic nucleus on Parkinsonian voice. Brain and language 2001;78:233-240. 10.Houeto JL, Damier P, Bejjani PB, Staedler C, Bonnet AM, Arnulf I, et al. Subthalamic stimulation in Parkinson disease: a multidisciplinary approach. Archives of Neurology 2000;57(4):461-465.
Subthalamic DBS replaces levodopa in Parkinson’s disease: Two-year follow-up 7 May 2002
Anthony E Lang Toronto Western Hospital Toronto Canada, G Kleiner-Fisman, JA Saint-Cyr, J Miyasaki, and A Lozano Send Correspondence to journal: Re: Subthalamic DBS replaces levodopa in Parkinson’s disease: Two-year follow-up sandi_moriarity{at}urmc.rochester.edu Anthony E Lang, et al.	By optimizing stimulation parameters of PD patients who underwent STN DBS, Vingerhoets et al. [1] minimized the amount of anti-parkinsonian medication required, maintaining many study patients off medication. We are concerned that this paper will lead other centers to regard elimination of medications as a specific treatment objective, with potential harmful consequences. Decreasing medications is desirable and may ameliorate side effects. However, stopping drugs can worsen motor signs, mood and cognition. [2, 3] Abrupt withdrawal of anti-parkinsonian medications poses unnecessary risks; fortunately none of the patients in this study suffered more obvious severe motor complications of this approach. To support medication withdrawal, the authors state that DBS programming if patients are taking medication is sub-optimal. However, we think medication cessation may adversely affect patients and in fact delay more effective programming adjustment. In this study three patients suffered post-operative confusion, and three developed new-onset depression. The potential for behavioral and cognitive adverse effects after surgery. The study noted a high incidence of dysarthria that may have been due to excessive drug withdrawal if limb symptoms were more effectively targeted by stimulation than oro-facial symptoms. Induction of dysarthia might also suggest current spread to cortico-bulbar tracts, which could be treated by reducing stimulation measurements and increasing medication. In the immediate post-operative period there may be significant clinical variability due to a microlesioning or insertional effect of the surgery. Attempts to optimize programming during this time are frustrating and not cost effective as the patients' symptoms vary from day to day. In contrast to the aggressive early programming (twice a day during the first week) applied in this study, we generally allow three weeks for post- operative outpatient recovery prior to programming. During this recovery period, when the microlesion and other non-specific surgical effects are resolving, medications are re-instituted as needed to maintain comfort and function. Based on our experience with several different post-operative programming schedules, our protocol now requires 3 weeks (on average) of post-operative outpatient recovery before programming begins. When programming starts, medications are withheld overnight before each day of programming, (i.e., when patients are in a practically defined off period). Measurements are then adjusted and patients are asked to take an optimal dose of levodopa/carbidopa. Manipulation of these measurements continues two to three times a week in conjunction with further medication adjustments. The goal is to achieve maximal symptomatic relief with minimal adverse events and to reduce and simplify medications. Occasionally drugs can be eliminated altogether. However, the virtue of complete elimination of medication as a goal unto itself is questionable unless one ascribes to the controversial and unproven concern that L-dopa, even in low doses, has neurotoxic effects on remaining dopaminergic neurons References: 1. Vingerhoets FJG, Villemure J-G, Temperli P, Pollo C, Pralong E, Ghika J. Subthalamic DBS replaces levodopa in Parkinson's disease. Two year follow-up. Neurology 2002;58:396-401. 2. Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V. Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 2001;56:548-551. 3. Ueda M, Hamamoto M, Nagayama H, Okubo S, Amemiya S, Katayama Y. Biochemical alterations during medication withdrawal in Parkinson's disease with and without neuroleptic malignant-like syndrome. J Neurol Neurosurg Psychiatry 2001; 71:111-113. 4. Trepanier LL, Kumar R, Lozano AM, Lang AE, Saint-Cyr J. Neuropsychological Outcome of GPi Pallidotomy and GPi or STN Deep Brain Stimulation in Parkinson's Disease. Brain and Cognition 2000;42:324-347. 5. Moro E, Scerrati M, Romito LM, Roselli R, Tonali P, Albanese A. Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson's disease. Neurology 1999; 53:85-90. 6. Mayeux R, Stern YMK, Cote L. Reappraisal of temporary levodopa withdrawal ("drug holiday") in Parkinson's disease. New Engl J Med 1985;313:724-728. 7. Lang AE. Sudden Confusion with Levodopa Withdrawal. Mov Disord 1987; 2(3):223. 8. Montastruc JL, Rascol O, Senard JM. Treatment of Parkinson's disease should begin with a dopamine agonist. Mov Disord 1999; 14:725-730. 9. Weiner WJ. The initial treatment of Parkinson's disease should begin with levodopa. Mov Disord 1999; 14:716-724.