Letters to the Editor Related to New Topics

Pathogenesis of PD: Missing the Point

Lerner and Bagic1 have to be congratulated for their hy-pothesis on PD pathogenesis. They suggest that the sequenceof the brain changes in PD follows specific and repeatablepatterns in all cases, as well as that a prion-like processunderlies neurodegeneration. These ideas could explain sev-eral features of PD, such as the high prevalence of olfactory,autonomic, or sleep abnormalities. However, any pathogenichypothesis should also explain:

1. The variable rate of progression.2. The heterogeneous presentation.3. The persistent asymmetry of motor symptoms and signs.4. The progressive worsening and somatotopic spreading of

the same symptom, meaning that neurons displaying simi-lar gene expression profile, intracellular enzymatic ma-chinery, and signaling pathways are differentially affectedby the process.

5. The case of young-onset cases: whereas they must havesevere disease to present so early, disability progressesslowly.

None of them are covered in the article.1 Certainly, PD isa multisystem disorder. The view of PD resulting from thesequential pathological involvement of brain nuclei is basedon the work by Braak,2 which has received strong criticisms.3

It relies on the presence of a-synuclein inclusions, Lewybodies, and Lewy neurites in the brain of subjects’ dead ofdifferent causes. However, clinical information wasextremely limited, some of the subjects included did not de-velop neither motor nor cognitive symptoms during life, stag-ing was independent of disease duration, and neuronal losswas not recorded. Despite these limitations, Braak’s findingshave been interpreted as an open door to presymptomatic di-agnosis according to the presence of abnormalities resultantfrom this pattern of involvement (i.e., hyposmia, REMbehavior disorder, constipation,. . .). Compelling evidencesuggests that a-synuclein inclusions not closely correspond tothe severity of neuronal loss, neuronal dysfunction, or clinicalexpression. There is a gap between pathology and clinicalpicture. Thus, even admitting that pathology could follow apredefined order, the view of PD as a disease that starts withhyposmia, sleep disturbances, and constipation, follows withmotor symptoms and ends with dementia, is not always true.Thus, the predictive value of premotor symptoms is relative.The prevalence of a-synuclein inclusions in the brain of oldindividuals dead without any neurological dysfunction isaround 30%, whereas the prevalence of PD in this group ofage is 2%.

Further arguments come from the development of nondo-paminergic symptoms. A recent study showed that age andseverity of PD but not duration of illness, act as independentrisk factors for developing dementia.4 Furthermore, the brainof the majority of parkinsonian patients displaying dementiapresents abundant changes characteristic of Alzheimer’s dis-ease. The relationship between dementia, aging, PD, andassociated pathologies needs clarification. Additionally, rateof progression is more determinant of PD outcome than itsmultisystemic nature. It is likely linked to compensatorymechanisms and, thus, to the age at onset of the disease, aswell as to the aging process. In fact, the older the age ofonset, the worst the prognosis. These arguments do not ruleout the proposed hypothesis.1 However, they challenge itsapplicability in the clinical setting without considering thecontribution of just mentioned factors which, indeed, fill thegap between pathology and clinical features.

PD do not fulfill key criteria to be diagnosed as a prionop-athy. Nonetheless, abnormal forms of a-synuclein seem topropagate in the brain of PD patients affecting differentnuclei in different phases of the disease process. The findingof Lewy bodies and a-synuclein deposits in nigral fetal neu-rons transplanted over a decade earlier into the striatum5

could support the existence of a prion-like pathogen as thecause of PD.6 However, alternative possibilities, such asthe presence of a pathogenic circulating factor that promotesa-synuclein phosphorylation and aggregation, should beconsidered.

In a few years, we will define genetic susceptibility pro-files and pathological changes in the brain but neither who isgoing to develop clinical symptoms of PD nor its outcome.Further insight into the role of compensatory mechanisms,aging, and associated pathologies in PD is needed to eluci-date these issues. These factors account for the heterogeneityof PD. Unfortunately, none of them are mentioned in recentreviews,7 which contribute to spread the false image of PDas a homogeneous and monolithic entity.

Gurutz Linazasoro*Centro de Investigacion Parkinson

Policlınica Gipuzkoa, Parque Tecnologico MiramonSan Sebastian, Spain

*E-mail: glinazasoro@terra.es

References

1. Lerner A, Bagic A. Olfactory pathogenesis of idiopathic Parkinsondisease revisited. Mov Disord 2008;23:1076–1084.

2. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen EN, Braak E.Staging of brain pathology related to sporadic PD. NeurobiolAging 2003;24:197–211.

3. Linazasoro G. Parkinson complex vs clinically significant Parkin-son’s disease. Eur J Neurol 2007;14:721–728.

Published online 29 September 2008 in Wiley InterScience

(www.interscience.wiley.com). DOI: 10.1002/mds.22327

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Movement DisordersVol. 25, No. 1, 2010, pp. 122–132� 2008 Movement Disorder Society

4. Aarsland D, Kvaløy JT, Andersen K, et al. The effect ofage of onset of PD on risk of dementia. J Neurol 2007;254:38–45.

5. Kordower JH, Chu Y, Hauser RA, Freeman TB, C WOlanowCW. Lewy body-like pathology in long-term embryonicnigral transplants in Parkinson’s disease. Nat Med, doi:10.1038/nm1747.

6. Braak H, Del Tredici K. Assessing fetal nerve cell grafts inParkinson’s disease. Nat Med, doi:10.1038/nm1748.

7. Marras C, Lang AE. Neurology 2008;70:1996–2003.

Selective MAO-B Inhibitors have Low

Potential for the Tyramine Effect

Despite accumulating data to suggest that administrationof rasagiline (Azilect) at approved dosages is safe without di-etary modification, some patients, physicians (nonmovementdisorder specialists), and pharmacists have expressed safetyconcerns owing to the tyramine dietary precautions thatappear in the manufacturer’s package insert.1 To addressthese concerns, deMarcaida et al. published some additionalsafety data on rasagiline in their article, ‘‘Effects of TyramineAdministration in Parkinson’s Disease Patients Treated WithSelective MAO-B Inhibitor Rasagiline.’’2

deMarcaida et al. reported the results of tyramine chal-lenges in 110 patients from the TEMPO and PRESTO*studies who had Parkinson’s disease and were treated withrasagiline monotherapy (1–2 mg/day) or rasagiline (0.5–1 mg/day) in combination with levodopa.2–4 Results werereassuring in that no patient receiving rasagiline monotherapy(n 5 38) had changes in blood pressure or heart rate thatwere suggestive of a tyramine interaction. However, amongthe 55 patients treated in the combination therapy group, 3receiving rasagiline 0.5 mg/day showed systolic blood pres-sure elevations of more than 30 mm Hg over three consecu-tive measurements after the tyramine challenge. Althoughthese changes did not occur in a time course typically sug-gestive of tyramine ingestion, the possibility that the delayedgastric emptying or intestinal absorption associated with PDaltered the time course, cannot be ruled out.

It is of more than passing interest in determining whetherthis rise in systolic blood pressure seen in the PRESTO studyis of true clinical significance. Further study of blood pres-sure changes in patients treated with selective monoamineoxidase type-B (MAO-B) inhibitors may be needed to ensurethat we are not inadvertently elevating our patients’ systolicblood pressure. The recent revelation of valvular abnormal-ities associated with pergolide after so many years of regularuse shows the value of postmarketing drug surveillance oftrends suggested in premarketing trials.

Some selective MAO inhibitors at higher dosages may beassociated with the tyramine response. Oral selegiline (Dep-renyl), another selective inhibitor of MAO-B for Parkinson’sdisease, loses its selectivity when administered at dosesgreater than 20 mg/day.5 The safety of another recentlyapproved MAO-B inhibitor, Zydis selegiline (Zelapar), anorally disintegrating formulation of selegiline absorbedthrough the buccal mucosa, was also examined after an oraltyramine challenge.6 In an open-label, randomized, parallel-group study, 24 patients were given Zydis selegiline 1.25mg/day or conventional selegiline 10 mg/day for 14 days andwere challenged with tyramine 400 mg. In all patients receiv-ing conventional selegiline 10 mg, the threshold dose of tyra-mine required to elicit the pressor response was significantlyreduced (from 400 to 200 mg; P < 0.0001). Unlike conven-tional selegiline tablets (10 mg dose), Zydis selegiline1.25 mg did not potentiate the tyramine effect before or after14 days of treatment.6 A similar study with the Zydis selegi-line 2.5 mg dose would be advisable. Moreover, although norise in systolic blood pressure was seen in the premarketingstudies of Zydis selegiline, it may also be wise to evaluateblood pressure changes in currently treated patients. Emsam,the transdermal selegiline patch for major depression, is notadministered through a gastric delivery route. Althoughhigher doses have shown a loss of selective MAO-B inhibi-tion, the results of a recent tyramine challenge showed thatEmsam is safe to use at the recommended starting dose(6 mg/24 hour) without dietary tyramine restriction.7 How-ever, this study did not assess the safety of available higherdoses of Emsam.

The valuable contribution of selective MAO-B inhibitionin the treatment of patients with Parkinson’s disease isaccompanied by a robust safety profile demonstrated overalmost 30 years of clinical use. Further investigation into thelong-term safety of the newer agents Azilect and Zelapar willprovide clearer assurances concerning effects on blood pres-sure, as well as potential for interactions with diet and othermedications, such as antidepressants.

Stuart H. Isaacson, MD*Parkinson’s C.O.R.E.

Institute of Boca RatonBoca Raton, Florida, USA

*E-mail: isaacson@ParkinsonsCenter.org

References

1. Azilect1 [package insert]. Kfar Saba, Israel: Teva PharmaceuticalIndustries Ltd.; 2006.

2. deMarcaida JA, Schwid SR, White WB, et al. Effects of tyramineadministration in Parkinson’s disease patients treated with selectiveMAO-B inhibitor rasagiline. Mov Disord 2006;21:1716–1721.

3. Parkinson Study Group. A controlled trial of rasagiline in early Par-kinson disease: the TEMPO Study. Arch Neurol 2002;59: 1937–1943.

4. Parkinson Study Group. A randomized placebo-controlled trial ofrasagiline in levodopa-treated patients with Parkinson disease andmotor fluctuations: the PRESTO study. Arch Neurol 2005;62:241–248.

5. Schulz R, Antonin KH, Hoffmann E, et al. Tyramine kinetics andpressor sensitivity during monoamine oxidase inhibition by selegi-line. Clin Pharmacol Ther 1989;46:528–536.

*TEMPO, Rasagiline Mesylate [TVP-1012] in Early Monotherapyfor Parkinson’s Disease Outpatients; PRESTO, Parkinson’s Rasagi-line: Efficacy and Safety in the Treatment of ‘‘Off.’’

Published online 12 November 2008 in Wiley InterScience

(www.interscience.wiley.com). DOI: 10.1002/mds.22334

123LETTERS TO THE EDITOR

Movement Disorders, Vol. 25, No. 1, 2010

6. Clarke A, Brewer F, Johnson ES, et al. A new formulation of selegi-line: improved bioavailability and selectivity for MAO-B inhibition.J Neural Transm 2003;110:1241–1255.

7. Blob LF, Sharoky M, Campbell BJ, et al. Effects of a tyramine-enriched meal on blood pressure response in healthy male volunteerstreated with selegiline transdermal system 6 mg/24 hour. CNSSpectr 2007;12:25–34.

Performance of the Scale for Assessment

of Positive Symptoms in Parkinson’s

Disease Psychosis

We read with interest the recent Movement DisordersTask Force recommendations for scales to assess psychosisin Parkinson’s disease (PD).1 They defined several recom-mended scales, cautioning that no scale captures the fullrange of PD psychosis and highlighting that treatmentresponsiveness has not been established. We report a second-ary data analysis evaluating the treatment responsiveness ofthe Scale for Assessment of Positive Symptoms (SAPS).

The SAPS fulfills criteria as a recommended scale. It is astructured patient interview developed for schizophrenia,2

containing five domains: hallucinations, delusions, bizarrebehavior, positive formal thought disorder, and inappropriateaffect, with higher scores indicating more severe psychosis.We analyzed data from the psychosis and clozapine in Par-kinson’s disease trial conducted by the Parkinson StudyGroup.3 Fifty-four subjects completed the 4-week randomizedtrial of clozapine versus placebo. Data collected for psychiat-ric assessment included the Mini-Mental Status Examination(MMSE), Clinical Global Impression–Change, and SAPS.

We assessed the distribution of SAPS values by domain forbaseline and final visits, both overall and divided into MMSE> 24 (nondemented) or MMSE � 24 (demented). To measurethe responsiveness, we calculated effect sizes, defined as thechange from baseline divided by the standard deviation (SD)of the change. We constructed two linear regression models.In one model, the independent variable of interest wasMMSE, and the model adjusted for age, gender, baselineSAPS scores, and total UPDRS scores. In the other, CGIchange was the variable of interest with adjustment for age,gender, and baseline SAPS, MMSE, and total UPDRS scores.

Demographic characteristics for this population have beenreported.3 The mean total score for the baseline SAPS was21.6 (SD, 12.6); for hallucinations, 9.3 (4.2); delusions, 5.8(5.1); and positive formal thought disorder, 4.4 (5.6). Themean was 1.7 (3.2) for bizarre behavior and 0.4 (1.1) forinappropriate affect. The demented cohort had a higher totalSAPS score of 24 (vs. 18), driven primarily by the thoughtdisorder domain (6.1 vs. 2.4). Demented and nondementedcohorts had similar means for hallucinations and delusions(9.8 vs. 8.7 and 6.0 vs. 5.5, respectively).

Total score improved 39%, and both the SAPS total andindividual domain scores improved. Changes in hallucina-tions and delusions accounted for 83% of the total scorechange. The demented cohort showed less change (total scorechange 26.16 vs. 210.04 for nondemented cohort), althoughMMSE scores were not significantly associated with respon-siveness to treatment. The effect size of the SAPS was20.73 overall and 20.91 for hallucinations. In the regressionanalysis, each point increase on baseline SAPS was associ-ated with a 0.54 point decrease in SAPS change (95% CI[20.76, 20.31], P < 0.0001).

Improvement in CGI correlated with improvement in theSAPS, driven primarily by the hallucinations and delusionsdomains (Fig. 1). In 7 cases (13%), the SAPS improved butCGI rating was worse. In these cases, hallucinations anddelusions improved, but scores for bizarre behavior wors-ened. In the regression analysis, each unit change in CGI wasassociated with a 4.53 point change in the total SAPS (95%CI [2.37, 6.69], P 5 0.0001).

These results confirm that the SAPS is responsive tochange in PD psychosis. Change in SAPS was largely drivenby the hallucination and delusion domains, which are themost common manifestations of PD psychosis.4 Subjects withworse psychosis were less responsive to treatment change.Therefore, the apparent effect of cognitive impairment ontreatment change may be a result of confounding, as subjectswith cognitive impairment had higher total SAPS scores.Other medical or psychiatric comorbidities that were notincluded in our analyses may mediate treatment response,and these findings should be examined in other data sets.However, our findings challenge the notion that the severityof cognitive impairment independently limits treatmentresponse in PD psychosis. Overall, the regression analysissuggests that CGI is strongly associated with SAPS scores.Based on this analysis, a change in total SAPS score of 4 to5 points appears clinically meaningful.

Acknowledgments: The data analysis was supported byACADIA Pharmaceuticals. The original trial was funded inpart by a grant (FD-R-001416-02) from the Orphan DrugDivision of the Food and Drug Administration and in part bythe Parkinson Study Group. We thank Dr. Joseph Friedmanfor his thoughtful review of the manuscript.

Potential conflict of interest: Bernard Ravina has served as a con-sultant for ACADIA Pharmaceuticals.

Published online 1 May 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22575

FIG. 1. Sensitivity to change: SAPS score versus CGI score.

Movement Disorders, Vol. 25, No. 1, 2010

124 LETTERS TO THE EDITOR

Tiffini S. Voss, MD*Alicia F.D. Brocht, BA

Bernard Ravina, MD, MSCEDepartment of Neurology

University of Rochester School ofMedicine and Dentistry

Rochester, New York, USA*E-mail: tiffini.voss@ctcc.rochester.edu

References

1. Fernandez HH, Aarsland D, Fenelon G, et al. Scales to assess psy-chosis in Parkinson’s disease: critique and recommendations. MovDisord 2008;23:484–500.

2. Andreasen NC. The scale for assessment of positive symptoms(SAPS). Iowa City, IA: The University of Iowa; 1984.

3. The Parkinson Study Group. Low-dose clozapine for the treatmentof drug-induced psychosis in Parkinson’s disease. N Engl J Med1999;340:757–763.

4. Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria forpsychosis in Parkinson’s disease: report of an NINDS, NIMHwork group. Mov Disord 2007;22:1061–1068.

Botulinum Toxin Type A for Painful Limbs

Moving Extremities

We read with great interest the recently published articlein your distinguished journal by Alvarez et al.1 The authorsperformed a retrospective review of cases of painful legsand moving toes (PLMT) or painful limbs moving extrem-ities (PLME) and among others reported that GABAergicagents seem most effective. The authors discuss the limiteddegree of efficacy with other treatment approaches, includ-ing local anesthetic nerve blocks and injections of botuli-num toxin type A. Their electrophysiological testingshowed involvement of dystonic mechanisms in the patho-genesis of PLMT.

Relating to the effective treatment options for PLME, thereis substantial data in favor of the use of botulinum toxin typeA injections. In the retrospective review chart of Alvarezet al.,1 GABAergic agents were administered in the majorityof cases, whereas none of the patients was treated with botuli-num toxin injections. We therefore suggest that this might bethe reason for why authors are conclusive and supportive tothe use of GABAergic agents over botulinum toxin injections.On the contrary, our experience2,3 bolsters the argument thatbotulinum toxin injections should be considered in the treat-ment of PLMT. This treatment strategy seems to provide bothsignificant pain relief and improvement of involuntary move-ments because of reduction of muscle spindle discharge andsubsequent decreased activity of gamma loop and central sen-sitization.4 Botulinum toxin injections also exert antisympa-

thetic, antiglutamergic, and anti-inflammatory effects and inhi-bition of local pain neurotransmitters.5,6

In summary, we suggest that the use of botulinum toxininjections in the treatment of PLME should be consideredbased on the available clinical data. Our view is supportedby the significant contributing role dystonic mechanismsseem to play in the pathogenesis of the PMLE.

Acknowledgments: Dr. Papapetropoulos is currentlyemployed in Biogen Idec.

Andreas A. Argyriou, MD, PhD*Department of Neurology

‘‘Saint Andrew’s’’ General Hospital of PatrasPatras, Greece

*E-mail: andargyriou@yahoo.gr

Spyridon Papapetropoulos, MD, PhDDepartment of Neurology

University of MiamiMiller School of Miami

Florida, USA

References

1. Alvarez MV, Driver-Dunckley EE, Caviness JN, Adler CH, Evi-dente VG. Case series of painful legs and moving toes: clinicaland electrophysiologic observations. Mov Disord 2008;23:2062–2066.

2. Eisa M, Singer C, Sengun C, Russel A, Jabbari B, Papapetropou-los S. Treatment of painful limbs/moving extremities with botuli-num toxin type A injections. Eur Neurol 2008;60:104–106.

3. Singer C, Papapetropoulos S. A case of painless arms/moving fin-gers responsive to botulinum toxin A injections. ParkinsonismRelat Disord 2007;13:55–56.

4. Bhidayasiri R, Truong DD. Expanding use of botulinum toxin.J Neurol Sci 2005;235:1–9.

5. Papapetropoulos S, Argyriou AA. Painful limbs/moving extrem-ities. Acta Neurol Scand 2008;117:224–230.

6. Dressler D, Thompson PD, Gledhill RF, Marsden CD. The syn-drome of painful legs and moving toes. Mov Disord 1994;9:13–21.

Dopaminergic System in Peripheral Blood

Mononuclear Cells in Parkinson’s Disease

We read with interest the article published by Djaldettiet al. entitled ‘‘Lesions outside the CNS in Parkinson’s dis-ease’’.1 As stated by the authors, understanding of the clinicalfeatures and progression of Parkinson’s disease (PD) haschanged significantly following the proposal by Braak et al.2

of different pathological stages in the progression of the dis-ease in the CNS. They have clearly shown that the degenera-

Published online 7 May 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22602

Potential conflict of interest: Nothing to report.Published online 4 September 2009 in Wiley InterScience

(www.interscience.wiley.com). DOI: 10.1002/mds.22742

Movement Disorders, Vol. 25, No. 1, 2010

125LETTERS TO THE EDITOR

tive process in PD is much more extensive than originallydescribed and also affects the peripheral autonomic system.Djaldetti et al. provide a detailed review of the anatomical,physiological, and clinical features of lesions in organs out-side the CNS that are involved in PD and describe their rele-vance to the etiology, pathogenesis, and diagnosis of this dis-ease. A section dealing with the changes observed in periph-eral blood is also included in the review. In this section, theauthors mention the recent evidence by Kim et al.3 ofincreased expression of alpha-synuclein in peripheral bloodmononuclear cells (PBMC) as a potential link between theCNS and the peripheral immune system. However, we couldnot find any mention on a number of studies from our groupand others dealing with the characterization of the changes ofthe dopaminergic system in PBMC from patients with PD. Inparticular, human PBMC synthesizes catecholamines, includ-ing dopamine, and expresses dopamine receptors and the do-pamine transporter on their cell membrane. Changes of theexpression of dopamine receptors in PBMC have beenreported in PD,4,5 as well as the reduction of intracellular do-pamine concentration and tyrosine-hydroxylase immunoreac-tivity.6 In addition, a number of studies also showed thereduction of dopamine transporter immunoreactivity inPBMC from patients with PD.7–9 Although this latter phe-nomenon has also been observed in other neurodegenerativedisorders, such as multiple system atrophy10 or amyotrophiclateral sclerosis,11 and appears, therefore, not specific for PD,we believe that these findings deserve to be mentioned asfurther evidence of the involvement of peripheral dopaminer-gic system in PD. PBMC may as well represent a usefulmodel that can be used to further investigate the adaptationof endogenous dopaminergic systems to pharmacologicalinterventions.

Francesco E. Pontieri, MD*Carlo Colosimo, MD

Department of Neurological SciencesUniversity ‘Sapienza’

Rome, Italy*E-mail: fe.pontieri@gmail.com

References

1. Djaldetti R, Lev N, Melamed E. Lesions outside the CNS in Par-kinson’s disease. Mov Disord 2009;24:793–800.

2. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN,Braak E. Staging of brain pathology related to sporadic Parkin-son’s disease. Neurobiol Aging 2003;24:197–211.

3. Kim S, Seo JH, Suh YH. alpha-synuclein, Parkinson’s disease,and Alzheimer’s disease. Parkinsonism Relat Disord 2004;10:S9–S13.

4. Nagai Y, Ueno S, Saeki Y, Soga F, Hirano M, Yanagihara T.Decrease of the D3 dopamine receptor mRNA expression in lym-phocytes from patients with Parkinson’s disease. Neurology1996;46:791–795.

5. Barbanti P, Fabbrini G, Ricci A, et al. Increased expression ofdopamine receptors on lymphocytes in Parkinson’s disease. MovDisord 1999;14:764–771.

6. Caronti B, Tanda G, Colosimo C, et al. Reduced dopamine inperipheral blood lymphocytes in Parkinson’s disease. Neuroreport1999;10:2907–2910.

7. Caronti B, Antonini G, Calderaro C, et al. Dopamine transporterimmunoreactivity in peripheral blood lymphocytes in Parkinson’sdisease. J Neural Transm 2001;108:803–807.

8. Pellicano C, Buttarelli FR, Circella A, et al. Dopamine trans-porter immunoreactivity in peripheral blood lymphocytes dis-criminates Parkinson’s disease from essential tremor. J NeuralTransm 2007;114:935–938.

9. Buttarelli FR, Capriotti G, Pellicano C, et al. Central and periph-eral dopamine transporter reduction in Parkinson’s disease. Neu-rol Res 2009 [Epub ahead of print].

10. Buttarelli FR, Circella A, Pellicano C, et al. Dopamine trans-porter immunoreactivity in peripheral blood lymphocytes in mul-tiple system atrophy. J Neural Transm 2009;116:161–165.

11. Buttarelli FR, Circella A, Pellicano C, Pontieri FE. Dopaminetransporter immunoreactivity in peripheral blood mononuclearcells in amyotrophic lateral sclerosis. Eur J Neurol 2006;13:416–418.

Nocturnal Eating in Restless Legs Syndrome

We read with interest the recent study by Provini et al.,1

which showed an increased prevalence of sleep-related eatingdisorder (SRED) in patients with restless legs syndrome(RLS). The ‘‘out-of-control’’ nocturnal eating behaviors thatthey observed in RLS patients were strikingly similar to thecompulsive and binge eating that we2 and others3 haveobserved in patients treated with dopamine agonists. In ourexperience, nocturnal eating is a common clinical feature ofdopamine agonist-related compulsive eating in Parkinson’sdisease.2 Similar impulse control disorders (ICDs) have alsobeen reported in patients treated with dopamine agonists forother conditions, including RLS.4–7

Although the authors reported no differences in dopami-nergic medication usage in RLS patients with and withoutSRED, they showed a trend in this direction (67% versus52%, P 5 0.20) that might have reached statistical signifi-cance if they had discriminated between dopamine agonistsand levodopa and/or included a quantitative comparison ofdopamine agonist use in the two groups. The authors alsoreported higher Maudsley Obsessive-Compulsive Inventoryscores in RLS subjects with SRED, suggesting that thesepatients may have had other comorbid compulsive tenden-cies; this is comparable to the frequent occurrence of otherICDs in patients with dopamine agonist-related compulsiveeating.2,8 The authors’ observation of SRED in untreatedRLS patients, however, raises the possibility of a biologicallink between RLS and SRED.

We recommend further study to evaluate the extent towhich SRED in RLS patients is a side-effect of dopamineagonists versus a direct or indirect consequence of the dis-ease. We congratulate the authors on bringing this importantissue to attention.

Disclosures: Dr Waters has received honoraria for speaking forBoehringer-Ingelheim and GlaxoSmithKline.

Published online 30 September 2009 in Wiley InterScience

(www.interscience.wiley.com). DOI: 10.1002/mds.22797

126 LETTERS TO THE EDITOR

Movement Disorders, Vol. 25, No. 1, 2010

Melissa J. Nirenberg, MD, PhD*Department of Neurology and Neuroscience

Weill Cornell Medical CollegeNew York, New York, USA

*E-mail: mjnirenb@med.cornell.edu

Cheryl Waters, MDDepartment of Neurology

Columbia University Medical CenterNew York, New York, USA

References

1. Provini F, Antelmi E, Vignatelli L, et al. Association of restlesslegs syndrome with nocturnal eating: a case-control study. MovDisord 2009;24:871–877.

2. Nirenberg MJ, Waters C. Compulsive eating and weight gainrelated to dopamine agonist use. Mov Disord 2006;21:524–529.

3. Giladi N, Weitzman N, Schreiber S, Shabtai H, Peretz C. Newonset heightened interest or drive for gambling, shopping, eatingor sexual activity in patients with Parkinson’s disease: the role ofdopamine agonist treatment and age at motor symptoms onset.J Psychopharmacol 2007;21:501–506.

4. Driver-Dunckley ED, Noble BN, Hentz JG, et al. Gambling andincreased sexual desire with dopaminergic medications in restlesslegs syndrome. Clin Neuropharmacol 2007;30:249–255.

5. Quickfall J, Suchowersky O. Pathological gambling associatedwith dopamine agonist use in restless legs syndrome. Parkinson-ism Relat Disord 2007;13:535–536.

6. Tippmann-Peikert M, Park JG, Boeve BF, Shepard JW, SilberMH. Pathologic gambling in patients with restless legs syndrometreated with dopaminergic agonists. Neurology 2007;68:301–303.

7. Evans AH, Butzkueven H. Dopamine agonist-induced pathologicalgambling in restless legs syndrome due to multiple sclerosis. MovDisord 2007;22:590–591.

8. Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, AhlskogJE. Pathological gambling caused by drugs used to treat Parkinsondisease. Arch Neurol 2005;62:1377–1381.

Tongue Protrusion and Feeding Dystonia:

A Hallmark of Chorea-Acanthocytosis

Video

Neuroacanthocytosis syndromes are a group of rare disor-ders characterized by neurodegeneration and thorny erythro-cytes.1 Chorea-acanthocytosis (ChAc, OMIM 200150) is themain entity within this group and is one differential diagnosisof Huntington’s disease (HD).1 Besides VPS13A sequencing2

demonstration of absence of its protein product (chorein) onWestern blot3 can be used alternatively. In early stages, thephenotype often comprises dysphagia and tongue dystonia4

and appears quite indicative of ChAc. Here, we report twocases in which action-induced tongue protrusion was a strik-ing and early finding.

Case 1: This 30-year-old woman presented with orofacialchorea, dysphagia, dysarthria, and vocalizations. At age 28,after repeatedly biting her cheeks and tongue, she was diag-nosed with borderline personality disorder. She had two gen-eralized tonic-clonic seizures at age 29. On examination, sheshowed chorea of the limbs and reduced ankle reflexes.Increasing orofacial and limb chorea, chronically elevatedcreatine kinase (CK) levels and acanthocytosis (20%) sug-gested a diagnosis of ChAc. Absence of chorein in erythro-cyte membranes4 was found.

Case 2: This 30-year-old woman developed throat clickingand bruxism at age 24. Dysphagia and feeding dystonia werefirst noted at the age of 25, along with dysarthria, memorylapses, and vocal tics. She subsequently began biting hertongue and developed involuntary stereotypic movements,seizures, cognitive decline, and gait difficulties. On examina-tion, she showed dysarthria, chorea, dystonia, ataxia, andhyporeflexia. Laboratory testing was significant for acantho-cytosis and elevated CK levels. Heterozygous mutations werefound in VPS13A (Case 23).5

Especially while eating, both patients demonstrate strikinginvoluntary tongue movements and accompanying jaw open-ing. Forceful protrusion of the tongue only occurs during thisaction (see video), following which the patients are able to vol-untarily retract the tongue. In a videofluoroscopic swallowstudy (VFSS) of Case 2, the pharyngeal phase was intact,whereas her oral phase was impaired by the tongue protrusion.Once the food bolus passed the upper sphincter of the esopha-gus, deglutition was carried out normally. Both patients triedto bypass the oral phase by strongly pressing their lips togetherto close their mouths while chewing, by extending the head ifthe tongue protruded, or else by extending the neck so thatfood fell into the pharynx posterior to the tongue, greatlyincreasing the risk of aspiration. Swallowing was effortful assuggested by the accompanying eye closure. In the VFSS, thetongue is not protruding against occluded teeth but is com-bined with wide opening of the jaw.

The second patient’s video shows that dysarthria in ChAcis marked by syllable iterations at the beginning of wordsand by impaired initiation of speech. When talking, thetongue of neither patient showed marked protrusion. How-ever, since jaw closure occasionally was incomplete, it waspossible to observe slight dystonic movements of the tongue,moving anterior to the teeth.

Prominent tongue protrusion dystonia in ChAc occurswhen placing solid food into the mouth, with chewing andswallowing food or with manipulations in the orolingualregion but was absent at rest, in contrast to the spontaneoustongue protrusion described in other diseases.4

Dysphagia in ChAc differs from that observed in Hunting-ton’s disease (HD) who encounter difficulties mainly becauseof head and neck hyperextension, tachyphagia, and nonpro-truding lingual chorea during the oral phase.6 Furthermore,movement disorder in HD directly affects also the pharyngealand esophageal phases, while these appear to be intact in ourChAc patients. Action-induced tongue protrusion dystonia asseen in ChAc is not described in HD.

Nonfood objects like toothpicks or cloth do not provoketongue dystonia but may be used as a sensory trick, or as a

Additional Supporting Information may be found in the onlineversion of this article.

Potential conflict of interest: The authors report no conflicts of in-terest in this manuscript.

Published online 24 November 2009 in Wiley InterScience

(www.interscience.wiley.com). DOI: 10.1002/mds.22863

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mechanical obstruction to avoid involuntary jaw closure.The combination of masseter muscle and tongue protrusiondystonia appears to be the cause of the common mutilationsof tongue, lips, and cheeks in ChAc and may result in sig-nificant weight loss and lethal infection.7 Mild tongue dys-tonia was observed on talking, swallowing saliva, and drink-ing. Being aware of these involuntary movements, patientssometimes incorporate them into parakinesias such as lipsmacking.

We suggest that action-induced tongue protrusion andfeeding dystonia is a highly specific hallmark for ChAc, oftenseen early in the course of disease. Particularly in combina-tion with chronically elevated CK levels in young adults, thissymptom has high diagnostic value.

Legends to the Video

Sequence 1. Patient 1 shows slight speech impairmentsuch as iterations at the beginning of words. Tongue protru-sion and jaw opening occur when she places a morsel offood in her mouth. Please, note the absence of further abnor-mal movements.

Sequence 2. Patient 2 displays an almost identical action-induced tongue protrusion while eating.

Sequence 3. VFSS sequence of Patient 2 shows feedingand chewing interrupted by tongue protrusion dystonia, withsubsequent normal esophageal phase.

Sequence 4. Patient 2 displays dysarthria and iterations whiletalking about her tongue movements and eating difficulties.

Acknowledgments: The authors thank Mrs. AndreaHofmayer (Asklepios, Bad Tolz, Germany) and Mrs. DoroKuhnau (Rehabilitation Center, Nittenau, Germany) for theiradvice on speech pathology.

Financial Disclosure: Benedikt Bader: Supported by theAdvocacy for Neuroacanthocytosis Patients, supported by theBayerische Forschungsallianz, received travel funding fromthe Bundesministerium fur Bildung und Forschung; Ruth H.Walker: Supported by Intellyst Medical Communication, forspeaking on Huntington’s disease, supported by Scienta

Healthcare education for advice on construction of aHuntington’s disease case study for CME-accredited on-lineprogram; Mathias Vogel: none; Mario Prosiegel: none;Jacqueline McIntosh: none; Adrian Danek: Receives travelfunding from Pfizer, Editorial board of ‘‘Zeitschrift furGerontoneurologie,’’ receives royalties from publishing‘‘Klinische Untersuchung der hoheren Hirnleistungen’’ (Kohl-hammer Verlag, 2008), has received speaker honoraria fromMerz, Pfizer, and Neuro-Update, receives research support asPrincipal Investigator from Bayerische Forschungsstiftung (ofFederal Government of Bavaria), Munchner Universitatsge-sellschaft, Deutsch-Franzosische Hochschulstiftung, andAdvocacy for Neuroacanthocytosis Patients, has served as anexpert witness for German courts of justice in medico- legalcases, supported by the Advocacy for NeuroacanthocytosisPatients.

Author Roles: B. Bader: Conception, organization, and exe-cution of research project, design of data analysis and patients,writing of the first draft of the manuscript; R.H. Walker:Review and critique of data analysis and patients, review andcritique of manuscript; M. Vogel: Data interpretation andreview and critique of data analysis and patients, review andcritique of manuscript; M. Prosiegel: Data interpretation andreview and critique of data analysis and patients, review andcritique of manuscript; J. McIntosh, Design, data interpretation,and review and critique of data analysis and patients, reviewand critique of manuscript; A. Danek: Conception of researchproject, review and critique of manuscript.

Benedikt Bader, MD*Neurologische Klinik und Poliklinik

Ludwig-Maximilians-UniversitatMunchen, Germany

*E-mail: benedikt.bader@med.uni-muenchen.de

Ruth H. Walker, MB, ChB, PhDDepartment of Neurology

James J. Peters Veterans Affairs Medical CenterBronx, New York

Mount Sinai School of MedicineNew York, New York

FIG. 1. While eating a pretzel, Patient 1 with ChAc demonstrates action-induced tongue protrusion.

128 LETTERS TO THE EDITOR

Movement Disorders, Vol. 25, No. 1, 2010

Mathias Vogel, PhDClinic of Neuropsychology

Klinikum BogenhausenMunchen, Germany

Mario Prosiegel, MDCenter for Dysphagia

Fachklinik Bad HeilbrunnBad Heilbrunn, Germany

Jacqueline McIntoshWolfson Neurorehabilitation Centre

London, United Kingdom

Adrian Danek, MDNeurologische Klinik und Poliklinik

Ludwig-Maximilians-UniversitatMunchen, Germany

References

1. Walker RH, Jung HH, Dobson-Stone C, et al. Neurologic pheno-types associated with acanthocytosis. Neurology 2007;68:92–98.

2. Rampoldi L, Dobson-Stone C, Rubio JP, et al. A conservedsorting-associated protein is mutant in chorea-acanthocytosis. NatGenet 2001;28:119–120.

3. Dobson-Stone C, Velayos-Baeza A, Filippone LA, et al. Choreindetection for the diagnosis of chorea-acanthocytosis. Ann Neurol2004;56:299–302.

4. Schneider SA, Aggarwal A, Bhatt M, et al. Severe tongue protru-sion dystonia: clinical syndromes and possible treatment. Neurol-ogy 2006;67:940–943.

5. Dobson-Stone C, Danek A, Rampoldi L, et al. Mutational spec-

trum of the CHAC gene in patients with chorea-acanthocytosis.

Eur J Hum Genet 2002;10:773–781.

6. Kagel MC, Leopold NA. Dysphagia in Huntington’s disease: a

16-year retrospective. Dysphagia 1992;7:106–114.7. Lossos A, Dobson-Stone C, Monaco AP, et al. Early clinical hetero-

geneity in choreoacanthocytosis. Arch Neurol 2005;62:611–614.

Singing-Induced Cervical Dystonia

Video

Dystonia is a syndrome characterized by involuntary, sus-tained, patterned, or repetitive muscle contractions of oppos-ing muscles causing twisting movements or abnormal pos-tures.1 Task, specific dystonia is a form of action, dystoniawith non-coordinated movements and involuntary musclecontractions that occurs only at the attempt of performingspecific motor tasks (e.g., writer’s cramp, task-specific dysto-nia in piano and tabla players, musicians with embouchuredystonia and praying-induced dystonia).1–7 On a recent paper

published by Conti et al.,6 the authors reviewed all publishedcases of musician’s hand dystonia, explored the pathophysio-logical mechanisms involved, and clinical implications. Asmany as 8% of musicians may be affected during theircareers.6,7 Many theories were proposed to explain the under-lying mechanisms. One of these theories is the abnormal acti-vation of basal ganglia, motor cortices, and cerebellar hemi-spheres as occurs in patients with writer’s cramp2 and thedeficiency of homeostatic control of the range of modifiabil-ity of sensorimotor circuits as shown by Quartarone et al.2 incases of writer’s cramp using transcranial magnetic stimula-tion. Finally, recent studies support a dual role for geneticand environmental factors in the development of focal task-specific dystonia of musicians’ hand.6

We report an unusual presentation of a task-specific dys-tonia in a 24-year-old man. The patient started his singingcareer of Brazilian country music, at the age of 18 years.After live performances, he noticed a significant cervicaldiscomfort. A few months later, he started to present whilesinging higher frequency notes, left torticollis with mildlaterocollis to the same side associated with difficulties tokeep the voice normally pitched, always only while sing-ing. When he tried to keep his head on a neutral positionhis voice changed to a high-pitched, coarse, or strangledtone. The phenomenon did not manifest while singinglower frequency notes as well during normal speech. Hedenied previous head trauma or any neurological condi-tions. Neurological examination at rest was normal, butwhen asked to sing Brazilian country music, he immedi-ately developed left torticollis and a mild left laterocolliswith severe right sternocleidomastoid muscle (SCM) hyper-trophy (see Video). Laboratory tests and cranial CT scanwere normal. Electromyography demonstrated prolongedbursts on the right SCM only when singing.

This patient was diagnosed with a task-specific cervicaldystonia. His treatment consisted in intramuscular injectionsof botulinum toxin type A (BT-A; Dysport, Biosintetica, SaoPaulo, Brazil). In the left splenius capitis (300 IU) and in theright SCM (150 IU).

On follow-up after 3 weeks, the dystonic symptoms andthe SCM hypertrophy were significantly improved. Neverthe-less, the patient complained that his voice became lesspowerful after the procedure, and declined subsequent botuli-num toxin injections. The patient was re-examined after6 months and reported that the symptoms returned after thethird month, moderately less intense than before treatment.

Task-specific focal dystonia occurs mainly in highlyskilled manual tasks, and are usually related to occupation(piano players, architects, writers, and shoemakers). Rarecases were described in oromandibular region (e.g., embou-chure dystonia in brass players). There are two reported casesof unusual task-specific dystonia: praying-induced dystoniaobserved in a Turkish patient who developed slurred speechwhen reciting Islamic prayers, and a focal dystonia of thejaw developed by an auctioneer, which occurred only duringhis selling patter and resolved on stopping.2–4,7 Jankovic andAshoori7 published an exceptional review of movement dis-orders in musicians and dystonia appears to be by far themost common.

The present case illustrates an unusual and to the best ofour knowledge, never before reported case of task-specificcervical dystonia elicited by the singing act.

Additional Supporting Information may be found in the onlineversion of this article.

Potential conflict of interest: Nothing to report.Published online 24 November 2009 in Wiley InterScience

(www.interscience.wiley.com). DOI: 10.1002/mds.22880

Movement Disorders, Vol. 25, No. 1, 2010

129LETTERS TO THE EDITOR

Legend to the Video

This 24-year-old man, Brazilian country music singer, wasreferred to the author (GF), because after the shows he suf-fered from cervical discomfort and difficulties to keep thevoice normally pitched when singing, as he presented a turn-ing of the head to the left. On the first video (prior to the useof BT), when singing Brazilian country music is clearly dem-onstrated a left-torticollis with severe right sternocleidomas-toid muscle (SCM) hypertrophy. On the second video, thedystonic symptoms and also the SCM hypertrophy hadvanished.

Author’s Roles: I certify that I have made substantialcontributions to the intellectual content of the SubmittedPublication Material as described below. Giorgio Fabianiwas involved in the conception and design, acquisition ofdata, analysis and interpretation of data, drafting of allof the Submitted Publication Material, critical revision ofall of the Submitted Publication Material for importantintellectual content. Renato P Munhoz was involved in thedrafting of part of the Submitted Material, critical revisionof all of the Submitted Publication Material for importantintellectual content. Helio Teive was involved in the super-vision, drafting of part of the Submitted Material, criticalrevision of all of the Submitted Publication Material forimportant intellectual content.

Giorgio Fabiani, MD*Renato P Munhoz, MD

Helio Teive, MDMovement Disorders Unit, Neurology Service

Federal University of ParanaCuritiba, Parana, Brazil

*E-mail: giorgio@berthierfabiani.com.br

References

1. Fahn S, Bressman SB, Marsden CD. Classification of dystonia.Adv Neurol 1998;78:1–10.

2. Quartarone A, Siebner HR, Rothwell JC. Task-specific hand dys-tonia: can too much plasticity be bad for you? Trends Neurosci2006;29:192–199.

3. Scolding NJ, Smith SM, Sturman S, Brookes GB, Lees AJ. Auc-tioneer’s jaw: a case of occupational oromandibular hemidystonia.Mov Disord 1995;10:508–509.

4. Ilic TV, Potter M, Holler I, Deuschl G, Volkmann J. Praying-induced oromandibular dystonia. Mov Disord 2005;20:385–386.

5. Frucht SJ, Fahn S, Greene PE, et al. The natural history of em-bouchure dystonia. Mov Disord 2001;16:899–906.

6. Conti AM, Pullman S, Frucht SJ. The hand that has forgotten itscunning—lessons from musicians’ hand dystonia. Mov Disord2008;23:1398–1406.

7. Jankovic J, Ashoori A. Movement Disorders in musicians. MovDisord 2008;23:1957–1965.

Pain and Dyskinesia in Parkinson’s Disease

We read with interest the article by Lim et al.1 about painand dyskinesia in Parkinson’s disease (PD). They proposedthat similar mechanisms mediate both manifestations in PD.Here, we describe a case that provides further insight into therelationship between pain and levodopa-induced dyskinesiain PD.

A 48-year-old male physician developed right-hand resttremor and bradykinesia as presenting features of PD, 11years ago. ‘‘Wearing-off’’ motor fluctuations ensued some 5years later under treatment with levodopa-carbidopa and sub-sequently, peak dose dyskinesia became problematic in theright arm.

Pain in the legs started 8 years after motor symptoms; thisevolved toward increasing intensity over the next year andbecame generalized by gradual spreading from the legs to thetrunk, over a few months, until reaching the upper limbs.Pain was maximal in the legs with a predominant ‘‘stocking-like’’ distribution at onset and was described as dull, burning,and not induced by tactile or stretching stimuli but showinghigh sensitivity to cold water. Pain was permanent but withfluctuations in intensity. The most painful periods coincidedwith ‘‘off’’ motor periods and mild improvement was notedin the ‘‘on’’ motor state. Evaluation of peripheral nerves andcentral somatosensory conduction was normal. All otherdiagnostic tests were normal. Treatment for pain was startedwith gabapentin up to 2,400 mg a day, which resulted in amild improvement. Oxcarbamazepine, amitriptiline, tramadol,and carbamazepine were added sequentially, without addi-tional benefit.

When we saw him, the patient reported severe pain dur-ing ‘‘off’’ periods. UPDRS-motor scale was 31 in the ‘‘off’’(after 24 hours without medication) and 6 in the ‘‘on’’ andassociated with moderate to severe dyskinesia predomi-nantly in the axial and upper limb body segments. The painwas not associated with color skin changes or any other pe-ripheral manifestations, but was clearly so invalidating as tointerfere with his well-being and performance of daily lifeevents. Pain abated considerably during ‘‘on’’ periods whensevere dyskinesia was present; however, pain remainedalmost unaltered during ‘‘off’’ and ‘‘on without dyskinesia,’’despite the fact that dystonic postures or rigidity were notpresent (Fig. 1).

After several attempts to control the condition with stand-ard treatments, apomorphine subcutaneous infusion (9 mg/hour) was started. This caused a marked improvement inclinical condition and marked attenuation of ‘‘off’’ period andthe severe pain. He continued to experience incapacitatingpain at night and in the early morning and developed severesubcutaneous nodules related to apomorphine. Subthalamicnucleus deep brain stimulation (STN-DBS) was thereforeindicated. After surgery and DBS adjustments, motor fluctua-tions and dyskinesia were markedly reduced, and the painwas almost absent most of the day, although L-dopa equiva-

Potential conflict of interest: Nothing to report.Published online 24 November 2009 in Wiley InterScience

(www.interscience.wiley.com). DOI: 10.1002/mds.22874

Movement Disorders, Vol. 25, No. 1, 2010

130 LETTERS TO THE EDITOR

lent dose was not reduced significantly. A good degree ofsymptomatic control has persisted for more than 3 years.

This case exemplifies the presence of pain as a disablingnonmotor fluctuation, which was more incapacitating than themotor manifestations, as has previously been reported.2 Inour patient, the threshold for pain response to dopaminergicstimulation was higher than the dopaminergic threshold forthe ‘‘on’’ response and may be even above the dyskinesiathreshold, as pain was only abolished when severe dyskinesiawas present (‘‘supra on’’ threshold). This different thresholdcould make the recognition and proper management of thisnonmotor fluctuation difficult.3 In our patient, the combina-tion of dopaminergic drugs (which remained unchanged) andDBS may have had a synergistic interaction, as has beenshown for other parkinsonian features.4

The case reported here exemplified the possibility of painin PD not directly related to abnormal muscular activity,such as ‘‘off’’ period dystonia. We would therefore like tosuggest that in our case, pain has a central origin and has theclinical features of neuropathic pain. The mechanism bywhich pain may arise in PD despite adequate treatment forcontrol of motor features is obscure.

Dopamine has been postulated as a modulator for the proc-essing of painful experience, particularly in the mesolimbicsystem originating in the ventral tegmental area.5 A lower painthreshold and more extensive cortical activation induced bypain (measured by H2

15O PET) have been recognized in PDpatients, suggesting a link between dopamine loss and hyper-sensitivity to pain stimuli.6 This is in keeping with a role for thebasal ganglia in sensory processing. In fact, there is experimen-tal data showing cortical somatosensory (including nocicep-tive) input to the striatum and physiological activation of stria-tal regions in response to nociceptive peripheral stimulation. Inthe DA depleted state, the striatum may fail to adequately selectout sensory afferent activity, giving rise to pain.7 Why this isonly present in some patients is unclear, but this should beincluded as part of the clinical spectrum of PD.

Acknowledgment: This work was supported by FIMA,University of Navarra.

Financial Disclosures: C. Juri—Honoraria: UCB (Spain),Employment: University of Navarra; M. C. Rodriguez-Oroz—Hono-raria: GSK, UCB, and Medtronic (Spain), Grants: Spanish Ministryof Science, Employment: University of Navarra; J. A. Burguera—Honoraria: GSK and Novartis (Spain), Employment: National HealthSystem; J. Guridi—Honoraria: GSK and Medtronic (Spain), Employ-ment: University of Navarra; J. A. Obeso—Advisory Boards: GSK(UK), MERZ (Germany), Honoraria: GSK, Novartis, and UCB(Spain), Grants: Spanish Ministry of Science and Education, Euro-pean Union, Employment: University of Navarra.

Author Roles: Carlos Juri, Maria C. Rodrıguez-Oroz, and Jose A.Obeso were involved in the research project (conception, organiza-tion, and execution) and in manuscript writing (first draft, review,and critique). Juan Andres Burguera was involved in research project(conception) and in manuscript writing (review and critique). JorgeGuridi was involved in research project (conception, organization,and execution) and in manuscript writing (review and critique).

Carlos Juri, MDNeurosciences Division

Department of Neurology and NeurosurgeryClinica Universitaria and Medical School

CIMA and CIBERNED, University of NavarraPamplona, Spain

Deptartment of Neurology, Medical School, PontificiaUniversidad Catolica de Chile

Santiago, Chile

Maria C. Rodrıguez-Oroz, MD, PhDNeurosciences Division

Department of Neurology and NeurosurgeryClinica Universitaria and Medical School

CIMA and CIBERNED, University of NavarraPamplona, Spain

FIG. 1. Schematic representation of the fluctuations in pain complaint (line) in relation to each dose of levodopa and motor status.

Movement Disorders, Vol. 25, No. 1, 2010

131LETTERS TO THE EDITOR

Juan A. Burguera, MDService of Neurology, Hospital Universitario

‘‘La Fe’’Valencia, Spain

Jorge Guridi, MD, PhDJose A. Obeso, MD, PhD*

Neurosciences DivisionDepartment of Neurology and NeurosurgeryClinica Universitaria and Medical School

CIMA and CIBERNED, University of NavarraPamplona, Spain

*E-mail: jobeso@unav.es

References

1. Lim SY, Farrell MJ, Gibson SJ, Helme RD, Lang AE, Evans AH.Do dyskinesia and pain share common pathophysiological mecha-nisms in Parkinson’s disease? Mov Disord 2008;23:1689–1695.

2. Rahman S, Griffin HJ, Quinn NP, Jahanshahi M. Quality of life inParkinson’s disease: the relative importance of the symptoms.Mov Disord 2008;23:1428–1434.

3. Muzerengi S, Lewis H, Edwards M, et al. Non-motor symptomsin Parkinson’s disease: an underdiagnosed problem. Aging Health2006;2:967–982.

4. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep

brain stimulation in Parkinson’s disease: a multicentre study with

4 years follow-up. Brain 2005;128:2240–2249.5. Scott DJ, Heitzeg MM, Koeppe RA, Stohler CS, Zubieta JK. Var-

iations in the human pain stress experience mediated by ventral

and dorsal basal ganglia dopamine activity. J Neurosci 2006;26:

10789–10795.6. Brefel-Courbon C, Payoux P, Thalamas C, et al. Effect of

levodopa on pain threshold in Parkinson’s disease: a clinical

and positron emission tomography study. Mov Disord 2005;20:

1557–1563.7. Juri C, Rodrıguez-Oroz MC, Obeso JA. The pathophysiological

basis of sensory disturbances in Parkinson’s disease. J Neurol Sci

(in press) doi:10.1016/j.jns.2009.08.018.

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