Do nonmotor symptoms in Parkinson's disease differ from normal aging?

Extreme Task Specificity inWriter’s Cramp

Ejaz A. Shamim, MD, MS,1,2* Jason Chu, BS, MS,1,3

Linda H. Scheider, BS,1,4 Joseph Savitt, MD, PhD,5

H.A. Jinnah, MD, PhD,6 and Mark Hallett, MD1

1Human Motor Control Section, National Institute of Neurological

Disorders and Stroke (NINDS), National Institutes of Health (NIH),

Bethesda, Maryland, USA; 2Department of Neurology, Kaiser

Permanente Mid-Atlantic Permanente Medical Group, Suitland,

Maryland, USA; 3Neurosurgery Resident, Emory University School of

Medicine, Atlanta, Georgia, USA; 4Virginia Commonwealth University

School of Medicine, Richmond, Virginia, USA; 5Department of

Neurology, Johns Hopkins University School of Medicine, Baltimore,

Maryland, USA; 6Departments of Neurology, Human Genetics, and

Pediatrics, Emory University, Atlanta, Georgia, USA

ABSTRACTBackground: Focal hand dystonia may be task spe-cific, as is the case with writer’s cramp. In early stages,task specificity can be so specific that it may be mis-taken for a psychogenic movement disorder. Methods:We describe 4 patients who showed extreme taskspecificity in writer’s cramp. They initially only hadproblems writing either a single letter or number.Although they were largely thought to be psychogenic,they progressed to typical writer’s cramp. Conclu-sions: Early recognition of this condition may providean opportunity for early initiation of treatment. VC 2011Movement Disorder Society

Key Words: dystonia; movement disorders; clinicalneurology

Dystonias are characterized by excessive involuntarycontractions of muscles leading to abnormal postur-ing. Dystonias that affect discrete body parts, such asfocal hand dystonia (FHD), may be task specific. Typi-cally, FHD occurs in individuals who repeatedly per-form very precise tasks for prolonged periods, usuallyunder stressful conditions. As a result, musicians, typ-ists, dart throwers, billiard players, and others can beaffected with life-altering dysfunctions. Animal modelshave shown the importance of repetitive activities inthe development of writer’s cramp (WC).1 Hereditaryfactors are also important.2

Task specificity in FHD is poorly understood. Allother aspects of hand function are usually unaffectedand the neurological examination is normal. Since theinitial recorded description of task specificity in FHDby Sir Charles Bell3 and the description of WC byGowers4 in the 1800s, this specificity has puzzledclinicians. The unusual task specificity led to it beingclassified as a psychogenic movement disorder untilthe 1980s, when it was recognized, together withother dystonias, as an organic entity.5 Here, wedescribe 4 patients who had ‘‘extreme task specificity’’as an early manifestation of WC. Three of the fourinitially were thought to have a psychogenic move-ment disorder.

Patients and Methods

Patient 1

A 55-year-old right-handed Caucasian male pre-sented with a 1-year history of difficulty in signing hisname. He signed his name 200 to 1,000 times per dayfor the past several years under stressful conditionswhere deadlines had to be met and employees andbills had to be paid. His initial symptom was difficultywith initiating his signature, which starts with the let-ter ‘‘J’’ (Video 1). Only in the context of signing hisname was this difficult. Initially, when he printed orwrote this letter in other contexts, there were no

------------------------------------------------------------------------------------------------------------------------------Additional Supporting Information may be found in the online version of this article.

*Correspondence to: Ejaz A. Shamim, Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke,National Institutes of Health (MSC 1428), 10 Center Drive, Room 7D37, Bethesda, MD 20892, USA; [email protected]

Funding agencies: This endeavor was supported, in part, by the Intramural Program of the National Institutes of Health or NS067501.Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the online version of this article.

Received: 6 December 2010; Revised: 27 April 2011; Accepted: 12 May 2011Published online 28 June 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.23827

B R I E F R E P O R T S

Movement Disorders, Vol. 26, No. 11, 2011 2107

problems. Later, he began to have trouble with the let-ter ‘‘J’’ even in other contexts, and a diagnosis of WCwas more obvious.On examination, he used excessive pressure while

writing and had mirror movements with his righthand when he wrote with the left; his neurological ex-amination was otherwise normal. Using a stamp tosign his name has been very helpful.

Patient 2

A 49-year-old left-handed Caucasian male pre-sented with a 3-year history of progressive difficultyin writing the number ‘‘7.’’ He only had troublemaking the vertical line down. This progressed toinvolve the number ‘‘9’’ and the letter ‘‘C,’’ in thesame manner. He felt a cramping sensation in theforearm while making these vertical lines. Writingthe number ‘‘1’’ was not a problem. He later haddifficulty with all aspects of writing (Video 2). Hewas a mechanic for over 20 years. Three years ago,he started carving birds for 2 hours daily. His freetime was spent carving, which required him to makevery precise short vertical movements with his hands,using the right index finger and thumb to stabilizethe carving tool. He had to be gentle yet forcefulwhen making these repetitive movements of the arm,hand, wrist, and finger. Ultimately, he had difficultycarving.His neurological examination showed mirror move-

ments in his left hand while writing with his righthand. He held the pen in an awkward position withfingers and wrists flexed (Video 2). He stretched hishands frequently while writing.He tried medicines without benefit, including primi-

done, gabapentin, propranolol, or carbidopa/levodopa.He was told by physicians, neurologists, and psychia-trists that the ailment was psychological. Approxi-mately 2 years after the onset of symptoms, he wasdiagnosed with WC. Currently, using a thick pen helpsalleviate the cramping sensation and carving remains aproblem.

Patient 3

A 52-year-old right-handed Caucasian woman pre-sented with a 10-year history of trouble writing theletters ‘‘m’’ and ‘‘n.’’ She was an accounting executiveand her job required a great deal of writing with lotsof stress and frequent deadlines. She worked 70 to 80hours weekly. The writing later affected all letters andnumbers, and she had difficulty writing even shortthank-you notes and frequently broke pens because ofthe amount of pressure she exerted. She never had dif-ficulty writing on a blackboard. Her ability to play thepiano was unaffected. She had normal electrodiagnos-tic studies and MRI of the brain and cervical spine.She saw many physicians and her symptoms were con-

sidered a manifestation of underlying emotional stress,so she stopped working.Her neurological examination was normal. With

writing, her thumb, fingers, and wrist flexed and shefelt a cramping sensation in her forearm (Video 3).She used excessive pressure when writing. With con-tinued writing, the pen fell out of her hand. She hadmirror movements with her right hand as she wrotewith her left.

Patient 4

A 52-year-old right-handed Caucasian man pre-sented with an 8-year history of trouble writing. Hewas an accountant and cartographer for theNational Guard. He participated in daily drillswhere he had to make a dot on a map and circlethe dot and then write a couple of words wherebombing practice was to occur. Although these werejust practice drills, they were very tense situations.He started having difficulty making the dot. Hewould try to make a dot, but could not place thepen on the map. His superiors told him the problemwas stress related. He soon developed difficulty writ-ing words. He then sought the help of physicians,psychiatrists, and orthopedic surgeons without anyanswers. He was also a banjo player, and subse-quently noticed that his fingers would curl whileplaying. He was diagnosed with FHD approximately11 years after onset.The patient’s neurological examination was notable

for awkward posturing with hyperextension at thewrist joint and fingers, causing frequent change in hisgrip while writing (Video 4). With playing the banjo,his fingers curled and he was unable to extend them(Video 4). He had mirror movements with the righthand while he wrote with the left hand.For several years BTX helped, but this later became

ineffective. He has stopped playing the banjo andbegan typing.

Discussion and ConclusionAlthough task specificity in focal dystonias is a

well-known phenomenon, the nature of this specific-ity is not well understood. Because of the curious na-ture of task specificity, patients are sometimesthought to have a psychogenic problem, leading tosignificant frustration until a diagnosis is established.Only 1 of the 4 patients was diagnosed in a rela-tively short period of time. The other 3 patients wentfrom one physician to the next until a diagnosis wasestablished. In one case, it took more than 10 years.Early recognition can be life altering,6 may decreasefrustration in an already disheartened individual, andmay allow the patient to function with appropriatetreatment.

S H A M I M E T A L .

2108 Movement Disorders, Vol. 26, No. 11, 2011

Some clinicians may argue that patient 1 may havehad writer’s block, which might be a psychologicalphenomenon, but WC would seem more likely. Pres-sured writing and history of repetitive movement areseen in patients with WC. The development of dysto-nia in the right hand when he was asked to write withthe left hand represents a phenomenon called ‘‘mirrordystonia,’’ which is frequently seen in patients withWC. Jedynak et al. reported that it was seen in 44%of the 65 patients they studied with WC.7 This patientrepresents a good example of how WC diagnosis canbe confusing, even for experts, in the earliest stage ofthe disease.In the etiology of FHD and WC, performing a very

precise repetitive task for prolonged periods is a fre-quent trigger. Epidemiological studies in musicianswho are required to perform very precise repetitivemovements for prolonged periods under stressful con-ditions8 have supported this notion. The importanceof performing repetitive activity in patients with WCwas recognized even in the earliest description of thedisease in the late 1800s.4 All 4 of our patients per-formed repetitive activities for long periods. Forpatient 2, daily carving and mechanical activities mayhave triggered the FHD. None of our patients hadaffected family members.Unusual task specificity can be seen in other focal

dystonias and can be considered bizarre, leading to apsychogenic diagnosis. Perhaps it was this bizarreexceptional specificity that led to the descriptive term‘‘professional neuroses,’’ which was later confused asa psychological phenomenon.9 Unusual task specificitycan be seen in many focal dystonias.10–14 With em-bouchure dystonia, trumpet players may begin withdystonia with certain ranges of notes, which later gen-eralizes to all notes.14 The underlying mechanism lead-ing to loss of specificity over time is not clear. Loss ofsurround inhibition in patients with FHD may lead toabnormal plasticity of other parts of the brain overtime.15

It is important for physicians and, especially, neurol-ogists and psychiatrists to be wary of the fact thatWC can start as a very task-specific problem involvingonly a single letter or number in patients performingrepetitive writing or fine motor tasks during stressfulsituations. Early recognition can help allay frustrationfor patients and provide some explanation to an al-ready disheartened individual.

Legends to the VideoVideo 1. Extreme task-specificity in writer’s cramp:

video 1. Dystonic features of patient 1 are depicted

here. He uses excessive pressure when he writes, asnoted by his hands turning red while writing.Video 2. Extreme task specificity in writer’s cramp:

video 2. There are two video clips of the patientdepicting dystonic features. The first clip demonstratesthe problems with writing certain numbers. The sec-ond clip is a follow-up after more than 1 year, whichillustrates his writing posture with generalized writer’scramp.Video 3. Extreme task specificity in writer’s cramp:

video 3. Dystonic features of patient 3 are depictedhere. She had to change her handgrip to allow her towrite. The video depicts the only hand grip thatwould allow her to write. Otherwise, she is unable towrite.Video 4. Extreme task specificity in writer’s

cramp: video 4. Dystonic features of patient 4 aredepicted here. The first video clip illustrates theproblems with writing and the second with playingthe banjo.

Acknowledgment: We thank D. Schoenberg for skillful editing.

References1. Byl NN, Merzenich MM, Cheung S, Bedenbaugh P, Nagarajan

SS, Jenkins WM. A primate model for studying focal dystoniaand repetitive strain injury: effects on the primary somatosensorycortex. Phys Ther 1997;77:269–284.

2. Tarsy D, Simon DK. Dystonia. N Engl J Med 2006;355:818–829.

3. Bell C. The Nervous System of the Human Body. Washington,DC: Duff Green; 1833.

4. Gowers W. A Manual of the Diseases of the Nervous System.Philadelphia: P. Blakiston; 1888.

5. Sheehy MP, Marsden CD. Writers’ cramp—a focal dystonia.Brain 1982;105:461–480.

6. Pullman S, Hristova A. Musician’s dystonia [editorial]. Neurology2005;64:186–187.

7. Jedynak PC, Tranchant C, de Beyl DZ. Prospective clinical studyof writer’s cramp. Mov Disord 2001;16:494–499.

8. Frucht SJ. Focal task-specific dystonia in musicians. Adv Neurol2004;94:225–230.

9. Marsden CD, Sheehy MP. ‘‘Writer’s cramp.’’ Trends Neurosci1990;13:148–539.

10. Sachdev P. Golfers’ cramp: clinical characteristics and evidenceagainst it being an anxiety disorder. Mov Disord 1992;7:326–332.

11. Song IU, Kim JS, Kim HT, Lee KS. Task-specific focal hand dys-tonia with usage of a spoon. Parkinsonism Relat Disord 2008;14:72–74.

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

13. Bonanni L, Thomas A, Scorrano V, Onofrj M. Task-specificlower lip dystonia due to mantra recitation. Mov Disord 2007;22:439–440.

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

15. Frucht SJ. Embouchure dystonia—portrait of a task-specific cra-nial dystonia. Mov Disord 2009;24:1752–1762.

16. Hallett M. Neurophysiology of dystonia: The role of inhibition.Neurobiol Dis 2011;42:177–184.

E X T R E M E T A S K S P E C I F I C I T Y I N W R I T E R ’ S C R A M P


Do Nonmotor Symptoms inParkinson’s Disease Differ from

Normal Aging?

Syam Krishnan, MD, DM,1 Gangadhara Sarma, MA,1

Sankara Sarma, PhD,2 and Asha Kishore, MD, DM1*

1Comprehensive Care Centre for Movement Disorders, Sree Chitra

Tirunal Institute for Medical Sciences and Technology, Kerala, India;2Achutha Menon Centre for Health Science Studies, Sree Chitra

Tirunal Institute for Medical Sciences and Technology, Kerala, India

ABSTRACTBackground: Nonmotor symptoms in Parkinson’s dis-ease are frequent and affect health-related quality oflife of patients. The severity and domains of nonmotorsymptoms involved in Parkinson’s disease and normalaging have not been compared before.Methods: We performed a prospective case–controlstudy to assess the frequency and severity of nonmo-tor symptoms in patients with Parkinson’s disease (n 5174) and age-matched normal controls (n 5 128) usingthe Non-Motor Symptoms Scale.Results: Nonmotor symptoms in Parkinson’s diseasewere ubiquitous, more frequent, and more severe thanin normal aging, particularly in women. Cardiovascular,mood/cognition, and perceptual problems/hallucina-tions domains were rarely involved in age-matchedcontrols. Age had no effect and sex some influence onnonmotor symptoms in Parkinson’s disease. In con-trast, in controls, nonmotor symptoms increased withage, and sex had no effect.Conclusions: Nonmotor symptoms in Parkinson’s dis-ease differ from those in aging in frequency, severity,sex predilection, and domain involvement. VC 2011Movement Disorder Society

Key Words: nonmotor symptoms; Non-Motor Symp-toms Scale; Parkinson’s disease; Hoehn and Yahrstage; quality of life

------------------------------------------------------------*Correspondence to: Dr. Asha Kishore, Professor of Neurology,Comprehensive Care Centre for Movement Disorders, Sree Chitra TirunalInstitute for Medical Sciences and Technology, Kerala, India 695011;[email protected]

Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 6 January 2011; Revised: 29 April 2011; Accepted: 12 May2011Published online 9 June 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23826

Parkinson’s disease (PD) is one of the most commonneurodegenerative diseases of the elderly1 and untilrecently was considered a predominantly motor disor-der. The frequent occurrence of nonmotor symptoms(NMS) and its impact on quality of life of PD patientsare now widely reported.2–5 The developmentof severe NMS in PD influences rates of nursinghome placement and adds to the cost of health care ofPD.6–8 The burden of NMS has not yet been com-pared with normal aging, and no distinct patterns ofNMS that could differentiate NMS of PD from nor-mal aging have been identified. This information couldhelp neurologists recognize nonmotor symptomsrelated to PD and manage them early.Most previous studies on NMS in PD have used the

NMS Questionnaire (NMS Quest), a screening tool todetect the presence of NMS but not intended as agrading or rating instrument.9,10 The Non-MotorSymptom Scale (NMSS) is a recently developed andvalidated tool to assess the frequency and severity ofvarious domains of NMS in PD.11–14 NMSS questionsalso address symptoms that are not specific to PD andare prevalent in normal populations, resulting fromaging or menopause in women and common under-diagnosed conditions such as benign prostatic hyper-plasia and mood, cognitive, and sleep disorders in theelderly.The aim of our study was to make a quantitative

comparison of NMS and its domains of involvementin PD and age-matched normal controls in order toassess the burden of NMS in PD in excess of normalaging and to identify any distinct patterns of PD-related NMS.

Patients and MethodsWe performed a single-center case–control study

using NMSS in 174 consecutive PD patients attendingthe Movement Disorders Clinic of our tertiary referralhospital and 128 age-matched apparently normal con-trols. All patients satisfied the United Kingdom Parkin-son’s Disease Society Brain Bank DiagnosticCriteria.15 The controls were gathered from amongthe hospital staff and friends and relatives (excludingspouses and caregivers) of patients and hospital staffwho did not have any neurological disease on inter-view and examination. All study subjects (and caregiv-ers, whenever necessary) were interviewed by the sameneurologist. The interview of patients was done in thedrug ‘‘on’’ state. Hoehn and Yahr (H and Y) stage inthe drug ‘‘off’’ state was used to measure disease se-verity. The assessment period of NMSS was the 1month prior to interview. The NMSS comprises 30questions in 9 domains.11 Each question is scored as amultiple of severity (0–3) and frequency (1–4). Stand-ard English versions were used for those well-versed in


K R I S H N A N E T A L .

English. A translation to the regional language doneby a bilingual clinical psychologist experienced in sim-ilar tasks was used for native-language users. The va-lidity of the NMSS translation has already beenestablished in non-English-speaking Chinese popula-tions.14 The protocol was approved by the TechnicalAdvisory Committee and the Institutional Ethics Com-mittee of the institute.

Statistical Methods

The chi-square and Fisher’s exact tests were usedto compare the frequency of NMS in the 2 groups.Mean NMS scores were compared using the Mann–Whitney U test. Spearman’s correlation coefficientwas used for nonparametric correlations. Correla-tion coefficients more than 0.65 were arbitrarilychosen as indicative of strong correlations. Valuesless than 0.25 were considered indicative of negligi-ble correlation, and those in between were taken asindicative of weak to moderate correlation. ANOVAwas used with age and sex as covariates to ensurethat the differences in group comparisons did notresult from age or sex.

ResultsAll 174 patients and 128 normal controls completed

the assessment. There was no significant differencebetween patients and controls in mean age (PD, 59.56 10.4 years; controls, 60.3 6 7.3 years; P ¼ .5) ormale:female sex distribution (PD, 121:53; controls,87:41; P ¼ .8). The mean duration of motor symp-toms in PD was 8.5 6 5.0 years. Fourteen patientswere H and Y stage 1, and 37 were stage 4 or above.The mean H and Y stage was 2.8 6 1.0. All patientswere on treatment.

Nonmotor Symptoms in PD Patientsand Normal Controls

Nonmotor symptoms in PD patients and normalcontrols are shown in Table 1. All patients had atleast 1 NMS. Eighty-seven of 128 controls (68.0%)reported NMS. There was a higher frequency of NMSin all 9 domains in PD compared with controls (P <.001 for all comparisons). The mean total NMSS scoreand the subscores in all 9 domains were also higheramong patients, even after adjustment for age and sex(P < .001 for all comparisons).

Relation of NMSS Scores to Age,Hoehn and Yahr Stage, Duration ofMotor Symptoms, and Sex in PD

The relation of NMSS scores to age, Hoehn andYahr stage, duration of motor symptoms, and sex inPD is shown in Table 2. There was no significant cor-relation between age and total NMSS score; onlyscores in the domains of gastrointestinal tract and uri-nary symptoms showed a significant but very weakcorrelation with age. The total NMSS score as well asthe scores of 7 of 9 domains showed only weak corre-lations with the duration of motor symptoms. In con-trast, total NMSS score showed a strong andsignificant correlation with Hoehn and Yahr stage; all9 domains showed weak to moderate correlationswith severity of PD (Table 2). Women with PD hadhigher scores in 4 domains: (1) cardiovascular (men,1.2 6 1.9; women, 2.5 6 2.9; P ¼ .001), (2) sleep/fa-tigue (men, 7.9 6 7.2; women, 11.9 6 8.3; P ¼.001),(3) mood/cognition (men, 11.9 6 13.4; women 16.96 14.2; P ¼ .03), and (4) urinary (men, 5.6 6 6.6;women, 10.2 6 8.0; P � .001). No significant differ-ence between men and women with PD was noted in4 domains (perceptual problems/hallucinations, atten-tion/memory, gastrointestinal tract, and miscellaneousdomains), whereas men had higher scores for the

Table 1. Frequency of nonmotor symptoms and mean NMSS scores in patients and normal controls

Nonmotor symptom domain

Subjects with nonmotor symptoms

P value

NMSS scores

P value

Patients

(n ¼ 174), n (%)

Normal controls

(n ¼ 128), n (%)

Patients,

mean (SD)

Controls,

mean (SD)

Cardiovascular 78 (44.8%) 5 (3.9%) < .001 1.6 (2.3) 0.1 (0.7) < .001Sleep/fatigue 156 (89.7%) 49 (38.3%) < .001 9.1 (7.8) 0.8 (1.2) < .001Mood/cognition 154 (88.5%) 15 (11.7%) < .001 13.5 (13.8) 0.2 (0.7) < .001Perceptual problems/hallucinations 78 (44.8%) 1 (0.8%) < .001 2.5 (4.6) 0.01 (0.09) < .001Attention/memory 133 (76.4%) 61 (47.7%) < .001 5.1 (5.9) 0.8 (1.0) < .001Gastrointestinal tract 123 (70.7%) 38 (29.7%) < .001 4.6 (5.1) 0.5 (0.9) < .001Urinary 139 (79.9%) 64 (50.0%) < .001 7.0 (7.3) 1.1 (1.5) < .001Sexual function 92 (52.9%) 35 (27.3%) < .001 6.1 (9.1) 0.5 (1.0) < .001Miscellaneous 140 (80.5%) 14 (10.9%) < .001 6.5 (7.0) 0.2 (0.5) < .001Total 174a (100%) 87a (68.0%) < .001 55.8 (38.6) 4.2 (5.2) < .001

NMSS, Non-Motor Symptoms Scale; P < .05 was considered significant. aSubjects with at least 1 nonmotor symptom domain involved.

D O N M S I N P D D I F F E R F R O M N O R M A L A G I N G ?


sexual domain (men, 7.3 6 9.3; women, 3.5 6 8.2; P¼ .01). Total NMSS score was significantly higher inwomen (men, 50.8 6 37.5; women, 67.4 6 39.0; P ¼.009).

Age and Sex Influences on NonmotorSymptoms in Controls

Total NMSS score and subscores of all domains cor-related with age; the correlation was strong for thedomains of sleep/fatigue, attention/memory, gastroin-testinal tract, and urinary symptoms. Only 1 controlsubject reported symptoms in the perceptual problems/hallucinations domain and hence was not analyzed forcorrelations. No significant sex differences wereobserved in the control group, except for lower scoresfor sexual symptoms reported by normal women (P ¼.002). Mean age of women did not differ between thecontrol group (59.90 6 6.5 years) and the patientgroup (60.50 6 10.1 years, P ¼ .7).

DiscussionWe report the results of the first case–control study

using NMSS examining the severity as well as the fre-quency of NMS in PD patients and normal controls.We found that the frequency of NMS was 100% inPD patients; every patient had at least 1 NMS. The se-verity of NMS was higher in PD, particularly inwomen, and also showed a strong association with theseverity of motor symptoms measured by Hoehn andYahr staging but was unrelated to age. Two thirds ofnormal controls reported NMS, which were less severethan in PD and showed an association with aging.NMS in the cardiovascular, mood/cognition, and per-ceptual problems/hallucinations domains were rarelyinvolved in controls and emerged as distinct subsets ofNMS in PD.Community-based studies have revealed that symp-

toms of sleep dysfunction,16 gastrointestinal symp-toms,17 and sexual dysfunction18 are reported by

around 50% of the elderly population. Neuropsychiat-ric symptoms like depression, apathy, irritability, anxi-ety, and changes in nighttime behavior are alsocommonly reported by normal elderly.19 Nonpsychoticsymptoms can occur in 25% of normal elderly sub-jects, whereas psychotic symptoms are rare.19 Ourstudy also identified that perceptual problems and hal-lucinations domain-involvement was rarely reportedby controls.Our observation that NMSS scores correlated best

with Hoehn &Yahr stages and was weakly correlatedwith duration of motor symptoms of PD is concordantwith earlier reports.9,12,20 The frequency and severity ofNMS increase with the progression of PD and are inde-pendent of age, and this is consistent with current con-cepts of the pathophysiology of nonmotor symptoms inPD.21–23 Even though correlation of Lewy body densityor location with severity of most NMS has not beendemonstrated in clinicopathological studies, the strongercorrelation of NMS burden with severity of motor dis-ability than with duration of disease is compatible withBraak’s hypothesis that involvement of the autonomicnervous system and lower brain stem occurs prior toinvolvement of the substantia nigra and spreads ros-trally with more diffuse involvement of the cortex andbrain stem as the disease advances.22,23 However, theBraak hypothesis has logistical concerns,24 and the roleof Lewy bodies in the pathogenesis of PD—whetherneurotoxic, protective, or an epiphenomenon—is stilldebated.25–28 The significant but weaker correlation ofNMSS scores with disease duration is in agreementwith an increase in alpha synuclein pathology in brainstem and neocortical locations with time. The extentand sites of involvement of alpha synuclein pathologycould therefore be an important determinant of the gen-esis of NMS in PD.We found that women with PD had more severe NMS

and more involvement of the cardiovascular, sleep/fa-tigue, mood/cognition, and urinary domains. A sex

Table 2. Correlation between NMSS scores and clinical variables in PD patients and controls

Non-Motor Symptoms

Scale scores

Patients Controls

Age Duration of PD Hoehn and Yahr stage Age

Cardiovascular R ¼ 0.13, P ¼ .08 R ¼ 0.36, P < .001 R ¼ 0.55, P < .001 R ¼ 0.32, P < .001Sleep/fatigue R ¼ 0.11, P ¼ .2 R ¼ 0.36, P < .001 R ¼ 0.50, P < .001 R ¼ 0.70, P < .001Mood/cognition R ¼ �0.11, P ¼ .15 R ¼ 0.21, P ¼ .005 R ¼ 0.44, P < .001 R ¼ 0.38, P < .001Perceptual problems/hallucinations R ¼ 0.21, P ¼ .005 R ¼ 0.29, P < .001 R ¼ 0.49, P < .001 a

Attention/memory R ¼ 0.21, P ¼ .005 R ¼ 0.28, P < .001 R ¼ 0.38, P < .001 R ¼ 0.73, P < .001Gastrointestinal tract R ¼ 0.30, P < .001 R ¼ 0.36, P < .001 R ¼ 0.58, P < .001 R ¼ 0.68, P < .001Urinary R ¼ 0.32, P < .001 R ¼ 0.32, P < .001 R ¼ 0.57, P < .001 R ¼ 0.74, P < .001Sexual function R ¼ �0.10, P ¼ .5 R ¼ 0.14, P ¼ .05 R ¼ 0.27, P < .001 R ¼ 0.52, P < .001Miscellaneous R ¼ �0.03, P ¼ .6 R ¼ 0.26, P ¼ .001 R ¼ 0.43, P < .001 R ¼ 0.48, P < .001Total NMSS score R ¼ 0.10, P ¼ .2 R ¼ 0.41, P < .001 R ¼ 0.69, P < .001 R ¼ 0.90, P < .001

NMSS, Non-Motor Symptoms Scale; P < .05 was considered significant.aOnly 1 control subject reported symptoms in the perceptual problems/hallucinations domain.

K R I S H N A N E T A L .


difference in NMS was observed in an earlier study,12

whereas its absence in the study of Chaudhuri andcolleagues9 can be explained on the basis of the ques-tionnaire used. We found no sex differences in NMS inthe control group except the relative lower frequency ofsexual complaints in women, which could be under-reporting because of sociocultural factors.The prevalence of nonmotor symptoms in PD

patients has been shown to be significantly higherthan in controls, using NMS Quest.9 Our study is alsothe first report of the severity of NMS in Indianpatients. A study in a Chinese population also revealeda frequency identical to ours (100%).5 A multicenterinternational study that used NMS Quest reportedNMS in 98.4% of PD patients.10 These data indicatethat NMS frequencies are similar across different pop-ulations and across any phenotypic expressions of PDthat may exist in these populations. The lower fre-quency of 88% in the report of Shulman and col-leagues2 can be explained by milder disease severity ofthe patients in the study and exclusion of some of thenonmotor aspects (like sexual and urinary dysfunc-tion, memory problems, and hallucinations) from thescreening.In conclusion, this case–control study identified that

NMS in PD patients is more frequent and severe thanin apparently normal, age-matched controls. NMSinvolving cardiovascular, mood, and perceptual disor-ders and hallucinations domains are more related toPD than aging. The NMS burden of PD is greater inwomen, is age independent, and is strongly associatedwith severity of motor symptoms. Our study alsohighlights the utility of the NMSS for the early identi-fication, quantification, and management of NMS inPD.

Acknowledgment: We are grateful to all subjects in the study fortheir participation. We also thank our research nurse, Mrs. Suja Bosco,for her assistance.

References1. Alves G, Forsaa EB, Pedersen KF, Dreetz Gjerstad M, Larsen JP.

Epidemiology of Parkinson’s disease. J Neurol. 2008;255(Suppl5):18–32.

2. Shulman LM, Taback RL, Bean J, Weiner WJ. Comorbidity ofthe nonmotor symptoms of Parkinson’s disease. Mov Disord.2001;16:507–510.

3. Global Parkinson’s Disease Survey Steering Committee. Factorsimpacting on quality of life in Parkinson’s disease: results froman international survey. Mov Disord. 2002;17:60–67.

4. Gallagher DA, Lees AJ, Schrag A. What are the most importantnon-motor symptoms in patients with Parkinson’s disease and arewe missing them? Mov Disord. 2010;25:2493–2500.

5. Li H, Zhang M, Chen L, et al. Non-motor symptoms are inde-pendently associated with impaired health-related quality of lifein Chinese patients with Parkinson’s disease. Mov Disord. 2010;25:2740–2746.

6. Aarsland D, Larsen J P, Tandberg E, Laake K. Predictors of nurs-ing home placement in Parkinson’s disease: a population-based,prospective study. J Am Geriatr Soc. 2000;48:938–942.

7. Findley L, Aujla M, Bain PG, et al. Direct economic impact ofParkinson’s disease: a research survey in the United Kingdom.Mov Disord. 2003;18:1139–1145.

8. Hagell P, Nordling S, Reimer J, Grabowski M, Persson U.Resource use and costs in a Swedish cohort of patients with Par-kinson’s disease. Mov Disord. 2002;17:1213–1220.

9. Chaudhuri KR, Martinez-Martin P, Schapira AHV, et al. Aninternational multicenter pilot study of the first comprehensiveself completed non motor symptoms questionnaire for Parkinson’sdisease: the NMSQuest study. Mov Disord. 2006;21:916–923.

10. Martinez-Martin P, Schapira AHV, Stocchi F, et al. Prevalenceof non-motor symptoms in Parkinson’s disease in an internationalsetting; study using non-motor symptoms questionnaire in 545patients. Mov Disord. 2007;22:1623–1629.

11. Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metricproperties of a novel non-motor symptoms scale for Parkinson’sdisease: results from an international pilot study. Mov Disord.2007;22:1901–1911.

12. Martinez-Martin P, Rodriguez-Blazquez C, Abe K, et al. Interna-tional study on the psychometric attributes of the Non-MotorSymptoms Scale in Parkinson disease. Neurology. 2009;73:1584–1591.

13. Chaudhuri KR, Martinez-Martin P. Quantitation of non-motor symp-toms in Parkinson’s disease. Eur J Neurol. 2008;15(Suppl 2):2–7.

14. Wang G, Hong Z, Cheng Q, et al. Validation of the Chinese non-motor symptoms scale for Parkinson’s disease: results from a Chi-nese pilot study. Clin Neurol Neurosurg. 2009;111:523–526.

15. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical di-agnosis of idiopathic Parkinson’s disease: a clinico-pathologicalstudy of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181–184.

16. Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB,Blazer DG. Sleep complaints among elderly persons: an epidemio-logic study of three communities. Sleep. 1995;18:425–432.

17. Chaplin A, Curless R, Thomson R, Barton R. Prevalence of lowergastrointestinal symptoms and associated consultation behaviourin a British elderly population determined by face-to-face inter-view. Br J Gen Pract. 2000;50:798–802.

18. Lindau ST, Schumm LP, Laumann EO, Levinson W, O’Muirchear-taigh CA, Waite LJ. A study of sexuality and health among olderadults in the United States. N Engl J Med. 2007;357:762–774.

19. Geda YE, Roberts RO, Knopman DS, et al. The prevalence ofneuropsychiatric symptoms in mild cognitive impairment and nor-mal cognitive aging: a population-based study. Arch Gen Psychia-try. 2008;65:1193–1198.

20. Dotchin CL, Jusabani A, Walker RW. Non-motor symptoms in aprevalent population with Parkinson’s disease in Tanzania. Par-kinsonism Relat Disord. 2009;15:457–460.

21. Chaudhuri KR, Healy DG, Schapira AHV. Non-motor symptomsof Parkinson’s disease: diagnosis and management. Lancet Neu-rol. 2006;5:235–245.

22. 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.

23. Olanow CW, Stern MB, Sethi K. The scientific and clinical basisfor the treatment of Parkinson disease. Neurology. 2009;72(Suppl4):S1–S136.

24. Burke RE, Dauer WT, Vonsattel JPG. A critical evaluation of theBraak staging scheme for Parkinson’s disease. Ann Neurol. 2008;64:485–491.

25. Caughey B, Lansbury PT. Protofibrils, pores, fibrils and neuro-degeneration: separating the responsible protein aggregates fromthe innocent bystanders. Annu Rev Neurosci. 2003;26:267–298.

26. McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW.Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci.2004; 16:2136–2148.

27. Olanow CW, Perl DP, DeMartino GN, McNaught KS. Lewy-body formation is an aggresome-related process: a hypothesis.Lancet Neurol. 2004;3:496–503.

28. Gandhi S, Wood NW. Molecular pathogenesis of Parkinson’s dis-ease. Hum Mol Genet. 2005;14:2749–2755.

D O N M S I N P D D I F F E R F R O M N O R M A L A G I N G ?


Movement Lateralization andBimanual Coordination in Children

with Tourette Syndrome

Laura Avanzino, MD, PhD,1,2 Davide Martino, MD, PhD,3

Marco Bove, PhD,2 Elisa De Grandis, MD, PhD,4

Andrea Tacchino, PhD,2 Elisa Pelosin, PhD,1

Marisol Mirabelli, MD,4 Edvige Veneselli, MD,4

and Giovanni Abbruzzese, MD1*

1Department of Neurosciences, Ophthalmology & Genetics and

Istituto Nazionale di Neuroscienze, University of Genoa, Genoa, Italy;2Department of Experimental Medicine—Section of Human

Physiology and Istituto Nazionale di Neuroscienze, University of

Genoa, Genoa, Italy; 3Department of Neurological and Psychiatric

Sciences, University of Bari, Bari, Italy; 4Operative Unit of Child

Neuropsychiatry, Department of Neurosciences, Ophthalmology and

Genetics, G. Gaslini Institute, University of Genoa, Genoa, Italy

ABSTRACTBackground: Gilles de la Tourette syndrome is a child-hood-onset disorder characterized by persistent motorand vocal tics fluctuating in severity. Although struc-tural changes observed in Gilles de la Tourette syn-drome concern brain structures involved in voluntarymotor control such as the basal ganglia, the frontopari-etal cortex, and the corpus callosum, movement later-alization and bimanual coordination have beenunderinvestigated.Methods: Using a sensor-engineered glove, we ana-lyzed the performance of repetitive externally pacedsingle-hand and bimanual finger movements in 11 chil-dren with Gilles de la Tourette syndrome.Results: When requested to perform sequential single-hand finger movements, patients with Gilles de la Tourettesyndrome showed longer touch duration, shorter move-ment time, and more errors than healthy subjects. Whenrequested to execute the task bimanually, healthy subjectsexhibited a slight loss in accuracy and an increase in touchduration compared with the single-hand task, whereaspatients with Gilles de la Tourette syndrome did not. Fur-ther, healthy subjects presented great asymmetry in termsof movement accuracy between left and right hands duringthe bimanual task, whereas patients with Gilles de la Tour-ette syndrome did not.

------------------------------------------------------------*Correspondence to: Prof. Giovanni Abbruzzese, Department ofNeurosciences, Ophthalmology and Genetics, University of Genoa,Via De Toni 5, 16132, Genoa, Italy; [email protected].

Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 9 August 2010; Revised: 16 May 2011; Accepted: 20 May2011Published online 7 July 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23839

Conclusions: These findings suggest that patients withGilles de la Tourette syndrome may present an abnormalprocess of sensorimotor integration, movement laterali-zation, and bimanual coordination during sequential fin-ger movements.VC 2011Movement Disorder Society

Key Words: tics; motor performance; sensorimotorintegration; bimanual coordination

Gilles de la Tourette syndrome (GTS) is a child-hood-onset disorder defined by persistent motor andphonic tics, often in comorbidity with attention deficithyperactivity and obsessive–compulsive disorders.1

Even if a clinically overt impairment in voluntarymovement execution is not observed in GTS, recentevidence suggested subclinical abnormalities in learn-ing, planning, and execution of voluntary move-ments.2 Several reports documented abnormalities inthe execution of fine motor tasks, seemingly related todysfunctional integration of sensory information proc-essing with organization of motor output.3–6 Further-more, abnormalities of manual dexterity in GTS havebeen highlighted on the Purdue Pegboard test whenperformed either with the dominant hand or withboth hands simultaneously.7

Magnetic resonance imaging studies demonstratedstructural changes in regions involved in motor con-trol such as basal ganglia, prefrontal and parieto-occi-pital cortices, and subcortical and corpus callosum(CC) white matter tracts.8–12 Whereas the basal gan-glia and frontal-parietal cortices seem crucial forlearning, planning, and correctly executing specificgoal-directed movements,13 the CC plays an importantrole in bimanual coordination,14,15 and in the abilityto lateralize upper limb movements through transcal-losal inhibitory mechanisms16 that have been found tobe impaired in GTS.17

On the basis of these findings, we investigated move-ment lateralization and bimanual coordination in chil-

dren with GTS by evaluating the performance of single-hand and bimanual externally paced finger movements.

We expected GTS patients to show abnormal kinematicparameters of single-hand finger movements secondary

to altered mechanisms of sensorimotor integration andabnormal lateralization of finger movements while

shifting from single-hand to bimanual motor execution,secondary to abnormal CC function. To this aim, a

recently developed sensor-engineered glove18 was usedto analyze the kinematics of finger opposition move-

ments. Recordings from this system allowed us to eval-uate spatial accuracy in motor performance and to

separately measure the time spent on sensory processingand preparation for movement from time spent on


A V A N Z I N O E T A L .

motor action, thus representing a useful approach tostudying sensorimotor integration.

Patients and MethodsEleven children (2 females; mean age 6 SD, 11.8 6

2.75 years; range, 8–15 years) were recruited from theDivision of Child Neuropsychiatry of the Gaslini Insti-tute, Italy. They all met DSM-IV criteria for the diag-nosis of GTS,19 were naive to medications acting onthe central nervous system, and were without psychi-atric or neurological comorbidities. Demographic andclinical features are summarized in Table 1. The Ital-ian version of the structured clinical interview forDSM-IV axis I disorders20 was used to exclude atten-tion deficit/hyperactivity disorder, obsessive–compul-sive disorder and depression. Severity of tics was ratedusing the Yale Global Tic Severity Rating Scale(YGTSS)21; mean 6 SD YGTSS subscore amongpatients was 16.72 6 7.85. Thirteen healthy subjects(HSs) without a history of neurological or psychiatricdisorders were recruited from local schools in thesame geographical area (4 females; mean age 6 SD,12.07 6 2.21 years; range, 9–15 years). Participantswere consistent right-handers according to theEdinburgh handedness inventory.22 The study wasapproved by the local ethics committee, and writtenconsent was obtained from all participants accordingto the Declaration of Helsinki.Subjects were seated in a comfortable chair and

wore a sensor-engineered glove (Glove Analyzer Sys-tem, eTT s.r.l., Genova, Italy) on both hands. Subjectswere shown the finger sequence task (opposition of

thumb to index, medium, ring, and little fingers) justonce and then, with eyes closed, they were asked toperform it following an acoustic cue paced at 1, 1.5,and 2 Hz. We used 3 frequencies because differentstrategies are used for sensorimotor processing whenthe movement rate is increased.18 Subjects randomlyperformed a single-hand task with the right hand anda bimanual task using both hands simultaneously. Foreach frequency and condition, a 1-minute trial wasrecorded, followed by a 1-minute rest. We evaluatedthe following kinematic parameters: touch duration(TD; contact time between the thumb and another fin-ger), intertapping interval (ITI; time between the endof the contact between the thumb and another fingerand the beginning of the subsequent contact the time),and the number of correct movements expressed as apercentage of the total number of movementsrequested. Kinematic parameters were analyzed toexplore: (1) performance on the single-hand task withthe right hand, (2) movement lateralization (compari-son of right hand performance on single-hand andbimanual tasks), (3) bimanual coordination (compari-son of right- and left-hand performance during thebimanual task, (4) correlation of behavioral and clini-cal features.

Statistical Analysis

Differences between groups in sex (using v2 statis-tics) and age (using the unpaired t test) were analyzed.Changes in TD, ITI, and the percentage of correctmovements were subjected to analysis of variance forrepeated measures (RM-ANOVA) with the variableGROUP (patients, healthy) as between-subject factorand RATE (1, 1.5, and 2 Hz) as within-subject factor.To analyze movement lateralization, right-hand pa-rameters on single-hand and bimanual tasks werecompared using RM-ANOVA with the variableGROUP as between-subject factor, and RATE andTASK (single-hand, bimanual) as within-subject fac-tors. To analyze bimanual coordination, right- andleft-hand parameters on the bimanual task were com-pared using RM-ANOVA with the variable GROUPas between-subject factor and RATE and SIDE (right,left) as within-subject factors. When RM-ANOVAgave a significant result (P < .05), post hoc analysiswas performed using t tests, applying the Bonferronicorrection for multiple comparisons where necessary.Finally, linear regression analysis adjusted for age andsex was used to explore the correlation betweenYGTSS severity subscore and the following: single-hand task performance, movement lateralization(measured as bimanual/single-hand ratios for all kine-matic parameters), and bimanual coordination (meas-ured as left hand/right hand ratios on the bimanualtask for all kinematic parameters). All statistical analy-ses were performed with SPSS 13.0.

Table 1. Demographic features of healthy subjects andGilles de la Tourette (GTS) patients and clinical severity

in GTS patients evaluated with the Yale Global TicSeverity Rating Scale (YGTSS)

Healthy subjects GTS patients

Demographic features

Demographic

features YGTSS

Subject Age Sex Patient Age Sex Motor Phonic Total

1 14 F 1 8 M 6 3 92 14 F 2 15 M 6 14 203 9 M 3 9 F 4 1 54 14 F 4 14 M 15 10 255 12 M 5 12 M 8 15 236 11 M 6 10 M 6 6 127 14 M 7 14 M 14 13 278 9 M 8 11 F 13 10 239 13 M 9 14 M 13 7 2010 13 M 10 15 M 14 0 1411 10 M 11 8 M 5 1 612 15 M13 9 F

M, male; F, female.

M A N U A L C O O R D I N A T I O N I N T O U R E T T E S Y N D R O M E


ResultsAge and sex were comparable between groups (age, P

¼ .80; sex, P ¼ .65). All results are reported in Figure 1.

Single-Hand Task

On the single-hand task, patients showed longerTD and shorter ITI than did HSs (GROUP: TD, F1,22¼ 17.14; P < .001; ITI, F1,22 ¼ 20.62; P < .001).Patients also exhibited a lower number of correctmovements than did HSs (GROUP, F1,22 ¼ 7.69;P ¼ .011).

Movement Lateralization

Comparing right-hand parameters, HSs showed anincrease in TD and a decrease in ITI on the bimanualtask compared with the single-hand task, whereaspatients did not (TD: TASK*GROUP, F1,22 ¼ 3.95; P¼ .045 [post hoc, single-hand < bimanual: GTS, P ¼.57; HS, P ¼ .005]; ITI: TASK*GROUP, F1,22 ¼ 5.31;

P ¼ .031 [post hoc, single-hand > bimanual: GTS, P¼ .56; HS, P ¼ .01]). During the bimanual task HSsshowed a slight loss in accuracy with a reduced num-ber of correct movements, whereas the performance ofpatients did not worsen, showing a level of accuracywith their right hand in the bimanual task comparableto that of HSs in the same condition (TASK*GROUP,F1,22 ¼ 5.32; P ¼ .031 [post hoc, patients > healthy:single hand, P ¼ .01; bimanual, P ¼ .15]).

Bimanual Coordination

When requested to execute a bimanual finger motortask, HSs exhibited large asymmetry in terms of accu-racy between hands. Conversely, patients showed lessasymmetry between hands than HSs with regard tothe number of correct movements (SIDE*GROUP,F1,22 ¼ 4.34; P ¼ .048 [post hoc, right > left: GTS,P ¼ .43; HS, P ¼ .001]). No significant differencesbetween groups were found for TD (SIDE*GROUP,

FIG. 1. Motor behavior parameters in healthy subjects (HSs) and patients with Gilles de la Tourette syndrome (GTS) during the execution of single-hand finger sequence with the right hand (single-hand RH) and during bimanual finger sequence with the right (bimanual RH) and left (bimanual LH)hands. A–F: ordinate, value of TD and ITI in milliseconds; G–I: ordinate, %CORR_MOV in percentage on total movements. Means 1 standard errorsof mean (SEM) of data are shown.



F1,22 ¼ 0.002; P ¼ .97) and ITI (SIDE*GROUP, F1,22¼ 0.036; P ¼ .85) comparing right and left hands.

Correlation of Behavioral and Clinical Features

Because we did not observe a main effect of theGROUP*RATE interaction in all conditions, correla-tion analyses were performed averaging the motor pa-rameter values at the 3 metronome rates. Linearregression analysis adjusted for age and sex failed toshow any significant correlation between tic severityand any of the kinematic parameters on the single-hand task (all P > .05). Likewise, bimanual/single-hand ratios (expressing movement lateralization) andleft hand/right hand ratios (expressing bimanual coor-dination) did not significantly correlate with tic sever-ity (all P > .05).

DiscussionOur behavioral results show significant differences

in the performance of finger movements betweenhealthy controls and patients with GTS. In the single-hand task, GTS patients exhibited longer touch dura-tion (TD), shorter intertapping interval (ITI), and asmaller number of correct movements. Although ITI islikely to represent a pure motor phase, TD may beregarded as the combination of a sensory phase and amotor preparation phase in which the subsequentmovement is correctly planned prior to execution.23

The selective increase of TD might be open to differ-ent explanations. Because subjects were explicitlyasked to follow the metronome cue, we could specu-late that the personal strategy of patients was to holdthe contact between fingers as long as possible,thereby reducing movement time and movement vari-ability in order to synchronize their movement withthe metronome more precisely. At the same time, thisreduction in movement time might have played a rolein reducing the performance accuracy of the correctfinger movement sequence. Alternatively, the increasedcontact time might reflect abnormalities in the process-ing of sensory information necessary during planningand execution of complex motor actions, thus sup-porting abnormalities in sensorimotor integrationprocesses that have been described in GTS in neuro-physiological and behavioral studies using grip-forceexperiments.3–6

There is limited information available on GTSpatients regarding movement lateralization and bima-nual coordination. Georgiou et al24 documented thatGTS patients manifest a greater symmetry of motorperformance between the 2 hands during execution offast goal-directed movements. This is consistent withthe observation of a reduced inhibitory drive from theleft to the right hemispheres in GTS.17 The presentstudy, designed to compare dominant hand perform-

ance in the single hand with respect to a bimanualtask and dominant versus nondominant hand perform-ance in a bimanual task, showed interesting findings.We first observed that HSs exhibited a slight loss inaccuracy and an increase in TD on the bimanual taskcompared with the single hand, whereas GTS patientsdid not. Second, HSs presented a great asymmetry inmovement accuracy between the left and right handsduring the bimanual task, whereas GTS patients didnot. Our behavioral data obtained in HSs were con-sistent with previous findings. Several reports docu-mented that the CC continues to mature structurallyfrom infancy into adulthood with a strong influenceon CC function.25 Interhemispheric inhibition isweaker in children than in adults, leading to the pres-ence of mirror movements and abnormalities in motorbehavior that correlate with age and maturation of theCC, with particular impairment of the performance onsingle-hand tasks involving the nondominant hand oron bimanual tasks.26–28

On this basis, we can speculate that HSs probablyneed to increase contact time during bimanual tasks inorder to adapt the sensory and motor preparationphases to the execution of a more complex anddemanding task, nevertheless presenting modificationsin motor performance and a great asymmetry betweenleft- and right-hand performance. Conversely, motorperformance findings in GTS patients suggest that vol-untary finger movements are less lateralized, leadingto a more balanced performance when both sensori-motor cortices are engaged at the same time, forexample, during bimanual tasks. Overall, these find-ings might be explained in light of the altered struc-tural and functional organization of interhemisphericconnections observed in GTS patients that are likelyto be the consequence of compensatory mechanismsdeveloped to counteract the manifestation oftics.10,11,17 One possible interpretation for our resultsis that if GTS patients undergo plastic compensatorychanges within networks related to interhemisphericmodulation of motor execution, such compensationmight lead to a functional gain on bimanual executionat the expense of a reduced accuracy during single-hand movements. An alternative explanation is thatthe structural and functional differences in the CC inGTS might facilitate the occurrence of mirror-likemovements in children with this condition. Anincrease in mirror-like movements in GTS mightinduce a similar number of errors on each side duringbimanual tasks. An excessive mirror overflow hasbeen recently described in children with attention-defi-cit/hyperactivity disorder,29 but evidence in favor of asimilar motor pattern in GTS is lacking and needs tobe verified in future studies. Finally, because in GTSpatients motor performance was already impaired inthe single-hand task, we cannot exclude a floor effect

M A N U A L C O O R D I N A T I O N I N T O U R E T T E S Y N D R O M E


possibly masking further modifications in motor per-formance on the bimanual task.In the present study no significant correlation

between tic severity and motor performance wasobserved. This finding may suggest that abnormalitiesin finger movements might represent a subclinical traitof GTS, independent from the severity of clinicalexpression of the disease itself, and has to be confirmedin a larger study.In conclusion, the present findings indicate that

patients with GTS manifest subclinical abnormalitiesin finger motor performance, characterized by abnor-mal movement lateralization and bimanual coordina-tion during sequential finger movements. Futurestudies designed to correlate motor performance withCC structural and functional data are necessary tosupport a possible link between movement lateraliza-tion, bimanual coordination, and developmentalchanges in the corpus callosum in GTS.

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ette syndrome and tic disorders: a decade of progress. J Am AcadChild Adolesc Psychiatry. 2007;46:947–968.

2. Eddy CM, Rizzo R, Cavanna AE. Neuropsychological aspects ofTourette syndrome: a review. J Psychosom Res. 2009;67:503–513.

3. Georgiou N, Bradshaw JL, Phillips JG, Bradshaw JA, Chiu E.Advance information and movement sequencing in Gilles de laTourette’s syndrome. J Neurol Neurosurg Psychiatry. 1995;58:184–191.

4. Serrien DJ, Nirkko AC, Loher TJ, Lovblad KO, Burgunder JM,Wiesendanger M. Movement control of manipulative tasks inpatients with Gilles de la Tourette syndrome. Brain. 2002;125:290–300.

5. Nowak DA, Rothwell J, Topka H, Robertson MM, Orth M.Grip force behavior in Gilles de la Tourette syndrome. Mov Dis-ord. 2005;20:217–223.

6. Bloch MH, Sukhodolsky DG, Leckman JF, Schultz RT. Fine-motor skill deficits in childhood predict adulthood tic severityand global psychosocial functioning in Tourette’s syndrome. JChild Psychol Psychiatry. 2006;47:551–559.

7. Margolis A, Donkervoort M, Kinsbourne M, Peterson BS. Inter-hemispheric connectivity and executive functioning in adults withTourette syndrome. Neuropsychology. 2006;20:66–76.

8. Peterson BS, Staib L, Scahill L, et al. Regional brain and ventricu-lar volumes in Tourette syndrome. Arch Gen Psychiatry. 2001;58:427–440.

9. Peterson BS, Thomas P, Kane MJ, et al. Basal ganglia volumes inpatients with Gilles de la Tourette syndrome. Arch Gen Psychia-try. 2003;60:415–424.

10. Plessen KJ, Wentzel-Larsen T, Hugdahl K, et al. Altered interhe-mispheric connectivity in individuals with Tourette’s disorder.Am J Psychiatry. 2004;161:2028–2037.

11. Plessen KJ, Gruner R, Lundervold A, et al. Reduced white matterconnectivity in the corpus callosum of children with Tourette syn-drome. J Child Psychol Psychiatry. 2006;47:1013–1022.

12. Thomalla G, Siebner HR, Jonas M, et al. Structural changes inthe somatosensory system correlate with tic severity in Gilles dela Tourette syndrome. Brain. 2009;132:765–777.

13. Doyon J, Benali H. Reorganization and plasticity in the adultbrain during learning of motor skills. Curr Opin Neurobiol.2005;15:161–167.

14. Kennerley SW, Diedrichsen J, Hazeltine E, Semjen A, Ivry RB.Callosotomy patients exhibit temporal uncoupling during contin-uous bimanual movements. Nat Neurosci. 2002;5:376–381.

15. Bonzano L, Tacchino A, Roccatagliata L, Abbruzzese G, Man-cardi GL, Bove M. Callosal contributions to simultaneous bima-nual finger movements. J Neurosci. 2008;28:3227–3233.

16. Duque J, Murase N, Celnik P, et al. Intermanual differences inmovement-related interhemispheric inhibition. J Cogn Neurosci.2007;19:204–213.

17. Baumer T, Thomalla G, Kroeger J, et al. Interhemispheric motornetworks are abnormal in patients with Gilles de la Tourette syn-drome. Mov Disord. 2010;25:2828–2837.

18. Bove M, Tacchino A, Novellino A, Trompetto C, Abbruzzese G,Ghilardi MF. The effects of rate and sequence complexity on re-petitive finger movements. Brain Res. 2007;1153:84–91.

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21. Leckman JF, Riddle MA, Hardin MT, et al. The Yale GlobalTic Severity Scale: initial testing of a clinician-rated scale oftic severity. J Am Acad Child Adolesc Psychiatry. 1989;28:566–573.

22. Oldfield RC. The assessment and analysis of handedness: theEdinburgh inventory. Neuropsychologia. 1971;9:97–113.

23. Georgiou N, Bradshaw JL, Phillips JG, Bradshaw JA, Chiu E.Advance information and movement sequencing in Gilles de laTourette’s syndrome. J Neurol Neurosurg Psychiatry. 1995;58:184–191.

24. Georgiou N, Bradshaw JL, Phillips JG, Cunnington R, Rogers M.Functional asymmetries in the movement kinematics of patientswith Tourette’s syndrome. J Neurol Neurosurg Psychiatry. 1997;63:188–195.

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Increased Muscle Belly andTendon Stiffness in Patients withParkinson’s Disease, as Measured

by Myotonometry

Jarosław Marusiak, PhD,1* Anna Jaskolska, PhD,1

Sławomir Budrewicz, MD, PhD,2

Magdalena Koszewicz, MD, PhD,2 and Artur Jaskolski, PhD1

1Department of Kinesiology, Faculty of Physiotherapy, University

School of Physical Education, Wroclaw, Poland; 2Department of

Neurology, Medical University of Wroclaw, Wroclaw, Poland

ABSTRACTBackground: Based on Davis’s law, greater tonus ofthe muscle belly in individuals with Parkinson’s diseasecan create greater tension in the tendon, leading tostructural adjustment and an increase in tendon stiff-ness. Our study aimed to separately assess passivestiffness in the muscle belly and tendon in medicatedpatients with Parkinson’s disease, using myotonometry.Methods: We tested 12 patients with Parkinson’s dis-ease and 12 healthy matched controls. Passive stiff-ness of muscle belly and tendon was estimated bymyotonometry, electromyography, and mechanomyog-raphy in relaxed biceps and triceps brachii muscles.Results: Compared with controls, patients with Parkin-son’s disease had higher stiffness in the muscle bellyand tendon of the biceps brachii and in the tendon ofthe triceps brachii. In patients with Parkinson’s disease,there was a positive correlation between muscle bellystiffness and parkinsonian rigidity in the biceps brachii.Conclusion: Patients with Parkinson’s disease have higherpassive stiffness of themuscle belly and tendon than healthymatched controls.VC 2011MovementDisorder Society

Key Words: Parkinson’s disease; rigidity; musclepassive stiffness; myotonometry; rehabilitation

------------------------------------------------------------*Correspondence to: Dr. Jarosław Marusiak, Department of Kinesiology,Faculty of Physiotherapy, University School of Physical Education, Al.Paderewskiego 35, Building P4, Wroclaw, Poland, 51-612 Wroclaw,Poland; [email protected]

Funding agencies: This study was supported by a grant (N N404166934) from the Ministry of Science and Higher Education of Poland.Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 19 February 2011; Revised: 19 May 2011; Accepted: 23May 2011Published online 28 June 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23841

Previous studies have shown that patients with PDhave increased passive stiffness in muscles.1–5 Thesestudies showed increased stiffness in the contractilepart of the muscle (i.e., myotonometric measurementsof the biceps brachii [BB] muscle belly3 or extensordigitorum muscle belly4) or of the whole muscle-ten-don unit (i.e., measurements of elbow dynamometrictorque and electromyographic activity from the bicepsand triceps brachii [TB] muscles1,2). Greater tonus ofthe parkinsonian muscle belly occurs in PD patientsduring daily life, and is caused by changed neuraldrive7–14 and atrophy-related stiffening of the mus-cle.3,5,15,16 According to Davis’s law6 (i.e., soft tissueadjusts its structure in response to interacting condi-tions), this increased muscle tone can create greaterlong-lasting tension in the muscle tendon, which caninduce structural adjustment and increased stiff-ness.17,18 The previously reported greater stiffness inthe muscle belly3,4 and hypothesized stiffening of mus-cle tendon in PD may together contribute to anincreased tonic stretch reflex7–10 and shortening reac-tion,11–14 which are considered potential mechanismsof parkinsonian rigidity at the spinal level. Separateassessment of passive stiffness in the muscle belly andtendon in PD has not yet been reported, although itcan be evaluated by myotonometry, a reliable,19

sensitive3,4,20,21 method for measuring mechanicalproperties in human soft tissues. Findings from thepresent study can contribute to a better understandingof parkinsonian rigidity mechanisms and may alsohave therapeutic and diagnostic implications.

Our aim was to assess passive stiffness of the bellyand tendon of BB and TB muscles in medicated (i.e.,‘‘on phase’’) patients with PD by means ofmyotonometry.


Subjects

Twelve PD patients (women n ¼ 7, men n ¼ 5, meanage 716 8 years, body mass 726 14 kg, height 1626 7cm) and 12 healthy matched elderly controls (women n¼ 8, men n ¼ 4, mean age 746 7 years, body mass 70610 kg, height 1606 9 cm) participated in our study.

PD patients were clinically and physiologicallytested during their on phase (medication: levodopa[Madopar and Sinemet CR]) to avoid the influence ofmuscle activity on stiffness measurements in relaxedmuscle and thus to assess passive stiffness (a visco-elastic property). Patients were mildly affected (scoreof 1 on the Hoehn and Yahr scale; n ¼ 2) or moder-ately affected by PD (score of 2, n ¼ 1; score of 2.5, n¼ 5; and score of 3, n ¼ 4; median value of Hoehnand Yahr score for PD group, 2.5). According to theUPDRS (motor section, point 22), rigidity in the testedupper extremity ranged from slight (score of 1; n ¼

S T I F F N E S S I N P A T I E N T S W I T H P A R K I N S O N ’ S D I S E A S E


5), mild to moderate (score of 2; n ¼ 6), up to markedrigidity (score of 3, n ¼ 1; median value of rigidityscore for PD group, 2.0). The clinical evaluation wasperformed first and was blinded to all physiologicalmeasurements conducted.Illness duration ranged from 3 to 20 years (mean,

8 6 4), and age of disease onset ranged from 43 to71 years (mean, 63 6 9). Patients gave written consentbefore the study, which was approved by the localethics committee and was done in accord with theHelsinki Declaration.

Experimental Procedure

Muscle-stiffness measurements in relaxed BB andTB were performed by a Myoton-3 device (Muomee-tria AS; Tallinn, Estonia) over the bellies (BB-shorthead, TB-long head) and tendons of the muscles.Because the device’s testing end must be perpendicu-

lar to the skin surface and parallel with the gravityvector,19 measurements were done with the subjectlying down (i.e., supine position for BB and prone forTB), with upper extremities along the trunk and fore-arm between pronation and supination. After subjectswere instructed to relax their muscles, an experimenterplaced the testing end of the Myoton-3 on the skinsurface overlying the muscle belly (mb) and/or muscletendon (mt) of the BB and/or TB and performed 20consecutive records of stiffness in the following order:BBmb!BBmt!TBmb!TBmt.Before myotonometric measurements for each mus-

cle, resting surface electromyographic (EMG) andmechanomyographic (MMG) signals were simultane-ously recorded from the same location over the musclebellies (three 3-second trials), using a custom-madeEMG/MMG probe (details of the probe and its mon-tage are described elsewhere22). Online visual inspec-tion and offline analysis (i.e., root mean square[RMS]) of both signals were performed to check thatmuscles were at rest.Resting elbow-joint angle (EJA) was measured by the

standard protocol, with the subject in a standing posi-tion with upper extremities relaxed along the trunk, byuse of a hand-held stainless-steel goniometer (SaehanCorporation, Dangjin-gun, South Korea). Three meas-urements of EJA were taken for each subject.

Statistical AnalysisMuscle stiffness (S-MYO [N/m]) is expressed as a

mean value calculated from 20 consecutive myotono-metric records, whereas the RMS-EMG [lV] andRMS-MMG [mV] were calculated from the three rest-ing trials. The EJA [i.e., in degrees] was an averagevalue from three measurements.The intraclass correlation coefficient was used to

determine trial-by-trial reproducibility of the myotono-metric, EMG, and MMG measurements. The Kolmo-

gorov-Smirnov test was used to determine whether thetested parameters satisfied conditions for normal dis-tribution. The Mann-Whitney and Student’s t-tests(where appropriate) were used to test statistical signifi-cance of intergroup differences, if any. In PD patients,Spearman’s correlation coefficient (q) was calculatedto test the association of the myotonometric measure-ments of stiffness with clinical ratings of parkinsonianrigidity. P � 0.05 was taken as statistically significantfor all analyses.

Results

Measurement Reproducibility

Excellent23 reproducibility of myotonometric meas-urements of stiffness, RMS-EMG, and RMS-MMG wasfound in the control group and PD patients (Table 1).

Electromyography, Mechanomyography, andMyotonometric Stiffness

The RMS-EMG and RMS-MMG of the BB and TBdid not differ significantly between groups (P > 0.05;Table 1). Compared with controls, the PD group hadsignificantly higher muscle belly and tendon stiffness inthe BB (P < 0.05; Table 1) and tendon stiffness in theTB (P < 0.05); despite the clear tendency toward highervalues in the PD group, there was no significant inter-group difference in the TB’s belly stiffness (P > 0.05;Table 1). There was only one significant (P < 0.05)positive correlation of parkinsonian rigidity scores,with BBmb stiffness in the PD group (Table 2).

EJA

Despite the tendency toward lower values for EJA inPD patients than in controls, the difference was notstatistically significant (control, 156 6 6 degrees; PD,151 6 9 degrees; P ¼ 0.149), whereas the ratio ofEJA to BB myotonometric stiffness was significantlylower in PD patients than in the control group (EJA/S-MYO BBmb: control, 0.53 6 0.06 degrees/N/m; PD,0.44 6 0.07 degrees/N/m; P ¼ 0.001; EJA/S-MYOBBmt: control, 0.43 6 0.04 degrees/N/m; PD, 0.38 60.08 degrees/N/m; P ¼ 0.012).

DiscussionThe simultaneous occurrence of statistically signifi-

cant intergroup difference in the stiffness of musclebelly and tendon (except for TBmb), with the lack ofintergroup difference in RMS-EMG and RMS-MMG,indicates that myotonometric stiffness measurementswere made at rest in both groups and are related tointrinsic viscoelastic properties of the muscle belly andtendon and not to active muscle stiffness.

Higher Muscle-Belly Stiffness in PD

The higher stiffness of BBmb in our PD group isconsistent with findings from previous studies thatused myotonometry3,4 and dynamometry with EMG,1

M A R U S I A K E T A L .


and can be explained by atrophy of the muscle fibersand replacement with connective tissue3,5,15,16 and byadaptive structural alterations in muscle17,18 associ-ated with changed neuromuscular drive in PD.7–14 Thelack of a significant difference in TBmb stiffnessbetween groups might be related to different contribu-tions of TB and BB activity to parkinsonian rigid-ity,12,24 resulting in different structural adjustments ineach muscle and different belly stiffness. This explana-tion is in line with results from others studies12,24 andwith the significant positive correlation we foundbetween parkinsonian rigidity scores and BBmb stiff-ness and lack of such a relationship for TBmb in thePD group. Assuming that the muscle tendon and bellyadjust to each other,17,18 our results of significantintergroup differences in TBmt stiffness and a cleartendency for higher TBmb stiffness in PD could meanthat the adaptive structural changes took place in par-kinsonians’ TBmb, but to a lesser extent.

Higher Muscle Tendon Stiffness in PD

There are no reports of separate measurement ofmuscle tendon passive stiffness in PD using myoton-ometry, but studies have shown that higher tensiontransmitted to human muscle tendon can change itsstructure, leading to increased stiffness.17,18 Thus, thestimulus for increased tendon stiffness in our PDgroup could have been related to the long-lasting influ-ence of parkinsonian rigidity, creating higher tensionin the muscle tendon. Therefore, the positive correla-tion between rigidity score and muscle tendon stiffnesscould be expected. However, we did not find such a cor-relation. This can be related to the fact that the greatesttendon’s structural adjustments to changed biomechani-cal conditions occur during the first few months,18

whereas illness duration in our PD patients was in arange 3 to 20 years. Our hypothesis on the influence ofrigidity on tendon stiffness is indirectly confirmed by

the Burne and Lippold13 findings of a higher thresholdof Golgi-organ activation in PD.13 The increasedthreshold can result from the influence of elevated long-lasting stiffness of the tendon fibers on Ib neural affer-ent fibers. Golgi-organ’s adaptation to long-lasting ten-sion in the tendon caused by an external load wasobserved in hind-limb muscles of rats and cats.25,26

EJA in PD and Healthy Controls

A more flexed elbow joint in relaxed-state PDpatients than in controls has been previously reported1

and was related to higher passive stiffness in musclesand connective tissues, creating a new set of length-tension curves in elbow-joint muscles. Therefore, higherBBmb and BBmt in our PD group should have caused asmaller EJA. Our results showed such a tendency,although it was not statistically significant. However,the ratios of EJA to myotonometric stiffness of BBmband BBmt were lower in PD patients than in controls,confirming the hypothesis of Watts et al.1 on the inter-action between muscle passive stiffness and EJA.

Table 2. Correlation of myotonometric measurements ofstiffness with clinical ratings of rigidity

Correlated variables

Correlation

q P

S-MYO BBmb and UPDRS rigid 0.532* 0.050S-MYO BBmt and UPDRS rigid 0.040 0.892S-MYO TBmb and UPDRS rigid 0.467 0.092S-MYO TBmt and UPDRS rigid 0.108 0.713

*Statistically significant correlation.Abbreviations: q, Spearman correlation coefficient; S-MYO, myotonometricmeasurements of stiffness; BB, biceps brachii muscle; mb, muscle belly;UPDRS rigid, rating of rigidity; mt, muscle tendon; TB, triceps brachii muscle.

Table 1. Intergroup comparison and trial-by-trial reproducibility of myotonometric measurements of stiffness,electromyogram amplitude, and mechanomyogram amplitude

Variables

Intergroup comparison Reproducibility

CO, mean 6 SD PD on, mean 6 SD P CO, ICC PD on, ICC

S-MYO BBmb [N/m] 296 6 37 352 6 40* 0.002 0.832 0.933S-MYO BBmt [N/m] 367 6 40 410 6 60* 0.024 0.945 0.982S-MYO TBmb [N/m] 314 6 35 343 6 48 0.103 0.886 0.939S-MYO TBmt [N/m] 365 6 40 459 6 93* 0.004 0.957 0.987RMS-EMG BB [lV] 7 6 4 7 6 9 0.135 0.875 0.854RMS-EMG TB [lV] 6 6 4 7 6 1 0.521 0.899 0.997RMS-MMG BB [mV] 4 6 2 3 6 3 0.615 0.896 0.852RMS-MMG TB [mV] 5 6 2 5 6 3 0.699 0.812 0.921

Reproducibility rating (Sleivert and Wenger, 1994): unacceptable ICC, <0.60; average ICC, 0.60–0.79; excellent ICC, 0.80–1.00.*Statistically significant intergroup difference.Abbreviations: CO, healthy aged controls; PD on, medicated patients with Parkinson’s disease; SD, standard deviation; ICC, intraclass correlation coefficient;S-MYO, myotonometric measurements of stiffness; BB, biceps brachii muscle; mb, muscle belly; mt, muscle tendon; TB, triceps brachii muscle; RMS-EMG,electromyogram amplitude; RMS-MMG, mechanomyogram amplitude.

S T I F F N E S S I N P A T I E N T S W I T H P A R K I N S O N ’ S D I S E A S E


Significance of Findings From the PresentStudy

Based on our findings, we can hypothesize how ri-gidity emerges during passive extension of the forearmaround the elbow joint in PD, applied during neuro-logical assessment of this symptom. The higher passivestiffness of BBmb and BBmt in PD can increase thetonic stretch reflex7–10 by shifting its threshold towarda shorter muscle-tendon unit length (i.e., leftward onthe length-tension curve), as it was found in spasticpatients.27 As a result, greater force (i.e., resistance) isgenerated at a given muscle length in the stretched BB.Additionally, lower BB inhibition via Ib afferenta-tion13 (because of an increased threshold of Golgi-organ activation from long-lasting increased BBmtstiffness) cannot alleviate increased stretch reflex inthe muscle. Simultaneously, a shortening reactionoccurs in the TB,11–14 as a result of centrally inducedactive shortening to adjust the length of the muscle tochanged biomechanical conditions. In healthy people,the shortening reaction can be alleviated via Ib affer-ent fibers that project to inhibiting interneurons con-nected to the TB motoneuron pool. However, theincreased activation threshold of Ib afferent fibers inthe Golgi organ13 of the TB (related to higher stiffnessin the tendon) may cause lower flow in Ib afferentfibers, leading to less inhibition of TB motoneurons inthe spinal cord and increasing the shortening reactionin the muscle in PD.11–14 The increased tonic stretchreflex7–10 and higher muscle passive stiffness1–5 in thelengthened muscle, together with the increased short-ening reaction in the shortened muscle,11–14 gives con-stant (i.e., lead-pipe) resistance to passive movement,related to higher active stiffness in both muscles,which is called parkinsonian rigidity. This hypothesiswill be tested in a future study. The knowledge aboutan influence of mechanical properties of muscle bellyand tendon on parkinsonian rigidity can have thera-peutic and diagnostic implications.

ConclusionWe conclude that patients with PD have higher pas-

sive stiffness of the muscle belly and tendon thanhealthy matched controls.

Acknowledgment: We thank very much the PD patients andhealthy elderly subjects for participation in our study.

References1. Watts RL, Wiegner AW, Young RR. Elastic properties of muscles

measured at the elbow in man: II. Patients with parkinsonian ri-gidity. J Neurol Neurosurg Psychiatry 1986;49:1177–1181.

2. Fung VS, Burne JA, Morris JG. Objective quantification of restingand activated parkinsonian rigidity: a comparison of angularimpulse and work scores. Mov Disord 2000;15:48–55.

3. Marusiak J, Kisiel-Sajewicz K, Jaskolska A, Jaskolski A. Highermuscle passive stiffness in Parkinson’s disease patients than incontrols measured by myotonometry. Arch Phys Med Rehabil2010;91:800–802.

4. Ratsep T, Asser T. Changes in viscoelastic properties of skeletalmuscles induced by subthalamic stimulation in patients with Par-kinson’s disease. Clin Biomech 2011;26:213–217.

5. Dietz V, Quintern J, Berger W. Electrophysiological studies ofgait in spasticity and rigidity. Evidence that altered mechanicalproperties of muscle contribute to hypertonia. Brain 1981;104:431–449.

6. Tippett SR, Voight ML. Functional Progression for Sport Rehabil-itation. Champaigne, IL: Human Kinetics; 1995:4.

7. Meara RJ, Cody FW. Relationship between electromyographic ac-tivity and clinically assessed rigidity studied at the wrist joint inParkinson’s disease. Brain 1992;115:1167–1180.

8. Noth J, Schurmann M, Podoll K, Schwarz M. Reconsideration ofthe concept of enhanced static fusimotor drive in rigidity inpatients with Parkinson’s disease. Neurosci Lett 1988;84:239–243.

9. Berardelli A, Sabra AF, Hallett M. Physiological mechanisms ofrigidity in Parkinson’s disease. J Neurol Neurosurg Psychiatry1983;46:45–53.

10. Lee RG. Pathophysiology of rigidity and akinesia in Parkinson’sdisease. Eur Neurol 1989;29:13–18.

11. Angel RW, Lewitt PA. Unloading and shortening reactions in Par-kinson’s disease. J Neurol Neurosurg Psychiatry 1978;41:919–923.

12. Andrews CJ, Burke D, Lance JW. The response to muscle stretchand shortening in parkinsonian rigidity. Brain 1972;95:795–812.

13. Burne JA, Lippold OC. Loss of tendon organ inhibition in Parkin-son’s disease. Brain 1996;119:1115–1121.

14. Xia R, Rymer WZ. The role of shortening reaction in mediatingrigidity in Parkinson’s disease. Exp Brain Res 2004;156:524–528.

15. Rossi B, Siciliano G, Carboncini MC, Manca ML, Massetani R,Viacava P, Muratorio A. Muscle modifications in Parkinson’s dis-ease: myoelectric manifestations. Electroencephalogr Clin Neuro-physiol 1996;101:211–218.

16. Glendinning DS, Enoka RM. Motor unit behavior in Parkinson’sdisease. Phys Ther 1994;74:61–70.

17. Narici MV, Maganaris CN. Adaptability of elderly humanmuscles and tendons to increased loading. J Anat 2006;208:433–443.

18. Narici MV, Maganaris CN. Plasticity of the muscle-tendon com-plex with disuse and aging. Exerc Sport Sci Rev 2007;35:126–134.

19. Bizzini M, Mannion AF. Reliability of a new, hand-held devicefor assessing skeletal muscle stiffness. Clin Biomech 2003;18:459–461.

20. Veldi M, Vasar V, Hion T, Vain A, Kull M. Myotonometry dem-onstrates changes of lingual musculature in obstructive sleepapnoea. Eur Arch Otorhinolaryngol 2002;259:108–112.

21. Gavronski G, Veraksits A, Vasar E, Maaroos J. Evaluation ofviscoelastic parameters of the skeletal muscles in junior triath-letes. Physiol Meas 2007;28:625–637.

22. Jaskolski A, Andrzejewska R, Marusiak J, Kisiel-Sajewicz K, Jas-kolska A. Similar response of agonist and antagonist muscles aftereccentric exercise revealed by electromyography and mechano-myography. J Electromyogr Kinesiol 2007;17:568–577.

23. Sleivert GG, Wenger HA. Reliability of measuring isometric andisokinetic peak torque, rate of torque development, intergratedelectromyography, and tibial nerve conduction velocity. Arch PhyMed Rehabil 1994;75:1315–1321.

24. Levin J, Krafczyk S, Valkovic P, Eggert T, Claassen J, Botzel K.Objective measurement of muscle rigidity in parkinsonian patientstreated with subthalamic stimulation. Mov Disord 2009;24:57–63.

25. Nordstrom MA, Enoka RM, Reinking RM, Callister RC, StuartDG. Reduced motor unit activation of muscle spindles and tendonorgans in the immobilized cat hindlimb. J Appl Physiol 1995;78:901–913.

26. Treffort N, Picquet F, Petit J, Falempin M. The structure andresponse properties of Golgi tendon organs in control and hypo-dynamia-hypokinesia rats. Exp Neurol 2005;195:313–321.

27. Calota A, Feldman AG, Levin MF. Spasticity measurement basedon tonic stretch reflex threshold in stroke using a portable device.Clin Neurophysiol 2008;119:2329–2337.

M A R U S I A K E T A L .


Feeding Dystonia in McLeodSyndrome

Andreas R. Gantenbein, MD,1 Nathalie Damon-Perriere, MD,2

Jorg E. Bohlender, MD,3 Marie Chauveau, MD,2

Chrystelle Latxague, PhD,2 Marcelo Miranda, MD,4

Hans H. Jung, MD,1* and Francois Tison, MD, PhD2

1Department of Neurology, University Hospital Zurich, Zurich,

Switzerland; 2Department of Neurology, University Hospital

Bordeaux, Bordeaux, France; 3Department of Oto-Rhino-

Laryngology, Division of Phoniatry, University Hospital Zurich, Zurich,

Switzerland; 4Department of Neurology, Clinica Las Condes,

Santiago, Chile

ABSTRACTBackground: The X-linked McLeod syndrome belongsto the group of neuroacanthocytosis syndromes and hasa Huntington-disease–like phenotype with a choreaticmovement disorder, cognitive alterations, and psychiatricsymptoms. Another neuroacanthocytosis syndrome, theautosomal recessive chorea-acanthocytosis, has a simi-lar presentation, but distinct clinical features, believed tobe characteristic, such as tongue protrusion dystonia,feeding dystonia, and rubber-man–like appearance.Methods: This work comprised a case series of 3patients with McLeod syndrome.Results: The 3 patients with McLeod syndrome devel-oped severe feeding dystonia and tongue protrusion aswell as rubber-man–like appearance in 1 patient duringthe course of the disease.Conclusion: These observations indicate that there isan extended phenotypic overlap between McLeod syn-drome and chorea-acanthocytosis. VC 2011 MovementDisorder Society

Key Words: McLeod syndrome; neuroacanthocytosis;feeding dystonia

------------------------------------------------------------*Correspondence to: Prof. Hans H. Jung, Department of Neurology,University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich,Switzerland; [email protected]

Funding agencies: C.L. and F.T. have been supported by the EC-funded (E-Rare JTC 2009) EMINA project (European MultidisciplinaryInitiative on Neuroacanthocytosis).Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 10 January 2011; Revised: 13 May 2011; Accepted: 23 May2011Published online 28 June 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23843

McLeod neuroacanthocytosis syndrome (MLS) is anX-linked disorder with central nervous system (CNS)features similar to Huntington’s disease (HD).1,2 MLSis caused by mutations in the XK gene encoding forthe XK protein, which represents the Kx blood-groupantigen on red blood cells (RBCs), but has an as yetundetermined function in the CNS and neuromuscularsystem.1 On RBCs, the XK protein is covalently linkedto the Kell protein, another blood-group antigen, andthe two proteins probably form a functional complex.1

In the muscle and CNS, however, the two proteins aredifferentially expressed, suggesting independent func-tions.3,4 The XK protein has substantial homologies tothe CED8 protein in the nematode, Caenorhabditiselegans, where it controls the timing of developmentalapoptosis,5 thus suggesting a potential implication in aneurodegenerative mechanism.

The CNS manifestations of MLS usually start in thethird or fourth decade and comprise a choreatic move-ment disorder, psychiatric symptoms, cognitive decline,and tonic-clonic seizures.1,2,6 Neuroradiological evalu-ations demonstrate a progressive striatal atrophy andimpairment of glucose metabolism.6,7 Neuromuscularmanifestations include axonal sensorimotor neuropa-thy, neurogenic muscle atrophy, myopathy, and cardio-myopathy.8 Diagnosis of MLS is suggested by the HD-like features, additional neuromuscular manifestation,and the laboratory findings of elevated creatine kinase(CK) levels and the presence of the McLeod blood-group phenotype.

Although the core neuroacanthocytosis (NA) syn-dromes share an HD-like phenotype, distinction fromMLS to the autosomal-recessive chorea-acanthocytosis(ChAc) is generally made by the later age of onset andthe absence of particular clinical features, includingtongue protrusion and feeding dystonia as well as aspecific gait pattern called ‘‘rubber man appearance.’’9

Herein, we present 3 patients with MLS with feedingand tongue protrusion dystonia, demonstrating thatthere is a broader phenotypic overlap between the dif-ferent NA syndromes than formerly believed.


Patient A

The clinical, neuroimaging, and genetic findings ofpatient A have been presented, in part, in previousstudies.6,10 He carried the McLeod blood-group phe-notype, had RBC acanthocytosis, and elevated CK lev-els. He was reported to have motor restlessness and atic-disorder developing after the age of 20 years,which had been interpreted as a psychiatric disorder.The first neurological examination, at 40, revealed apersonality disorder, moderate generalized chorea, andmoderate subcortical cognitive deficits.6 Tendonreflexes were absent and there was a slight, general


F E E D I N G D Y S T O N I A I N M C L E O D S Y N D R O M E

muscular atrophy, but no palsies. At 44, augmentationof chorea, cognitive deficits, and muscular atrophywas documented (Table 1).At 49, an additional gait disorder with frequent falls

developed, with a rubber-man appearance and fre-quent head dropping (see Video, Segment 1). Therewas also severe feeding dystonia with consecutiveweight loss, necessitating gastric tube feeding. Thepatient was not able to form a proper bolus and toinitiate the swallowing act. He got used to lying onhis back to allow passive sliding of food toward thepharynx with consecutive initiation of the swallowing(see Video, Segment 2). However, he mostly soiled hisclothes and the floor. He also frequently coughed, buthad no aspiration pneumonias up to the time ofexamination.Videofluoroscopic swallowing study (VFSS) in a sit-

ting position with 2 mL of liquid swallow demon-strated strong involuntary dystonic and dyskinetictongue movements in the oral preparatory and oralphases. Inadequate lip closure and tongue protrusionresulted in anterior leakage of the bolus. Poor orolin-gual control and the resulting ineffective onset of thepharyngeal phase led to residues in the oral cavity.Additionally, the disorganized onset of the pharyngealphase shows a predeglutitive liquid loss to the vallecu-lae and pyriform sinuses, resulting in laryngeal pene-tration. However, no signs of laryngeal aspiration ornasal regurgitation during repetitive sequences ofswallowing were observed. The residues in thepharynx caused by an impairment of pharyngeal bolustransport were without signs of postdeglutitive aspira-tion (see Video, Segment 3).

Patient B

This patient, born from a nonconsanguineous mar-riage, developed generalized tonic-clonic seizures atthe age of 35 years.* Choreic movements appeared atage 56 and worsened progressively. At the time ofexamination, he was 65. Chorea was severe and inca-pacitating, affecting all four limbs, trunk, and neckwith generalized hypotonia, dysarthria, and gait insta-bility. The patient also presented behavioral problems(i.e., obsessive-compulsive disorder, increased appetitefor sweets, and psychosocial withdrawal) and atten-tion and dysexecutive cognitive deficits (i.e., deficit ofinhibition with interferences at the Stroop test,reduced verbal fluency, i.e., the Issacs test, preservedMini-Mental State Examination ¼ 29). Head dropswere also noticed. In addition, the patient had ahypertrophic cardiomyopathy and a mild axonal neu-ropathy. Brain MRI showed bilateral atrophy of thecaudate nuclei and the putamen. Diagnosis of MLSwas based upon negative HD molecular diagnosis,

Table

1.Clinicalcharacteristics

Patient

Age[y]

Ageofonset[y]

Symptoms

Head

drops

Tongue

protrusions

Weightloss

(inlast

year)(kg)

BMI[kg/m

2]

Bloodtests

CK

level[U/L]

(norm

alvalue)

Genetictesting

CerebralMRI

A51

20Chorea,muscularatrophy,

cognitive

deficits,

gaitdisorder

(‘‘rubber

man’’)

þþ

919.2

Acanthocytosis,

McLeodphenotype

400–5,000(<

190)

Pointmutationin

exon

3of

theXK

gene

(977C>

T)

Atrophyof

caudate

nucleiandputamen

B65

35Chorea,tonic-clonicseizures,

dysarthria,gaitinstability

þþ

1519.5

Acanthocytosis,

McLeod

phenotype

718(<

145)

Fram

eshift

mutation

oftheXK

gene

(c.722delT)

Atrophyof

caudate

nucleiandputamen

C60

47Chorea,muscularatrophy,

cognitive

deficits,

feedingdystonia

–þ

1019.0

Acanthocytosis

500(<

200)

5-bp

deletioninexon

2of

theXK

gene

(c.938-942delCTCTA)

Caudateatrophy

BMI,bodymassindex;CK,creatinekinase.

*Partly presented in Chauveau M et al., Head drops are alsoobserved in the McLeod syndrome. Mov Disord, in press.

G A N T E N B E I N E T A L .


presence of acanthocytes, elevated serum CK (718 UI/L, N < 145), absent expression of erythrocyte Kpa

and Kpb antigens, and a frame-shift mutation of theXK gene (c. 722delT). His drug regimen included tet-rabenazine (112.5 mg/day t.i.d.), valproic acid (1,500mg/day b.i.d.), and phenobarbital (150 mg/day).Swallowing difficulties appeared at age 61, along

with dysarthria. There were bucco-lingual apraxia andfeeding dystonia with tongue protrusion in attempts toswallow solids, semisolids, and liquids. Involuntarytongue protrusions were most severe with solids.There was passive pulmonary aspiration with liquids.Swallowing difficulties increased with a weight loss of15 kilos (�20% of the initial weight in approximately1 year, body mass index decreasing from 24.6 to 19.5kg/m2). In an effort to overcome swallowing problems,the patient adopted an extended posturing of his neckand abruptly lyed down on his back (see Video, Seg-ment 4). These movements might be amplified byhypotonia and were sometimes associated with invol-untary movement disorders, such as head drops andback-arching dystonia. We added this notion to theclinical description. Videofluoroscopy demonstratedimpaired oral phase with tongue protrusion and jaw-opening dystonia. Passive propulsion of the bolus tothe posterior pharynx required a brisk, backwardhyperextension of the head, neck, and trunk. The pha-ryngeal and laryngeal phases were also impaired, withcervical painful choking, along with noisy forced ex-piratory efforts, coughing, and pulmonary aspirationswith liquids. Because of increasingly severe malnutri-tion, a gastrostomy was performed.

Patient C

Patient C, a chemical engineer, is the elder of twobrothers affected with MLS, as previously described(patient 58). He presented at age 56 and reported a 9-year history of a choreatic movement disorder associ-ated with episodic major depression. He notedreduced ability to concentrate at work and diminishedability to control his emotions in everyday life. Inaddition, he showed compulsive checking and orderingin symmetry and exactness as well as stockpiling ofvarious goods. Upon neurological examination, hewas alert and fully oriented. Cognitive testing demon-strated a mild impairment. There was a slightlyreduced Mattis dementia rating-scale score (137/144points, normal >142), and an abnormal Wisconsincard-sorting test (i.e., failure to keep criteria and per-severations). There were normal values for the Strooptest, digital span reversal, Grober-Buschke test, normalverbal fluency, and Frontal Assessment Battery score.There was mild facial masking and monotonousspeech. In addition, generalized chorea, tic-like gri-macing, shoulder shrugging, and sniffing wereobserved. There was moderate atrophy of all limbs,

with mild paresis. Deep tendon reflexes were absent.Blood examination after dilution with heparinized iso-tonic saline demonstrated 29% of acanthocytes. Cere-bral MRI showed marked caudate atrophy. Moleculargenetic analysis of the XK gene demonstrated a 5-bp(base-pair) deletion in exon 2 of the XK gene (c. 938-942delCTCTA).After 4 years of follow-up, he developed progressive

parkinsonian features of the akinetic-rigid type with-out tremor. Feeding dystonia appeared in the last 4months of this year. Each time he tried to eat, pro-nounced tongue protrusion hampered food intake (seeVideo, Segment 5).

DiscussionTongue protrusion and feeding dystonia has been

described in several extrapyramidal disorders, includingchorea-acanthocytosis (ChAc), pantothenate-kinase–associated neurodegeneration, Lesch-Nyhan syndrome,as well as in postanoxic and tardive dystonia.11 InChAc, in particular, tongue protrusion, feeding dysto-nia, and in combination with elevated CK levels hasbeen considered to be of high diagnostic value.12 Theusual age of onset is also younger in ChAc than in MLS.In HD, by contrast, most patients demonstrated hyper-kinetic features, including rapid, nonprotruding lingualchorea, swallow dyscoordination, repetitive swallows,prolonged laryngeal elevation, inability to stop respira-tion, and frequent eructation, and videofluoroscopydemonstrated respiratory and laryngeal chorea, pharyn-geal space retention, and aspiration.13 A minority ofpatients had a hypokinetic swallowing disorder, includ-ing mandibular rigidity and slow lingual chorea.13

The feeding dystonia in the MLS patients describedherein shares many similarities with the one observedin ChAc. In addition, the rubber-man–like appearanceobserved in 1 patient was also believed to be charac-teristic for ChAc. Our observations demonstrate aconsiderable phenotypic overlap between these twocore neuroacanthocytosis syndromes. On the otherhand, we did not observe tongue and lip biting in our3 MLS patients, as seen in another report.2

Although MLS is caused by mutations in the XKgene encoding for the XK protein, which shares sub-stantial homologies to the CED8 protein in the nema-tode, C. elegans, where it controls the timing ofdevelopmental apoptosis,1,5, thus suggesting a poten-tial implication in a neurodegenerative mechanism.ChAc, by contrast, is caused by mutations in theVPSA13 gene encoding for chorein, which is an evolu-tionarily conserved protein probably involved in pro-tein sorting.14 Besides the erythrocyte acanthocytosisand elevated CK levels as a sign of neuromuscularinvolvement, ChAc and MLS share a selective degener-ation of the striatum, as observed in different imagingstudies.6,15 However, pathological findings are

F E E D I N G D Y S T O N I A I N M C L E O D S Y N D R O M E


unspecific and include neuronal loss and astrocyticgliosis.16,17 Because the exact function of the involvedgenes in erythrocytes, as well as the neuromuscularand nervous systems, are not resolved as yet, consider-ations about common pathogenetic mechanisms of thetwo disorders remain speculative.

ConclusionIn conclusion, the two neuroacanthocytosis syn-

dromes, ChAc and MLS, share an extended phenotypicoverlap. In patients having feeding dystonia, elevatedCK levels, and erythrocyte acanthocytosis, not onlyanalysis for ChAc using a chorein Western blot of eryth-rocytes, but also serological analysis for the presence ofthe McLeod blood-group phenotype, or alternativelygenetic testing of the XK gene, should be performed.

Legends to the VideoSegment 1. Gait examination of patient A, with typical

rubber-man appearance and frequent head dropping.Segment 2. Patient A is first in a sitting position eat-

ing a cake. The oral stage shows signs of orolingualdyscoordination with tongue protrusion when thepatient is fed with hard consistencies. Noticeable isalso the repeated backward head jerks, facilitating theswallowing of the bolus in the pharyngeal phase. Inthe second part, the patient is eating and drinking inhis habitual position, lying on the back on the floor,taking the advantage of stability and adjusted gravity.The head shifting is markedly reduced, as comparedto the sitting position.Segment 3. Videofluoroscopic swallowing study

(VFSS) of patient A in a sitting position with 2 mL ofliquid swallow demonstrate strong involuntary dys-tonic and dyskinetic tongue movements in the oralpreparatory and oral phases. Inadequate lip closureand tongue protrusion result in anterior leakage of thebolus.Segment 4. Patient B is eating yogurt with difficul-

ties. In addition, he shows frequent head drops. In aneffort to overcome swallowing problems, the patientdeveloped hyperextension spasms forcing him to liedown on his back.

Segment 5. Patient C shows the repetitive tongueprotrusions while eating a piece of white bread.

References1. Jung HH, Danek A, Frey BM. McLeod syndrome: a neurohaema-

tological disorder. Vox Sang 2007;93:112–121.

2. Danek A, Rubio JP, Rampoldi L, et al. McLeod neuroacanthocy-tosis: genotype and phenotype. Ann Neurol 2001;50:755–764.

3. Jung HH, Russo D, Redman C, Brandner S. Kell and XK immu-nohistochemistry in McLeod myopathy. Muscle Nerve 2001;24:1346–1351.

4. Lee S, Sha Q, Wu X, Calenda G, Peng J. Expression Profiles ofMouse Kell, XK, and XPLAC mRNA. J Histochem Cytochem2007;55:365–374.

5. Stanfield GM, Horvitz HR. The ced-8 gene controls the timing ofprogrammed cell deaths in C. elegans. Mol Cell 2000;5:423–433.

6. Jung HH, Hergersberg M, Kneifel S, et al. McLeod syndrome: anovel mutation, predominant psychiatric manifestations, and dis-tinct striatal imaging findings. Ann Neurol 2001;49:384–392.

7. Valko PO, Hanggi J, Meyer M, Jung HH. Evolution of striataldegeneration in McLeod syndrome. Eur J Neurol 2010;17:612–618.

8. Hewer E, Danek A, Schoser BG, et al. McLeod myopathy revis-ited: more neurogenic and less benign. Brain 2007;130:3285–3296.

9. Thomas M, Jankovic J. Neuroacanthocytosis. In: Noseworthy J,editor. Neurological therapeutics: principles and practice. 2nd ed.Milton Park, Abingdon, Oxon, UK: Informa Healthcare; 2006,2882–2889.

10. Walker RH, Jung HH, Tison F, Lee S, Danek A. Phenotypic vari-ation among brothers with the McLeod neuroacanthocytosis syn-drome. Mov Disord 2007;22:244–248.

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

12. Bader B, Walker RH, Vogel M, Prosiegel M, McIntosh J, DanekA. Tongue protrusion and feeding dystonia: A hallmark of cho-rea-acanthocytosis. Mov Disord 2010;25:127–129.

13. Kagel MC, Leopold NA. Dysphagia in Huntington’s disease: a16-year retrospective. Dysphagia 1992;7:106–114.

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

15. Henkel K, Danek A, Grafman J, Butman J, Kassubek J. Head ofthe caudate nucleus is most vulnerable in chorea-acanthocytosis:a voxel-based morphometry study. Mov Disord 2006;21:1728–1731.

16. Danek A, Neumann M, Brin MF, Symmans WA, Hays AP.Cerebral Involvement in McLeod Syndrome: The First AutopsyRevisited. In:Walker RH,Saiki S,Danek A, editors. Neuroacantho-cytosis Syndromes II. Berlin Heidelberg, Germany: Springer,2008, 205–215.

17. Geser F, Tolnay M, Jung HH. The Neuropathology of McLeodSyndrome. In:Walker RH,Saiki S,Danek A, editors. Neuroacan-thocytosis Syndromes II. Berlin Heidelberg, Germany: Springer,2008:197–203.

G A N T E N B E I N E T A L .


Hypersexuality and PathologicalGambling in Parkinson’s Disease:A Cross-Sectional Case–Control

Study

Ingrid de Chazeron, PhD,1,2* Pierre-Michel Llorca, MD,PhD,1,2 Isabelle Chereau-Boudet, MD,1,2 Olivier Blanc,1,2

Jean Perriot, MD,2 Lemlih Ouchchane, PhD,3

Miguel Ulla, MD,1,4 Berengere Debilly, MD,1,4

Philippe Derost, MD,1,4 and Franck Durif, MD, PhD1,4

1Univ Clermont 1, UFR Medecine, Clermont-Ferrand, France; 2CHU

Clermont-Ferrand, Psychiatry B, Clermont-Ferrand, France; 3CHU

Clermont-Ferrand, Department of Biostatistics, Clermont-Ferrand,

France; 4CHU Clermont-Ferrand, Neurology A, Clermont-Ferrand,

France

ABSTRACTBackground: Substance and behavioral addictionshave already been described separately or in combina-tion in Parkinson’s disease. However, no comparisonsof the prevalence of addictive behaviors in patientswith Parkinson’s disease and the general populationhave been published. The objective of this study wasto compare the prevalence and characteristics ofaddictions (gambling, hypersexuality, tobacco, andalcohol) in patients with Parkinson’s disease and in amatched, paired sample from the general population.Methods: After matching for age, sex, and completefield questionnaires on addictions, we had 115 data sets.Results: No difference was observed between Parkin-son’s disease and control populations concerning path-ological gambling (0.87% vs 0.87%, P 5 .99), tobaccoaddiction (1.7% vs 1.7%, P 5 .99), and alcohol de-pendence (2.6% vs 3.5%, P 5 .71). The Parkinson’sdisease group showed 2 cases of sexual addiction(1.7% vs 0, P 5 .15).Conclusions: Our results indicate that patients withParkinson’s disease do not have specific profiles fortobacco or alcohol addiction and pathological gam-bling compared with the general population. VC 2011Movement Disorder Society

------------------------------------------------------------*Correspondence to: Dr. Ingrid de Chazeron, Univ Clermont 1, UFRMedecine, EA3845, Rue Montalembert, Clermont-Ferrand, F-63000France; [email protected]

Funding agencies: This study was sponsored by a Hospital Program forClinical Research (local funding), Clermont-Ferrand University Hospital,Clermont-Ferrand, France.Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 16 July 2010; Revised: 27 April 2011; Accepted: 19 May2011Published online 6 July 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23845

Key Words: Parkinson’s disease; addiction

Impulse control disorders or addiction behaviors areoften reported during the posttreatment evolution ofparkinsonian patients; they include pathological gam-bling (PG),1 compulsive shopping,2 eating disorders,3

and hypersexuality.4 The global prevalence of addic-tive disorders in Parkinson’s disease (PD) is estimatedto be around 14%.5 However, it is unknown whetherthe prevalence of addictive behaviors in PD differsfrom that observed in the general population (aftercontrolling for sex and age). In fact, some addictionssuch as pathological gambling6 seem more frequent inParkinson’s disease and others, such as addiction toalcohol and tobacco, less frequent. Many studies havereported a lower prevalence of smoking and alcoholconsumption (known as the most common substanceaddictions) in PD than in the general population.7–9

Based on those observations, we proposed a descrip-tive epidemiological study to define the prevalenceand characteristics of addictions (gambling and hyper-sexuality, tobacco and alcohol) in PD patients com-pared with a matched paired sample originating fromthe general population.


Study Design

From September 1, 2006, to August 31, 2007, allconsecutive patients with idiopathic PD according tothe Queen Square Brain Bank criteria10 referred asoutpatients to the Unit of Movement Disorder of Cler-mont-Ferrand Hospital, France, were screened. Exclu-sion criteria were atypical Parkinsonism, dementia(Mini–Mental Status Examination < 24), deep brainstimulation, and inability to complete the survey. Dur-ing the same period, the control sample was recruitedfrom people who had an appointment for a free healthcheckup, referred from the National Health System.Exclusion criteria were parkinsonism and the inabilityto complete the survey. Each subject from the controlgroup was selected for 1-to-1 matching on sex andbirth date (66 years). All subjects gave written con-sent to participate in this study.

General and Clinical Evaluation

Sociodemographic data were collected for all partici-pants: age, sex, occupation. For PD patients, informa-tion on duration of disease and antiparkinsoniantreatment was also collected. All eligible participantscompleted a survey including the Fagerstrom Test forNicotine Dependence,11 the Alcohol Use Disorders


H Y P E R S E X U A L I T Y / P A T H O L O G I C A L G A M B L I N G I N P D

Identification Test,12 the South Oaks Gambling Screen(SOGS),13 and the Hypersexuality questionnaire,14

which is a shorter and French-language version of theSexual Addiction Screening Test.

Results

Characteristics of Population

We examined a consecutive series of 159 idiopathicPD subjects and a series of 188 controls. Distribution ofmissing data in PD patients and controls was not signifi-cantly different (Table 1). After screening all the com-pleted filed questionnaires, 139 PD patients wereselected, and after age- and sex-matching the controls,we obtained 115 patients and controls, as detailed inTable 2. No differences in age, sex ratio, situation, andoccupational class characteristics were found betweenthe 2 matched groups (Parkinson’s disease and controlgroups; Table 1). The mean disease duration of the PDgroup was 7.4 years (SD, 4.0 years; range, 1–20 years),mean daily levodopa dose was 631 mg/day (SD, 436mg/day), and mean daily dopamine agonist dose was130 mg/day (SD, 168 mg/day), calculated on the basisof levodopa correspondences adapted from Thoboiset al.15 Ten patients (8.7%) were without agonist or L-dopa, 40 (34.8%) with L-dopa alone, 4 (3.5%) withagonist alone, and 61 (53.0%) with agonist(s) adjunct.

Addiction Characteristics

Patients with pathological gambling or who were‘‘at risk gamblers’’ or with sex addiction were not sig-nificantly more frequent in the PD group, than in thecontrol group (Table 2).For tobacco addiction (classified as nonsmoker, low/

no dependence, medium dependence), there was nostatistically significant difference in patterns between115 PD patients and paired controls, even though

there were twice as many smokers in the control pop-ulation as among the PD patients.The prevalence of current (referral within the previ-

ous 12 months) alcohol abstinence among PD patientswas nearly twice the prevalence among the paired con-trols, and harmful alcohol use among the controlgroup was significantly more frequent (P ¼ .04). ThreePD patients and 4 paired controls had alcohol depend-ence (Table 2).

DiscussionThis study is original in comparing addictive profiles

in PD patients with a sex- and age-matched generalpopulation sample.

Table 1. Sociodemographic details of PD patients and controls

PD patients

PD patients who completed

self-questionnaire

PD ‘‘matching’’

patients

Control ‘‘matching’’

patients

No. of patients 159 139 115M:F 95:64 85:54 69:46Age (y), mean (SD) 66.0 (9.8) 66.0 (9.5) 66.9 (5.8) 66.3 (5.9)Occupational situation (%)Working 27 (17.0%) 25 (18.0%) 12 (10.4%) 10 (8.7%)Retired 115 (72.3%) 99 (71.2%) 92 (80.0%) 101 (87.8%)Disability 17 (10.7%) 15 (10.8%) 11 (9.6%) 4 (3.5%)

Last occupational class when working or retired (%)Craft trade and firm managers 23 (16.2%) 20 (16.1%) 19 (18.3%) 6 (5.4%)Upper managerial staff and professionals 15 (10.6%) 14 (11.3%) 8 (7.7%) 24 (21.6%)Intermediary occupations 17 (12.0%) 15 (12.1%) 11 (10.6%) 13 (11.7%)Clerks and employees 87 (61.2%) 75 (60.5%) 66 (63.4%) 68 (61.3%)

Statistical analysis was performed using the SAS 9.1 software package.Comparisons on paired proportions were made with v2 tests or Fisher exact tests.

Table 2. Addiction profile of matched PD patients andcontrols (n ¼ 115)

PD patients Controls

Smokers (%) 3 (2.6%) 6 (5.2%)Tobacco dependence levels (%)a

Low or no dependenceb 2 (66.6%) 5 (83.3%)Medium dependenceb 1 (33.3%) 1 (16.7%)

Has never had an alcoholic drink (current) (%) 37 (32.2%)f 21 (18.3%)Alcohol dependence levels in drinkers (%)a

Alcohol dependentc 3 (3.8%) 4 (4.3%)Alcohol harmful userc 2 (2.6%) 10 (10.6%)f

Low risk of alcohol-related problemsc 73 (93.6%) 80 (85.1%)Gambling addiction levels (%)a

At risk gamblerd 14 (12.2%) 12 (10.4%)Pathological gamblerd 1 (0.9%) 1 (0.9%)

Sex addict (%)e 2 (1.7%) 0

aBowker/McNemar test.bNo (0–2 FTND score), low (3–4 FTND score), medium (5–6 FTND score)tobacco dependence FTND score.c‘‘Alcohol dependent’’ has an AUDIT cutoff of 11 and 8 for ‘‘harmful users.’’dCut SOGS score of 5 or more is interpreted as evidence of ‘‘pathologicalgambling’’; a score between 1 and 4 suggests an ‘‘at-risk gambler.’’eSex addiction is defined for a score up to 8 in the HS questionnaire.fP < 0.05.gP < .01.Statistical analysis was performed using the SAS 9.1 software package.

C H A Z E R O N E T A L .


In our samples, pathological gambling did not occurmore frequently in PD patients than in the generalpopulation, in contrast to sexual addiction.In our sample, the prevalence of ‘‘problem gam-

bling’’ (at risk and pathological) was 13.1%. It washigher than the observations of Crockford et al in200816 (9.3%) and Singh et al in 200717 (9.3%). Therate of pathological gambling was lower than thosepresented by Voon et al in 2006,18 Avanzi et al in2006,6 and Weintraub et al in 20105 (5.0%). Thediscrepancy in results may be related to differentmethods of evaluating and characterizing thegambling.In our study, identification of pathological gam-

blers was done using the same screening instru-ment (SOGS) as the one used by Voon et al18 butwith a cut point different from that used in theoriginal articles by Lesieur and Blume.13 From amethodological point of view, we preferred a moreclinically relevant cut point, as suggested byShaffer and Hall.19 If we class PD patients scoring� 3 as pathological gamblers, as did Voon et al,18

compared with �5, as in our study, we find arate of 2.6%, which is in their described range of1.7%–3.4% for the prevalence of PG. Avanzi etal,6 also using the SOGS with a lifetime observa-tion, found a prevalence of PG close to 6%. Thedifference could be explained by the periodexplored (lifetime or past 30 days) and also bythe sample sizes of the groups studied. Weintraubet al5 used the Massachusetts Gambling Screeninstrument, which has been reported to be a lesssuitable measure for screening purposes comparedwith the SOGS.20

In the population we studied, the prevalence of PG didnot differ between the PD and the control groups. Thisresult contrasts with the literature. In the study by Avanziet al,6 0.25% of the general population was diagnosed tohave PG compared with 6.12% in the PD population.Two possible explanations may have influenced the resultsin the general population. First, until recently, gamblingwas generally viewed negatively by Italian citizens, andspecific antigambling programs have been developed inschools.21 Second, in this context, a PG screening proce-dure was introduced, consisting of an interview by a gen-eral practitioner. The low prevalence obtained in thisgeneral population may be related to information bias(underdeclaration). Our PG prevalence in the general pop-ulation is closer to the one described in Europe,22 acceptedas being around 1%–2%.The prevalence of pathological hypersexuality

observed in our PD patients group was 1.7%. Voon etal18 suggested a current prevalence of 2.0%, Wein-traub et al5 around 3.5%. This last prevalence differsfrom ours probably because the screening instrumentused (MIDI) needs at least 2 positive responses to

diagnose compulsive sexual behavior compared with 5in our study. Singh et al in 200717 described a preva-lence of around 10%. However, in their study, all thepatients included had been exposed to dopamine ago-nists, which was not the case in our study. In the con-trol group, we found no cases of pathologicalhypersexuality, but it is generally acknowledged thatthe highest level of sexual addiction is establishedbetween ages 36 and 50.23

Because tobacco smokers have a well-documentedlower incidence of PD compared with the general pop-ulation, tobacco dependency in PD patients is notstudied. First of all, looking at the prevalence of smok-ing, we found a 50% higher prevalence of smoking inthe control group than in patients with PD. This hasalso previously been observed in other studies.24,25

This proportion of smokers is lower (2.6%, n ¼ 3)but close to recent data on a large sample (3.8%5).Tobacco dependence seemed not to differ between thecontrol and PD groups.Significantly fewer PD patients drink alcohol com-

pared with the control population. Our proportion offully abstinent PD patients (32.2%) is similar to thatdescribed in the study of Hernan et al.9 PD patientswho were screened positively for harmful drinkingwere significantly fewer than in the control popula-tion. However, no difference between the 2 groups ofsubjects was observed concerning alcohol dependence.Taken together, these data confirm the lower preva-

lence of tobacco smokers and drinkers in PD patientscompared with the controls, but they also suggest aclose prevalence of alcohol and tobacco dependence inthe 2 populations. This comparison should be consid-ered with caution in view of the small numbers ofcases, and further work is needed to determinewhether changes in alcohol and tobacco dependenceare specific for PD. We must notice that codependen-cies exist: 1 case of dopamine dysregulation syndrome(DDS) and tobacco medium dependence and at riskgambler, 1 case of DDS and at risk gambler, and 1case of DDS and alcohol (alcohol dependent).The most surprising result of this work is that the

prevalence of pathological/at-risk gambling is nothigher in PD population in the controls and also thatalcohol and tobacco dependence did not differbetween the 2 groups, although further studies areneeded to confirm this finding. Beyond elucidatingsome underlying causes of addiction, this study alsohighlights the lack of addiction-specific assessmentinstruments. The challenge for the future is to detectpatients through a good routine screening instrumentthat could save cost and time.

Acknowledgements: We gratefully acknowledge the contribution of

the people who were involved in recruitment, particularly Mrs. Christine

Delaigue and Mr. Didier Delhaye.

H Y P E R S E X U A L I T Y / P A T H O L O G I C A L G A M B L I N G I N P D


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C H A Z E R O N E T A L .


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