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doi:10.

1093/brain/awn363

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BRAIN
A JOURNAL OF NEUROLOGY

Case-control study of writers cramp


,3,4 I. Pironneau,5 S. Sangla,1 V. Cochen de Cock,6 A. Teixeira,1 E. Roze,1,2 A. Soumare A. Astorquiza,7 C. Bonnet,1 J. P. Bleton,7,8 M. Vidailhet1,9 and A. Elbaz1,3,4
1 2 3 4 5 6 7 8 9 pital Pitie -Salpe trie ` re, Paris F-75013, France Department of Neurology, Ho CNRS, UMR 7102, Paris F-75005, France UPMC Univ Paris 6, Paris F-75005, France Inserm, U708, Paris F-75013, France Clinical Investigation Center, Saint-Antoine University Hospital, Paris F-75012, France National Center for MSA, Sleep Department and Department of Neurology, Purpan Hospital, Toulouse, France pital Sainte Anne, Paris F-75014, France Department of Neurology, Stroke Unit, Centre R. Garcin, Ho Inserm, U894, Paris F-75005, France Inserm, U679, Paris F-75013, France

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Correspondance to: Dr E. Roze, le des Maladies du Syste ` me Nerveux, Po pital de la Salpe trie ` re, Service de Neurologie, Ho pital, 75651 Paris Cedex 13, France 47-83 Bd de lHo E-mail: emmanuel.roze@psl.aphp.fr

Task-specic focal dystonias are thought to be due to a combination of individual vulnerability and environmental factors. There are no case-control studies of risk factors for writers cramp. We undertook a case-control study of 104 consecutive patients and matched controls to identify risk factors for the condition. We collected detailed data on medical history and writing history as part of hobbies or occupation. Cases had a college or university degree more frequently than controls [OR = 4.6 (1.320.5), P = 0.01]. The risk of writers cramp increased with the time spent writing each day (P-trend = 0.001) and was also associated with an abrupt increase in the writing time during the year before onset (OR = 5.7, 95% CI = 1.333.9, P = 0.02). Head trauma with loss of consciousness [OR = 3.5 (1.015.7), P = 0.05] and myopia [OR = 4.1 (1.712.0), P = 0.0009] were both associated with the condition but it was not signicantly associated with peripheral trauma, left-handedness, constrained writing, writing in stressful situations or the choice of writing tool. The doseeffect relationship between writers cramp and the time spent handwriting each day, and the additional burden of acute triggers such as an abrupt increase in the writing time in the year before onset, point to a disruptive phenomenon in predisposed subjects. Homeostatic regulation of cortical plasticity may be overwhelmed, resulting in dystonia.

Keywords: dystonia; case-control; risk factors; cortical plasticity; head trauma

Introduction
Writers cramp (WC) is a primary adult-onset task-specic focal dystonia characterized by abnormal movements or posturing of the upper limb, because of inappropriate muscle contractions that interfere with writing movement. It is generally accepted that task-specic focal dystonias are due to a combination of

individual vulnerability and environmental factors. However, little is known about risk factors for task-specic dystonias, including WC. Based on case series and personal experience, some authors have suggested a link between periods of stereotyped, repetitive, highly skilled gestures and the onset of task-specic dystonia (Hochberg et al., 1990; Chen and Hallett, 1998; Hallett, 2006).

Received June 10, 2008. Revised November 27, 2008. Accepted December 10, 2008. Advance Access publication January 29, 2009 The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Case-control study of writers cramp WC has been linked to activities that require intensive or accurate writing tasks (Jedynak et al., 2001; Hallett, 2006; Quartarone et al., 2006) and to stressful and uncomfortable writing (Jedynak et al., 2001). Likewise, increases in practice time and changes in technique or repertoire have been implicated in musicians cramp (Tubiana, 2003; Conti et al., 2008). A history of upper limb injury has also been linked to WC (Sheehy and Marsden, 1982; Rosenbaum and Jankovic, 1988; Marsden and Sheehy, 1990). Local body injuries may be involved in other adult-onset focal dystonias, including blepharospasm and laryngeal, oromandibular, shoulder and cervical dystonia (Defazio et al., 1998, 2003; Sankhla et al., 1998; Schrag et al., 1999; Frucht et al., 2000; Wright and Ahlskog, 2000; Jankovic, 2001; Schweinfurth et al., 2002; Papapetropoulos et al., 2008). As WC is linked to a specic task, writing characteristics, handedness and medical conditions that can induce constraints when writing may inuence the risk of the condition. Finally, head trauma may be a risk factor for primary adult-onset dystonia, even in the absence of overt brain lesions (Lee et al., 1994; Defazio et al., 1998). As there is no available case-control study of WC, we conducted a study of 104 case-control pairs to identify the risk factors.

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classication (Institut National de la Statistique et des Etudes Economiques). After including a case, the research nurse searched the hospitals inpatient computer database for persons of similar age and gender hospitalized in the above-mentioned wards, and generated a list of potential controls. She then visited these persons in random order until she identied a suitable control who reported no history of writing difculties and who agreed to participate.

Risk factor interview


Participants were interviewed face-to-face by the same trained research nurse. Some of the questions posed to the cases referred to the date of WC onset; a corresponding index date was thus chosen for each control, dened as the study date minus the matched cases disease duration. Before starting the interview, we asked the cases if they had any opinion on the possible causes of WC. The participants were asked whether they considered themselves right-handed, left-handed, or ambidextrous. Handedness was also determined with the Edinburgh scale. We estimated the total time spent writing each day (with/without interruption) in the year preceding WC onset or the index date (never/rarely; 51 h; 13 h; 36 h; 46 h). We also asked whether there had been an unusual increase in the amount of writing at any particular date and, if so, when. Participants were asked to describe the size (small, normal or large) and style of their writing (normal, jerky) before WC onset (or the index date). They were also questioned about hobbies that involved writing, drawing, painting, sewing, embroidering or playing music instruments. We obtained data on various medical conditions through standardized interviews, including head trauma, ophthalmologic and psychiatric disorders, and diseases or trauma of the neck and upper limbs requiring medical/nursing care. Each professional episode was identied and coded with the ISCO1988 classication, using a specic code for studies after high school. For each episode, we obtained the following information: start/end year; personal occupation; employers activity; amount of usual/uninterrupted daily writing (none, 51 h, 13 h, 36 h, 46 h); use of a typewriter, computer, or mouse; repetitive movements; rapid note-taking; stenography; writing in boxes/tight lines/constrained spaces, on cards, music sheets, carbon paper, or notes; writing instruments; and writing in public or stressful situations. Variables were collected using a semiquantitative coding (never, rarely, often, nearly every day).

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Patients and Methods


Cases
We identied all patients with WC seen during a 30-months period (200203, 2008) at our movement disorders clinic. Because our aim was to obtain information on exposures occurring prior to disease onset, we only included patients with a WC history of 10 years or less and we excluded patients with longer disease duration to reduce the risk of errors in exposure assessment; this cut-off was chosen a priori. Patients with secondary extension to the neck as a spreading of the initial upper limb dystonia or to the opposite limb were eligible. Because the relation between WC and primary writing tremor is controversial, we excluded patients with primary writing tremor. We excluded patients with a history of neurological disorders (brain tumor, stroke, Parkinsons disease, multiple sclerosis) or abnormal neurological ndings other than dystonia, and patients who declared having used neuroleptic drugs in the year preceding WC onset. Sensory disturbances were ruled out by standard physical examination. Patients were interviewed by a research nurse who also took a video with a standardized protocol. The videos were rated by two reviewers (E.R. and J.-P.B.) to describe the phenomenology of WC. Consultatif sur The research protocol was approved by the Comite ` re de Recherche dans le le Traitement de lInformation en Matie (CCTIRS) and Commission Nationale de Domaine de la Sante s (CNIL). The patients gave their informed lInformatique et des Liberte consent to be videotaped.

Measures
The research nurse measured the metacarpophalangeal joint of both thumbs, in exion and extension, using a goniometer. She also looked for subluxation of the thumbs.

Statistical methods
Odds ratios (ORs), 95% condence intervals (CIs) and two-tailed P-values were estimated by conditional logistic regression for matched sets. Signicance was assumed at P  0.05. Relevant exposures were considered to be those occurring before disease onset in the cases and before the index date in the controls. Most of the participants reported several professional episodes. We dened two types of professional exposure variables. First, we dened maximum exposure variables as the maximal frequency/amount of a given characteristic across all the occupations. Second, we dened cumulative exposure variables by weighting the frequency/amount

Controls
Controls were persons admitted to the Orthopedics, Cardiology, Endocrinology, Gynecology or Obstetrics and Internal Medicine departments of the same hospital. One control was matched to each case, based on age (5 years), gender and broad socio-professional categories based on the rst level (eight groups) of the 2003 INSEE

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E. Roze et al. The participants characteristics are shown in Table 1. The distribution of age at onset was suggestive of a bimodal distribution, with two peaks around 20 and 45 years. Cases were more likely than controls to live outside the Paris region. There was no difference in handedness between the cases and controls. WC was classied as: exion (n = 57), extension (n = 23), pronation or supination (n = 6); a video was not obtained for 13 cases and was not interpretable for another ve cases. One patient subsequently developed mild cervical dystonia as a spreading of the initial upper limb dystonia; WC was still the main and more disabling symptom. Eight patients developed controlateral WC when they attempted to learn to write with the non dominant hand. In the year preceding WC onset (or the index date), cases spent more time per day writing than controls, and the OR increased with the writing time (Table 2). During the year preceding WC onset (or the index date), the cases reported an unusual increase in the amount of writing more frequently than the controls, whereas there was no such difference in other periods (Table 2). In addition, cases were more likely than controls to use cursive writing, while controls were more likely than cases to use a printed style, but these differences were not statistically signicant (Table 2). Cases (21%) were more likely than controls (15%) to write for leisure, but the difference was not statistically signicant [OR = 1.4 (0.73.1), P = 0.37]. Frequent leisure writing in limited spaces (boxes, tight lines, cards, cross-words) was not signicantly associated with WC [OR = 1.5 (0.82.7), P = 0.20]. There was no association between WC and the preferred leisure writing instrument (data not shown). There was no association between WC and playing musical instruments [OR = 1.0 (0.61.8), P = 0.98]; cases (21%) were more likely than controls (14%) to play piano, but the difference was not statistically signicant [OR = 2.0 (0.94.6), P = 0.11]. There were no differences for other hobbies (data not shown).

of a given characteristic by the corresponding number of years, and then summing the resulting value across all occupations. Analyses were adjusted for age, sex and place of residence (inside or outside the Paris region). We then built a multivariable model including all variables with P-values of 0.05 in the rst stage, and used a backwards selection procedure, with a P-value of 0.05 being required to stay in the model. Two separate multivariable models were used, one with and the other without occupational data, since all subjects did not have occupational data. Multivariable models were built using exact conditional logistic regression. As the date of WC onset is difcult to determine precisely, we performed lagged sensitivity analyses by excluding exposures in the 5 years before disease onset (or the index date). Additional sensitivity analyses were performed by excluding patients or without a video, and by performing analyses stratied by age at onset and disease duration in cases. To study the relation between WC and the timing of exposure to writing, we analysed the relation between the risk of WC and the amount of professional writing each year before WC onset (or the index date) and represented our ndings in graphic form (lowess smoother). Data were analysed with SAS (v9.1) and STATA (v10.0) software.

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Results
We identied 109 WC cases who met the inclusion criteria, of whom 105 (96%) agreed to participate in the study. One case was excluded due to diagnostic misclassication after video review. The remaining 104 cases were matched to 104 controls. The acceptance rate among the controls was 95%; their departments of recruitment were: gynecology (n = 18), maternity (n = 12), orthopedics (n = 30), endocrinology (n = 30), cardiology (n = 6), internal medicine (n = 8). Only 42 cases expressed opinions as to possible causes of WC, as follows: writing or taking quick notes (n = 13); psychological factors (n = 11); accidents, medical conditions (n = 6); repetitive movements (n = 4); and others (n = 8).

Table 1 General characteristics of WC cases and controls


Characteristics Age at study (median, range) Age at WC onset (median, range) Disease duration Female sex, % (n) Residence, % (n) Paris Paris suburbs Outside Paris region Stopped work for health reasons, % (n) Handedness (declared), % (n) Right Left Ambidextrous Left handedness (Edinburgh scale), % (n)b Cases N = 104 51 44 6 62 20 65 15 5 87 5 8 6 (2082) (1677) (010) (64) (21) (67) (16) (5) (91) (5) (8) (6) Controls N = 104 51 (1880) 62 (64) 43 47 10 8 88 7 5 8 (45) (49) (10) (8) (92) (7) (5) (8) 1.0 2.8 3.1 0.8 1.0 0.7 1.6 0.8 OR (95% CI)a (reference) (1.55.4) (1.28.1) (0.32.3) (reference) (0.22.3) (0.54.9) (0.32.2)

Pa
0.002 0.02 0.64 0.57 0.41 0.59

a ORs (95% CI) and P-values were calculated using conditional logistic regression. b We excluded from the computation of the Edinburgh score two items referring to writing or drawing, as cases with WC may have changed hands to perform these activities. Laterality quotient scores were calculated by subtracting the number of tasks performed with the left hand from the number of tasks performed with the right hand; this number was then divided by the total number of tasks performed. Scores lower than zero indicate left-handedness, while scores above zero indicate right handedness. The comparison of the mean scores between cases and controls showed no difference (P = 0.43).

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Table 2 Characteristics of writing (occupational and leisure combined) in cases with WC and controls
Characteristics Cases n (%) Controls n (%) OR (95% CI)a 1.0 (reference) 2.8 (0.516.2) 7.0 (1.435.8) 12.7 (2.079.6)

Pa

Number of daily hours of writing in the year before WC onset (cases) or the index date (controls) Exceptional (hr/day) 4 (4) 11 (10) 51 18 (17) 37 (36) 13 47 (45) 35 (34) 43 35 (34) 21 (20)

0.0002

Number of daily hours of uninterrupted writing in the year before WC onset (cases) or the index date (controls) Exceptional (hr/day) 8 (8) 26 (25) 1.0 (reference) 51 52 (50) 50 (48) 3.7 (1.49.9) 13 33 (32) 23 (22) 4.7 (1.613.4) 43 11 (10) 5 (5) 10.1 (2.247.7) Unusual increase in the amount of writing In the year before WC onset (cases) or the index date (controls) At any other earlier time Characteristics of writing before WC onset Small size Jerky style Preferred type of writing Printing Cursive 24 (23) 46 (44) 20 (19) 20 (19) 21 (20) 97 (93) 6 (6) 51 (49) 13 (13) 11 (11) 28 (27) 88 (85) 6.6 (2.120.6) 0.7 (0.41.3) 1.5 (0.73.3) 1.6 (0.73.7) 0.7 (0.41.5) 2.5 (0.96.6)

0.002 0.001 0.29 0.32 0.29 0.40 0.07

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a ORs (95% CI) and P-values were calculated using conditional logistic regression and adjusted for age, sex and place of residence.

Cases reported a history of head trauma more frequently than controls (Table 3). The mean (SD) interval between head trauma and WC onset was 19 (15) years. Cases also reported a history of head trauma with loss of consciousness more frequently than controls (Table 3). The mean (SD) interval between head trauma with loss of consciousness and WC onset was 17 (13) years. The cases reported a more frequent history of visual decits, and particularly myopia and astigmatism, than the controls, while there was no difference in presbyopia or hypermetropia (Table 3). Cases reported more frequently than controls a history of trauma or disease of the neck; this difference was not statistically signicant for specic conditions (i.e. osteoarthritis, trauma) due to small numbers (Table 3). Cases reported a history of trauma of the dominant upper limb more frequently than controls but the difference was not statistically signicant (Table 3). There was no signicant association of WC with history of carpal tunnel syndrome or cervico-brachial neuralgia (Table 3). The carpal tunnel syndrome was diagnosed in the year preceding WC onset in four out of ve cases, and cervico-brachial neuralgia in the 5 years before WC onset in ve out of six cases. Tendinitis (of the elbow or shoulder) tended to be reported more frequently by cases than controls, although the difference was not signicant; the median interval between tendinitis and WC onset was 6 years (range 242 years). Cases did not report more frequently than controls having seen a psychiatrist [OR = 0.7 (0.41.3), P = 0.30] or having been treated or hospitalized for depression [OR = 1.5 (0.73.1), P = 0.26]. There was no association between WC and cigarette smoking [OR = 1.0 (0.51.8), P = 0.98] or regular alcohol consumption [OR = 0.9 (0.41.9), P = 0.93].

Subluxation of the thumb of the dominant hand was not signicantly more frequent in cases (7%) than in controls (4%) [OR = 2.9 (0.715.5), P = 0.17]. There were no differences in the mean maximal angles of the metacarpophalangeal joint of the dominant thumb, in either extension or exion (data not shown). Ninety-nine cases and matched controls reported having been employed at least once and/or having been a college/university student. The distribution of the ISCO-88 occupational categories (rst level) is shown in Supplementary Table 1. The Scientic and intellectual professionals and Craft and related trades workers were more frequent in cases than in controls, but these differences were not statistically signicant; the only signicant difference concerned Service workers and shop and market sales workers (less frequent among cases than controls). In addition, more cases than controls said they held college/university degrees. Table 4 shows the participants occupational characteristics. As part of their occupation, cases spent signicantly more time than controls writing each day. Use of a fountain pen, computer or mouse was more frequent among cases than controls. The Fig. 1 shows the relation between WC and the daily time spent writing as part of occupation (3 h versus 53 h), computed for each year before WC onset (or the index date). The curve suggests a U-shaped relation, with the strongest association occurring in the year preceding WC onset. Table 5 shows the results of multivariable analyses including (Model 2) and not including (Model 1) occupational data. Independently of the model, the amount of daily writing, an unusual increase in the amount of writing in the year preceding WC onset (or the index date), a history of head trauma with loss of consciousness, and myopia were retained in the nal model. College/university education was also retained in Model 2.

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Table 3 Selected medical conditions in cases with writers cramp (WC) and controls.
Characteristics History of head trauma No 1 41 1 History of head trauma with loss of consciousness No 1 41 1 Any ophthalmologic history Myopia Presbyopia Astigmatism Hypermetropia Otherb Any neck disorder Osteoarthritis Trauma Other Scoliosis Trauma or disease of dominant upper limbc Trauma needing medical or nursing care Carpal tunnel syndrome Cervico-brachial neuralgia Tendinitis (elbow, shoulder) Other upper limb disorderd
a b c d e

Cases n (%) 76 21 7 28 85 15 4 19 89 50 54 35 5 10 24 10 8 6 33 24 5 7 8 11 (73) (20) (7) (27) (81) (15) (4) (19) (86) (48) (52) (34) (5) (10) (23) (10) (8) (6) (32) (23) (5) (7) (8) (11)

Controls n (%) 93 9 2 11 97 6 1 7 79 25 58 17 5 10 10 3 4 1 28 15 2 3 1 9 (89) (9) (2) (11) (93) (6) (1) (7) (76) (24) (56) (16) (5) (10) (10) (3) (4) (1) (27) (14) (2) (3) (1) (9)

OR (95% CI)a

Pa

1.0 3.0 5.9 3.6 1.0 2.6 6.9 3.3 2.9 3.9 0.6 2.2 0.9 1.1 2.2 2.5 1.6 9.2 1.1 1.9 2.1 1.2 5.7 1.0

(reference) (1.18.2) (1.131.0) (1.58.8) (reference) (0.88.5) (0.967.5) (1.29.5) (1.0 8.4) (1.88.4) (0.21.4) (1.04.7) (0.23.4) (0.43.1) (1.04.8) (0.79.7) (0.55.7) (1.082.1) (0.62.1) (0.94.0) (0.411.7) (0.35.1) (0.747.2) (0.42.7)

0.005e 0.005e

0.02 0.02 0.05 0.0004 0.23 0.05 0.87 0.88 0.04 0.18 0.44 0.05 0.80 0.10 0.41 0.81 0.11 0.98

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ORs (95% CI) and P-values were calculated using conditional logistic regression and adjusted for age, sex and place of residency. Strabismus, exopthalmus, colour-blindness, cataract, glaucoma, optic neuritis. Dominant upper limb according to the Edinburgh scale. Including articular cysts or effusions, exostosis, bone tumours, infections. Trend test.

Excluding exposures in the 5 years before disease onset (or the index date) or patients without a video did not modify our ndings (data not shown). In addition, the associations reported overall were not modied by age at onset or disease duration (data not shown).

Discussion
This is the rst case-control study of WC. We investigated the role of risk factors tentatively identied in previous reports or suggested by pathophysiological studies of dystonia. We found a doseeffect relation between the amount of time spent writing each day and WC. The strongest association with writing time occurred in the year preceding WC onset, suggesting a triggering role. Other writing characteristics such as left-handedness or constrained writing were not associated with WC. Myopia and head trauma, but not peripheral trauma, were associated with WC. The relation between WC and the amount of handwriting, with an additional trigger represented by an unusual increase in the writing time in the year preceding WC onset, may reect two

aspects of the same disruptive phenomenon. Our ndings are in keeping with the deleterious effect of intensive motor training observed in a primate model of focal dystonia (Byl et al., 1996). Indeed, a maladaptive response can occur when motor training in highly skilled movements is pushed to extremes (Perlmutter and Thach, 2007). An increase in practice time and difculty are also associated with musicians cramp (Tubiana, 2003; Conti et al., 2008). In such situations, homeostatic mechanisms that regulate cortical plasticity may be overwhelmed, resulting in the consolidation of abnormal motor programs with altered muscle activation patterns. Patients with focal dystonia have been found to have excessive sensorimotor cortex plasticity (Quartarone et al., 2003, 2007; Weise et al., 2006; Tisch et al., 2007), and an impaired homeostatic regulatory response (Quartarone et al., 2005). These abnormalities may explain why some subjects are more prone to dystonia in conditions that require increased adaptive responses, and may represent an endophenotype of the disease (Defazio et al., 2007; Quartarone et al., 2007). In this context, it is conceivable that myopia increases adaptive requirements for the correct performance of motor tasks, which may account for the association between myopia and WC.

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Table 4 Characteristics of occupational writing in 99 cases with WC and matched controls


Characteristics Usual writing Number (h/day)b 53 36 46 Cases n (%) Controls n (%) OR (95% CI)a

Pa

31 (31) 42 (42) 26 (26)

58 (59) 31 (31) 10 (10) 45 (46) 34 (34) 20 (20)

1.0 (reference) 3.0 (1.36.7) 23.5 (5.1107.1) 1.0 (reference) 2.2 (0.95.5) 9.9 (3.231.4)

50.0001

Number of hours/day weighted by the number of yearsc 1st tertile 25 (25) 2nd tertile 30 (30) 3rd tertile 44 (44) Uninterrupted writing Number (h/day)b 53 36 46

50.0001

75 (76) 17 (17) 7 (7)

92 (93) 6 (6) 1 (1) 45 (46) 29 (29) 25 (25) 29 30 38 25 20 37 18 27 26 22 35 27 29 (29) (30) (38) (25) (20) (37) (18) (27) (26) (22) (35) (27) (29)

1.0 (reference) 11.1 (2.648.3) 20.6 (2.0208.84) 1.0 (reference) 2.0 (0.94.4) 3.6 (1.58.5) 1.3 1.2 0.7 1.4 1.0 1.7 3.1 2.4 1.4 3.1 2.5 1.7 1.2 (0.62.7) (0.52.9) (0.31.5) (0.63.0) (0.52.0) (0.64.5) (1.27.8) (0.87.0) (0.63.3) (1.28.0) (1.05.9) (0.83.4) (0.62.3)

0.0008

Number of (h/day) weighted by the number of yearsc 1st tertile 28 (28) 2nd tertile 33 (33) 3rd tertile 38 (39) Other characteristics of writingd Writing in boxes Writing in narrow lines Writing on cards Writing on carbon paper Writing on notes/slips Use of pencil Use of fountain pen Use of ballpoint pene Use of felt pen Use of computer Taking quick notes Writing in stressful situations Writing in public 30 26 32 25 22 44 27 35 34 34 41 35 36 (30) (26) (32) (25) (22) (44) (27) (35) (34) (34) (41) (35) (36)

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0.0005 0.77 0.86 0.24 0.55 0.99 0.31 0.002 0.09 0.44 0.02 0.17 0.17 0.50

a ORs (95% CI) and P-values were calculated using conditional logistic regression and adjusted for age, sex and place of residency. b Based on the maximal amount of writing declared for all occupations held. c For each occupation, we multiplied the number of years of work by an index based on the daily number of hours of writing (none = 0, 51 h = 0.5, 13 h = 2, 36 h = 4, 46 h = 8) reported by the participant for that specic occupation. We then summed the resulting values over all occupations held by the participant, in order to generate a cumulative measure of the amount of writing throughout the occupational history. d For all characteristics, we multiplied the number of years of work by an index (never or rarely = 1, often or every day = 1). We then summed the resulting values over all occupations held by the participant, in order to generate a cumulative measure for each characteristic throughout the occupational history. These cumulative variables were categorized in three levels (never, below the median, above the median). For simplicity, we only report the percentages and ORs corresponding to persons classied above the median values of these variables. P-values were computed with trend tests. e Because few participants reported never using ballpoint pens, for this variable we report the percentages and ORs corresponding to persons that were classied in the 3rd tertile of the cumulative variable.

The idea that certain writing tools could favor the development of WC has been proposed more than 100 years ago (Gowers, 1888). In univariate analyses, we found an association between WC and occupational writing with fountain pens. However, this association disappeared after adjusting for the number of daily hours of writing. Head trauma has been implicated as a triggering factor in primary dystonia (Lee et al., 1994), and a case-control study of primary adult-onset dystonia showed an association with prior head trauma with loss of consciousness (Defazio et al., 1998). By contrast, two case-control studies failed to identify an association between head trauma and cranial dystonia (Behari et al.,

2000; Martino et al., 2007). These discrepancies may be related to the etiologic heterogeneity of cranial dystonias relative to other primary adult-onset dystonias, including WC. In WC, the association with prior head trauma may be due to subtle damage in certain brain areas, as proposed in Parkinsons disease (Bower et al., 2003; Goldman et al., 2006; Dick et al., 2007) and amyotrophic lateral sclerosis (Chen et al., 2007). Alternatively, head trauma may induce transient dysfunction in brain areas involved in the pathophysiology of dystonia and trigger prolonged changes in their functioning. Patients with WC may over-report events such as head trauma (recall bias) (Sackett, 1979). However, none of our cases attributed WC to head trauma, and most did

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E. Roze et al. not consider that WC resulted from brain dysfunction. The association between head trauma and WC also held for head trauma with loss of consciousness, which was less likely to be underreported by the control subjects. In univariate analyses, we found an association between a history or trauma of the neck and WC, but we did not nd a signicant association for specic conditions owing to small numbers; in addition, this variable was not retained in multivariable models, probably because it was associated with a history of head trauma. We did not nd a statistically signicant association between upper-limb trauma and WC. This nding may be due to a lack of statistical power to detect small effects of relatively rare events. By contrast, an association has been reported between other primary adult-onset focal dystonias and peripheral trauma (Defazio et al., 1998, 2003; Sankhla et al., 1998; Schrag et al., 1999; Frucht et al., 2000; Wright and Ahlskog, 2000; Jankovic, 2001; Schweinfurth et al., 2002; Papapetropoulos et al., 2008). It has been suggested that peripheral trauma can alter sensory inputs and lead to CNS reorganization and motor dysfunction (Jankovic, 2001). Our ndings do not support a major role of local trauma in WC. College/university education was associated with WC. There was no association between WC and most job categories, possibly because several of the occupational categories comprised jobs that required large amounts of writing. We were unable to study the association between WC and more specic occupations, owing to the small numbers of cases in each category. In univariate analyses, Service workers and shop and market sales workers were less frequent in cases than in controls but this variable was not retained in multivariable models. Our results may be affected by recall bias. In particular, the cases might have reported details of their writing history more accurately than the controls. However, the results were unchanged when we excluded the 13 cases who believed that WC was due to writing. In addition, data on the amount of writing were collected in two ways. First, we asked the participants to estimate the average amount of daily writing in the year preceding WC onset (or the index date in the control group), and asked them to dene certain characteristics of their writing. Second, occupational data were collected chronologically and separately for each occupation, without referring to WC onset; this approach is less prone to the recall bias, as it replaces the writing history in the context of the occupational history, which helps to retrieve information. The two methods yielded very similar results. WC is a rare disorder, and the study population, although large, may have been inadequate to study the inuence of rare exposures. For example, subluxation of the dominant thumb occurred in 4% of the controls; 220 case-control pairs would have been necessary to detect a signicant OR of 2.9; the Supplementary gure shows the power of the study (104 matched case-control pairs) to detect an association between WC and an exposure for different ORs and frequencies of the exposure among controls. In addition, the multivariable models yielded ORs with large condence intervals and conrmatory studies of sufcient size are needed to conrm these ndings. We did not perform a population-based study of WC and did not identify all WC patients in a dened population;

Figure 1 Odds ratios for the amount of daily occupational writing (3 h or more versus 53 h) computed for each year before WC onset in cases or the index date in controls. Point estimates of odds ratios are shown as black dots. The dashed line is a lowess smoother and the dotted horizontal line corresponds to an odds ratio of 1. Odds ratios are adjusted for age, sex and place of residency.

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Table 5 Multivariable models.


Characteristics Model 1b Number of daily hours of writing Unusual increase in writing timec Head trauma with loss of consciousness (one or more) Myopia Model 2 Number of daily hours of writing Unusual increase in writing timec Head trauma with loss of consciousness (one or more) Myopia College or university degree
d

OR (95% CI)a 5.7 (1.333.9) 3.5 (1.015.7) 4.1 (1.712.0) 5.4 (1.049.6) 4.7 (1.029.5) 4.8 (1.717.1) 4.6 (1.320.5)

Pa
0.02e 0.02 0.05 0.0009 0.001e 0.05 0.05 0.001 0.01

a ORs (95% CI) and P-values were calculated using exact conditional logistic regression. Both models are adjusted for age, sex, and place of residency. b Model 1 (104 pairs) includes a variable assessing the overall amount of daily writing in the year preceding WC onset for cases or the index date in controls, as well as other writing or medical history data associated with WC in univariate analyses and two adjustment variables forced in the model (age and place of residence). The following variables were not retained in the nal model: astigmatism, disease or trauma of the neck. c In the year before WC onset (cases) or the index date (controls). d In model 2 (99 pairs), the variable assessing the amount of writing was dened based on occupational history. We included in the full model the other variables that remained associated with WC in model 1 (unusual increase in writing time, head trauma, myopia), occupational variables associated with WC in univariate analyses, and two adjustment variables forced in the model (age and place of residence). The following variables were not retained in the model: writing frequently with fountain pen (as part of occupation), using frequently a computer (as part of occupation), Service workers and shop and market sales workers job category. e Trend test.

Case-control study of writers cramp in particular, we did not identify patients who did not seek medical attention and it is likely that a proportion of patients with WC are undiagnosed. Therefore, the results of the present study apply to patients seeking care for WC at a movement disorders clinic. As in any hospital-based case-control study, the choice of control subjects is difcult. We were concerned about a possible referral bias, as our department is a tertiary referral center for movement disorders and has a catchment area larger than the Paris region. In a preliminary feasibility study with 28 case-control pairs, controls were relatives of patients visiting our department for disorders other than dystonia. However, controls recruitment proved to be difcult. To limit a potential referral bias, we adopted two complementary strategies in the design and analytical stages. First, we selected controls from among in-patients on a variety of wards, and matched them to cases for age and gender, and also for socio-professional status in order to ensure similar access to specialized medical care. The drawback of this approach is that we may have overmatched cases and controls with respect to their occupations. Second, we adjusted our analyses for residence inside or outside the Paris region. The feasibility study and the main study yielded similar estimates for the main variables, suggesting that a referral bias is unlikely to have affected our ndings. Standardized videos were taken in order to characterize the type of WC and could not be obtained or were of insufcient quality for 18 patients due to technical reasons; however, the video reviewers considered that the medical records of these patients provided sufcient evidence that they were affected with WC in all cases. In addition, excluding them from the analyses did not modify our ndings (data not shown). In conclusion, we have identied several potential risk factors for WC. The main one was the daily amount of writing. In addition, the association with the amount of writing in the year preceding the onset of WC suggests a triggering role. It remains to be shown whether the identication of these risk factors can help to develop preventive strategies or to modify the course of WC and other task-specic dystonia.

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` re and Floria Edouard for We thank Constance Flamand-Rouvie helping in the preparation of the manuscript.

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Supplementary material
Supplementary material is available at Brain online.

Acknowledgments
et de This study was supported by the Institut National de la Sante dicale and the Assistance Publique - Ho pitaux de la Recherche Me Paris at the Clinical Investigation Center of Saint-Antoine rie Biousse (Atlanta) for University Hospital. We thank Dr Vale her comments on the ophthalmologic data. This research was supported by an unrestricted grant from Allergan. A cha is supported by a PhD fellowship from Fondation pour Soumare dicale. We thank Laurence Franc oise, Dr Brucker, la Recherche Me Dr Haroche and Dr Caumes for their help in recruiting controls.

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