Benign hereditary chorea: Clinical and neuroimaging features in an Italian family

Brief Reports

Characteristic Head Drops andAxial Extension in Advanced

Chorea-Acanthocytosis

Susanne A. Schneider, MD, PhD,1,2

Anthony E. Lang, MD,3 Elena Moro, MD,3

Benedikt Bader, MD,4 Adrian Danek, MD,4

and Kailash P. Bhatia MD1*

1Sobell Department of Motor Neuroscience and MovementDisorders, UCL, Institute of Neurology, Queen Square,

London, United Kingdom; 2Schilling-Section ofNeurogenetics, Department of Neurology, University ofLubeck, Lubeck, Germany; 3Morton and Gloria ShulmanMovement Disorders Centre, Toronto Western Hospital,University of Toronto, UHN, Toronto, Ontario, Canada;

4Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universitat Munchen, Munich, Germany

Video

Abstract: Chorea-acanthocytosis is a rare autosomal reces-sive neurodegenerative disorder with a complex clinicalpresentation comprising of a mixed movement disorder(mostly chorea and dystonia), seizures, neuropathy andmyopathy, autonomic features as well as dementia andpsychiatric features. Because the differential diagnosisis wide, clinical clues and red flags are important.We report here our observation of characteristic neckand trunk flexion and extension spasms in four caseswith advanced chorea-acanthocytosis. � 2010 MovementDisorder Society

Key words: chorea-acanthocytosis; acanthocytes; neuroa-canthocytosis; head drops; trunk flexion; trunk extension;orobulbar features

INTRODUCTION

Chorea-acanthocytosis is a rare autosomal recessive

adult-onset neurodegenerative disorder due to VPS13Agene mutations, encoding chorein.1,2

Clinical manifestations consist of a mixed movement

disorder, seizures, neuropathy, myopathy, autonomic

features, dementia, and psychiatric features.3 The dif-

ferential diagnosis is wide. Acanthocytes are not

always detected by the screening test of the peripheral

blood smear. Hence, clinical clues and red flags are an

important aid for clinicians.

In evaluating patients with chorea-acanthocytosis in our

tertiary referral centers, we have observed typical flexions

of neck (presenting as head drops) and trunk as a charac-

teristic feature in advanced chorea-acanthocytosis which

in our view have not been explicitly described before. We

feel that these features may be a pathognomic clinical

sign for chorea-acanthocystosis and a useful clue toward

the diagnosis, particularly if self-mutilatory mouth move-

ments or feeding-related tongue dystonia are also present.

We illustrate our observations by videos including a series

of videos over time for Case 1 showing that head drops

become prominent late in the disease course. All patients

gave written informed consent. A summary of the demo-

graphic and clinical details are shown in Table 1.

Case 1

This 40-year-old patient developed slowly progres-

sive frontal lobe dysfunction from age 32, followed by

chorea and slurred speech from age 34. He developed

falls at age 36. At age 38, he developed difficulty eat-

ing with tongue biting. On examination then he had

generalized chorea, intermittent mild head drops, gait

ataxia, and severe bruxism (Video Segment 1). At age

39, he presented with his first generalized tonic-clonic

seizure and developed autonomic dysfunction with pro-

gressive loss of bladder control.

On last follow-up, aged 40, memory function was

relatively preserved. He was depressed; however,

aggression, self-injurious behaviour, or psychosis were

absent. Saccades were hypometric. He had orobulbar

involvement with marked dysarthria, slow tongue

movements, and swallowing difficulties. Because

of severe bruxism culminating in tongue biting and

damage of his teeth, he wore a gum shield. He had

*Correspondence to: Kailash P. Bhatia, Sobell Department ofMotor Neuroscience and Movement Disorders, The National Hospitalfor Neurology and Neurosurgery, UCL, Institute of Neurology, Lon-don WC1N 3 BG, United Kingdom. E-mail: [email protected]

Potential conflict of interest: Nothing to report.Received 29 October 2009; Revised 9 December 2009; Accepted

25 January 2010Published online 11 June 2010 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.23052

1487

Movement DisordersVol. 25, No. 10, 2010, pp. 1487–1504� 2010 Movement Disorder Society

generalized chorea and his head drops had become

more severe resulting in head and face injuries (Video

Segment 2). His gait was very unstable and lurching.

Investigations demonstrated presence of 5% acantho-

cytes. The protein assay4 revealed absent chorein. Cre-

atine kinase (CK) was raised to 224 at age 39 and to

429 on last follow-up, at age 40 (normal <150). Cop-

per studies were normal. Genetic testing was negative

for Huntington’s disease, DRPLA, SCA17, and juncto-philin-3 (HDL2). VPS13A testing was not performed.

Electrophysiological studies suggested mild myopathy

and mild chronic sensory motor axonal neuropathy.

Tetrabenazine worsened his depression and had to be

withdrawn. He continues to receive botulinum toxin

injections in the masseter muscles to alleviate the brux-

ism, antidepressants, benzodiazepines and, for seizure

control, valproate. In view of loss of bladder control, a

catheter had to be inserted.

There was no family history of neurological disease.

His sister was asymptomatic. She had normal (how-

ever, at the lower limit of the normal range) levels of

chorein in the protein assay.4

Case 2

This woman from an extended French-Canadian kin-

dred with VPS13A mutations5,6 presented at age 43

with a 6-year history of generalized abnormal move-

ments. Her parents were first cousins. One sister and

two cousins, also the products of a consanguineous

marriage, were similarly affected. Examination at age

43 demonstrated moderate generalized chorea with

dystonia of the trunk and legs, mild action hand

tremor, and absent lower limb deep tendon reflexes.

Mild ‘‘tic-like’’ behavior was noted including humming

and mild swearing. At age 45, her trunk and knees

began to ‘‘give-way’’. While sitting unsupported her

trunk would occasionally extend forwards or back-

wards involuntarily (Video Segment 2).

Peripheral smear demonstrated 10% acanthocytes.

CK levels were 3212. CT scans demonstrated caudate

atrophy. Fluorodeoxyglucose positron emission tomog-

raphy revealed absence of FDG uptake in the caudate-

putamen area. Neuropsychological assessment showed

only mild reduction in verbal fluency and procedural

learning. She failed trials of multiple medications.

Case 3

This 32-year-old man, one of the affected cousins of

Patient 2, was seen for consideration of bilateral globus

pallidus internus (GPi) deep brain stimulation (DBS)

surgery.

At age 22, he noted clumsiness in his hands and

dysarthria. He developed involuntary movements of his

tongue and jaw, with severe biting of his cheeks and

tongue. He also developed facial tics, anterocollis, and

opisthotonus. He fell while walking, due to imbalance

and involuntary leg movements. When kneeling, there

were involuntary backward trunk movements. His older

brother was in a nursing due to the same disease and

had exactly the same backward movements. His dys-

phagia and dysarthria progressively worsened. He had

feeding dystonia needing to lie down to drink liquids

and to push the food inside his mouth with his fingers

or a fork. Genetic analysis at age 24 revealed he was

compound heterozygous for the French Canadian foun-

der mutation EX70_EX73del5 and a splice site

(c.424211G>T) VPS13A gene mutation.

On exam, speech was dystonic and severely slurred.

There was severe drooling. He had what were inter-

preted as tics involving blinks and shoulder shrugs. He

had occasional simple vocalizations (‘‘hmm’’ sounds).

He also had compulsive nose picking and skin scratch-

ing to the point of bleeding and wore gloves to prevent

him from this behavior. His head was held mostly

flexed. He demonstrated prominent backwards trunk

movements, which occasionally caused him to knock

his head quite hard on the wall behind him and he

wore a soft helmet as a protection (Video Segment 3).

Hand movements were slow, but tone was normal.

A variety of medications provided only partial relief.

Botulinum toxin injections of the masseters and ptery-

goid muscles markedly reduced cheek and tongue bit-

ing. Bilateral GPi DBS surgery was performed at age

31 with clinical improvement.

Case 4

This 36-year-old male patient is taken from the

archival video database of Professor David Marsden’s

and was previously reported by Hardie et al. as Case

18.7 There was a 3-year history of progressive speech

impairment, dysphagia, intermittent muscle spasms

affecting the left-sided limbs, and difficulty walking

with occasional falls. On examination, there were a

fine slow tongue tremor at rest and action tongue dys-

tonia and facial dystonia when speaking. His speech

was dysarthric. He spontaneously made intermittent

loud sucking and blowing noises and his head dropped

intermittently (Video Segment 4). Optic fundi and eye

movements were normal. Limb tone and power were

normal, but rapid finger movements were mildly

impaired in the left hand. There was leg dystonia when

walking. Tendon reflexes were all reduced. Plantar

1488 S.A. SCHNEIDER ET AL.

Movement Disorders, Vol. 25, No. 10, 2010

responses were flexor. About 5% acanthocytes was

present in peripheral blood. CK was elevated at 692.

Mutation analysis revealed a VPS13A mutation in exon

57.8

DISCUSSION

Movements in chorea-acanthocytosis are often com-

plex. Chorea, dystonia with prominent orofacial

involvement, tics and parkinsonism have all been

described.

We noted the occurrence of sudden and striking

movements of the trunk and head, sometimes resem-

bling sudden loss of tone as seen in negative myoclo-

nus. In more severe Cases (#2 and 3), the trunk move-

ments were profound causing drops from the waist

downward so that the head would go into the lap. In

less severe presentations, there were characteristic head

drops with ballistic flexion of the neck as seen in two

of our Patients (#1 and 4).

Case 3 had axial drops but also equally sudden and

striking extensor movements. Thus, in addition to sud-

den loss of tone resulting in the head to drop, exten-

sion movements are equally possible. Interestingly, we

noted intrafamilial homogeneity of the movement.

Patient 3 and his similarly affected brother showed

exactly the same backward movements. Overall, these

axial movements appeared to be a distinctive feature

which may be a clue towards the diagnosis.

As a consequence, one of our patients (Case 1) had

various injuries at the back of his head and the fore-

head. This was initially misinterpreted as self-injurious

behaviour which may also occur in chorea-acanthocy-

tosis.9 However, psychiatric assessment revealed no

suggestion to support voluntary self-injurious tenden-

cies in our case.

The type of myoclonus-like movements we describe

here may also be seen in myoclonic disorders, for

example Unverricht-Lundborg disease.10 However, in

the latter, myoclonus is generalized, whereas in our

patients it predominantly affected the trunk or neck.

Also, the overall phenomenology in chorea-acanthocy-

tosis is much more complex.

The differential diagnosis of a mixed movement dis-

order with both myoclonic jerks and dystonia also

includes myoclonus dystonia (DYT11). However, the

onset of myoclonus dystonia is usually very early in

life with ‘‘lightening jerks’’ in contrast to neuroacan-

thocytosis where onset is in adulthood. In addition,

none of our patients had a beneficial response to

TABLE 1. Demographic and main clinical characteristics of Cases 1–4

Case 1 Case 2 Case 3 Case 4

Age at onset 32 37 22 33Age at last follow-up 40 47 32 36Age when video was taken 38 and 40 47 32 36Previously reported as No previous reports Dobson-Stone et al.,

2005 Cases 4–7Dobson-Stone et al.,

2005 Case 4–3Hardie et al., 1991,

Case 18;Dobson-Stone et al.,2002 Case 32

Family history Negative Positive Cousin of Case 2 n.k.Onset symptom Frontal lobe dysfunction

(32); chorea (34)Nervous breakdown

(34) and chorea (37)Clumsiness, dysarthria Speech impairment,

muscle spasms,gait difficulty

Predominant movement disorder Chorea Chorea, leg dystonia,action tremor, tic-likevocalizations

Dystonia, motorand vocal tics, neckand and gait problems

Tongue dystonia,tongue tremor,leg dystonia

Onset of axial flexion/extensor spasms

38 45 24 n.k. precisely

Description of axial flexion/extensor spasms

Head drops Trunk flexion forwardto 90 degrees

Head and trunk flexionand extension

Head drops

Onset of oromandibular features 38 n/a 23 33Cognitive function Relatively well

preservedRelatively well

preservedReduced judgement ability n.k.

Psychiatric features Depression Nervous breakdown Poor judgement n.k.Self-injurious behaviour Absent Absent Present AbsentEffective Treatment Btx for head drops None Btx for cheek biting;

Bilateral GPi DBS;n.k.

Numbers in brackets refer to the age when this symptom or sign was first noted.n.k., not known; n/a, not applicable; Btx, botulinum toxin injections; GPi DBS, globus pallidus internus deep brain stimulation surgery.

1489AXIAL JERKS IN CHOREA-ACANTHOCYTOSIS


alcohol which is a characteristic feature DYT11 dysto-

nia. Furthermore, inheritance in the latter is autosomal

dominant in contrast to chorea-acanthocytosis where

inheritance is recessive.

The differential diagnosis of sudden head move-

ments furthermore includes tic disorders. Although two

of our patients exhibited tic-like features like vocaliza-

tions (Cases 2 and 3) and motor tics (Case 3), Patients

1 and 4 had no tics and denied any inner urge to

move. Also, tics can usually be suppressed, but Cases

2 and 3 had no control over their axial movements.

Finally, there is phenotypic overlap with stereotypic

‘‘head banging’’ as seen in mentally disabled children11

for example those with Down syndrome, autism, or

following amphetamine poisoning.12

The classification of the movements we observed is

not straight forward. As discussed earlier, there are simi-

larities to myoclonus and tics; however, they could also

represent a choreic movement especially as the direction

included both flexion and extension. The movements

could also be dystonic, in view of the prominent opis-

thotonus with dystonic arching present in Case 3. Inter-

estingly and perhaps related, a pattern of trunk flexion

(‘‘feet-clasping posture’’) is a characteristic feature in the

R6/2 Huntington’s disease mouse model.13

Treatment responses ranged from very good to

unsatisfactory. In one Patient (#1), the head move-

ments could be alleviated by botulinum toxin injec-

tions. Patient 2 failed trials of multiple medications. In

Patient 3, bilateral GPi DBS markedly improved swal-

lowing, axial dropping, and extensor movements.

We encourage physicians to look for these clinical

signs, the spectrum of which ranges from mild to

severe, and if present to screen for acanthocytes.14 A

technically much simpler and more sensitive laboratory

parameter in chorea-acanthocytosis, however, is deter-

mination of CK which generally is elevated.15 Protein

assays4 or genetic testing1,2 can confirm the diagnosis.

Legends to the Video

Segment 1. Patient with chorea-acanthocytosis. The

first part of the clip, shows the patient aged 38. While

sitting there is generalized chorea with intermittent

head drops (resembling a sudden loss of tone). The

patient is also asked to shortly take the toothbrush out

of his mouth which he uses to protect his teeth from

clenching. After having done this, there is severe brux-

ism. The second part of the clip shows the patient at

age 40 when walking. His forward head drops have

become more severe. His gait is very unstable and

with intermittent loss of tone in the legs.

Segment 2. The patient (shown at age 47) with cho-

rea-acanthocytosis has generalized chorea. When sitting,

she demonstrates involuntary sudden forward flexions of

the trunk.

Segment 3. This patient with genetically proven

chorea-acanthocytosis (compound heterozygous:

EX70_EX73del and c.424211G>T VPS13A muta-

tions) was recorded prior to GPi DBS surgery at age

32. When walking there is involuntary loss of tone in

the legs and also sudden head drops. The postural sta-

bility is markedly impaired.

Segment 4. The patient aged 36 years with chorea-

acanthocytosis makes loud sucking and blowing noises.

Towards the end of the clip, there are intermittent

involuntary forward head drops.

Acknowledgments: This research was supported by anintramural research grant by the University of Lubeck, Ger-many (SAS). BB and AD are funded partially by the Advo-cacy for Neuroacanthocytosis Patients (London, UK). Weacknowledge The Advocacy for Neuroacanthocytosis Patientsat www.naadvocacy.org, and Ginger and Glenn Irvine forsupporting to offer the chorein protein test free of charge.

Financial Disclosures: SAS: Sources of support: NovartisFoundation for Therapeutic Medicine. University of Lubeck,Germany (Employment). AEL: Advisor: Biovail, Boerhinger-Ingelheim, Cephalon, Ceregene, Eisai, Medtronic, LundbeckA/S, NeuroMolecular, Novartis, Solvay, Taro, Teva; Grants:Canadian Institutes of Health Research, Dystonia MedicalResearch Foundation, Michael J. Fox Foundation, NationalParkinson Foundation, Ontario Problem Gambling ResearchCentre, Parkinson’s Disease Foundation, Taro; Speaker orother support: GSK, UCB. EM: Honoraria for lecturing fromMedtronic. BB: BB is supported by the Advocacy for Neuroa-canthocytosis Patients; by the Bayerische Forschungsallianz;and by the Bundesministerium fur Bildung und Forschung.AD: Grants from Bayerische Forschungsstiftung and Bayeri-sche Forschungsallianz, Munchner Universitatsgesellschaft,Deutsch-Franzosische Hochschulstiftung, and the Advocacy forNeuroacanthocytosis Patients. Honoraria as speaker fromMerz, Pfizer, and Neuro-Update. KB: Advisor/honoraria/finan-cial support to speak/attend meetings from GSK, Boehringer-Ingelheim, Ipsen, Merz, and Orion pharma companies. Grantsby the Dystonia Society UK and the Halley Stuart Trust.

Author Roles: Conception (KB), Organization (SAS,AEL, EM, KB), Execution (SAS, AEL), Chorein Westernblot (BB), Manuscript Writing of the first draft (SAS, AEL),and review and critique (KB, EM, BB, AD).

REFERENCES

1. Rampoldi L, Danek A, Monaco AP. Clinical features and molec-ular bases of neuroacanthocytosis J Mol Med 2002;80:475–491.

2. Ueno S, Maruki Y, Nakamura M, et al. The gene encoding anewly discovered protein, chorein, is mutated in chorea-acantho-cytosis Nat Genet 2001;28:121–122.

3. Schneider SA, Walker RH, Bhatia KP. The Huntington’s disease-like syndromes: what to consider in patients with a negative

1490 S.A. SCHNEIDER ET AL.


Huntington’s disease gene test Nat Clin Pract Neurol 2007;3:517–525.

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

5. Dobson-Stone C, Velayos-Baeza A, Jansen A, et al. Identificationof a VPS13A founder mutation in French Canadian families withchorea-acanthocytosis Neurogenetics 2005;6:151–158.

6. Al-Asmi A, Jansen AC, Badhwar A, et al. Familial temporallobe epilepsy as a presenting feature of choreoacanthocytosisEpilepsia 2005;46:1256–1263.

7. Hardie RJ, Pullon HW, Harding AE, et al. Neuroacanthocytosis.A clinical, haematological and pathological study of 19 casesBrain 1991;114:13–49.

8. Dobson-Stone C, Danek A, Rampoldi L, et al. Mutational spec-trum of the CHAC gene in patients with chorea-acanthocytosisEur J Hum Genet 2002;10:773–781.

9. Walker RH, Liu Q, Ichiba M, et al. Self-mutilation in chorea-acanthocytosis: manifestation of movement disorder or psychopa-thology? Mov Disord 2006;21:2268–2269.

10. Chew NK, Mir P, Edwards MJ, et al. The natural history ofUnverricht-Lundborg disease: a report of eight genetically provencases Mov Disord 2008;23:107–113.

11. Shoumitro DEB. Self-injurious behaviour as part of genetic syn-dromes BR J PSYCH 1998;172:385–388.

12. Espelin DE, Done AK. Amphetamine poisoning: effect-iveness of chlorpromazine N Engl J Med 1968;278:1361–1365.

13. Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the HDgene with an expanded CAG repeat is sufficient to cause a pro-gressive neurological phenotype in transgenic mice Cell 1996;87:493–506.

14. Storch A, Kornhass M, Schwarz J. Testing for acanthocytosis aprospective reader-blinded study in movement disorder patientsJ Neurol 2005;252:84–90.

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

Benign Hereditary Chorea:Clinical and NeuroimagingFeatures in an Italian Family

Elena Salvatore, MD, PhD,1 Luigi Di Maio, MD, PhD,1

Alessandro Filla, MD,1 Alfonso M. Ferrara, MD,2

Carlo Rinaldi, MD,1 Francesco Sacca, MD,1

Silvio Peluso, MD,1 Paolo E. Macchia, MD, PhD,2

Sabina Pappata, MD,3 and Giuseppe De Michele, MD1*

1Department of Neurological Sciences, Federico IIUniversity, Naples, Italy; 2Department of Endocrinology andMolecular and Clinical Oncology, Federico II University,Naples, Italy; 3Biostructure and Bioimaging Institute, CNR,

Naples, Italy

Video

Abstract: Benign hereditary chorea is an autosomal domi-nant disorder characterized by early onset nonprogressivechorea, caused by mutations of the thyroid transcriptionfactor-1 (TITF-1) gene. Clinical heterogeneity has beenreported and thyroid and respiratory abnormalities maybe present. We describe 3 patients of an Italian familycarrying the S145X mutation in the TITF-1 gene withmild motor delay, childhood onset dyskinesias, and subtlecognitive impairment. A child in the third generation pre-sented with congenital hypothyroidism and neonatal respi-ratory distress. Imaging studies in 2 patients showed mildventricular enlargement and empty sella at magnetic reso-nance imaging and hypometabolism of basal ganglia andcortex at 18-Fluoro-2-deoxy-glucose positron emissiontomography. � 2010 Movement Disorder Society

Key words: benign hereditary chorea; thyroid transcrip-tion factor-1; congenital hypothyroidism; MRI; FDG-PET

Benign hereditary chorea (BHC) is an autosomal

dominant disorder characterized by childhood onset

chorea with little or no progression into adult life.

Mental deterioration does not occur, but slightly lower

I.Q. scores have been reported. Mutations in the thy-roid transcription factor-1 (TITF-1) gene on chromo-

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

Elena Salvatore and Luigi Di Maio contributed equally to thestudy, and both should be considered as first authors.

*Correspondence to: Dr. Giuseppe De Michele, Dipartimento diScienze Neurologiche, Universita degli Studi di Napoli Federico II,Via Pansini 5, I-80131, Napoli, Italy. E-mail: [email protected]

Potential conflict of interest: Nothing to report.Received 23 September 2009; Revised 28 December 2009;

Accepted 28 January 2010Published online 11 June 2010 in Wiley InterScience (www.


1491BENIGN HEREDITARY CHOREA IN AN ITALIAN FAMILY


some 14q have been identified as causative in several

families, most of them recently reviewed.1,2 A second

locus (8q21) for BHC has been recently mapped in

two Japanese families with adult onset chorea.3

The TITF-1 gene is a homeodomain-containing tran-

scription factor essential for the organogenesis of lung,

thyroid, and basal ganglia.4 Thus, it is not surprising

that the clinical spectrum in families carrying TITF-1mutations includes thyroid and lung disorders, such as

congenital hypothyroidism and respiratory distress. The

putative mechanism of disease results from gene hap-

loinsufficiency and reduced protein product.

We previously described molecular and functional

data of the novel TITF-1 S145X mutation in an Italian

pedigree.5 Here, we report in detail the clinical features

and the neuroimaging data of the family.

CASE REPORTS

This three-generation family shows three affected

individuals, one for each generation, all carrying a pre-

viously unreported mutation of the TITF-1 gene. The

genetic defect and the molecular mechanisms have

been described in the previous article.5 The index

patient was Patient 1, who had been referred for exclu-

sion of Huntington’s disease (HD). The information

that her father (Pt. 2) had abnormal movements and

that her son (Pt. 3) had congenital hypothyroidism led

to the clinical suspicion of BHC and to the molecular

analysis of the TITF-1 gene.

Patient 1, 26 years old, began walking at the age of

18 months, but she was clumsy and fell repeatedly.

Her gait much improved around puberty. Mild general-

ized choreic movements appeared at the age of 7 years

and remained stable thereafter. No mental or behav-

ioral abnormalities were present, she did not encounter

difficulties at school, and she was graduated at a Hotel

school. During puerperium, when she was 19 years

old, her chorea worsened and she presented with a

postpartum psychosis, characterized by depression and

aggressiveness toward the newborn and successfully

treated with risperidone and lamotrigine.

At the age of 23 years she was admitted to our hos-

pital. Neurological examination showed generalized

choreic movements (video) and was otherwise normal.

Neuropsychological evaluation demonstrated long term

verbal memory deficit and low-normal score at Raven

Matrices test.

Molecular analysis of HD gene and laboratory test-

ing were normal, a part from elevation of thyroid-stim-

ulating hormone.5 Thyroid hormone replacement was

started. Brain magnetic resonance imaging (MRI)

revealed ventricular dilatation, more marked in the

posterior part of lateral ventricles (Fig. 1a–c) and par-

tial empty sella (Fig. 1d). Brain 18-Fluoro-2-Deoxy-

Glucose Positron Emission Tomography (FDG-PET)

showed slight relative hypometabolism of the caudate

nuclei and of the medial frontal and temporo-parietal

cortices (Fig. 2). The patient was treated with tetrabe-

nazine up to 75 mg daily, with mild improvement. At

the age of 26 years she withdrew the therapy abruptly

and presented marked worsening of chorea, irritability,

emotional lability, poor sleep, inappropriate dress, and

behavior. She was admitted to our hospital again,

treated with quetiapine, 75 mg/daily, and discharged

improved after a week.

Patient 2, the proband’s father, 56 years old, had

meningitis at the age of 6 months. Subsequent motor

development was delayed with walking starting at the

age of 5 years and normal language skills. His school

performances were poor. Since childhood, slight, spo-

radic, hyperkinesias were present, which mainly

involved the abdomen and had been stable over time.

He did not report improvement by alcohol. He worked

as a school-caretaker and had a normal social life. At

examination jerky abdominal movements were evident;

mild and rare choreic movements were present in other

body regions (video). Neuropsychological evaluation

showed short term verbal and spatial memory deficit,

slight attentional deficit, and constructive apraxia.

Thyroid hormone screening showed primary hypo-

thyroidism with increased TSH and mildly reduced

FT3. Brain MRI evidenced slight, asymmetrical ven-

tricular dilatation, more marked in the right side and in

the posterior part of lateral ventricles (Fig. 1e–g), and

complete empty sella (Fig. 1h). FDG-PET demon-

strated relative hypometabolism of basal ganglia, more

prominent in the caudate nuclei, and a slight relative

hypometabolism of the left temporo-parieto-occipital

cortex (Fig. 2). Tetrabenazine, up to 50 mg daily, was

prescribed, but the drug was withdrawn for insomnia

and nervousness.

Patient 3, the 5 years old proband’s son, born at term

by cesarean delivery because of transverse position,

received continuous positive airway pressure therapy

for neonatal respiratory distress. The infant presented

with multiple congenital anomalies: severe bilateral

vesicoureteral reflux with pyelectasis and megabladder,

patent foramen ovale, and congenital hypothyroidism

for which thyroid replacement treatment was started.

Psychomotor development was delayed: sitting at

10 months, walking at 26 months, first words at 26

months, at present only few words in vocabulary and

lack of sphincter control. His I.Q. was 76 at the age of


1492 E. SALVATORE ET AL.

4 years. He is a pleasant boy, has no behavioral prob-

lem and developed normal social relationships. At the

age of 4 years he developed slight, generalized choreic

movements (video).

Molecular analysis: Direct sequencing of the TITF-1gene showed, in all the 3 patients, the new heterozy-

gous mutation C609A in exon 2, resulting in a substi-

tution of serine at codon 145 for a stop codon

(S145X). The mutation predicted a truncated protein of

about 14.5 kDa that lacks the entire homeodomain and

the carboxy-terminus portion.5

DISCUSSION

BHC shows heterogeneity of the clinical presentation

within and among the families. In the present family

the neurologic presentation, characterized by mild

motor delay, early-onset dyskinesias, and slightly lower

intelligence, was quite similar in the 3 patients,

although the abnormal movements are somewhat differ-

ent among individuals. Although chorea is the move-

ment disorder characteristic of BHC, dystonia, myo-

clonic jerks, and ataxia have been also described.6 The

distinction among chorea, myoclonus, and jerky dysto-

nia may be difficult. The diagnosis of chorea, which is

characterized by a random flow of rapid, unpredictable

abnormal movements,7 better applies to Patients. 1 and

3, whereas the sudden, more predictable and repetitive

abdominal jerks in Patient 2 seem to be more consistent

with myoclonus. As described in other patients with

BHC,6 dyskinesias, contrary to myoclonus-dystonia,

were not worsened by action nor improved by alcohol.

Concerning extra-neurologic features subclinical

hypothyroidism was present in Patients 1 and 2, whereas

FIG. 1. Axial T2-weighted (Pt. 1 a–c; Pt. 2 e–g) and sagittal T1-weighted (Pt. 1 d; Pt. 2 h) MR images. Dilatation of supratentorial ventricularsystem is evident in both patients. Enlargement of the third ventricle is also evident in Patient 2. In both patients there is evidence of empty sella,partial in Patient 1, complete and prominent in Patient 2.



Patient 3 had congenital hypothyroidism and neonatal

respiratory distress. Anticipation and more severe phe-

notype in subsequent generations have been suggested,8

but not demonstrated in BHC. Environmental factors

and genetic background might also influence the clinical

expression. A review of the reported cases1,2,6,9–16

reveals 11 cases of congenital hypothyroidism due to

TITF-1 mutations in patients with de novo mutations or

with no information about parental phenotype or geno-

type, 11 (including the present one) with maternal inher-

itance of the allele carrying the mutation, and one with

paternal inheritance.16 However, there are also reports of

maternal inheritance without congenital hypothyroidism.

The predominance of maternal inheritance of congenital

hypothyroidism in BHC may be due to chance or may

be related to imprinting or maternal environment.

It remains unclear if some peculiar features of our

patients, as postpartum psychosis in Patient 1 and urinary

tract malformations in Patient 3, are related to the muta-

tion. Psychosis occurred in two previously reported

patients16,17 and hypospadia has been described before

recognition of the molecular defect.18,19 We are not

aware of a role of TITF-1 in urinary tracts organogenesis,

although the gene is expressed in small cell carcinoma of

the urinary bladder.20 We suggest special attention to uri-

nary tract malformations in patients with BHC.

Imaging data also appear to be heterogeneous in

BHC. CT/MRI findings are usually normal, but ventric-

ular dilatation and other abnormalities have been also

reported.10,21,22 A cystic mass in the posterior part of

the sella turcica has been described in two cases.22 In

the 2 patients investigated by us, MRI showed ventric-

ular dilatation, more evident at trigone and occipital

horn level, whereas in HD ventricular enlargement

mostly affects the frontal horns.23 Empty sella was

present in both patients, more marked in Patient 2,

which has the longest disease duration. Haploinsuffi-

ciency of the TITF-1 gene could lead to congenital

deficiency of the sellar diaphragm, which is a frequent

cause of an enlarged sella. FDG-PET scan was

reported to be normal in 4 patients with BHC,9

although a study performed when the molecular diag-

FIG. 2. Axial images of brain 18F-deoxy-glucose uptake obtained with PET in a 39 years control, in Patient 1 and in Patient 2. The images werespatially normalized into the Montreal Neurological Institute (MNI) space and normalized to globals. The scale shows values of highest uptake inred and lowest uptake in blue. In Patient 1 a mild reduction of tracer uptake is present in the caudate nuclei and in the medial frontal and tem-poro-parietal cortex, bilaterally. The basal ganglia hypometabolism is more marked in Patient 2, involving more the caudate than the putamenregions. In Patient 2 there is also a mild temporo-parietal metabolism reduction on the left side. L left, R right.

1494 E. SALVATORE ET AL.


nosis was not available showed caudate hypometabo-

lism.24 More recently reduction of technetium 99 m

ethyl cysteinate dimer uptake has been demonstrated in

the basal ganglia of two children studied by SPECT.25

Using FDG-PET we showed cortex and basal ganglia

hypometabolism in both Patient 1 and Patient 2. These

findings are consistent with the significant reduction of

striatal and neocortical interneurons demonstrated by

immunohistochemical staining in BHC26 and with the

patients’ choreic syndrome and mild cognitive impair-

ment. The pattern of metabolic changes is similar, but

less severe than that found in HD,23 consistently with

the milder, non progressive BHC phenotype.

Legends to the Videos

Segment 1. Patient 1 examination shows general-

ized, moderate to marked, choreic movements involv-

ing the face, the neck, the trunk, the limbs, both proxi-

mally and distally. Finger-to-nose and walking do not

worsen the abnormal movements. Mild unsteadiness is

also evident.

Segment 2. Slightly staggering gait and mild limb

choreic movements, not worsened by action, in Patient

2. Brisk abdominal wall contractions are evident.

Segment 3. In Patient 3 mild choreic movements

involved the trunk and the four limbs, both proximally

and distally, not worsened by action. Brisk myoclonic-

like movements are also evident. Tottering was prob-

ably too marked for his age.

Acknowledgments: Financial Disclosures: Elena Salva-tore, Luigi Di Maio, Alfonso M. Ferrara, Carlo Rinaldi, Fran-cesco Sacca, Silvio Peluso, Paolo E. Macchia, and SabinaPappata: report no disclosures. Alessandro Filla: funded byresearch grants and serves as study coordinator of a projectfunded by the EUROSCA association. Giuseppe De Michele:receives research support from the EURO-HD Network.

Author Roles: Salvatore E.—Organization and executionof research project, writing of the first draft of the manu-script. Di Maio L.—Organization and execution of researchproject, writing of the first draft of the manuscript. Filla A.—Review and critique of manuscript. Ferrara AM.—Executionof research project. Rinaldi C.—Execution of research projectand writing of the first draft of the manuscript. Sacca F.—Execution of research project. Peluso S.—Execution ofresearch project. Macchia PE.—Organization of research pro-ject. Pappata S.—Execution of research project and reviewand critique of manuscript. De Michele G.—Conception ofresearch project and review and critique of manuscript.

REFERENCES

1. Kleiner-Fisman G, Lang AE. Benign hereditary chorea revisited:a journey to understanding. Mov Disord 2007;22:2297–2305.

2. Carre A, Szinnai G, Castanet M, et al. Five new TTF1/NKX2.1mutations in brain-lung-thyroid syndrome: rescue by PAX8 syn-ergism in one case. Hum Mol Genet 2009;18:2266–2276.

3. Shimohata T, Hara K, Sanpei K, et al. Novel locus for benignhereditary chorea with adult onset maps to chromosome 8q21.3q23.3. Brain 2007;130:2302–2309.

4. Breedveld GJ, van Dongen JW, Danesino C, et al. Mutations inTITF-1 are associated with benign hereditary chorea. Hum MolGenet 2002;11:971–979.

5. Ferrara AM, De Michele G, Salvatore E, et al. A novel NKX2.1mutation in a family with hypothyroidism and benign hereditarychorea. Thyroid 2008;18:1005–1009.

6. Asmus F, Devlin A, Munz M, Zimprich A, Gasser T, ChinneryPF. Clinical differentiation of genetically proven benign heredi-tary chorea and myoclonus-dystonia. Mov Disord 2007;22:2104–2119.

7. Schrag A, Quinn NP, Bhatia KP, Marsden CD. Benign hereditarychorea–entity or syndrome? Mov Disord 2000;15:280–288.

8. Breedveld GJ, Percy AK, MacDonald ME, et al. Clinical andgenetic heterogeneity in benign hereditary chorea. Neurology2002;59:579–584.

9. Kleiner-Fisman G, Rogaeva E, Halliday W, et al. Benign heredi-tary chorea: clinical, genetic, and pathological findings. AnnNeurol 2003;54:244–247.

10. do Carmo Costa M, Costa C, Silva AP, et al. Nonsense mutationin TITF1 in a Portuguese family with benign hereditary chorea.Neurogenetics 2005;6:209–215.

11. Asmus F, Horber V, Pohlenz J, et al. A novel TITF-1 mutationcauses benign hereditary chorea with response to levodopa. Neu-rology 2005;64:1952–1954.

12. Devos D, Vuillaume I, de Becdelievre A, et al. New syndromicform of benign hereditary chorea is associated with a deletion ofTITF-1 and PAX-9 contiguous genes. Mov Disord 2006;21:2237–2240.

13. Moya CM, Perez de Nanclares G, Castano L, et al. Functionalstudy of a novel single deletion in the TITF1/NKX2.1 homeoboxgene that produces congenital hypothyroidism and benign choreabut not pulmonary distress. J Clin Endocrinol Metab 2006;91:1832–1841.

14. Provenzano C, Veneziano L, Appleton R, Frontali M, CivitarealeD. Functional characterization of a novel mutation in TITF-1 ina patient with benign hereditary chorea. J Neurol Sci 2008;264:56–62.

15. Maquet E, Costagliola S, Parma J, et al. Lethal respiratory failureand mild primary hypothyroidism in a term girl with a de novoheterozygous mutation in the TITF1/NKX2.1 gene. J Clin Endo-crinol Metab 2009;94:197–203.

16. Glik A, Vuillaume I, Devos D, Inzelberg R. Psychosis, short stat-ure in benign hereditary chorea: a novel thyroid transcription fac-tor-1 mutation. Mov Disord 2008;23:1744–1747.

17. de Vries BB, Arts WF, Breedveld GJ, Hoogeboom JJ, NiermeijerMF, Heutink P. Benign hereditary chorea of early onset maps tochromosome 14q. Am J Hum Genet 2000;66:136–142.

18. Chun RW, Daly RF, Mansheim BJ, Jr, Wolcott GJ. Benign fami-lial chorea with onset in childhood. JAMA 1973;225:1603–1607.

19. Burns J, Neuhauser G, Tomasi L. Benign hereditary non-progres-sive chorea of early onset. Clinical genetics of the syndrome andreport of a new family. Neuropadiatrie 1976;7:431–438.

20. Jones TD, Kernek KM, Yang XJ, et al. Thyroid transcription fac-tor 1 expression in small cell carcinoma of the urinary bladder:an immunohistochemical profile of 44 cases. Hum Pathol 2005;36:718–723.

21. Iwatani N, Mabe H, Devriendt K, Kodama M, Miike T. Deletionof NKX2.1 gene encoding thyroid transcription factor-1 in twosiblings with hypothyroidism and respiratory failure. J Pediatr2000;137:272–276.

22. Krude H, Schutz B, Biebermann H, et al. Choreoathetosis, hypo-thyroidism, and pulmonary alterations due to human NKX2–1haploinsufficiency. J Clin Invest 2002;109:475–480.



23. Montoya A, Price BH, Menear M, Lepage M. Brain imaging andcognitive dysfunctions in Huntington’s disease. J Psychiatry Neu-rosci 2006;31:21–29.

24. Suchowersky O, Hayden MR, Martin WR, Stoessl AJ, Hilde-brand AM, Pate BD. Cerebral metabolism of glucose in benignhereditary chorea. Mov Disord 1986;1:33–44.

25. Mahajnah M, Inbar D, Steinmetz A, Heutink P, Breedveld GJ,Straussberg R. Benign hereditary chorea: clinical, neuroimaging,and genetic findings. J Child Neurol 2007;22:1231–1234.

26. Kleiner-Fisman G, Calingasan NY, Putt M, Chen J, Beal MF,Lang AE. Alterations of striatal neurons in benign hereditarychorea. Mov Disord 2005;20:1353–1357.

Long-Term Effect of UnilateralPallidotomy on Levodopa-Induced

Dyskinesia

Galit Kleiner-Fisman, MD, FRCPC,1,2*Andres Lozano, MD, PhD, FRCPS,3

Elena Moro, MD, PhD,1 Yu-Yan Poon, RN,1

and Anthony E. Lang, MD, FRCPC1

1Morton and Gloria Shulman Movement Disorders Center,Toronto Western Hospital, University of Toronto,

Toronto, Ontario, Canada; 2Baycrest Geriatric Hospital,University of Toronto, Toronto, Ontario,

Canada; 3Department of Neurosurgery, TorontoWestern Hospital, University of Toronto, Toronto,

Ontario, Canada

Abstract: Unilateral pallidotomy has been effectively usedto treat parkinsonism and reduce levodopa induced dyski-nesia (LID). We sought to determine the long-term effectsof pallidotomy on LID in 10 patients who had initialbenefit from pallidotomy but went on to require DBS sur-gery for symptom progression. The Dyskinesia RatingScale (DRS) was used to rate and quantify LID in ablinded fashion. Though sample size was small, there wasa trend towards a reduction in LID lasting up to 12 yearssuggesting that posteroventral pallidotomy may providesustained benefit in reducing LID. � 2010 MovementDisorder Society

Key words: Parkinson’s disease; pallidotomy; dyskinesia

In the era before DBS, as well as currently, in many

countries around the world, unilateral postero-ventral

pallidotomy as a treatment for Parkinson’s disease

(PD) has been the surgical alternative of choice. Pallid-

otomy ameliorates parkinsonism and is particularly

effective in reducing levodopa-induced dyskinesia

(LID) most prominently in the contralateral hemibody.1

Despite initial control of disabling symptoms, parkin-

sonism generally worsens several years following pal-

lidotomy and many patients have subsequently under-

gone STN DBS when their symptoms again became re-

sistant to medical regimens.2–4

No long-term follow-up studies have blindly eval-

uated the persistent effects of unilateral pallidotomy on

LID. It has been our personal experience that the anti-

dyskinetic effects may be evident many years after the

original surgery and Hariz reported that these effects

could last up to 13.5 years.5

We sought to determine the long-term effect of pal-

lidotomy on dyskinesia in a selected sample of patients

who had previously undergone pallidotomy and were

undergoing preoperative evaluation for STN DBS due

to symptom progression. Given the extensive preopera-

tive assessment for DBS, ON/OFF evaluations were

available for review in these patients. We evaluated ef-

ficacy of pallidotomy on dyskinesia by comparing con-

tralateral and ipsilateral dyskinesia at the STN-DBS

preoperative evaluation. We postulated that there

would be a difference between sides due to lasting

effects of pallidal lesioning with less severe dyskinesia

contralateral to the previous surgery.

PATIENTS AND METHODS

Patient Population

Ten patients (8 male) with PD and prior pallidotomy

on average 7.3 years (range 2–12 years) earlier were

evaluated for consideration of STN DBS. All patients

were felt to have obtained an initial good response to

pallidotomy with respect to parkinsonism and particu-

larly LID. Not all patients had received pallidotomy at

our center; pre and postoperative LID scores were

available in 6 of the 10. Before DBS patients were

evaluated under the protocol of the Core Assessment

Program for Intracerebral Transplantation6 (CAPSIT)

before STN DBS surgery. Dyskinesia was assessed

using the Dyskinesia Rating Scale (DRS) (maximum

score for unilateral limbs 5 8). The dosage of anti-par-

kinsonian medication required by the patient was

recorded; levodopa equivalent doses (LED) were calcu-

lated in a manner described elsewhere.7 Evaluations

*Correspondence to: Dr. Galit Kleiner-Fisman, Morton and GloriaShulman Movement Disorders Center, Toronto Western Hospital,University of Toronto, 399 Bathurst Street, McL-7, Toronto, Ontario,M5T 2S8 Canada. E-mail: [email protected]

Potential conflict of interest: None reported.Received 4 March 2009; Revised 27 May 2009; Accepted 8

October 2009Published online 21 June 2010 in Wiley InterScience (www.


1496 G. KLEINER-FISMAN ET AL.


were made while the anti-parkinsonian medication was

in effect (medication-on period) and following overnight

withdrawal from medication (medication-off period).

These assessments were video-taped and a blinded-rater

(blinded to patient, side of previous pallidotomy, and

medication state) quantified and identified the type of

dyskinesia utilizing the DRS.

Statistical Analysis

Effectiveness of initial pallidotomy on dyskinesia

was assessed comparing pre and postoperative DRS

scores using the Wilcoxon sign-rank test. Pairwise

comparisons were made between the limbs ipsilateral

and contralateral to prior pallidotomy for ‘‘ON’’ dyski-

nesia and ‘‘OFF’’ dystonia using a paired t-test.

RESULTS

All patients had undergone pallidotomy contralateral

to their most severely affected side (parkinsonism and

LID). The available data demonstrated that at 12

months following pallidotomy patients had a significant

reduction in dyskinesia: ipsilateral dyskinesia (mean

reduction 1.25 points; minimum change 0 points, maxi-

mum change 2.5 points, P 5 0.04), contralateral dyski-

nesia (mean reduction 2 points; minimum change 1

point, maximum change 3.5 points, P 5 0.03), and

axial dyskinesia (mean reduction 1.75 points; minimum

change 0 points, maximum change 2 points P 5 0.05).

Mean age at pallidotomy was 51.5 6 5.9 with disease

duration before pallidotomy of 9.5 6 2 years. Mean

LED at the time of pallidotomy was 754.3 6 450 mg

and at time of STN DBS was 1287.8 6 419.2 mg.

The results of blinded assessment of dyskinesia

before STN DBS are displayed in Table 1. There was

a small difference in LID between sides with a trend

toward less LID in the contralateral versus the ipsilat-

eral limbs (P 5 0.09). In 5 of 8 patients, who demon-

strated on-period LID, these were more severe (mark-

edly in 3) on the side ipsilateral to the previous pal-

lidotomy. There was no difference in OFF dystonia

found between limbs.

DISCUSSION

Pallidotomy has a prolonged effect on contralateral

dyskinesia with previous studies having reported bene-

fit lasting up to 13.5 years even when akinesia and

other PD symptoms had returned.5 Other studies have

also reported sustained benefit from unilateral pallidot-

omy on contralateral dyskinesia.1,8,9 None of these

studies evaluated LID in a blinded fashion. In this

study, only patients who were undergoing subsequent

DBS were included due to availability of data, and

therefore, this may be a biased cohort of patients with

suboptimal outcomes given the need for further inter-

vention. There are other patients who underwent pallid-

otomy at our Center who have had sustained long-term

improvement of LID (as evidenced by on-period clini-

cal assessments demonstrating minimal or no dyskine-

sia contralateral to their previous surgery); however,

video-taped CAPSIT evaluations of these patients

were not available for blinded review. Our evaluated

patients were all felt to have had an initial good

effect on LID from pallidotomy; however, progression

of parkinsonian symptoms necessitated consideration

of DBS.

Although sample size in our case series was too

small to achieve statistical significance, there was a

trend toward significance lasting up to 12 years fol-

lowing the original surgery, consistent with previous

reports of sustained benefit. This finding again sug-

gests that postero-ventral pallidotomy remains a rea-

sonable alternative therapy for disabling LID, espe-

cially in patients for whom DBS surgery is not a ther-

apeutic option.

Financial Disclosures: GKF: honoraria from Santhera,Teva Pharmaceuticals. AL: consultant for Medtronic, ElyLilly, Cergene, and St. Jude. YYP: Nothing to disclose. EM:consultant to and honoraria from Medtronic. AEL: advisor,Allon Therapeutics, Biovail, Boehringer-Ingelheim, Cepha-lon, Ceregene, Eisai, Medtronic, Lundbeck A/S, Neuromolec-ular, Novartis, Merck Serono, Solvay, Taro, Teva; grantsfrom Canadian Institutes of Health Research, Dystonia Medi-cal Research Foundation, Michael J. Fox Foundation,

TABLE 1. Dyskinesia characteristics

Yrs sincepallidotomy

DRSipsilateral(ON)

DRScontralateral

(ON)

OFFdystonia

(ipsilateral)

OFFdystonia

(contralateral)

1. 12 4 0 2 02. 5 4 2 0 03. 4 4 5 0 14. 10 4 5 0 05. 9 0 1 2 06. 2 0 0 0 17. 9 2 0 0 08. 7 6 1 0 09. 7 0 0 0 010. 8 7 0 0 0Mean 7.3 3.1 1.4

DRS, dyskinesia rating scale.


1497LONG-TERM EFFECT OF UNILATERAL PALLIDOTOMY ON LID

National Parkinson Foundation, Ontario Problem GamblingResearch Centre, Parkinson’s Disease Foundation, Taro;speaker fees or other support from GSK, UCB.

REFERENCES

1. Fine J, Duff J, Chen R, et al. Long-term follow-up of unilateralpallidotomy in advanced Parkinson’s disease. N Engl J Med2000;342:1708–1714.

2. Kleiner-Fisman G, Fisman DN, Zamir O, et al. Subthalamic nu-cleus deep brain stimulation for Parkinson’s disease after success-ful pallidotomy: clinical and electrophysiological observations.Mov Disord 2004;19:1209–1214.

3. Ondo WG, Silay Y, Almaguer M, Jankovic J. Subthalamic deepbrain stimulation in patients with a previous pallidotomy. MovDisord 2006;21:1252–1254.

4. Mogilner AY, Sterio D, Rezai AR, Zonenshayn M, Kelly PJ,Beric A. Subthalamic nucleus stimulation in patients with a priorpallidotomy. J Neurosurg 2002;96:660–665.

5. Hariz MI, Bergenheim AT. A 10-year follow-up review ofpatients who underwent Leksell’s posteroventral pallidotomy forParkinson disease. J Neurosurg 2001;94:552–558.

6. Langston JW, Widner H, Goetz CG, et al. Core assessment pro-gram for intracerebral transplantations (CAPIT). Mov Disord 1992;7:2–13.

7. Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J, FlemingJ. Excessive daytime sleepiness and sudden-onset sleep in Parkin-son disease: a survey by the Canadian Movement DisordersGroup. JAMA 2002;287:455–463.

8. Strutt AM, Lai EC, Jankovic J, et al. Five-year follow-up of uni-lateral posteroventral pallidotomy in Parkinson’s disease. SurgNeurol 2008.

9. Vitek JL, Bakay RA, Freeman A, et al. Randomized trial of pal-lidotomy versus medical therapy for Parkinson’s disease. AnnNeurol 2003;53:558–569.

Increased Reaction Time PredictsVisual Learning Deficits in

Parkinson’s Disease

Lucio Marinelli, MD, PhD,1* Bernardo Perfetti, PhD,2

Clara Moisello, PhD,2 Alessandro Di Rocco, MD,3

David Eidelberg, MD,4 Giovanni Abbruzzese, MD,1

and Maria Felice Ghilardi, MD2*1Department of Neurosciences, Ophthalmology and Genetics,University of Genova, Italy; 2Department of Physiology andPharmacology, CUNY Medical School, New York, New York,USA; 3Department of Neurology, NYU, New York, New York,USA; 4Center for Neurosciences, The Feinstein Institute forMedical Research, North Shore-Long Island Jewish Health

System, Manhasset, New York, USA

Abstract: To determine whether the process involved inmovement preparation of patients in the early stages of Par-kinson’s disease (PD) shares attentional resources with vis-ual learning, we tested 23 patients with PD and 13 healthycontrols with two different tasks. The first was a motor taskwhere subjects were required to move as soon as possible torandomly presented targets by minimizing reaction time.The second was a visual learning task where targets werepresented in a preset order and subjects were asked to learnthe sequence order by attending to the display without mov-ing. Patients with PD showed higher reaction and movementtimes, while visual learning was reduced compared with con-trols. For patients with PD, reaction times, but not move-ment times, displayed an inverse significant correlation withthe scores of visual learning. We conclude that visual declar-ative learning and movement preparation might share simi-lar attentional and working memory resources. � 2010Movement Disorder Society

Key words: Parkinson’s disease; executive function;attention; motor control

Motor slowness in Parkinson’s disease (PD) is a gen-

eral term that encompasses: akinesia, a poverty of move-

ment production and delay in movement initiation; bra-

dykinesia, a reduction in movement speed; and hypoki-

nesia, a reduction in movement size.1 In experimental

motor tasks, akinesia is reflected by increased reaction

times, a finding often reported in patients with PD.1

*Correspondence to: L. Marinelli, Department of Neurosciences,Ophthalmology and Genetics, via De Toni 5, University of Genova,16132 Genova, Italy. E-mail: [email protected] or M.F. Ghilardi,Department of Pharmacology and Physiology, Harris Hall 202, 138thstreet and Convent Avenue, City University of New York MedicalSchool, New York, New York 10031. E-mail: [email protected]

Potential conflict of interest: Nothing to report.Received 11 August 2009; Revised 19 January 2010; Accepted 16

March 2010Published online 21 June 2010 in Wiley InterScience (www.


1498 L. MARINELLI ET AL.


During the few hundred milliseconds between stimu-

lus presentation and movement onset, many processes

take place, including attentional and stimulus processing,

decision making, and movement programming. Some of

these processes and resources are also engaged during

visuospatial learning that occurs without movement.2 In

fact, activation of frontoparietal areas, the likely neural

substrate of these processes, occurs during many tasks,

independent of the modality and of the learning load.3,4

It is now well known that PD impairs not only

motor functions but also attentional and learning proc-

esses.5 However, the connection between the two defi-

cits has not been explored.

Here, we hypothesize that if movement preparation

shares neural resources with visual spatial learning, in

patients with PD, abnormalities in reaction time and

impairment of sequence learning that requires no

movement should be correlated.


Twenty-three patients with idiopathic PD (17 men

and 6 women; mean age 6 SE: 60.0 6 6.8 years)

in early stages of the disease (Hoehn and Yahr stages

I–II) and 13 age-matched healthy controls (6 men and

7 women; 56.5 6 2.7 years) participated in the study.

All subjects were right-handed, underwent a clinical

interview to determine that he or she did not meet the

DSM-III-R criteria for depression or dementia, scored

more than 27 at Mini-Mental State Examination, and

had a normal brain MRI.

Mean UPDRS score (part 3) of patients with PD was

8.8 (1.8, SE). The most involved side was the right in 10

patients and the left in the remaining 13 patients.

At the time of testing, all patients were in stable con-

ditions. Thirteen patients were drug-naive; 4 had been

treated with deprenyl alone, 4 with levodopa (L-dopa)/

carbidopa, and 2 with a combination of dopamine ago-

nists and L-dopa/carbidopa. However, all patients were

drug-free for at least 12 hours before testing. Written

informed consent was obtained from all participants

under a protocol approved by the institutional review

board of the participating institutions.

Detailed features of the tasks have been previously

reported.6,7 Briefly, in both tasks, one of eight targets

appeared on a screen with a common starting point, in

synchrony with a tone at 1-second intervals. Each trial

block lasted for 90 seconds.

The two tasks, which were presented in a random-

ized order, were:

1. Motor task: targets were presented in a pseudorandom

and unpredictable order. Movements were performed

on a digitizing tablet with the right dominant hand.

Instructions were to reach each target as soon as possi-

ble, minimizing reaction time but avoiding target

anticipation. Target distance was 1.8 cm.

2. Visual learning task: subjects were instructed to learn the

order of a repeating sequence of eight targets that was

presented in the 90-second block. At the end of the block,

verbal reports about the sequence order were collected.6,7

For each movement we computed: reaction time,

movement duration, peak velocity, hand-path length,

and spatial error.6,7

At the end of the visual block, declarative scored

were computed from 0 (unawareness of a sequence) to

8 (complete correct sequence).6,7

Factorial analysis of variance was performed to

compare patients with PD and healthy controls’ values.

Linear regression analyses were also performed to

determine correlations between kinematic and other

variables. Level of significance was P < 0.05.

RESULTS

There was no difference between the performance indi-

ces of treated and drug-naıve patients and between right

and left hemiparkinsonian patients. Therefore, patients’

data were combined and compared with those of controls.

Data are summarized in Figure 1. On average, reac-

tion times were prolonged in patients with PD when

FIG. 1. Kinematic and learning indices. Mean 6 SE of kinematicand learning indices (* see text for statistics).

1499REACTION TIME PREDICTS VISUAL LEARNING IN PD


compared with controls [F(1,34)5 5.6, P 5 0.02]. Simi-

larly, in patients with PD, movement durations were sig-

nificantly longer [F(1,34) 5 8.0, P 5 0.008] and peak of

velocity reduced [F(1,34) 5 6.9, P 5 0.01]. Spatial ac-

curacy, expressed by spatial error, was similar in the two

groups [F(1,34) 5 1.9, P 5 0.2]; however, hand-path

lengths were reduced in patients with PD when com-

pared with controls [F(1,34) 5 9.0, P 5 0.005].

The declarative scores reflecting visual learning

were significantly lower in patients compared with

controls [F(1,34) 5 13.2, P 5 0.0009], indicating

impairment in visuospatial learning.

We then ascertained whether declarative scores in

the visual task were associated to kinematic measure-

ments. In patients with PD, declarative scores were

negatively correlated with reaction times: the higher

the reaction time, the lower the declarative score (r 520.66, P 5 0.0006). No significant correlations were

found between declarative scores versus movement

times (r 5 20.23, P 5 0.3), peak velocity (r 5 0.05,

P 5 0.8), or hand-path length (r 5 20.20, P 5 0.4).

In addition, there were no correlations between

UPDRS (part 3) scores and either reaction times (r 50.06, P 5 0.8), movement times (r 5 0.12, P 5 0.7),

hand-path length (r50.21, P 5 0.5), or declarative

scores (r 5 20.13, P 5 0.7). In patients with

PD, there was no significant correlation between reac-

tion times and movement duration or peak velocity

(r 5 0.29, P 5 0.2). As expected, movement time and

peak velocity values were instead highly correlated

(r 5 20.87, P < 0.0001).

Finally, in healthy controls we did not find any cor-

relation between learning scores with either reaction

time (r 5 0.39, P 5 0.2) or movement time (r 50.004, P 5 1.0).

DISCUSSION

This study shows that, in agreement with previous

work, in patients with early stage PD increased reac-

tion times and impaired visual sequence learning are

significantly correlated: patients with higher reaction

times are also more impaired in sequence learning,

suggesting that movement preparation shares resources

with learning of visuospatial sequences.

Increased reaction time in patients with PD is con-

sidered the experimental hallmark of akinesia.1 Our

motor task also captured other characteristic features of

PD: hypokinesia, with reduced hand-path length and

bradikinesia,1 with significant increases in movement

time and reductions of peak velocity. Interestingly, the

clinical motor UPDRS scores did not correlate with

any of the kinematic measures. This lack of correspon-

dence is likely due to the fact that motor UPDRS

scores reflect global motor impairment, as this scale

embraces multiple motor aspects. Interestingly, in our

PD population, reaction and movement time did not

correlate, adding evidence that their respective neural

mechanisms may not overlap.

As previously shown,5,6 our patients with PD display

abnormal visual sequence learning, a learning that is

declarative and explicit in nature, requires no motor

involvement but loads working memory and attention

buffers, possibly like movement preparation. Patients

with PD also show alteration in visuospatial and cen-

tral executive abilities.8 It has been suggested that all

these deficits stem from malfunction of the frontoparie-

tal network.9 In fact, this network is engaged in many

and various facets of cognitive control, as it might be

responsible for the active representation of attended

and goal-relevant stimuli, and thus for promoting

adequate domain-dependent information processing.2 In

fact, even the simple shift between attended stimuli

leads to an update of this network.10

The exclusive correlation of declarative scores with

reaction times, but not with other kinematic parame-

ters, suggests that, first, the neural resources for move-

ment preparation and those for visuospatial learning

partly overlap and, second, PD significantly hampers

such resources. Moreover, these data suggest that

motor and cognitive functions are not completely inde-

pendent processes but share similar resources, implying

that some motor and nonmotor parkinsonian signs

might have common neural bases. Such results are im-

portant in designing novel rehabilitative approaches to

improve specific aspects of motor performance and the

quality of life of patients.

Acknowledgments: This study was supported by NationalParkinson Foundation, McDonnell Foundation (MFG), andNIH grant R01NS054864 (MFG).

Financial Disclosures: Giovanni Abbruzzese: AdvisoryBoard: Novartis and Lundbeck; Honoraria: Boehringer.

Author Roles: L. Marinelli: research project organizationand execution, writing the first draft of the manuscript. B.Perfetti: statistical analysis design and execution, manuscriptcritique. C. Moisello: statistical analysis design and execu-tion, manuscript critique. A. Di Rocco: statistical analysisreview and critique, manuscript review and critique. D.Eidelberg: research project conception, statistical analysisreview and critique, manuscript review and critique. G.Abbruzzese: statistical analysis review and critique, manu-script review and critique. M.F. Ghilardi: research projectconception, statistical analysis review and critique, manu-script review and critique.


1500 L. MARINELLI ET AL.

REFERENCES

1. Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysi-ology of bradykinesia in Parkinson’s disease. Brain 2001;124:2131–2146.

2. Miller EK, Cohen JD. An integrative theory of prefrontal cortexfunction. Ann Rev Neurosci 2001;24:167–202.

3. Funahashi S. Prefrontal cortex and working memory processes.Neuroscience 2006;139:251–261.

4. Rounis E, Stephan KE, Lee L, et al. Acute changes in frontopari-etal activity after repetitive transcranial magnetic stimulation overthe dorsolateral prefrontal cortex in a cued reaction time task. JNeurosci 2006;26:9629–9638.

5. Doyon J. Motor sequence learning and movement disorders. CurrOpin Neurol 2008;21:478–483.

6. Ghilardi M, Eidelberg D, Silvestri G, Ghez C. The differentialeffect of PD and normal aging on early explicit sequence learn-ing. Neurology 2003;60:1313–1319.

7. Ghilardi MF, Silvestri G, Feigin A, et al. Implicit and explicitaspects of sequence learning in pre-symptomatic Huntington’sdisease. Parkinsonism Relat Disord 2008;14:457–464.

8. Kemps E, Szmalec A, Vandierendonck A, Crevits L. Visuo-spa-tial processing in Parkinson’s disease: evidence for diminishedvisuo-spatial sketch pad and central executive resources. Parkin-sonism Relat Disord 2005;11:181–186.

9. Nakamura T, Ghilardi MF, Mentis M, et al. Functional networksin motor sequence learning: abnormal topographies in Parkin-son’s disease. Hum Brain Mapp 2001;12:42–60.

10. Hon N, Epstein RA, Owen AM, Duncan J. Frontoparietal activitywith minimal decision and control. J Neurosci 2006;26:9805–9809.

Psychogenic Paralysis andRecovery After Motor Cortex

Transcranial Magnetic Stimulation

Nathalie Chastan, MD, PhD*and Dominique Parain, MD, PhD

Department of Neurophysiology, Rouen University Hospital,Rouen, France

Abstract: Psychogenic paralysis presents a real treatmentchallenge. Despite psychotherapy, physiotherapy, antide-pressants, acupuncture, or hypnosis, the outcome is notalways satisfactory with persistent symptoms after long-term follow-up. We conducted a retrospective study toassess clinical features and to propose an alternativetreatment based on repetitive transcranial magneticstimulation (rTMS). Seventy patients (44 F/26 M, meanage: 24.7 6 16.6 years) experienced paraparesis (57%),monoparesis (37%), tetraparesis (3%), or hemiparesis(3%). A precipitating event was observed in 42 patients,primarily as a psychosocial event or a physical injury.An average of 30 stimuli over the motor cortex contra-lateral to the corresponding paralysis was delivered atlow frequency with a circular coil. The rTMS waseffective in 89% of cases, with a significantly betteroutcome for acute rather than chronic symptoms. Inconclusion, motor cortex rTMS seem to be very effec-tive in patients with psychogenic paralysis and could beconsidered a useful therapeutic option. � 2010 Move-ment Disorder Society

Key words: conversion disorder; motor paralysis; trans-cranial magnetic stimulation; motor cortex

Psychogenic disorders imply that the patient has no

voluntary control over the production of symptoms,

with no known organic syndrome to explain the symp-

toms. Psychogenic disorders are frequently related to

the motor system,1 as psychogenic paralysis,2–6 and

present a real treatment challenge.

The initial aim of this study was to evaluate clinical

features of patients with psychogenic paralysis. We

performed a retrospective study of 70 adults and chil-

dren. The second aim was to assess a promising new

*Correspondence to: Dr. Nathalie Chastan, CHU de Rouen—Hopi-tal Charles Nicolle, Service de Neurophysiologie, 1 rue de Germont,76031 Rouen Cedex, France. E-mail: [email protected]

Potential conflict of interest: The authors confirm that there was noconflict of interest. The authors have no financial disclosures or addi-tional information to disclose.

Received 11 November 2009; Revised 28 January 2010; Accepted23 March 2010

Published online 21 June 2010 in Wiley InterScience (www.


1501PSYCHOGENIC PARALYSIS AND RTMS


treatment based on repetitive transcranial magnetic

stimulation (rTMS), which is known to modulate corti-

cal excitability, for patients with psychogenic paralysis

characterized by a decreased activation of the primary

motor cortex.7 Motor-evoked potentials have been sug-

gested to be useful in the diagnosis of psychogenic pa-

ralysis, as they are normal.8–10 As some patients,

before the onset of this study, had recovered immedi-

ately after several magnetic stimulations used for diag-

nostic motor-evoked potentials, we decided to apply

rTMS to these patients.


Patients

We retrospectively reviewed the medical records of

70 patients with psychogenic paralysis who received

therapeutic rTMS between April 1999 and November

2008 in the Neurophysiology Department of the

Rouen University Hospital. The rTMS was used for

routine diagnostic purposes for each patient. The

study was approved by the local Ethics Committee.

The nature, onset, duration of the symptoms, and

precipitating events were recorded. We defined symp-

toms as acute or subacute symptoms, <30-day or

>30-day duration at the moment of the rTMS admin-

istration, respectively.

The diagnosis was explained to each individual

patient, particularly regarding the nature of

‘‘functional’’ paralysis, i.e., a nervous system dysfunc-

tion without lesion. TMS was introduced principally as

a diagnostic test and sometimes as a treatment that

could possibly alleviate their symptoms. We tried to

avoid suggestion in most cases. We spent 15 minutes

explaining and performing the rTMS session.

Methods

An average of 30 stimuli delivered at low frequency

(the device allowed stimulation every 4–5 seconds)

and maximal intensity of 2.5 Tesla were attempted

with a circular coil (P/N 9784-00) during 2 to 3

minutes. Another session of 30 stimuli was sometimes

delivered a few minutes later in cases of incomplete

improvement. The rTMS was applied to the motor cor-

tex opposite from the corresponding paralysis or on

both sides for bilateral paralysis. The rTMS efficacy

was classified in two groups: effective (total recovery

or dramatic improvement) or ineffective (mild

improvement or failure). Patient follow-up was per-

formed in most cases by the general practitioner, pedi-

atrician, or neurologist.

Statistical Analysis

To assess the influence of certain characteristics on

outcome, the comparison of rTMS efficacy between

different situations (men versus women, etc.) was

measured using the Fisher’s exact test. The accepted

significance level was P < 0.05.

RESULTS

Seventy patients (44 women and 26 men) were

referred by different units: the Department of Pediatrics

(n 5 28), Neurology (n 5 19), Neurosurgery (n 5 11),

Orthopedics (n 5 7), Rheumatology (n 5 3), and Emer-

gency (n 5 2). They were aged 24.7 6 16.6 years (mean

6 SD; minimum–maximum: 8–79 years). The majority

of patients (41 patients, i.e., 59%) were adolescents

(Fig. 1).

All patients experienced an abrupt onset or rapidly

progressive onset of the paralysis. At least one precipi-

tating event was observed in 42 of 48 patients for whom

information was available: a physically traumatic event

(n 5 12, in the affected limbs [n 5 5] or in a diffuse

way [n 5 7], with a minor injury for six patients); a psy-

chosocial precipitating event (n 5 21, death of a relative

[n 5 2], family conflict [n 5 11], work conflict [n 5 3],

and academic problems [n 5 4]); cephalalgia (n 5 8);

malaise (n 5 8); an unusual physical effort (n 5 3); and

an infection (n 5 2).

The symptoms were a paraparesis (n 5 40, 57%),

monoparesis (n 5 26, 37%), tetraparesis (n 5 2, 3%),

and hemiparesis (n 5 2, 3%). Paraparesis affected sig-

nificantly more children than adults (P 5 0.0003) and

monoparesis more adults than children (P 5 0.01).

The motor symptoms were isolated (n 5 24, 34%)

or were associated with sensory symptoms (n 5 27,

39%), with pain (n 5 11, 16%), or with both sensory

FIG. 1. Age distribution of patients with a psychogenic paralysis.The number of patients in different age groups in units of 10 years.

1502 N. CHASTAN AND D. PARAIN


symptoms and pain (n 5 8, 11%). The symptoms me-

dian duration at the time of the consultation was 5

days (minimum–maximum: 1–1080, Fig. 2). The symp-

toms were acute in 55 patients (median duration: 4

days) and subacute (even chronic) in 15 patients (me-

dian duration: 240 days).

The patients’ medical history revealed the following:

a comorbid psychiatric disorder (n 5 28, anxiety

and depressive disorders [n 5 21], eating disorders

[n 5 3], and posttraumatic stress disorders [n 5 4]);

physical injury history different from the precipitating

event (n 5 15, in the same area of the current paraly-

sis [n 5 13] or in a diffuse way [n 5 2]); ‘‘back trou-

ble’’ (n 5 10, sciatica, spinal injury, or surgery); a per-

sonal neurologic pathology (n 5 8 with 6 migraine);

or a familial neurologic pathology (n 5 4).

The rTMS was effective in 62 patients (89%), with a

total recovery in 53 patients (immediately after rTMS

[n 5 43], quasi-immediately [within a few minutes or

hours, n 5 8], and a few days later [n 5 2]) or a dra-

matic improvement in nine patients. The rTMS was inef-

fective in eight patients (11%), with a mild improvement

(n 5 5) or a failure (n 5 3). It was significantly more

effective for acute symptoms than subacute symptoms

(P 5 0.009). No significant difference of rTMS outcome

was observed between children and adults, men and

women, symptoms characteristics, concerning the pre-

cipitating events, or patients’ medical history.

The symptoms recurred in eight patients, always with

the same paralysis, with a single recurrence of paralysis

(n 5 5) after a 160-day average delay and multiple

recurrences (n 5 3) after a 150-day average delay. The

rTMS was applied again in six of the eight patients with

recurrence and was effective for all patients.

DISCUSSION

Description of a Population with Psychogenic

Paralysis

Although many studies have described adults with

psychogenic paralysis,2–4,6,11,12 data are most limited

in children.13 As previously reported,2,6,11,13 the major-

ity of patients were women. Paraparesis appeared twice

as less in the literature probably because of the adult

population.3,11 Only two patients (two adults) experi-

enced a hemiparesis, whereas this symptom occurred

between 32% and 47% in the previously described

adult population,3,4,11 probably because of our predom-

inant pediatric population. As previously described, tet-

raparesis was a rare symptom.4,11

At least one precipitating event was observed in 42

patients, mainly a psychosocial precipitating event

(work or familial conflict)11 or a physical injury,14

although of a trivial nature that could be sufficient to

produce psychogenic symptoms.13

As previously described,11 medical history revealed

the importance of psychiatric comorbidity and organic

disease (physical injury in the paralyzed limb and pre-

vious back problems) as risk factors for psychogenic

paralysis.

Efficiency of Repetitive TMS on Psychogenic

Paralysis

Limited evidence exists regarding the optimal choice

of treatment in psychogenic disorders. In some patients

with mild symptoms, explanation and reassurance with

encouragement may be sufficient. In patients with

more resistant symptoms, a combination of psychother-

apy and physiotherapy may be helpful. Cognitive-be-

havioral therapy,15 antidepressants,16 hypnosis,17,18 and

acupuncture19 can also be effective. Despite all these

treatments, outcome is not satisfactory in all patients;

37% to 83% of patients continue to experience symp-

toms 2 to 16 years after diagnosis.2,3,6,12

In our study, rTMS applied over the motor cortex is

associated with a very good outcome in 89%. As previ-

ously described,2,3,13 the factor significantly associated

with a favorable outcome was acute onset of symptoms,

but not the age13 or the sex.12 In contrast to previous

studies, we did not find a significant good outcome for

patients with a comorbid psychiatric disorder.3 Despite

an improvement in paralysis, a psychologic follow-up is

sometimes required in certain patients.

Three studies have reported a therapeutic benefit

from diagnostic20 and rTMS21,22 in patients with psy-

chogenic paralysis. Four patients were treated with 15-

FIG. 2. Symptoms duration of patients with a psychogenic paralysisat the time of consultation. The number of patients in different symp-tom duration groups (d).


1503PSYCHOGENIC PARALYSIS AND RTMS

Hz rTMS sessions of motor cortex for 5 to 12 weeks,22

with variable benefits (one total recovery, two marked

improvement, and one failure). We have previously

reported a spectacular recovery immediately after only

one session of low frequency rTMS (50 stimuli) over

the motor cortex in a psychogenic aphonia.21

Why has rTMS proved so effective? First, the possi-

bility of a placebo effect cannot be ruled out because

of symptom variability in psychogenic paralysis and

the possible symptoms attenuation or disappearance

with suggestion and persuasion. Nevertheless, 89% of

rTMS efficacy is impressive and seemed be specific to

rTMS, without the same efficacy for other therapies

usually used.2,3,6,12 Second, rTMS delivered over the

motor cortex produces a muscular activation, allowing

the patient to become aware of the movement possibil-

ity that could help in their management. Third, we sug-

gest that rTMS may have the ability to restore an

appropriate cerebral connectivity by activating a sup-

pressed motor cortex. Functional magnetic resonance

imaging studies have demonstrated a decreased activa-

tion of primary motor7 and an increased activation of

prefrontal regions,23 suggesting an active inhibition

from prefrontal areas to primary motor areas.23–25

CONCLUSION

Our results suggest that motor cortex rTMS could be

an effective treatment in patients with psychogenic pa-

ralysis, although further randomized controlled trial

versus placebo is necessary. Nevertheless, the physio-

pathologic and rTMS efficacy mechanisms of psycho-

genic disorders remain unknown.

Acknowledgments: We thank Richard Medeiros, RouenUniversity Hospital Medical Editor, for editing the manuscript.

Financial Disclosures: Nathalie Chastan and DominiqueParain: stock ownership in medically related fields.

Author Roles: Nathalie Chastan: research project (concep-tion, organization, and execution); statistical analysis (design,execution, review, and critique); manuscript (writing of the firstdraft, review, and critique). Dominique Parain: research project(conception, organization, and execution); statistical analysis(review and critique); manuscript (review and critique).

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1504 N. CHASTAN AND D. PARAIN


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