Oxford Textbook of Movement Disorders This page intentionally left blank Oxford Textbook of Movement Disorders Edited by David J. Burn Institute for Ageing and Health Newcastle University, UK Series Editor Christopher Kennard 1 3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the Univer sity \200\231s objective of excellence in research, scholarship, and education by publishin g worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Oxford University Press 2013 Th e moral rights of the author have been asserted First Edition published in 2013 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval s ystem, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license or under terms ag reed with the appropriate reprographics rights organization. Enquiries concerning reproduct ion outside the scope of the above should be sent to the Rights Department, Oxford Universi ty Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer British Library Cataloging in Publication Data Data available ISBN 978 \200\2230 \200\22319 \200\223960953 \200\2236 Printed in China by C&C Off set Printing Co. Ltd Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and c linical procedures with the most up-to-date published product information and data sheets p rovided by the manufacturers and the most recent codes of conduct and safety regulations. T h e authors and the publishers do not accept responsibility or legal liability for any erro rs in the text or for the misuse or misapplication of material in this work. Except where o therwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding. Contents List of Contributors vii 11 Non-motor Symptom Management in Parkinson \200\231s Disease 99 Eduardo Tolosa, Carles Gaig, and Lillian Acevedo List of Abbreviations ix 1 Overview and Historical Perspective 1 Gerald Stern Approach to History Taking and Examinati on of the Movement Disorder Patient 5 David J. Burn Neuroanatomy for the Movement Disorder Specialist 11 Glenda M. Halliday, Rachel Tan, and Heidi Cartwright Functional Aspects of th e Basal Ganglia 21 Th omas Wichmann Electrophysiological Approaches to the Movement Disorde r Patient 33 Carla Cordivari Movement Disorders: Structural and Functional Imaging 43 David J. Brooks Genetic Techniques, Impact and Diagnostic Issues in Movement Disorders 53 Jos Br s and John Hardy Overview of Parkinsonism and Approach to Di \200 erential Diagnosis 61 Sabine Spielberger and Werner Poewe Parkinson \200\231s Disease: Premotor Features, Diag nosis, and Early Management 73 Anthony H.V. Schapira and David Gallagher Parkinson \200\231 s Disease: Advanced Disease, Motor Complications, and Management 83 Susan H. Fox, Binit Sha h, Richard Walsh, and Anthony Lang 12 Th e Many Faces of Parkinsonism: A Review of the Parkinson Look-alike Syndromes 117 Susanne A. Schneider and Christine Klein Multiple System Atrophy (MSA) 129 Gregor K. Wenning and F lorian Krismer Progressive Supranuclear Palsy and Corticobasal Degeneration 139 David R. Wi lliams Primary Dementia Syndromes and Parkinsonism 151 A.W. Lemstra, H. Seelaar, and J.C. v an Swieten 2 13 3 14 4 15 5 16 Essential Tremor and Other Tremors 163 Ste \200 en Paschen and G nther Deuschl Dystonia : An Overview 177 K.P. Bhatia, M. Stamelou, and S. Bressman Primary Dystonia 191 Antonio A. Elia and Alberto Albanese Other Dystonias 201 Julie Phukan and Th omas Warner Huntington \200\231s Disease 213 Roger A. Barker and Josef Priller 6 17 18 7 19 8 20 21 Huntington \200\231s Disease Look-alikes 223 Edward J. Wild and Sarah J. Tabrizi Non-degene rative Choreas 231 Francisco Cardoso 9 22 10 23 Wilson Disease 241 Oliver Bandmann Contents vi 24 Tic Disorders and Stereotypies 247 Erika F. Augustine and Jonathan W. Mink Myoclonus 257 Ma rina A.J. Tijssen Paroxysmal Movement Disorders 269 Melissa J. Armstrong and William Weiner Hereditary and Acquired Cerebellar Ataxias 281 George Koutsis and Nicholas W. Wood Drug-in duced Movement Disorders 303 Shyamal H. Mehta, John C. Morgan, and Kapil D. Sethi 29 Systemic Disease and Movement Disorders 315 Leslie J. Cloud and Joseph Jankovic Sleep-relat ed Movement Disorders 327 Paul J. Reading Psychogenic Movement Disorders 339 Isabel Pare s and Mark J. Edwards 25 30 26 31 27 Index 347 28 List of Contributors Lillian Acevedo Neurology Service, Hospital Cl nic de Barcelona, Universitat de Barcelona (UB), Institut d \200\231Investigacions Biom diques August Pi i Sunyer (IDIBAPS), Barcelon a, Spain Heidi Cartwright Neuroscience Research Australia and the University of New South Wales, Syd ney, Australia Leslie J. Cloud Virginia Commonwealth University, VCU Parkinson \200\231s Disease Research Center, Richmond, VA, USA Alberto Albanese Istituto Neurologico Carlo Besta, Milan, and Istituto di Neurologia, Unive rsit Cattolica del Sacro Cuore, Milan, Italy Carla Cordivari Th e National Hospital for Neurology and Neurosurgery and Institute of Neur ology, University College Hospitals, London, UK Melissa J. Armstrong Department of Neurology, University of Maryland School of Medicine, Ba ltimore, MD, USA Marina A.J. de Koning-Tijssen Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, Th e Netherlands Erika F. Augustine Department of Neurology, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA Oliver Bandmann Department of Neuroscience, Sheffi eld Institute of Translational Neuroscie nce, University of Sheffi eld, Sheffi eld, UK G nther Deuschl Department of Neurology, Christian-Albrechts-Universtit t Kiel, Kiel, Germany Mark J. Edwards Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institu te of Neurology, London, UK Roger A. Barker Department of Neurology and John van Geest Center for Brain Repair, Addenbr ooke \200\231s NHS Trust, Cambridge, UK Antonio A. Elia Istituto Neurologico Carlo Besta, Milan, Italy K.P. Bhatia National Hospital for Neurology and Neurosurgery, London, UK Susan H. Fox Movement Disorder Clinic, Toronto Western Hospital, University Health Network and Division of Neurology, University of Toronto, Canada Jos Br s Department of Molecular Neuroscience, Institute of Neurology, University Colle ge London, UK Carles Gaig Neurology Service, Hospital Cl nic de Barcelona, Universitat de Barcelona (UB) , Institut d \200\231Investigacions Biom diques August Pi i Sunyer (IDIBAPS), Barcelona, S pain S. Bressman Department of Neurology, Albert Einstein College of Medicine, New York, USA David Gallagher Department of Clinical Neurosciences, Institute of Neurology, University Co llege London, UK David J. Brooks Imperial College London, UK David J. Burn Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, U K Glenda M. Halliday Neuroscience Research Australia and the University of New South Wales, S ydney, Australia Francisco Cardoso Internal Medicine Department, Federal University of Minas Gerais, Belo Ho rizonte, MG, Brazil John Hardy Department of Molecular Neuroscience, Institute of Neurology, University College London, UK List of Contributors viii Joseph Jankovic Parkinson Disease Center and Movement Disorders Clinic, Department of Neuro logy, Baylor College of Medicine, Houston, TX, USA Kapil D. Sethi Movement Disorders Program, Georgia \200\231s Health Sciences University, Au gusta, GA, USA Binit Shah Movement Disorder Clinic, Toronto Western Hospital, University Health Network an d Division of Neurology, University of Toronto, Canada Christine Klein Department of Neurology, University of L beck, L beck, Germany George Koutsis Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK , and Department of Neurology, University of Athens Medical School, Athens, Greece Sabine Spielberger Department of Neurology, Medical University, Innsbruck, Austria M. Stamelou National Hospital for Neurology and Neurosurgery, London, UK Florian Krismer Division of Neurobiology, Department of Neurology, Medical University, Inns bruck, Austria Gerald Stern Department of Clinical Neurology, University College Hospitals, London, UK Anthony Lang Movement Disorder Clinic, Toronto Western Hospital, University Health Network and Division of Neurology, University of Toronto, Canada Sarah J. Tabrizi UCL Institute of Neurology and National Hospital for Neurology and Neurosu rgery, London, UK A.W. Lemstra Department of Neurology/Alzheimer Center, VU Medical Center, Amsterdam, Th e N etherlands Rachel Tan Neuroscience Research Australia and the University of New South Wales, Sydney, A ustralia Shyamal H. Mehta Movement Disorders Program, Georgia \200\231s Health Sciences University, Augusta, GA, USA Eduardo Tolosa Neurology Service, Hospital Cl nic de Barcelona, Universitat de Barcelona ( UB), Institut d \200\231Investigacions Biom diques August Pi i Sunyer (IDIBAPS), Barcelona , Spain Jonathan W. Mink Department of Neurology, University of Rochester, School of Medicine and D entistry, Rochester, NY, USA J.C. van Swieten Department of Neurology, Erasmus MC-University Medical Center Rotterdam, R otterdam, the Netherlands John C. Morgan Movement Disorders Program, Georgia \200\231s Health Sciences University, Au gusta, GA, USA Richard Walsh Movement Disorder Clinic, Toronto Western Hospital, University Health Network and Division of Neurology, University of Toronto, Canada Isabel Pare s Sobell Department of Motor Neuroscience and Movement Disorders, UCL Instit ute of Neurology, London, UK Th omas Warner Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurolo gy, London, UK Steff en Paschen Department of Neurology, University of Kiel, Kiel, Germany William Weiner (deceased) Department of Neurology, University of Maryland School of Medicin e, Baltimore, MD, USA Julie Phukan Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK Gregor K. Wenning Division of Neurobiology, Department of Neurology, Medical University, In nsbruck, Austria Werner Poewe Department of Neurology, Medical University, Innsbruck, Austria Th omas Wichmann Emory University, Atlanta, GA, USA Josef Priller Department of Neuropsychiatry, Charit \200\223 Universit tsmedizin Berl in, Berlin, Germany Edward J. Wild UCL Institute of Neurology and National Hospital for Neurology and Neurosurg ery, London, UK Paul J. Reading Th e James Cook University Hospital, Middlesbrough, UK David R. Williams Van Cleef Roet Center for Nervous Diseases, Monash University, Melbourne, Australia Anthony H.V. Schapira Department of Clinical Neurosciences, Institute of Neurology, Univers ity College London, UK Nicholas W. Wood Department of Molecular Neuroscience, UCL Institute of Neurology and UCL G enetics Institute, London, UK Susanne A. Schneider Department of Neurology, University of Kiel, Kiel, Germany H. Seelaar Department of Neurology, Erasmus MC-University Medical Center Rotterdam, Rotterd am, the Netherlands List of Abbreviations 18 FDG 123 I-FP-CIT 18 F-2-fl uoro-2-deoxyglucose 123 I-N- \211 -fl uoropropyl-2 -carbomethoxy-3 - (4-io dophenyl)nortropan 123 I-iodobenzamine [ 123 I] N -3-iodopro-pene-2- yl-2 -carbomethoxy- 3 -4-chlorophenyl tropane 3-hydroxykynurenine 5- hydroxytryptophan 6-hydroxydopamine Ame rican Association for the Study of Liver Diseases abetalipoproteinaemia anterior cingulate area alcoholic cerebellar degeneration angiotensin-converting enzyme adrenocorticotrophic h ormone Alzheimer \200\231s disease AIDS dementia complex autosomal dominant cerebellar atax ia acute disseminated encephalomyelitis attention defi cit \200\223hyperactivity disorder a ctivities of daily living autosomal dominant nocturnal frontal lobe epilepsy antiepileptic drug anterior forebrain pathway, alpha-fetoprotein argyrophilic grain disease acquired hepa tocerebral degeneration adrenoleucodystrophy alternating leg muscle activation amyotrophic lateral sclerosis action myoclonus renal failure syndrome antineuronal antibodies ataxia wi th oculomotor apraxia atypical parkinsonian disorder, adult-onset pri- mary dystonia autoso mal recessive cerebellar ataxia acute rheumatic fever ARSACS autosomal recessive spastic ataxia of Charlevoix-Saguenay anti-streptolysin ataxia telangie ctasia ataxia with vitamin E defi ciency bacterial artifi cial chromosome British anti-lewi site twice daily brain-derived neurotrophic factor benign familial chorea twice daily botul inum toxin base pair(s) Bereitschaft spotential behavioral variant of frontotemporal dement ia cerebellar ataxia with neuropathy and bilateral vestibular arefl exia syndrome corticoba sal degeneration comprehensive behavioral intervention for tics corticobasal syndrome crani al computed tomography 2- -carbomethoxy-3- -(4-fl uorophenyl)tropane confi dence inte rval Creutzfeldt \200\223Jakob disease centromedian nucleus of the thalamus cingulate motor area catechol- O -methyltransferase continuous positive airway pressure central pattern ge nerator controlled release CREB-binding protein cortical refl ex choreoathetosis/spasticity cerebrospinal fl uid cortico-striatal-thalamo-cortical computed tomography cerebrotendinou s xanthomatosis caudal zona incerta ASO ATA AVED BAC BAL bd BDNF BFC bid BoNT bp BP bvFTD CANVAS 123 I-IBZM 123 IPT 3-HK 5-HTP 6-OHDA AASLD ABL ACA ACD ACE ACTH AD ADC ADCA ADEM ADHD ADL ADNFLE CBD CBIT CBS cCT CFT CI CJD CM CMA COMT CPAP CPG CR CRB C-refl ex CSE CSF CSTC CT CTX CZi AED AFP AGD AHD ALD ALMA ALS AMRFS ANAB AOA APD ARCA ARF List of abbreviations x DA DAT DBA DBS DDS DIM DIP DLB DLPFC DM1 DRB DRD DRPLA DSM-IV dopamine agonist dopamine transporter dopamine-receptor blocking agent deep brain stimulati on dopamine dysregulation syndrome drug-induced myoclonus drug-induced parkinsonism dementi a with Lewy bodies dorsolateral prefrontal cortex myotonic dystrophy type 1 dopamine-recept or-blocking drug dopa-responsive dystonia dentatorubral-pallidoluysian atrophy Diagnostic a nd Statistical Manual of Mental Disorders IV dystonic tremor dihydrotetrabenazine diff usio n tensor imaging diff usion-weighted imaging episodic ataxia evidence based medicine ethyle ne cysteinate dimer excessive daytime sleepiness electroencephalography, electroencephalogr aphic, electroencephalogram excessive fragmentary myoclonus European Federation of Neurolog ical Societies episodic kinesigenic dyskinesia electromyography, electromyographic, electro myogram essential palatal tremor extrapyramidal side eff ects enhanced physiological tremor , exaggerated physiological tremor extended release essential tremor Frontal Assessment Bat tery fatty acid hydroxylase-associated neurodegeneration familial acanthocytosis with parox ysmal exertion-induced dyskinesias and epilepsy familial cortical myoclonic tremor and epil epsy US Food and Drug Administration frontal eye fi eld familial hemiplegic migraine fronta l intermittent rhythmic delta activity functional MRI freezing of gait Friedreich \200\231s ataxia frontotemporal dementia frontotemporal dementia with parkinsonism linked to chromos ome 17 frontotemporal lobe degeneration fragile X-associated tremor \200\223ataxia syndrome gamma-aminobutyric acid group A beta-haemolytic streptococcus glutamic acid decarboxylase glucocerebrosidase (oligodendro-)glial cytoplasmic inclusion GDNF GEPD GI GP GPe GPi GSS gSSEP GWAS HB \200\223HC HD HDAC HDL HFT HIV HMSN HPRT ICCA glial-derived neurotrophic factor generalized epilepsy and paroxysmal dyskinesia gastrointe stinal globus pallidus external pallidal segment, globus pallidus externus internal pallida l segment, globus pallidus internus Gerstmann \200\223Str ussler \200\223Scheinker disea se giant somatosensory evoked potentials genome-wide association studies hemiballism \200 \223hemichorea Huntington \200\231s disease histone deacetylase Huntington \200\231s diseas e-like hypnagogic foot tremor human immunodefi ciency virus hereditary motor and sensory ne uropathy hypoxanthine-guanine phosphoribosyltransferase infantile familial convulsions and paroxysmal choreoathetosis impulse control disorder interleukin idiopathic late-onset cereb ellar ataxia infantile neuroaxonal dystrophy induced pluripotent stem idiopathic REM sleep behavior disorder idiopathic restless legs syndrome idiopathic torsion dystonia intravenous immunoglobulin Kayser \200\223Fleischer ring kynurenine 3-mono-oxygenase Lewy body long-du ration response Lewy neurite lateral orbitofrontal cortex Lee Silverman Voice Treatment l - threo-dihydroxy-phenylserine primary motor cortex monoamine oxidase type B monoamine oxidas e inhibitor Montreal Cognitive Assessment mild cognitive impairment mediodorsal nucleus of the thalamus, myoclonus \200\223dystonia Movement Disorder Society magnetoencephalography m yoclonus epilepsy with ragged red fi bres Miller Fisher syndrome meta-iodobenzyl guanidine mitochondrial disorder mitochondrial recessive ataxia syndrome metachromatic leucodystrophy Mini Mental State Examination Montreal Cognitive Assessment medial orbitofrontal cortex 11 C-methylphenidate 1-methyl-4-phenyl-1,2,3-tetrahydropyridine magnetic resonance imaging mu ltiple sclerosis multiple system atrophy DT DTBZ DTI DWI EA EBM ECD EDS EEG ICD IL ILOCA INAD iPS iRBD iRLS ITD IVIG KFR KMO LB LDR LN LOFC LSVT l -threo-DOPS M1 MAO-B MAOI MCA MCI MD EFM EFNS EKD EMG EPaT EPS EPT ER ET FAB FAHN FAPED FCMTE FDA FEF FHM FIRDA fMRI FoG FRDA FTD FTDP-17 MDS MEG MERRF MFS MIBG MID MIRAS MLD MMSE MoCA MOFC MP MPTP MRI MS MSA FTLD FXTAS GABA GABHS GAD GBA GCI List of abbreviations xi MSLT MSN MSS MT NBIA NCC NCE NCI NCL NCS NFLE NICE Multiple Sleep Latency Test medium spiny striatal projection neuron Marinesco-Sj gren sy ndrome microtubule neurodegeneration with brain iron accumulation nested case \200\223contr ol, neurocysticercosis neuroacanthocytosis neuronal cytoplasmic inclusion neuronal ceroid l ipofuscinosis nerve conduction studies nocturnal frontal lobe epilepsy National Institute f or Health and Clinical Excellence National Institutes of Health neuronal intranuclear inclu sion National Institute of Neurological Disorders and Stroke and Society for Progressive Su pranuclear Palsy N -methyl- d -aspartate neuroleptic malignant syndrome not otherwise speci fi ed Niemann \200\223Pick disease type C neuropsychiatric symptoms oligoclonal band obsess ive \200\223compulsive disorder oppositional \200\223defi ant disorder orthostatic hypotens ion oromandibular dystonia odds ratio organic tremor obstructive sleep apnoea orthostatic t remor pure akinesia and gait freezing pediatric autoimmune neuropsychiatric disorders assoc iated with streptococcal infections primary antiphospholipid antibody syndrome periodic ata xia paraneoplastic cerebellar degeneration polymerase chain reaction Parkinson \200\231s di sease Parkinson \200\231s disease dementia, pervasive develop- mental delay PD-related prof i le paroxysmal exercise-induced dyskinesia percutaneous endoscopic gastrostomy positron em ission tomography parafascicular nucleus of the thalamus Parkinson \200\231s Fatigue Scale post-hypoxic myoclonus panthothenate kinase-associated neurodegeneration paroxysmal kinesig enic dyskinesia PLA2G6 -associated neurodegeneration periodic limb movement periodic limb m ovement disorder premotor cortex psychogenic movement disorder progressive myoclonic epilep sy progressive multifocal leucoencephalopathy PNFA PNKD PP PPA PPMS PPN PR PSD PSM PSP PsyT PT PWT QoL RBD RCT RD RDP REM r-HGH RLS RMD R OI ROS RR RS rTMS SANDO progressive non-fl uent aphasia paroxysmal non-kinesigenic dyskinesia psychogenic parkinson ism primary progressive aphasia primary progressive multiple sclerosis pedunculopontine nuc leus prolonged release periodic sharp discharge, postsynaptic density propriospinal myoclon us progressive supranuclear palsy psychogenic tremor psychogenic tremor primary writing tre mor quality of life REM sleep behavior disorder randomized controlled trial Refsum \200\231 s disease rapid-onset dystonia \200\223parkinsonism rapid eye movement recombinant human gr owth hormone restless legs syndrome rhythmic movement disorder region of interest reactive oxygen species relative risk Richardson \200\231s syndrome repetitive transcranial magnetic stimulation sensory ataxic neuropathy, dysarthria, and ophthalmoparesis sleep bruxism sequ encing by synthesis subcutaneous Sydenham \200\231s chorea spinocerebellar ataxia sporadic Creutzfeldt \200\223Jakob disease small-cell lung cancer sternocleidomastoid spasmodic dysp honia, Sydenham \200\231s disease short-duration response supplementary eye fi eld somatose nsory evoked potential systemic lupus erythematosus supplementary motor area substantia nig ra substantia nigra pars compacta single nucleotide polymorphism substantia nigra pars reti culata serotonin \200\223noradrenaline reuptake inhibitor standard of truth single photon e mission computed tomography stiff person syndrome symptomatic palatal tremor sepiapterin re ductase steroid-responsive encephalopathy associated with autoimmune thyroiditis somatosens ory evoked potential subacute sclerosing panencephalitis selective serotonin-reuptake inhib itor subthalamic nucleus NIH NII NINDS \200\223SPSP NMDA NMS NOS NPC NPS OCB OCD ODD OH OMD OR OrgT OSA OT PAGF PANDAS SB SBS s.c. SC SCA sCJD SCLC SCM SD SDR SEF SEP SLE SMA SN SNc SNP SNr SNRI SOT SPECT SPS S PT SR SREAT PAPS PATX PCD PCR PD PDD PDRP PED PEG PET Pf PFS PHM PKAN PKD PLAN PLM PLMD PMC PMD PME PML SSEP SSPE SSRI STN List of abbreviations xii SWEDDs TA TBZ TCS TD tds TDt TENS TH TIC scans without evidence of dopaminergic defi cit tardive akathisia tetrabenzine transcranial sonography tardive dyskinesia three times daily tardive dystonia transcutaneous electrical nerve stimulation tyrosine hydroxylase Tourette Syndrome International Database Consortium three times daily transcranial magnetic stimulation Tremor Investigation Group Tourette \200\231s syndrome task-specifi c tremor, triple stimulation test ubiquitin proteasome syst em UHDRS UMSARS UPDRS UPS UPSIT Unifi ed Huntington \200\231s Disease Rating Scale Unifi ed MSA Rating Scale Unifi ed Parki nson \200\231s Disease Rating Scale ubiquitin \200\223proteasome system University of Penns ylvania Smell Identifi cation Test UFMG Sydenham \200\231s Chorea Rating Scale ventral ante rior nucleus of the thalamus voltage-gated potassium channel visual hallucination ventroint ermedius nucleus of the thalamus ventrolateral nucleus of the thalamus vesicle monoamine tr ansporter density polysomnography with audiovisual recording ventral tegmental area vanishi ng white matter disease Wilson disease, Whipple \200\231s disease USCRS VA VGKC VH Vim VL VMAT2 VPSG VTA VWMD WD tid TMS TRIG TS TST UBS CHAPTER 1 Overview and Historical Perspective Gerald Stern \200\230A divine old age had slackened his mouth. He cast his spittle upon the ground and spat it out \200\231. Egyptian papyrus of 19th Dynasty c .1350 \200\2231200, describing an elderly king. and feet all tremble at once and when he walks, he falls forwards, he will not get well \200\231. Ancient history While early descriptions were inextricably infl uenced by mythol- ogy, magi c, religion, superstition, traditional philosophies, and interpretations by shamans, obviou s disorders of movement should have attracted \200\230clinical \200\231 attention. Interpr etation of texts, such as the above, continue to remain uncertain. Certain early observa- t ions were remarkably sophisticated. In the Holy City of Varanasi (formerly Benares), within the Hindu University of India, original Sanskrit texts and incunabula reveal the contribut ions of Ayurvedic medicine (5000 \200\2233000 BC ). In the world \200\231s oldest continuous civilization, the present People \200\231s Republi c of China, there is evidence stemming back to the second millennium BC indicating that Chi nese society had its medicine men comparable to the shamans of North Asian tribal societies (5). However, in 1963 Keele observed \200\230 it would seem probable that the first civilized people to free them- selves from purely magico-religious concepts of disease wer e the ancient Chinese \200\231 (6). As in Europe, early observers often had difficul ty in separating symptoms ( hou ), signs, syndromes, diseases ( chi ), causes, and treatmen ts. Catalogs of diseases became compendious. Thus in 992, the massive Imperial Grace Formul ary ( T \200\231ai-pin g sheng hui fang ) provided prescriptions for roughly a thousand dis tinct disorders (7). Diseases were then categorized into three bioentities: vata (psy- chomotor or life force), pitta (metabolic), and kapha (growth). Imbalance of vata gave rise to neurological disorder s, which were further divided into kampa (tremor), stambha (stiff ness), and vishada (depre ssion). Th ese could be compounded. Th us, kam- parata indicated shaking palsy. Among the p rescribed traditional medications were atmaghupta seed ( Mucuna pruriens ), contain- ing le vodopa, and extracts of three plants \200\224 aswaghanda root ( Withania somnifera ), bala ( Sida cordifolia ), and paraseekayavanee ( Hyoscyamus reticulatus ) \200\224all solanaceou s alkaloids similar to Atropa belladona (1). Th e latter were not introduced into European medicine until the nineteenth century, when they were used by a pupil of Charcot for the sy mptomatic treatment of Parkinson \200\231s disease. Chandra , the moon plant ( Rauwolfi a s erpentina ), long used as a sedative for recurring mania attributed to movements of the moo n (lunacy), was rediscovered by Nathaniel Kline when serving in India during the Second Wor ld War. He introduced it to America \200\224the fi rst eff ective medication for chronic sc hizophre- nia. It was soon discovered that sustained administration caused drug-induced par kinsonism and facilitated the recognition of dopamine as a neurotransmitter (2). Early Meso potamian litera- ture from the fi rst half of the second millennium, which resisted transla tion of cuneiform scripts on clay tablets until the twentieth century, was oft en precise a nd sophisticated (3). It includes a com- pelling early description and prognosis of Parkins on \200\231s disease (4): \200\230If his head trembles, his neck and spine are bent, but h e cannot stick out his tongue, his saliva fl ows from his mouth, his hands legs Some traditional concepts may appear alien to contemporary eyes. For example, the notion of health ( ch \200\231i ) was construed as a bal- ance between two fundamental forces, the \200\230 yin \200\231 and the \200\230 yang \200\231 (8), yet there are implied notions, which ring familiar to present neurol- ogists. In the earlier classics, excessive undiscip lined emotions were recognized causes of disease (psychosomatics?). Th e conditions of heal th were partly inborn (genomics?), and partly due to food and drink (epigenetics cum nutrig enics?). Certain neurological diseases were described in meticulous detail; the clinical fe atures and grim prognosis of rabies were set out in 556 BC \200\230 when a mad dog b ites someone, the patient becomes manic but if he remains well for 100 days he will r emain safe \200\231 (5). During the Ming period (1368 \200\2231644), there are at le ast six separate descriptions of condi- tions resembling the shaking palsy (9). With respec t to other neu- rodegenerations, in this vast ancient country where strongly held tradition al values embraced profound family concern for the eld- erly, disabilities such as ageing m ay have been simply regarded as a fact of life demanding respect and support. Claudius Galen (129 \200\223216), a Greek polymath from Pergamon, dominated Western medical science for over a thousand years until many of his opinions were refuted by Maimonides, V ersalius, and William Harvey. Galen dissected many animals, published nearly 500 treatises, and wrote extensively on trauma and the nervous Oxford Textbook of Movement Disorders 2 system (no doubt infl uenced by his experience as physician to the Roman School of Gladiato rs). He wrote in Greek but many of his works, translated later into Arabic (10), clearly do cument his exten- sive clinical experience and his insistence on a rational approach to med icine. Constantine reintroduced Greek medicine to Europe by patronage of translations of Ar istotle, Hippocrates, and Galen into Latin. From these sources, classical notions of moveme nt disorders are clearly documented. Galen recognized involuntary tremor ( vol- untariae fu nctionis laesio est impotentis ), tremor associated with stiff ness ( quomodo a rigore diff erat ), and the infl uence of tempera- ture ( aff etus frigidus est ). Amongst several lis ted causes, he distin- guished those related to poor nutrition ( causa alimenti indigentia ), those occurring in the mentally retarded ( est musculoram faculta- tis imbecillitus ), o cular tremor ( tremorum musculorum oculi ), and those related to psychiatric states includi ng depression ( tremores convus superveniens mente ob melancholium ), and clearly separated the shaking of epilepsy ( tremors convulsivos ). Willis authoritatively introduced the terms lenticular and striatum, using the terms synony mously when describing this structure as \200\230dissimilar to any other part of the brain \200\231 and quotes a sentence from Hainan \200\231s Arabic text of Galen concerning the g lutea, so iden- tifying striatum with glutea (12). Willis was also the fi rst to clearly di stinguish the striped anterior protruberance from the posterior non-striated lobe, which he called \200\230thalamus opticus \200\231, illustrating another probable misnomer. \200 \230Th alamus \200\231 means a room or cav- ity and had been used by Galen for the chambers of the heart. He described the recess of the inferior horn of the lateral ventricle at its upward end as thalame , a loophole, which receives the \200\230spirit \200\231 by way of the hollow optic nerves. Hainan aptly depicts this region as a \200\230sleeping tent \200 \231 ( hadjala ). Willis or his interpreters seem to have been more impressed by \200\230s leeping \200\231 than a \200\230tent \200\231 and thought of a bed rather than a bedroom. As the detailed anatomy of the central nervous system was advancing, new fi ndings continue d to be described in classical lan- guages. Just as traditionally, \200\230chorea \200\231 was derived from the Greek word for dance. In plays of ancient Greece, the chorus commente d on the dramatic action utilizing dance, gesture, and mimicry. In many plays the chorus ex pressed to the audience what the actors could not say or provided insights and explanations , so the full repertoire of gestures was employed. Similarly, during the eight- eenth and n ineteenth centuries, knowledge of Greek or Latin was employed to describe new anatomical de tails. Th e early scienti \201 c enlightenment In Europe, medieval physicians and anatomists redi scovered their heritage, albeit without the original Greek texts and usually through interm ediate Syriac manuscripts. In the absence of draw- ings and diagrams, translational errors may well have occurred. In the Anathomia of Mundius (1538), the authorized textbook of med- icine, there is a strange and fascinating confusion of Greek, Roman, Arabic, and medieval concepts (11). Mundinius states: Th e substantia innominata (1869) was the unnamed substance of Th eodore Meynert (13). D j rine attributed to Burdach (1882) the name globus pallidum. Th omas von Sommering (1788), in his doc- toral thesis \200\230De basi encephali et originibus nervorum \200\231, drew partic- ular attention to the diff erence in appearance between the ashen or gray matter (s ubstantiae cinereae) of the cortex and the brainstem: \200\230Th e mass is tinged a dark c olor which in adults resembles neither the whiteness of the medulla nor the cinereal parts of the brain, but is, so to speak, midway between the cinereal and the medul- lary parts of the brain \200\231. Later, the described a particular aggregation of dark substance within the cerebral peduncles. Sommering was familiar with the intimate relationship of the pigme nted substance to the emerging third nerve fi bres and noted that pigmentation was less dis tinct in the brains of newborn children and fetuses. At the base of the lateral ventricles lies a red sanguinous substance called vermis b ecause it looks like an earthworm and because it moves like it. Namely it can contract and block the communication from one ventricle to another [ancient and medieval natural p hiloso- phy located phantasy in the anterior ventricle, imagination into the medial ventric le, and memory into the posterior ventricle] if then, the individual wishes to suspen d cogitation, he elongates his worms and this prevents phantasy, memory and imagination fro m uniting and forming the \200\230common sense \200\231 Avicenna, the Arabic translator of Galen, had proposed \200\230ver- mis \200\231, whereas Galen speaks of choroid plexus and never vermis. Mundinius describes the wall of the latera l ventricle, to which the vermis is attached, as \200\230haunches \200\231. Galen, who had a sound knowledge of the ventricles of the brain and adjacent structures, probably because he was familiar with the writings of Herophilus who had performed human necropsies in the School of Anatomy at Alexandria (circa 300 BC ), referred to the basal ganglia as \200\230 glu- teal parts \200\231 or \200\230thighs \200\231. Frederick Lewy (whose name is given t o the Lewy body), a superb classical scholar as well as a seminal neu- ropathologist, was p uzzled and shrewdly wrote, \200\230It may be lur- ing to speculate whether the Greek skelo s (thigh) may have been read as skolex (worm) by the Syriac expositor who preceded the Arab ic translator Avicenna \200\231 (10). It was Th omas Willis who was responsible for much of the present nomenclature of the basal ganglia. In his Cerebri Anatome (1664), aided by the magnifi - cent illustrations of Christopher Wren, Willis brought welcome clarity (12): Alexander Munro (1783), the great Scottish anatomist did not seem to be aware of Sommering \200\231s priority: \200\230Nay in the middle sub- stance of the brain and cerebellum, hal fway between the surfaces of these and their ventricles and even within the crura cerebri I have found a great quantity of ciniterous matter \200\231. Blocq and Marinesco (1893 ) and Tr tiakoff were amongst the fi rst to relate \200\230S mmering \200\231s substance , tache noire or locus niger crurum cerebri \200\231, now accepted as the substantia nigra, to disordered movement (14, 15). Th e subthalamic nucleus also enjoyed a number of synonyms, including corps de Forel, discu s lentiformis by Meynert, and nucleus amygdaliformis by Stilling, but most authors associat ed it with the name of Luys. Luys clearly showed this nucleus in his fi ne woodcut illustra ted textbook (1876). He modestly, but erroneously, called the nucleus bandelette accessoire de l \200\231olive superiore (16). Th e mysterious \200\230nucleus accumbens \200\231 sim ply means the nucleus leaning against the septum. Meanwhile, the era of classical neuropath ol- ogy was accelerating, but not without controversy. In 1942, Lewy (10) observed the conf using apparent incompatibility between the autopsy fi ndings of those who had suff ered une quivocal movement disorders without gross demonstrable pathological changes, and In the foremost part of the brainstem, two prominent lentiform bodies which are characterized by up-and-downward radiating medullating fi bres, producing a striped appear ance on their cut sur- face (corpus striatum) Corpus striatum sive-medullae oblongata e apices sunt duo prominentiae lentiformis. CHAPTER 1 Overview and Historical Perspective 3 Present challenges In the following chapters, distinguished authorities provide com- prehen sive accounts of developments and advances in our under- standing of movement disorders. Pe rhaps a further and fi nal historical point may be made. On 28 April 1953 two young men rus hed across the narrow road from the Cavendish Laboratories, Cambridge, England and entered the Eagle pub. One announced to the startled drinkers, \200\230We have just discovered the secret of life \200\231. Apparently the crowd was not impressed. Francis Crick and his Ame rican colleague James Watson, without doing any experiments themselves but using paper cut- outs and metal rods and screws, had won the race to discover the structure of the double he lix. Competitors had included Linus Pauling, a twice-honored Nobel Prize Laureate. Two mont hs later their historic paper was published: \200\230Molecular structure of nucleic acids. A structure for deoxyri bose nucleic acid \200\231. Th is contained an equally famous thro w-away line: \200\230It has not escaped our notice that the specifi c pairing we have post u- lated immediately suggests a possible copying mechanism for the genetic material \200 \231 (26). frequent incidental fi ndings in those who had shown no clinical evidence of disease. To so me extent this was historically artefactual, as even by 1911, when light microscopy became routine, staining techniques were limited to the Weigert method. It was not until the Nissl stain became routine that microscopic details began to eluci- date clinico-pathological li nks. Pathological changes were found in conditions such as cho- rea (Alzheimer) (19) and Parkins on \200\231s disease (Lewy) (18), which appeared normal to the naked eye. Similarly, clinic al distinctions were becoming more precise. Th omas Sydenham (1726) described \200\230Chor ea St Viti \200\231, infectious chorea minor, and diff erentiated this from chorea major or \200\230dancing hysteria \200\231 (19). A non-infectious chronic hereditary form of chore a was reported by Dr Charles Walters when he wrote to Dunglison, his professor of medicine, on 5 May 1841. Th is was published the following year in the latter \200\231s Practice of Medicine . He wrote: somewhat common known among the common people as the \200\230magrums \200\231 essentially spasmodic action of all or almost all the vol- untary muscles the d isease is markedly hereditary very rarely, it takes its appearance before adult life it never ceases in all cases it gradually induces a state of more or less perfe ct dementia 