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 Th e molecular revolution had begun. Since then, we have wit- nessed a tsunami of data. So far, apart from a few Mendelian single-gene neurodegenerative disorders such as Huntington \200\231s dis- ease, tuberous sclerosis, spinal muscular atrophy, and myotonic dystrophies, the gap between genotype and phenotype remains vast and largely incomprehensible to clinic ians. It seems that a quan- tum leap or paradigm shift is now required for us to evolve fro m traditional disease defi nitions and embrace the concept that all disease manifestations must be understood in complex molecular terms (27). Defi nitions such as \200\230the emerg ent properties of molecu- lar networks as opposed to the core biological processes driven b y responses to changes in a small number of genes \200\231 do not yet come easily to clinic ians. Other reports followed: Gorman (1846) from Pennsylvania, Lyons from New York (1863), and fi nally on 15 February 1872 George Huntington read his famous paper summarizing his grandfat her \200\231s (Dr Abel Huntington), his father \200\231s, and his own combined experi- ence , stating: \200\230A form of this disease exists as far as I know almost exclusively in Lo ng Island the hereditary chorea \200\231 (20). In 1961, MacDonald Critchley (21) elegantly set out the histori- cal and geographical featu res of the illness, and how the largest of the American family groups could be traced back to East Anglia and the year 1630. Th ree young men left their native Suff olk vil- lage of Bures St Mary to settle in the American Colonies. Th ere was intriguing evidence that they left because of their psychopathic behavior. No fewer than seven of their daughters or gran ddaugh- ters were regarded as witches. Th e fi ft h generation of the Bures fam- ily showed unequivocal evidence of Huntington \200\231s disease and Mary Bures \200\231 descendants c onstituted the largest family group in New England. Th e Peck family group was another, and originated when intermarriage took place with an aff ected member of the Wells fam- ily. T h e fi rst member of this family originally dwelt 10 miles away from Bures (19). Perhaps a few fi nal Cassandra comments and questions might be permitted? New, increasingly subtle clinico-pathological correla- tions at a classical and molecular level will continu e to be discovered and rare new mutations and phenotypes will be charted, but there remains an urgent need to explain basic mechanisms. Not only why and when does a pathological proc ess commence, but why are the majority spared? Th e enigma of selective system vulnerabilit y has to be solved. Th e interval between the trigger or triggers to disad- vantageous gene tic processes and the appearance of demonstrable pathological events and \200\224even longe r \200\224before subtle clinical events can be recognized will need to be elucidated. What factors acceler- ate the disease for an unfortunate minority and what permits others to run a more benign course? What determines vulnerability for some and protection for others? On ly then will eff ective neuropro- tection and treatments become a reality and replace sympt omatic relief. Hopefully movement disorders will then enter their fi nal historical phase. Athetosis was fi rst described by William Hammond (1869), Surgeon General of the United Sta tes Army. He proposed the name from the Greek indicating loss of stability. Hammond predict ed (1871) that \200\230Th e phenomena indicated the implication of intra- cranial ganglia one possible seat is the corpus striatum \200\231 (22) but he had to wait for 20 year s until Gowers described a scar in the left optic thalamus in a patient with choreo-athetot ic move- ment in the rigid left arm (22). Finally, Westphal (1883) reported \200\230A case of a disease of the central nervous system without anatomi- cal changes, under the picture of a cerebrospinal gray degeneration \200\231 (24). In 1911, Alzheimer (17) showed that th e illness was associated with giant multilobular glia nuclei \200\230 all over the n ervous system although the corpus striatum, optic thalamus, hypothalamus, pons and dentate nuclei were the parts most severely diseased \200\231. In the following year Kinnier Wilson (25) described \200\230hepatolenticular degeneration \200\231. Th is seems an appropriate historical time to end the classical period of \200\230diseases of the basal ganglia \200 \231. References 1. Vaidya AB. Treatment of Parkinson \200\231s disease with cowhage plant \200 \224 Mucuna pruriens . Neurology (India) 1987; 26 : 171 \200\2236 . 2. Carlsson A, Lindqvist M, Magnusson T. 3,4-Dihydroxyphenylalanin e and 5-hydroxytryptopha n as reserpine antagonists. Nature 1957; 180 : 1200 . 3. Reiner E. Shurku collection of Sumerian and Arcadian incarnations. Graz : Archiv f r Orientschung Beheft , 1958. Oxford Textbook of Movement Disorders 4 15. Stern G. Th e language of the basal ganglia. J Neural Transm (Suppl) 1997; 4. Scurlock JA, Anderson BR. Diagnosis in Assyrian and Babylonian medi- 51 : 1 \200\2238 . cine . Chicago, IL : University of Illinois Press , 2005. 16. Luys J. Le cerveau et ses fonctions. Paris : Librairie Germer Bailli re , 1876. 17. Alzheimer A. \234 ber die anatomische grundlage der Huntingtonschen Chorea und die choreat ische Bewegungen uberhaupt. Neurol Zbl 1911; 30 : 891 . 18. Lewy FH. 5. Sivin N. Medicine in Chinese culture. In: J. Needham (ed.) Science and Civilisation in C hina , pp. 38 \200\2239 4 . Cambridge : Cambridge University Press , 2008. 6. Keele KD. Th e evolution of clinical methods in medicine. Fitzpatrick Lectures, Royal Co llege of Physicians. 1960 \200\2231 . London : Pitman , 1963. 7. Wang Huai-yin . Th ai phi ng sheng hui fang ( Encyclopedia grace formulary Die pathologische Anatomie der Paralysis agitans. Lewandowsky \200\231s Handb 1912; 3 : 920 . of the Th ai-phing-hsing-ku o Era , Sung ), 982. 19. Sydenham T (1726). Schedula monitoria de nova febris igressu. Opera universa , p. 526. Lugduni Batavorum apud Kerchem. 8. Sivin N. Traditional medicine in contemporary China , pp. 106 \200\2239 . Ann Arbor, MI : Center for Chinese Studies, University of Michigan , 1987. 20. Huntington G. On chorea. Med Surg Reporter 1872; 26 : 317 . 21. Critchley M. Th e black hole and other essays , pp. 210 \200\22319 . London : Pitman 9. Moff ett J. Personal communication. Needham Research Institute, Medical , 1961. Cambridge, 2001. 22. Hammond WA. A treatise on the diseases of the nervous system , pp. 322, 10. Lewy FH (1942). Th e diseases of the basal ganglia. Res Publ Assoc Res 654 . New York : Appleton , 1871. Nerv Ment Dis 1942; 21 : 1 \200\2232 0 . 23. Gowers WR. On athetosis and posthemiplegic disorders of movement. 11. Mundinus. Anathomia Mundini per carpum castigata et postmodus cum Med-chir Trans 1876; 59 : 271 . apostillis ornate et noviter , pp. 61 \200\22373 . Venice : Bernadinus , 1538. 24. Westphal C. \234 ber eine der Bilde der cerebrospinalen grauen Degeneration hlichen Erkrankung des centralen Nervensystem ohne anatomischen Befund, etc. Arch Psychiatr Nerven k ; 14 : 87 . 12. Willis T. Cerebri anatome cui accessit nervorum descriptio et usus. London: Roycroft , 1664. 13. Meynert T. \234 ber die geweblichen Veraenderungen in den Centralorganen des Nervensys tems bei einem Fall von Choreanminor. Allg Wiener med Zeitg 1868; 13 : 67 \200\2237 6 . 25. Wilson SAK. Progessive lenticular degeneration. Brain 1912; 34 : 295 . 26. Watson JD, C rick FHC. Molecular structure of nucleic acids. A structure for deoxyribose nucleic acid. Nature 1953; 171 : 737 . 14. Stern G. Th e eff ects of lesions in the substantia nigra. Brain 1996; 89 : 27. Bell J (2010) Redefi ning disease. Clin Med 2010; 10 : 584 \200\2239 4 . 449 \200\2237 8 . CHAPTER 2 Approach to History Taking and Examination of the Movement Disorder Patient David J. Burn Introduction Th e characteristic feature of all movement disorders is an abnor- mality of t he form and velocity of movements of the body. Th is rather vague defi nition disguises the sometimes bewildering spec- trum of abnormal movements, their distribution, temporal evolu - tion, underlying cause, and range of functional impacts. One of the reasons that many neu rologists (including myself) are drawn into this subspecialty is that it remains very clini cally based. Th us, an appreciation of the pattern of abnormal movements, enabling their ph enomenology to be determined, is essential before embarking upon the correct diagnostic pat hway. Failure to take this critical fi rst step and to adopt a \200\230scattergun \200\231 approach to investigations is likely to be both time-consuming and costly. example, may be regarded as having an akinetic \200\223rigid syndrome, but may also have pr ominent tremor. In such situations, it is best to categorize by the dominant movement disor der. Akinetic \200\223rigid disorders Th e terms akinesia, bradykinesia, or hypokinesia are all used in the literature, sometimes with confusing results. Strictly speaking akinesia implie s \200\230lack of movement \200\231. Since very few patients are completely unable to move , it may not be the most appropriate term for this group of disorders, but its use has beco me embed- ded in movement disorder folklore. Bradykinesia means \200\230slow movement \200 \231, whilst hypokinesia refers to poverty of movement, or movements that are smaller in am plitude than that intended. Akinesia has also been used as an umbrella term for bradyki- ne sia, hypokinesia, and, most importantly, the progressive fatigu- ing and decrementing of re petitive movements such as fi nger or foot tapping. Th e latter more than anything captures the essence of \200\230parkinsonism \200\231, or an akinetic \200\223rigid syndrome. Elic iting this in practice is not always easy and may require many repetitions to observe (>50 on occasion), whilst signifi cant tremor may con- found the interpretation. It is important not to perform the fi nger taps in tandem with the patient, since they may take visual cue from the examiner and appear spuriously better than they are with self-generated movements . Slowness of movement may sometimes be observed in pyramidal and cerebellar disturbances, underlining the importance of documenting fatigue and decrement as being specifi c to an ex trapyramidal disorder. Th e term \200\230movement disorder \200\231 has become synonymous with basal ganglia dise ase and extrapyramidal features. While it is true that many movement disorders arise from p athology within the basal ganglia, disorders such as myoclonus may arise from other neural structures, including the spinal cord. Moreover, the cor- relation between lesions within t he basal ganglia and the occur- rence and nature of any movement disorder produced is not a lways a close one. Given the extensive cerebral cortical connectivity of basal ganglia stru ctures, it is unsurprising that movement disorders are also frequently associated with cogn itive and neuropsychiatric problems. Indeed, these problems may precede and/or overshadow t he abnormal movements. Th e range of diff erent movement disorders and their causes are discussed in the ensuing c hapters of this book. Th is brief introduc- tion to the topic will deal primarily with clas sifi cation and broad issues relating to the approach to a patient with a suspected move- m ent disorder. Hyperkinetic disorders In general, recognition and diagnosis of this group of disorders is more challenging than the akinetic \200\223rigid syndromes. Some reviews have subclassifi e d these movements into jerky and non-jerky syn- dromes (1). Th e former comprises myoclonus , chorea, and tics, whilst non-jerky hyperkinetic disorders include tremor and dys- tonia ( 2). Th e division is somewhat arbitrary, and confusion may occur where the movement disorde r is mixed, as in so-called \200\230dys- tonic tics \200\231 for example. Classi \201 cation and de \201 nitions Movement disorders can be categorized into akineti c \200\223rigid and hyperkinetic; in other words, patients who either move too little or th ose who move too much. Th is simplistic approach is confounded where there are mixed signs. Someone with Parkinson \200\231s disease, for Oxford Textbook of Movement Disorders 6 Myoclonic movements are sudden, brief, shock-like involuntary movements which we all experi ence on occasion when falling off to sleep. Negative myoclonus occurs due to brief loss or inhibition of muscle tone. In the arms this may be due to asterixis, associ- ated with hepa tic or uraemic encephalopathy or carbon dioxide retention, whilst in the legs it may produc e a \200\230bouncing gait \200\231 in the context of the post-anoxic Lance \200\223Adams s yndrome. Myoclonus may be described in terms of its distribution (focal, multifocal, segmen tal or generalized), etiology (physiological, essential, epi- leptic or symptomatic), neuro physiology (cortical, subcortical, spi- nal and peripheral), and also by its triggers (spon taneous, action, stimulus-sensitive). Palatal myoclonus has been reclassifi ed as a tremor disorder. Stereotypies are purposeless voluntary movements carried out in a repetitive fashion, oft e n for long periods of time, and at the expense of all other activities. In contrast with ti cs, they are less paroxysmal, and may involve whole areas of the body. Hand wringing, typic al of Rett syndrome, is an example of a stereotypy. Head banging and body rocking, seen in mental retardation of diff erent aetiologies, are other commonly encountered examples of st ereotypies. History taking Th e value of a careful history and examination can never be underestimated, even if the diagnosis may seem apparent from the moment the patient fi rst walks into the clinic room. Regarding the history, one of my previous teachers in London used to say: \200\230If you have ten minutes with the patient, then spend nine taking the history \200 \231. Th is is sound advice, yet commonly overlooked in a busy clinic. Th e auditory startle response is a polysynaptic refl ex originating in the caudal brainste m which comprises a rapid eye blink followed by facial grimacing, fl exion of the head, tru nk, elbows, hips and knees, and raising of the shoulders in response to a sudden unex- pect ed noise. Abnormal excessive startle may occur in hyperek- plexia, as a manifestation of ep ilepsy, and various regional disorders of uncertain etiology (latah reaction, miryachit, an d the jumping Frenchmen of Maine). In a severe genetically determined form of startle disea se (major hyperekplexia, associated with a mutation in the alpha-1 subunit of the glycine r eceptor) the motor response may be associated with transient generalized muscle stiff ness and falls, with rapid recovery. \227\206 History of presenting complaint: It may be diffi cult to date the pre- cise onset of a movement disorder, but some idea of duration is important. Collateral history from a spouse or family member can be helpful here. Was the onset acute or gradual? It can also be helpful to ascertain where the problem began, and the nature of its spread. It can sometim es be useful to determine exacerbating and ameliorating factors, although most movement dis orders are made worse by anxiety. Beware of the person with parkinsonism who uses a proxy s ymptom such as weakness or clumsiness; most patients do not complain of bradykinesia! Occas ionally the per- son may not know why they are in clinic or why they were sent along; in my experience this has usually been the patient with chorea who is untroubled and largely una ware of their movement disorder. Always try to relate the symptoms to functional impact: wh at does it mean to the person in their everyday life? Th is will also have a bearing upon t reatment decisions. I usually ask a few screening cognitive and neuropsychiatric questions at this point, if they have not already been covered, along with sleep pattern and possible parasomnias. Having a spouse or care-giver avail- able at this point is particularly helpf ul. For example, the patient may be unaware or deny that they have been low in mood, iras- cible, or more apathetic. Collateral history can provide useful examples of cognitive impai rment, such as inadvertently leaving gas or water on, getting lost in previously familiar s urroundings, and so on. A bed-partner can describe better than anyone the likely occurrence of REM sleep behavior disorder, and may even admit to moving into the spare bedroom in ord er to get a better night \200\231s sleep! Chorea (from the Greek \200\230to dance \200\231) refers to quick, irregular, semi-purposi ve, and predominantly distal involuntary movements which can impart a \200\230fi dgety \200\231 look to the patient. Th e involuntary movements may sometimes be subtle, and decid ing whether the person is restless within the bounds of normality or whether they have chor ea can be diffi cult. Occasionally the patient may \200\230convert \200\231 the choreiform movement into a voluntary action (for example, a movement of the forearm may be converted into drawing the arm up to check the time on a wrist-watch). Subjects with chorea also have motor impersistence, and this may manifest in some wonder- fully descriptive signs such as the \200\230milk-maid grip \200\231 (inability to exert constant pressure whilst gently g ripping two of the examiner \200\231s fi n- gers) and \200\230trombone tongue \200\231 (ra pid partial protrusion and retrac- tion of the tongue when asked to keep it protruded). Ballism is generally considered as part of the choreic spectrum. Initially the mainly proxi mal, large-amplitude, violent \200\230fl inging \200\231 movements bear little resemblance to chorea, and may be associ- ated with exhaustion as well as injury (to both patient and others). Th ey are usually unilateral and result following vascular insult to the subthalam ic nucleus, or immediately surrounding structures. As time passes, however, the ballistic m ovements subside into a choreiform phenotype. Bilateral ballism is rare and is oft en cause d by metabolic abnormalities such as hyperglycaemia. \227\206 Past medical history: Omit this at your peril, since systemic dis- orders can man ifest as a movement disorder and the temporal association may not always be obvious. Exampl es include pre- vious infections, stroke, and connective tissue disease. I would also inclu de mental illness here, as this may signpost the need for a more detailed drug history, or provide clues to the diagnosis via a prodromal psychiatric disorder (e.g. neuroacanthocytos is, Huntington \200\231s). Tics are abrupt, jerky, non-rhythmic movements (motor tics) or sounds (vocal tics) that are temporarily suppressible by will power. Th ese movements are preceded by a feeling of disc omfort or an urge that is temporarily relieved by the tic. Th e distribution of tics is cla ssically in the head and neck region, and the arms. A tic may be simple (for example, winki ng, wrinkling of the nose) or complex (for example, copying the movements or gestures of ot hers \200\224echopraxia \200\224or touching objects). An ability to volun- tarily suppress the tic is a key feature of this movement disor- der, even though the suppression is associ ated with a build up of \200\230inner tension \200\231. \227\206 Drug history: Always consider drugs, both past and present, as a potential cause for the movement disorder. Tardive dys- kinesias (commonly stereotypic movements, oft en or ofacial in distribution, although a wide spectrum of drug-induced move- ment disorders has been described) may develop aft er relatively short exposure to the off ending agent, but c an persist for years. CHAPTER 2 Approach to History Taking and Examination of the Movement Disorder Patient 7 A full list of medications previously taken by the patient should be obtained from the prim ary care practitioner if necessary. A high index of suspicion is required. While dopamine r eceptor blocking agents are well known to cause drug-induced parkin- sonism and other tardi ve syndromes, agents such as valproate, amiodarone, and cinnarizine are less widely recogni zed to induce drug-induced movement disorders. If relevant, enquire about a history of drug abuse/ \200\230recreational \200\231 drug use. posturing, corrugation on attempting to draw an Archimedes spi- ral, or micrographia. \200 \230Fast micrographia \200\231 is said to be suggestive of pallidal lesions (7). Th ereaft er, the neurological examination should be rigorous and systematic. Watch the eye s whilst the person is holding a tar- get to ascertain whether they remain still, or descri be abnormal movements, such as small side-to-side movements. Th ese move- ments, described aft er their electro-oculographic appearance, are called macrosaccadic square-wave jerks. T h ey are particularly frequent in progressive supranuclear palsy (PSP). Abnormal eye moveme nts may also be helpful diagnostically, particularly sac- cadic movements in a person prese nting with an akinetic \200\223rigid syndrome (8). A normal saccadic eye movement is so fas t that the examiner should only be able to see the pupil at the beginning and the end of th e movement. In PSP the vertical and then horizontal saccadic eye movements are slowed to th e point where the excur- sion of the pupil is clearly visible throughout the movement. In c orticobasal degeneration there is typically a latent period between being given the command to look to one side and the eye move- ment itself (increased saccadic latency), although s accadic speed is near normal when it occurs. In Huntington \200\231s disease, early and con sistent fi ndings are an inability to suppress refl exive glances to novel visual stimuli w hich appear suddenly, and delayed initiation of voluntary saccades. \227\206 Family history: Drawing out the family pedigree can be helpful and avoids confusi on at a later date. False-negative family his- tories may have several reasons, not least p remature death of one or both parents (the cause of which may, in itself, be a clue). Non-p aternity, adoption, and consanguinity may all be relevant, but questioning in such areas ne eds to be sensitively handled, and possibly best deferred to more expert genetic counseling . \227\206 Social history: Smoking may be relevant if a paraneoplastic move- ment disorder i s being considered (3), while the ability of alcohol to suppress tremor, dystonia, and othe r movements should always be established. Th e amount of alcohol necessary to have a benefi - cial eff ect should also be recorded, since most movement disor- ders will be suppressed aft er 10 pints of beer! It is also important to establish the home circumstances (stairs to negotiate, access to the property, etc.), and whether the person is dependent upon socia l services for their care. Where necessary, consider previous travel abroad and sexual hist ory. Eyelid dysfunction, such as reduced blink frequency, blepharo- clonus, or apraxia of eyelid opening should be noted. In the upper limbs, subtle changes in extrapyramidal tone may be exaggerated by reinforcement or synkinesis \200\224that is, asking the person to do somethi ng with the opposite arm, such as pretending to paint a wall. Tremor may be revealed by req uesting the patient to perform serial seven subtractions from 100 with the arms resting com fort- ably on their lap in a semi-prone position. Eliciting progressive decrement of repeti tive movements to determine bradykinesia has been described above. \227\206 Systematic enquiry: A full enquiry is time-consuming, but with practice questions can be targeted to clues obtained in the his- tory. Sleep pattern may be relevant here, if it has not already been determined, along with olfactory and autonomic symptoms. Examination It is oft en helpful to call the patient in rather than relying upon a nurse to do this, since it aff ords the opportunity to watch the per- son walk in a larger area, tu rn, and encounter \200\230obstacles \200\231 such as doorways. More formal assessment of g ait should include the \200\230pull test \200\231 and rotation of the trunk to ascertain a xial rigidity. Th e inabil- ity of a patient to tandem walk for ten steps has been reported to diff erentiate patients with atypical parkinsonism from those with Parkinson \200\231s disease, although this fi nding needs to be independ- ently replicated (1). Examination of cerebellar function may be diffi cult in the presence of involuntary movemen ts and/or bradykinesia, but should still be documented. Th ere may have already been clues from listening to the patient \200\231s speech (slurred dysarthria) or examining slow-pursu it eye movements (jerky slow pursuit and/or gaze-evoked nystag- mus). Subtle heel \200\223t oe ataxia of gait may be observed in the patient with long-standing essential tremor, while ataxia may be noted in MSA, over and above parkinsonian features. Refl exes are oft en unremarkable in many movement disorders, although it is not uncommon t o elicit slightly brisker refl exes on the more aff ected side in early Parkinson \200\231s disease. Th ere may be generalized hyper-refl exia in patients with MSA and PSP, while in neuroacanthocytosis ankle jerks are classically absent. Observation during history taking allows the examiner to ascertain the nature of the moveme nt disorder at rest, and its extent. It may also highlight inconsistencies and distractibil ity in the movement disorder, and reveal excessive sighing (character- istic of multiple sy stem atrophy (MSA)) or other abnormal res- piratory patterns. A brief cognitive assessment may be required, and is most easily performed with pen and paper testing, using a simple sc ale such as the Montreal Cognitive Assessment (MCA) (4) or the Mini-Mental State Examinatio n (MMSE) (5). Th e lat- ter is insensitive to executive dysfunction, so if this is suspecte d the MMSE should be supplemented with the Frontal Assessment Battery (FAB) (6), or compone nts of this battery, such as a go \200\223no go task, verbal fl uency, or Luria test. Allow ance may need to be made for abnormal movement interfering with drawing in these tests, but some indication of global cognitive function can be obtained fairly easily in most people. Observing the person write can be informative and may reveal, for example, dystonic Asking the person to bring a video of their movement disorder can be helpful if it is inter mittent. Alternatively, if no problem is apparent, consider whether the disorder is task sp ecifi c (for exam- ple, a task-specifi c dystonia). In this situation, the patient may need to bring in a relevant piece of equipment, such as their guitar or a golf club, to demonst rate the problem! Diagnostic formulation As recommended in a recent review (1), addressing the following four questions consecutively is a helpful discipline in order to arrive at the correct diagnosi s. Oxford Textbook of Movement Disorders 8 1. Which types of movement disorder are present? On a surprising number of occasions the mo vement disorder is not \200\230pure \200\231 and several phenomena may be present in the s ame patient. Examples include MSA (bradykinesia, ataxia, tremor, polyminimyoclonus), Huntin gton \200\231s disease (chorea, dystonia, bradykinesia), and tar- dive movement disorders r elated to dopamine receptor blocking drugs. subjects with dystonic or essential tremor and abnormal in people with Parkinson \200\231s disease. Even where the clinical signs are unilat- eral, SPECT images not uncommonly show b ilateral abnormality, with reduced tracer binding in both putamens. In patients in whom the re was diagnostic uncertainty between degenerative parkinson- ism and non-degenerative trem or disorders, baseline imaging with 123 I-FP-CIT SPECT has shown 78% sensitivity and 97% sp ecifi city with reference to the \200\230gold standard \200\231 of clinical diagnosis at 3 years, compared with 93% and 46%, respectively, for baseline clinical diagnosis (9). 2. What is the dominant movement disorder type? Having identifi ed the diff erent component s, it is important to ascertain the domi- nant movement type, since this will critically st eer the diff erential diagnosis and investigational pathway. Th is may become more diffi cu lt in advanced disease states, where the initial character- istic movement disorder becomes masked by drug treatments, supervening progression, or secondary complications. Examples i nclude fl orid levodopa-induced dyskinesias in Parkinson \200\231s, or an akinetic \200\223 rigid patient with advanced Huntington \200\231s disease. In such situations collateral his tory, old video footage, obtaining \200\230foreign \200\231 medical records, or repeated e xaminations to capture variability in the condition may all play a part in clarifying the s ituation. Establishing the phenomenology of the movement disorder is essential in order to guide whic h line of more complex investiga- tions should be initiated. Th is avoids a potentially fru itless and expensive \200\230scattergun \200\231 approach. Oft en, the presence of additio nal clinical signs may allow the investigations requested to be refi ned even further. Do not overlook simple tests, such as a full blood count, urea and electrolytes, liver func tion tests, thyroid function tests, blood glucose, or chest X-ray. Th e results from such a screen may yield important diagnostic clues, saving time and money in the long run (and al so potential embarrassment!). 3. What are the associated features? Th e presence of additional \200\230gen- eral medical \200\231 and/or neurological features on examination can provide further clues to the diag nosis, guiding the diff erential diagnosis of the dominant movement disorder. Illustrative exam- ples would be corneal Kayser \200\223Fleischer rings associated with Wilson disease, dysgraphaesthesia associated with corticobasal degeneration or hypothyroidism, and pulmonar y abnormalities associated with some types of benign hereditary chorea. Th ere should be a low threshold to undertake serum caerulo- plasmin estimation, since Wils on disease may present with pro- tean movement disorders and is eminently treatable. At a c ut-off of 0.2g/L, serum caeruloplasmin is a simple screening test, although not very sensit ive, since 5 \200\22320% of homozygous carriers will have normal results. Th us, while an a bnormal result should prompt fur- ther screening (for example, ophthalmological assessment and uri- nary copper excretion), a normal serum caeruloplasmin level does not fully exclude Wilson disease. 4. What is the diff erential diagnosis? Having followed the above three steps it should be possible to draw up a diff erential diag- nosis, using the history to contextualize the sig ns. In some cases the diff erential may be exceedingly short, and a specifi c diagnosis mad e rapidly or a diagnostic test requested. But in other situ- ations it is excellent practic e to list possible diagnoses, starting with the most likely fi rst, since it is this list w hich will guide the fi rst wave of investigations. In the absence of a clear clinical diagnosis, supported or not by a single defi nitive diag nostic test, a staged approach to investiga- tion is recommended. Th us starting with relat ively sensitive but non-specifi c tests such as simple blood tests and an MRI brain scan ca n give useful signposts towards the next stage of more spe- cifi c imaging or genetic studi es, for example. Finally, tissue may be required for diagnostic evaluation in some situatio ns. Management considerations Some key general points that are worth remembering in clinic are illustrated in Box 2.1. Giving the diagnosis is done in a notoriously variable way and can have longer-term impact if done badly. For example, one international study suggested that satisfaction with the explanation of the condition of Parkinson \200\231s disease at diagno sis was a major determinant of subsequent quality of life (10).