Phenomenology,classification,and ...assets.cambridge.org/97811070/24618/excerpt/... · Section I Chapter 1 Generalprinciples Phenomenology,classification,and diagnosticapproachtopatientswith

Section I

Chapter

1General principles

Phenomenology, classification, anddiagnostic approach to patients withmovement disordersMarjolein B. Aerts, Joseph Jankovic, Bart P. van deWarrenburg, andBastiaan R. Bloem

IntroductionIn this introductory chapter, we will discuss the phe-nomenology of movement disorders and its import-ance in classification and diagnostic work-up inpatients presenting with one or more types of move-ment disorders. We will place great emphasis on themost important step in this diagnostic process, whichis the clinical approach based on recognition of thephenomenologic characteristics of the movement dis-order. An accurate clinical description and adequaterecognition of the type of movement disorder (ormultiple types, as is often the case) in turn forms thebasis for a tailored set of ancillary investigations toconfirm the clinical suspicion. Thanks to rapid tech-nological advancements (for example, in the fields ofgenetics and functional imaging), clinicians now havea battery of advanced ancillary investigations at theirdisposal. In this chapter, we will discuss the rationaluse of some of the most commonly required tests.However, we should point out that the clinical patternrecognition remains the vital starting point for anydiagnostic approach, and that many ancillary investi-gations offer relatively little added value over andabove the diagnostic accuracy of a clinical neuro-logical examination (Constantinescu et al. 2009; Seppiand Schocke 2005; Morris and Jankovic 2012).

Here, we propose a step-wise approach that can beused for the evaluation of patients with a movementdisorder. The algorithm, depicted in Figure 1.1,illustrates this diagnostic process (Abdo et al. 2010).The first step is the recognition of the dominant typeof movement disorder that is present in any givenpatient. The second step is to extract all relevant otherneurologic or non-neurological features, both from

the history and the neurological examination. Thesefirst two steps lead to a clinically based syndrome,with associated corresponding differential diagnosis.The third step should consist of a limited set of ancil-lary tests to further narrow down the differentialdiagnosis, and to hopefully prove the diagnosis.Our main purpose here is to illustrate this genericdiagnostic approach, and to give some examples ofhow this would work in clinical practice. It is not ourgoal to elaborate on the complete differential diagno-sis of the various types of movement disorders, norto discuss the clinical characteristics of the manyneurodegenerative disorders that can include one ormore movement disorders as part of their clinicalpresentation. This is discussed in more detail in otherchapters of this book. Elements of the diagnosticapproach illustrated here have been published else-where (Abdo et al. 2010; Aerts et al. 2012). Manyof the movement disorders described below areillustrated by videos (Videos 1.1 to 1.23).

The first step: recognition of thedominant type of movement disorderThe first step is to identify all the various types ofmovement disorders within a given patient, and tothen decide which of these is the dominant one.Some movement disorders occur in relative isol-ation, such as essential tremor (which may beaccompanied by mild ataxia manifested by difficul-ties in tandem gait or parkinsonism, such as resttremor or mild cogwheel rigidity), but not by othermovement disorders. However, the reality is thatmany patients manifest a combination of two or

Movement Disorders in Neurologic and Systemic Disease, ed. Werner Poewe and Joseph Jankovic. Published byCambridge University Press. © Cambridge University Press 2014.

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more movement disorders, and illustrations hereofare abundant. Examples include the presence of dys-tonia in many patients with hereditary and otherforms of parkinsonism or cerebellar ataxia (van Gaa-len et al. 2011), or the combination of ataxia andmyoclonus in Ramsay-Hunt syndrome (Lance 1986).Creutzfeldt-Jakob disease is another example of amixed movement disorder, characterized by variablecombinations of ataxia, myoclonus, and parkinson-ism. With careful observation, the presence of mul-tiple concurrent movement disorders is the rule,rather than the exception.

In such patients, it is essential to define which is thedominant movement disorder. This decision is of par-ticular importance as it greatly affects the next phasesof the diagnostic process. Indeed, the list of diseasesthat can be considered are widely different whenchorea is the predominant sign, as opposed to whendystonia dominates the clinical presentation. Conse-quently, the auxiliary tests that can be considered willalso differ considerably. Note that “dominant” can beinterpreted in two different ways here: either as themovement disorder that is most prominently present(i.e. it “dominates” the clinical presentation, forexample, marked and generalized dystonia in a patientwith DYT1 dystonia), or as a sign that most markedlyaffects – and helps to funnel – the diagnostic consider-ations (i.e. it “dominates” the diagnostic path that is

chosen, for example, presence of cerebellar ataxiawhich, even when subtle, opens the diagnostic ataxiapath). The dominant movement disorder will oftenbe the presenting symptom, although this is notnecessarily the case.

In the next sections, we will first highlight thecharacteristic features of the different types of move-ment disorders, using specific “labels” or “keywords”that may assist clinicians in their clinical patternrecognition. There are two main phenomenologicalcategories that are fairly easy to distinguish: a patienteither displays too little movement (hypokinesia) ortoo much movement (hyperkinesia) (Table 1.1). Thefirst category corresponds to the group of hypokineticdisorders, manifested chiefly by poverty or slownessof movement (bradykinesia), with Parkinson’s diseaseas the classic example. The second group consists ofthe hyperkinetic movement disorders. This lattergroup is much more heterogeneous, and may there-fore create greater challenges in clinical practice. Ithelps to separate this hyperkinetic category into twomain subdivisions: the first includes movements thathave a jerky character; the second includes move-ments without such a jerky character, but with othercharacteristic features (namely rhythmicity in tremor,and abnormal posturing in dystonia) (Table 1.1)(Abdo et al. 2010). The “jerky” group includes myo-clonus, chorea, and tics.

Figure 1.1 Flowchart illustrating theproposed work-up of movementdisorders

Section I: General principles

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Hypokinetic disordersA requirement here is to identify the presence of bra-dykinesia. Bradykinesia is often equated with slownessof movement, or with smaller-than-normal move-ments. However, bradykinesia is in fact defined bythe necessary presence of early fatiguing and progres-sive decrement of both the speed and amplitude ofrepetitive movements, such as sequential rapid fingeror foot tapping (Abdo et al. 2010; Aerts et al. 2012).Without such decrement there is no bradykinesia. Thisis important because slowness of movement occurs asa non-specific sign secondary to dysfunction in manybrain circuitries – for example, in patients with weak-ness, rigidity, or spasticity (“pyramidal slowing”) or asa form of compensation (for example, in patients withataxia who move more slowly to minimize dysmetria).Irregularity of movements or clumsiness is not suffi-cient to fulfill the criterion of ‘bradykinesia’ (Danieland Lees 1993). Indeed, patients with cerebellar ataxia,for example, often also exhibit irregular movements,but lack the classical decrement that is characteristicfor true bradykinesia. Depressed patients may alsomove less or more slowly, but again the decrement intheir repetitive movements is missing.

Whenbradykinesia has been identified convincingly,then the large group of hypokinetic disorders, oftenassociated with rigidity, hence the term “hypokinetic-rigid disorders,” can be considered as the underlyingexplanation. Deciding which of the many hypokinetic-rigid disorders is at play in any given patient depends

of course on steps 2 and 3 of the diagnostic process.Generally speaking, the group of hypokinetic-rigid dis-orders includes Parkinson’s disease (PD) (Videos 1.1 to1.3), including the many genetic variants, and the groupof look-alikes that are often bundled under the umbrellaterm “atypical parkinsonism” (AP). This latter groupof AP includes, among others, multiple systematrophy (MSA), progressive supranuclear palsy (PSP)(Video 1.4), dementia with Lewy bodies (DLB), vascularparkinsonism and corticobasal degeneration (CBD)(Videos 1.5 and 1.6).

The definition of PD is likely to change in theforeseeable future (Stern et al. 2012). For the timebeing, it is practical to define “parkinsonism,” whichaccording to the conventional core UK Brain Bankcriteria includes bradykinesia and at least one of thefollowing: rigidity, rest tremor, or postural instability(Daniel and Lees 1993). A diagnosis of possible PD isthen reinforced by the presence of one or more sup-portive signs, such as asymmetry at onset and duringthe later course of the disease, or a convincing andsustained response to levodopa. A classical, asymmet-ric pill-rolling rest tremor also suggests (but does notprove) the presence of PD, as we shall discuss in moredetail in the tremor section. Besides classification ofPD according to age at onset (young versus late onset),PD may be categorized according to clinical subtypesas either the tremor-dominant form of PD or pos-tural-instability-gait-difficulty (postural instabilitygait disorder (PIGD)) form of PD. The former gener-ally has a slow progression and favorable response to

Table 1.1 Classification of movement disorders

Category Type of movementdisorder

Keywords or “labels”

A. Too littlemovement

BradykinesiaHypokinesiaAkinesia

fatiguing / decrement with repetitive movements;some patients also refer to this motor abnormality as “weakness”;rigidity often accompanies bradykinesia;freezing or motor blocks may be considered examples of akinesia(absence of movement).

B. Too muchmovement

Jerky– Myoclonus– Chorea– Tics

shock-like;continuous jerk-like movements that flow randomly from one body partto another;tics (motor or phonic) are either simple or complex and are typically precededby a premonitory sensation or urge; when repetitive they may appearstereotyped; they are often transiently suppressible.

Non-jerky– Dystonia– Tremor

abnormal posturing, but may be rapid and repetitive (dystonic tremor);rhythmic, oscillatory movement produced by alternating or synchronouscontractions of antagonist muscles.

Chapter 1: Phenomenology, classification, and diagnostic approach

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medications, whereas the PIGD form of PD tends toprogress more rapidly and may be more likely associ-ated with cognitive decline (Jankovic 2008; Stebbinset al. 2013).

The various forms of AP also feature bradykinesia,rigidity, postural instability, and often a tremor (andoccasionally even a pill-rolling rest tremor), buttypically also present with other neurological signs(Fahn et al. 2011). These can either consist of other typesofmovement disorders (such as ataxia or polyminimyo-clonus in MSA), but also other neurological or non-neurological signs (such as motor recklessness in PSP,or oromandibular dyskinesias in drug-induced parkin-sonism). Concurrent dystonia per se does not help in thedifferential diagnosis between PD and AP, becausemany patients with PD (particularly those with a youngage at onset) manifest dystonia; exceptions include fixedlimb dystonia in CBD and early anterocollis in MSA.

Hyperkinetic movement disordersHyperkinetic movement disorders consist ofabnormal involuntary movements that have a broadrange of phenomenology and etiology (Albanese andJankovic 2012). Most of the hyperkinetic disorderscan be categorized into the jerky and the non-jerkymovement disorders (Table 1.1).

Jerky movement disordersMyoclonus

Myoclonus refers to the occurrence of sudden, brief, andabrupt movements (hence the keyword or label shock-like) (Videos 1.7 and 1.8). Physiological myoclonus isexemplified by jerk-like movements experienced bypeople on the brink of falling asleep (sleep or hypnicjerks). Myoclonic jerks are often ‘positive’, i.e. caused bymuscle contraction, but they can also be ‘negative’, dueto sudden loss of tone, also referred to as asterixis.Negativemyoclonus (asterixis) ismost characteristicallyseen in the context ofmetabolic encephalopathy, such ashepatic or uremic encephalopathy, but can also occur insome neurodegenerative disorders. The startle reflex,consisting of abrupt and often symmetrical movementstriggered by sudden (predominantly acoustic) stimuli, isalso considered part of the spectrum of myoclonus.Myoclonus can occur spontaneously (at rest), but isalso often present – and usually worsened – duringmovement (action myoclonus), or can be provoked byexternal tactile or acoustic stimuli (reflex myoclonusand startle responses) (Lozsadi 2012).

There are different ways to classify myoclonus.An important classification method is based on dis-tribution, i.e. focal, multifocal, axial, segmental, orgeneralized. This distribution pattern is an importantclue for the underlying neurological substrate, i.e. cor-tical, subcortical, brainstem, or spinal. In symptomaticmyoclonus, the movement disorder is secondary toother diseases or due to medication. One example ismyoclonus as a side effect of medication (for example,morphine, amantadine, serotonin-uptake inhibitors),or the negative myoclonus seen in patients withhepatic and other metabolic encephalopathies.

Chorea

Chorea classically refers to randomly flowing or“dance-like” movements (Videos 1.9 to 1.11). Despitethis “elegant” dancing character, each of the individualmovements in fact has a jerky nature, but together allthese jerks form a constellation of unpredictable andnon-rhythmic involuntary movements that flow ran-domly from one body part to the next. In the examin-ation room, chorea can be difficult to detect, becausepatients tend to incorporate their choreic movementswithin their normal movement repertoire (so-called“parakinesia”). This can be especially difficult whenchorea is subtle. In such patients, it is important toobserve the patient carefully for a prolonged period oftime, and to note in particular if the patient conveys afeeling of restlessness to the observer (the “fidgets”).Another challenge is the fact that it is often not thepatient who complains, but the family who commenton the fidgety movements of the patient (Walker2011). Chorea can be become very severe, as exempli-fied by the sometimes incapacitating levodopa-induced dyskinesias in patients with PD. Markedchorea involving large amplitude movements of prox-imal limb joints is termed ballism; the term “hemibal-lism” is used when the ballism is unilateral, involvingonly one half of the body (Video 1.12). Hemiballismhas been described classically as an acute, lateralizedsign signaling a subthalamic nucleus infarction, butcan also occur with lesions outside of the subthalamicnucleus and as part of the chorea spectrum in manyother disorders, including later stages of Huntington’sdisease. Note that Huntington’s disease – which is theclassic example of a hyperkinetic movement disorder –also includes bradykinesia as part of the clinical spec-trum, and this bradykinesia can even dominate thepresentation in young patients (the Westphal variant)or in patients with end-stage Huntington’s disease.


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A typical associated feature is motor impersis-tence, which can be identified by asking patients tomaintain a certain body position for a prolongedperiod of time (such as sticking out the tongue, ormaintaining a lateralized gaze), or by identifying afluctuating strength, for example sensing a variablestrength of the palmar grip while holding the patient’shand (the so-called “milkmaid’s grip”).

Tics

The final example of a jerky movement disorder isformed by tics. Like myoclonus and chorea, tics areabrupt and sudden, but tics can be distinguished frommyoclonus and chorea based on two different charac-teristics: tics are largely suppressible, at least for ashort time, and they are typically preceded by an urgeor rising discomfort that is relieved by performing theactual movement (Fahn et al. 2011).

Tics can be divided into simple or complex tics.Simple motor tics (for example, blinking, facial grim-acing, shrugging of shoulders) and simple phonic tics(for example, sniffing, throat clearing) typically involveonly a single muscle or regional group of muscles(Video 1.13). In contrast, complex motor tics includeseveral groups of muscles in a coordinated, sequentialpattern (for example, jumping, skipping) and complexphonic tics result in semantically meaningful utterances(for example, swearing using obscenities or profanities,referred to as “coprolalia”) (Video 1.14). One of themost characteristic features of tics, which differentiatesthis jerk-like movement from other myoclonus andchorea, is the presence of premonitory sensations(Jankovic and Kurlan 2011). Interestingly, tics can beeasily overlooked in the examination room, as thepatient often consciously or subconsciously suppressesthe tics during the doctor’s visit. It may be valuable toobserve the patient in the waiting room, and especiallywhile the patient is walking back after the visit (Zinnerand Mink 2010). Videotaped recordings of patientssitting in front of the camera without a doctor presentcan also be helpful.

Non-jerky movement disordersDystonia

The following is a description of dystonia based on a“consensus” statement (Albanese et al. 2013): “Dystoniais defined as a movement disorder characterized bysustained or intermittent muscle contractions causingabnormal, often repetitive, movements, postures, orboth. Dystonic movements are typically patterned and

twisting, and may be tremulous. Dystonia is often initi-ated or worsened by voluntary action and associatedwith overflow muscle activation.” However, dystoniaitself is by no means static, and is often accompaniedby movements, for example a tremor or other lessrhythmic movements within the same body part. Suchan irregular tremor is called a “dystonic tremor.” Thetremor can also occur in body parts other than the onesaffected by dystonia. For example, about 25 percent ofpatients with cervical dystonia have postural tremor intheir hands, but it is not clear whether that hand tremorrepresents coexistent essential tremor or some othertremor. Dystonia may be considered as an example ofabnormal sensory-motor integration in the brain, asthis helps to explain some relatively unique features ofdystonia (Patel et al. 2013).

Dystonia may be classified according to anatomicdistribution into focal, segmental, generalized, andunilateral (hemidystonia). Focal dystonia often startsas a task-specific movement or posture. Writer’scramp, for example, occurs exclusively during writingand not while performing other tasks with theaffected hand (Video 1.15). Other forms of suchtask-specific dystonia include golfer’s cramp andmusician’s cramp (Ashoori and Jankovic 2008; Dhun-gana and Jankovic 2013). Such forms of dystonia canbe more difficult to demonstrate in the examinationroom, but it can be helpful to ask the patient to bringalong the device that provokes the complaints, such asa golf club or musical instrument, and to demonstratewhat happens during the particular activity. Otherforms of dystonia may not be exclusively task-specific,but can still manifest a variable degree of severitydepending on the specific task, and many forms ofdystonia vary in intensity depending on the specificposition of the affected body part. Examples include aworsening of jerks when patients rotate their headaway from the direction towards which the dystonicmuscles are pulling the head, or a variation in dys-tonic intensity in the hands when patients are asked toslowly rotate their outstretched hands. Anotherstriking example of task-specificity relates to gait,which can be severely affected by dystonia, but withsurprisingly fewer problems during running orwalking backwards. Besides task-specific dystonia,there are examples of task-specific tremor, such asprimary writing tremor. Indeed, an overlap betweentask-specific tremor and dystonia is suggested by acase report of a patient with unilateral writing tremor(without dystonia), who later developed a true writer’s


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cramp in the other hand (Pita Lobo et al. 2013). Onecharacteristic element of dystonia is the beneficialeffect of a sensory trick (such as a gentle touch tothe affected body part), which can markedly alleviatethe dystonic manifestation. Another feature of dysto-nia is the development of abnormal posture or move-ment with voluntary activity of the contralateral bodypart, the so-called “mirror dystonia” (Video 1.15).

Examples of segmental dystonia include cranial-cervical dystonia, manifested by blepharospasm, oro-mandibular dystonia, and cervical dystonia (Videos1.16 and 1.17). Usually idiopathic, this form of dysto-nia, termed tardive dystonia, may occur as a result ofexposure to dopamine-receptor blocking drugs (neu-roleptics). Tardive dystonia also typically involves thetrunk and upper limbs (Video 1.18). DYT1 dystonia,an autosomal dominant dystonia of childhood-onset,is an example of generalized dystonia (Video 1.19).

The term athetosis was reintroduced by JohnMorrisin an account describing several characteristic cases thatfulfilled the original historical descriptions of this phe-nomenon (Morris et al. 2002). Although athetosis issometimes classified as a form of dystonia, it also hasthe characteristics of slow chorea in that the slow,wringing, predominantly distal movements are not pat-terned, which is the characteristic feature of dystonia,but are unpredictable in their direction and character.

In daily clinical practice, three factors help torefine the clinically based differential diagnosis andto guide the diagnostic path: the distribution of thedystonic signs (focal, multifocal, segmental, hemidys-tonia, or generalized); the age at onset; and the pres-ence of other neurological or non-neurologicalfeatures (Albanese et al. 2013). Commonly used etio-logical categories include primary, secondary, anddystonia-plus syndromes. Primary dystonia, such aswriter’s cramp, is often pure and, besides tremor, isnot accompanied by other movement disorders. Incontrast, dystonia-plus syndromes are typicallyaccompanied by other neurological signs and symp-toms, mostly myoclonus and parkinsonism. Second-ary dystonia can be seen in the context of a wide arrayof focal or more generalized brain lesions, such asstroke, demyelinization, and neurodegeneration withbrain iron accumulation (NBIA) (Klein and Ozelius2002; Ozelius et al. 2011; Schneider et al. 2013).

Tremor

Tremor is characterized by rhythmic, alternating(oscillatory) movements that can involve almost any

body part, including the head, chin, arms, and legs.Although the key descriptor is “rhythmic,” this rhyth-micity can be difficult to observe with the naked eye,because variations in tremor amplitude can create aseeming irregularity. Tremor can also be distin-guished based on its frequency, but this is not veryhelpful in clinical practice, because frequencies aredifficult to estimate with simple clinical observation.Moreover, the frequency spectra overlap considerablyacross the various tremor syndromes. In difficultcases, tremor recording, using clinical neurophysio-logical techniques (EMG, accelerometers, or both),can help to identify true rhythmicity (or multipleco-existent rhythms) and to determine the frequency(Deuschl et al. 1998; Elble and Deuschl 2011).

Tremor is usually classified according to thesituation in which the tremor occurs. Rest tremor isdefined as a tremor occurring in a limb that is com-pletely at rest, hence, it can only be established withcertainty if the limb is completely supported againstgravity and not moving actively. Voluntary move-ments often diminish the rest tremor, and sometimesthe tremor fully disappears. However, after assuming anew posture, the rest tremor can re-appear with asmall delay, and this has been termed the re-emergenttremor (Jankovic et al. 1999). This re-emergent resttremor, which has the same frequency (about 4 to 6Hz) as the rest tremor, must be distinguished from apostural tremor, which appears immediately afterassuming a new posture. Action tremor appears withvoluntary movements, and can be divided into pos-tural tremor, kinetic tremor, and intention tremor.The differentiation between kinetic tremor and inten-tion tremor lies in the amplitude of the tremor in thecourse of the movement trajectory. With intentiontremor, the amplitude increases when approachingthe target, whereas in kinetic tremor the amplituderemains fairly constant throughout the trajectory.Postural tremor is exemplified by essential tremor, anautosomal dominant tremor involving the hands, head(neck), face, voice, trunk, and legs that typicallyimproves with alcohol and beta blockers (Video1.20). A special category is orthostatic tremor, whichis a high frequency (15 to 20 Hz) tremor of the legsthat occurs when standing still, and which causes asubjective and progressive sense of instability. Thisinstability typically – but not always – disappears whenthe patient starts walking, even though the tremor canstill be detected using EMG during walking (Williamset al. 2010). This tremor has a fine amplitude and may


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not be seen but can be palpated or auscultated with astethoscope. It can be heard as a characteristic “heli-copter sound” in any muscle that acts against gravity(so also in the triceps brachii muscle when the subjectis supporting the body weight with the arms). The lastcategory is psychogenic tremor, which is characteris-tically inconsistent, sensitive to distraction, and whichvaries in frequency when the subject is asked to makerhythmic movements with other body parts (thepsychogenic tremor adopts the voluntarily imposedtremor frequency, ‘entrainment’) (Edwards and Bhatia2012; Hallett et al. 2011).

In addition to the above-described tremors, thereis a group of disorders that can be associated withslow tremor (1 to 3 Hz). These include Holmes’tremor, associated with lesions in the cerebellar out-flow pathways, and myorhythmia, manifested by slowtremor in the face (as seen typically in Whipple’sdisease) or limbs, suggestive of brainstem pathology,as in anti-NMDA receptor encephalitis (Baizabal-Carvallo et al. 2013).

Other movement disordersIn addition to the above disorders, there are severalothers that should be considered in the differentialdiagnosis. These include stereotypies, such as seen intardive dyskinesia (Waln and Jankovic 2013; Video1.21), peripherally induced movement disorders,such as hemifacial spasm (Yaltho and Jankovic2011; Video 1.22), and paroxysmal dyskinesias(Bhatia 2011).

The second step: frommovementdisorder to differential diagnosisThe second step is to proceed from the set of identi-fied movement disorder, based largely on phenomen-ology, to the differential diagnosis. Taken together,the pattern of one or more movement disorders, plusthe associated symptoms and signs, will lead to aclinically based (differential) diagnosis based on over-all pattern recognition.

For example, patients with ataxia telangiectasiamay demonstrate not only ataxia, but also a varietyof other movement disorders in addition to telangiec-tatic vessels in the eyes, multiple carcinomas, andrecurrent infections. Another illustrative examplewas discovered recently, in a clinically based

description consisting of a combination of early-onset ataxia, myoclonic seizures, skeletal deformities(in particular scoliosis), and a mildly elevated plasmaCK. As it turns out, this specific ‘syndrome’ fits with adiagnosis of North-Sea myoclonus, caused by muta-tions in the Golgi SNAP receptor complex 2 gene(GOSR2) (Corbett et al. 2011). Another example isthe expanding group of disorders categorized asNBIA, which can be manifested by childhood- oradult-onset hypokinetic or hyperkinetic movementdisorders (Dusek et al. 2012).

The third step: further narrowing thedifferential diagnosis or proving thediagnosisThe combined results of the first two steps can some-times be a specific constellation of signs and symp-toms that may lead directly to a diagnosis by patternrecognition. There are cases where no diagnostic testsare needed, for example in a patient presenting with aslowly progressive, asymmetrical hypokinetic-rigidsyndrome, with a classic pill-rolling rest tremor andan excellent response to levodopa. Most guidelinesrecommend against routine MRI brain scans inpatients presenting with otherwise typical Parkinson’sdisease (Cheng et al. 2010).

Often, however, the situation is not so clear-cutand further investigations are necessary to reach thefinal diagnosis. Examples of tests include laboratoryinvestigations, structural or functional neuroimaging,neurophysiology, or specific genetic tests. Rather thanusing everything we have at our disposal in a shotgunapproach, the ancillary investigations should beguided by the designated dominant movement dis-order, as discussed earlier. A multitude of ancillarytests can be requested. For many reasons, tests shouldbe chosen carefully and targeted to the main differen-tial, with an emphasis on potentially treatable condi-tions such as Wilson’s disease. Many tests haveincomplete sensitivity and specificity, which we needto be aware of. It is impossible to discuss all possibletests for the entire spectrum of movement disordersand the section below should not be regarded as adiagnostic manual. Rather, we attempt to touch onthe important categories of investigations in this area,with specific examples. Finally, we would like tounderscore two important diagnostic ‘weapons’: time(i.e. wait and see how the disease progresses, and


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whether new diagnostic signs arise); and treatmentresponse (as in the example of a patient with possibleParkinson’s disease).

Laboratory testsRoutine blood testsRelatively simple laboratory tests include copper andceruloplasmin levels to screen for Wilson’s disease,alpha-fetoprotein for ataxia telangiectasia or its vari-ants, vitamin deficiencies such as vitamin E deficiencyin ataxia or B12 in elderly patients with gait disorders,ruling out uremia in case of myoclonus, and creatinekinase for neuroacanthocytosis.

Metabolic screeningSeveral errors of inborn metabolism can lead tomovement disorders. Often, these diseases present inchildhood, and usually the phenotype conveys muchmore than just the movement disorder, includingcognitive deterioration and systemic features. Onecould consider lactate for mitochondrial disorders,cholestanol for cerebrotendinous xanthomatosis, verylong chain fatty acids for peroxisomal disorders suchas adrenoleukodystrophy, and lysosomal enzymes forGaucher’s disease.

MicrobiologySome central nervous system infections can result inmovement disorders, the best known example ofwhich is perhaps Whipple’s disease, which requirespositive PCRs for T. whipplei in blood and CSF (plusin bowel biopsy). Testing for HIV should be con-sidered in case of progressive and poorly understoodneurodegeneration.

Immunological testsAntibody screening should particularly be consideredin cases of more subacutely developing movementdisorders. In addition to the “classic” paraneoplasticantibodies, an increasing number of other antibodiesis being identified in immune-mediated central ner-vous system diseases, often non-paraneoplastic. Theseinclude, for example, anti-VKGC and anti-NMDAantibodies. Anti-GAD antibodies are associated withstiff person syndrome (Video 1.23). Positive antibodiesagainst thyroid peroxidase (TPO) point to a diagnosis

of Hashimoto encephalopathy (or SREAT) in the set-ting of subacute ataxia and myoclonus. Lastly, celiacdisease can be complicated by ataxia and chorea.Laboratory screening includes checking for antibodiesagainst gliadin, endomysium, and tissue transglutami-nase (Baizabal-Carvallo and Jankovic 2012).

Cerebrospinal fluid analysisCSF examination can rule out a central nervoussystem infection when suspected, and 14–3–3 proteinand tau levels are required when Creutzfeldt-Jakobdisease is considered. Studies also suggest that analyz-ing cerebrospinal fluid is of added value in the contextof differentiating between the degenerative parkinso-nian disorders. In PD, CSF biomarkers are generallywithin the normal range, while in MSA, CSF levels oftau protein, phospho-tau protein, and the neurofila-ments are elevated. In PSP, only the neurofilamentsmight be slightly raised. In DLB patients, beta-amyloid-42 concentrations can be lower, whereas theneurotransmitter metabolites are elevated (Aerts et al.2011a; Aerts et al. 2011b; Constantinescu et al. 2009).However, the utility of CSF studies for the individualpatient currently remains very limited.

Genetic testsThe number of gene mutations identified in the vari-ous movement disorders has increased tremendouslyover the past years. At present, the speed at which thisoccurs is amazingly high due to the availability ofnext-generation sequencing platforms. Already, thereare over twenty genetic subtypes of PD and of dysto-nia, almost sixty for hereditary spastic paraplegia, andabout forty for the dominant ataxias. The downside isthat it is almost impossible for clinicians to keep trackof these developments. Also, current classificationsystems are flawed and not suitable for selecting theappropriate genetic tests (Marras et al. 2012). Whilewe are still mostly requesting a limited number ofmolecular tests (with traditional Sanger sequencing),some labs already offer parallel sequencing of manygenes at once (in packages for a specific movementdisorder, for example “ataxia”) or even diagnosticexome sequencing. This will very soon change ourapproach to patients with a (suspected) movementdisorder and genetic tests such as whole exome ofgenome sequencing will be performed at earlier stagesin the diagnostic work-up.


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NeuroimagingNeuroimaging is often the very first step in thediagnostic work-up, and the first purpose is to ruleout (or demonstrate) that the movement disorder iscaused by structural abnormalities. Examplesinclude a cerebellar tumor causing ataxia, a pallidalinfarction leading to contralateral hemidystonia,extensive vascular white matter lesions in lowerbody parkinsonism (Mehanna and Jankovic 2013a)(Figure 1.2a), demyelinating diseases associatedwith movement disorders (Mehanna and Jankovic2013b), and NBIA (Dusek et al. 2012; Schneideret al. 2013).

Secondly, neuroimaging might show abnormal-ities that are specific for a disease or a limited number

of diseases. We have enumerated some of these MRIabnormalities in Table 1.2 (Mahlknecht et al. 2010).More advanced techniques include diffusion weightedimaging and diffusion tensor imaging. These tech-niques may detect changes in the microstructuralintegrity of nervous tissue earlier than conventionalT1- or T2-weighted MRI. Studies have demonstratedthat based on the regional apparent diffusion coeffi-cient (ADC), MSA-P and PSP (Nicoletti et al. 2006;Paviour et al. 2007), PSP and PD (Nicoletti et al.2008), and MSA-P and PD (Köllensperger et al.2008) can be discriminated, although overlappingADCs have also been described, which questions theutility for the individual patient (Nicoletti et al. 2006;Seppi et al. 2003).

Figure 1.2 MRI images – axial andsagittal. (a) Axial flair image depictingwhite matter lesions and cortical atrophyin a patient with vascular parkinsonism;(b) axial T2 image depicting a putamenalrim on both sides in a patient with MSA;(c) axial T2 image demonstrating the“hot cross bun sign” in a patient withMSA; and (d) sagittal T2 image showingmidbrain atrophy with the“hummingbird” sign in a patient with PSP.Source: MRI images kindly provided byF. J. A. Meijer, MD.


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Functional imagingPositron emission tomography (PET) and single-photon emission computed tomography (SPECT)are scintigraphic techniques to visualize the neuro-transmitter systems in the brain. With this approach,we can quantify the integrity of the dopaminergicsystem, the most common application of these tech-niques in the movement disorder field.

The post-synaptic part can be visualized withan IBZM-SPECT scan, whereas the pre-synaptictrajectory can be visualized with SPECT scans usingdopamine transporter (DAT) ligands such as [123I]beta-CIT, [123I]FP-CIT, or [99mTc]-TRODAT-1, and/or F(18)-DOPA-PET or 11C raclopride-PET scans(Figure 1.3). In PD, as well as in the other degenera-tive parkinsonian disorders, there is a loss of dopami-nergic neurons in the substantia nigra, and suchscintigraphic images will not distinguish betweenthese etiologies. When the differential includes vascu-lar parkinsonism, dystonic tremor, essential tremor,

or drug-induced parkinsonism, such scans are usefulas these are normal in these diseases. Table 1.3 listswhether DAT scan is abnormal in a variety of move-ment disorders (Brooks 2010).

Clinical neurophysiologyFirst, polymyographic recording with surface elec-trodes can assist in differentiating between some ofthe hyperkinetic movement disorders (for example,tremor versus myoclonus) and between organic andpsychogenic movement disorders (for example,demonstrating entrainment in psychogenic tremor),and can sometimes actually prove a diagnosis (forexample, a 15 to 20 Hz leg tremor during standing –orthostatic tremor). Secondly, neurophysiologicalmeasurements can further explore the neuroanatom-ical origin of a movement disorder, for example,distinguishing between a cortical, brainstem, spinal,or psychogenic myoclonus. In cortical myoclonus,one would expect short EMG bursts (less than 50

Table 1.2 Examples of movement disorders with rather specific features on conventional brain MRI

Disease Feature Caused by

Huntington’s disease Atrophy of the caudate nucleus

Pantothenate kinase-associatedneurodegeneration (PKAN)

Eye-of-the-tiger Bilateral T2-hypointensity of the medial globus pallidus(iron) with symmetric hyperintensities (cystic changes) inthe center thereof

Wilson’s disease Face of the giant panda More pronounced low intensity of the red nuclei andsubstantia nigra caused by abnormal hyperintensity ofthe surrounding tissue within the midbrain tegmentum(on T2)

Parkinson’s disease None None

Multiple system atrophy Pallidal hypointensity andputaminal hyperintense rimHot cross bun signOther

Darkened putamen (due to atrophy) with linearhyperintensity of the lateral border (T2) (Figure 1.2b)Cruciform hyperintensity within the pons causeddegeneration of ponto-cerebellar fibers (T2) (Figure 1.2c)Cerebellar atrophyAbnormal signal in the middle cerebellar peduncle (T2)

Progressive supranuclear palsy Midbrain>>pons atrophy,“Hummingbird,” “Penguin,”or “morning glory” signOther

Atrophy of the midbrain with relatively preserved volumeof the pons (sagittal T1/T2)Reduced midbrain diameter on transverse images(Figure 1.2d)Thinning of superior cerebellar peduncles

Corticobasal degeneration Asymmetric cortical atrophy

Parkinsonism due tomanganese intoxication

High T1-signal of bilateral pallidum


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