Muscle Selection for Focal Limb Dystonia

toxins

Review Muscle Selection for Focal Limb Dystonia

Barbara Illowsky Karp 1,* and Katharine Alter 2 ID

1 Combined NeuroScience IRB, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA 2 Department of Rehabilitation Medicine, National Institutes of Health, Bethesda, MD 20892, USA; [email protected] * Correspondence: [email protected]

Received: 23 October 2017; Accepted: 13 December 2017; Published: 29 December 2017

Abstract: Selection of muscles for botulinum toxin injection for limb dystonia is particularly challenging. Limb dystonias vary more widely in the pattern of dystonic movement and involved muscles than cervical dystonia or blepharospasm. The large variation in how healthy individuals perform skilled hand movements, the large number of muscles in the hand and forearm, and the presence of compensatory actions in patients with dystonia add to the complexity of choosing muscles for injection. In this article, we discuss approaches to selecting upper and lower extremity muscles for chemodenervation treatment of limb dystonia.

Keywords: limb dystonia; writer’s cramp’ musician’s cramp; lower limb dystonia; runners dystonia; chemodenervation; botulinum toxin; muscle selection; gait testing

1. Introduction

1.1. Background, Genetics, Pathophysiology: Focal Upper Limb Dystonia The current definition of dystonia describes it as “a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation [1]”. These features are exemplified by focal hand dystonia, especially those that are task-specific. Axis I of the 2013 revised consensus criteria for dystonia includes five descriptors: age at onset, body distribution, temporal pattern, and coexistence of other movement disorders and other neurological manifestations [1]. Within this nosology, focal hand dystonia is a condition of early-late adulthood; the usual age of onset is in the 4th–5th decade [2,3]. Limb dystonia, is “focal” when limited to a single limb or part of a single limb. However, the limbs are often involved in hemi-, segmental, multifocal, and generalized dystonias. Even in patients with writer’s cramp, the proximal arm muscles including the shoulder girdle may be involved and symptoms can be bifocal, affecting both hands. Adult onset focal limb dystonia frequently evolves to its full expression over weeks to months. Once fully manifest, adult onset limb dystonia tends to be static but can progress, even years later. Spread tends to be towards proximal muscles and to the contralateral limb [4–6]. Tremor, similar in nature to essential tremor, is a not uncommon accompaniment to limb dystonia [7]. Regarding axis II of the current dystonia classification schema, which characterizes dystonias based on etiology, the limbs are involved in many symptomatic dystonias including those associated with structural nervous system pathology. Many focal limb dystonias, unassociated with other neurologic signs, are currently considered sporadic, although as genes associated with dystonia continue to be identified, they are likely to be reclassified as inherited. About 25% of those with focal hand dystonia have a family history of dystonia [8–10]. Known genetic disorders can be identified

Toxins 2018, 10, 20; doi:10.3390/toxins10010020 www.mdpi.com/journal/toxins Toxins 2018, 10, 20 2 of 14 in some patients with apparently focal limb dystonia, such as dopa-responsive dystonia, DYT6 and others [11,12]. An association has also been reported for variants in the gene for arylsulfatase G with the focal task-specific dystonias writer’s cramp (WC) and musician’s cramp (MC) [13,14]. The pathophysiology of WC and MC has been particularly well-studied, as the limb in task-specific dystonia can be evaluated without activation of the dystonia, allowing comparison between dystonic and non-dystonic actions. In addition, the affected hand can be compared to the unaffected hand. Studies in WC and MC have shown a loss of inhibition at multiple levels and enhanced cortical plasticity [15–17]. Since many of these changes can be found bilaterally, they are trait states and do not fully explain the manifestation of dystonia. Focal limb dystonia of the upper or lower extremity is often task-specific, present only during the performance of a particular activity. In task-specific dystonia, other activities, including those using the same muscles, are performed normally. In task-specific focal limb dystonia, the muscles affected typically encompass those used during a repetitive activity. Thus, writer’s cramp is the most common focal hand dystonia, initially reported in the 18th century as “scrivener’s palsy” [18]. Similar symptoms in other professions led to the term “occupational palsies”, affecting tailors, cobblers, musicians and others performing skilled, usually fine-motor, repetitive tasks [7,19]. Estimates of the prevalence of focal hand dystonia range from 7–15/100,000 population [20,21]. Musician’s dystonia is thought to affect up to 1% of professional musicians [22]. Unlike most other adult onset focal dystonias that typically affect women, writer’s cramp affects men and women about equally, while musician’s dystonia is more prevalent in men [23]. Focal hand dystonia is associated with a diminished quality of life and can end careers of professional musicians [24,25]. Over-practice or overuse likely contributes to the emergence of dystonic symptoms, which may be a manifestation of a genetic predisposition. Personality factors may also contribute to its expression. In particular, musician’s dystonia has been associated with more anxiety, stress and perfectionism compared to musicians without dystonia [26].

1.2. Treatment of Focal Hand Dystonia Even before seeking medical attention, many patients with focal hand dystonia try to alter their performance of affected tasks, equipment or instruments. Those with writer’s cramp try altering their grip on the pen or new, often thicker, pens. Musicians try to adjust their technique or instrument. These approaches rarely provide more than minimal to mild beneﬁt. Oral medications are similarly ineffective. Given the lack of effective alternatives, botulinum toxin has become the treatment of choice for focal hand dystonia [27,28].

1.3. Botulinum Toxin for Focal Hand Dystonia There are many aspects to consider when approaching injection with botulinum toxin including selection of toxin type and brand, toxin dose and dilution. There are currently four marketed brands of toxin in the US, abotulinumtoxinA (Dysport®, IPSEN, Basking Ridge, NJ, USA), incobotulinumtoxinA (Xeomin®, Merz North American Headquarters, Raleigh, NC, USA), onabotulinumtoxinA (Botox®, Allergan Inc., Irvine, CA, USA) and rimabotulinumtoxinB (Myobloc®, Solstice Neurosciences, LLC, Louisville, KY, USA). None are approved by the U.S. Food and Drug Administration (FDA) for the treatment of focal hand dystonia (FHD) and there is little information available that informs the choice of toxin. Thus, toxin selection is frequently predicated on practitioner preference and familiarity, cost and convenience. Similarly, while there are dosing guidelines for the toxins approved for upper limb spasticity, there is little consensus information on dosing for focal hand dystonia, although the FHD doses are typically lower than those used to treat spasticity in the same muscles. The mean starting dose in one retrospective series of botulinum toxin (BoNT) for FHD was 25 units of onabotulinumtoxinA; optimal effective dose among patients continuing injections for at least 10 years was 50 units [3,29]. A retrospective series of 56 musicians treated for a mean 23 months reported a mean starting dose of abobotulinumtoxinA of 127 units and Toxins 2018, 10, 20 3 of 14

ﬁnal dose of 112 units [29]. In general, dosing starts at the low end of the potentially therapeutic range with titration over successive injection sessions until beneﬁt is maximized and weakness or other adverse effects are minimized [3]. The total dosing is, importantly, based at least in part on the particular muscles to be injected and the number of muscles to be included in a given session.

2. Muscle Selection for Upper Limb Botulinum Toxin Injection A key component of the key to success of botulinum toxin therapy for dystonia is appropriate selection of muscles for injection. Muscle selection in FHD is not straightforward: the forearm alone has approximately 20 muscles, including some muscles where separate component fascicles mediate individual digit actions. In addition, one or more than one muscle may contribute to the same movement or action. Table1 delineates major muscles contributing to different acting on elbow, wrist and ﬁnger joints (Table1).

Table 1. Muscles of upper extremity; primary muscles are in bold.

Elbow Flexion Extension biceps triceps brachialis anconeus brachioradialis Pronator teres ECR FCR Pronation Supination Pronator teres supinator Pronator quadratus biceps

Wrist Flexion Extension FCR ECR FCU ECU FDS EDC FDP EIP Palmaris longus EDM FPL EPL Radial deviation Ulnar deviation FCR FCU ECR ECU Fingers MP ﬂexion extension FDS EDC FDP EDM lumbricals EIP interossei lumbricals interossei PIP ﬂexion PIP extension FDS EDC FDP EIP abduction adduction Dorsal interossei Palmar interosei EDC FDS EIP FDS ADM Toxins 2018, 10, 20 4 of 14

Table 1. Cont.

Thumb flexion Extension proximal proximal FPB EPB OP APB FDI distal distal FPL EPL APL abduction adduction APL Add Pol APB FDI opposition OP ABP FPB FPL Add pol Add Pol: adductor pollicis; ADM: abductor digiti minimi; APB: abductor pollicis brevis; APL: abductor pollicis longus; ECR: extensor carpi radialis; ECU: extensor carpi ulnaris; EDC: extensor digitorum communis; EDM: extensor digiti minimi; EIP: extensor indicis propius; EPB: extensor pollicis brevis; EPL: extensor pollicis longus; FCR: flexor carpi radialis; FCU: flexor carpi ulnaris; FDI: first dorsal interosseous; FDP: flexor digitorum profundus; FDS: flexor digitorum superficialis; FPB: flexor pollicis brevis; FPL: flexor pollicis longus; OP: opponens pollicis.

Hand movement is intricate and tightly coordinated. Thus, the muscle interactions underlying fine hand motor functions are complex; the distortion of muscle interaction in dystonia adds to that complexity. The identification of which muscles are involved in dystonic movements is further complicated by the presence of compensatory muscle activity, which is often subconscious. Many patients have difficulty identifying which of their muscles are actively dystonic and which are involuntarily trying to counteract the dystonia. Muscle discomfort is similarly not a straightforward indication of dystonia, as it can also arise both from excessive dystonic contraction and anti-dystonic compensation. The first line of approach to muscle selection is a careful history. The pattern of abnormal contraction at the onset of symptoms should be discussed and may be a clue to the primary dystonic involvement. The patient should be questioned about how and which activities are solely or disproportionately affected and to report where they feel muscle tension. They should be asked about their perception of which areas are involved and direction of movement distortion. The next line of approach is physical examination. A careful neurologic examination should be done at least on initial evaluation to rule out non-dystonic conditions as a cause of the symptomatology. Abnormal sensory loss, reflex changes or weakness would indicate a non-dystonic disorder. The examination can then focus on the dystonia. The key to being able to interpret the findings on examination is a knowledge of functional anatomy, including which muscles cross each joint and can contribute to the pattern of posture and movement observed [30]. The patient should be examined initially at rest as, when FHD is severe, abnormal posture is present at rest (Figure1). There may be decreased arm swing or dystonic posturing on walking. Toxins 2018, 10, 20 5 of 14 Toxins 2018, 10, 20 5 of 13

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Figure 1. Hand dystonia at rest: posturing of both hands. Figure 1. Hand dystonia at rest: posturing of both hands. Next, the examinationFigure should 1. Hand focus dystonia on the atactivi rest:ties posturing provoking of both the hands. dystonia. The patient should Next,first be the asked examination to perform shouldthe activities focus as on normally the activities as possible provoking and then the again dystonia. using any The adaptations patient should first beor askedcompensatoryNext, to the perform examination actions the activitiesemployed. should focus as During normally on the the activi asexam possibletiesination provoking and with then theactions, dystonia. again the using patientsThe anypatient should adaptations should be or compensatoryaskedfirst be to asked point actions to out perform employed.anatomic the areasactivities During of tension as the normally examination and to as describe possible with how and actions, thethen dystonia again the patients using alters any shouldtheir adaptations intended be asked to pointpostureor out compensatory anatomic or performance. areas actions of tensionemployed. Throughout and During to describethese the evalexam howuations,ination the dystonia withthe practitionactions, alters the theirer patientsshould intended shouldhave posture anbe or performance.understandingasked to point Throughout outof whatanatomic thesethe actionareas evaluations, oflooks tension like theand wh practitioner ento describeperformed how should by the unaffected dystonia have an altersindividuals understanding their intended and the ofwhat patient’sposture orintended performance. pattern. ForThroughout example, thesea typical eval tripoduations, pen the grip practition has the erfingers should flexed have at thean the action looks like when performed by unaffected individuals and the patient’s intended pattern. metacarpalunderstanding and ofinterphalangeal what the action joints looks (Figure like 2).wh en performed by unaffected individuals and the For example, a typical tripod pen grip has the fingers flexed at the metacarpal and interphalangeal patient’s intended pattern. For example, a typical tripod pen grip has the fingers flexed at the jointsmetacarpal (Figure2). and interphalangeal joints (Figure 2).

Figure 2. Typical tripod pen grip in a right-handed writer.

In a right-handed individual,Figure 2. Typical the wrist tripod tends pen grip to bein aslightly right-handed flexed writer. when starting a sentence on the left side of a pieceFigure of paper 2. Typical and extends tripod as pen th gripe pen in moves a right-handed across the writer. paper to the right. In left- handedIn awriters, right-handed the wrist individual, may be morethe wrist flexed tends so that to be the slightly writing flexed is not when smeared starting as the a sentence pen moves on Infromthe a left right-handed left side to ofright. a piece However, individual, of paper in and theboth wristextends left- tendsand as right-handers,th toe pen be slightly moves theacross flexed position the when paper of startingwrist to the and aright. sentenceindividual In left- on the left sidefingershanded of a is writers, piece highly of thevariable paper wrist and during may extends be writing. more as flexed theTo fully pen so movesthatvisualize the acrosswriting the posture the is not paper of smeared all to fingers the as right. duringthe pen In writing left-handedmoves writers,whenfrom the leftevaluating wrist to right. may writer’s However, be more cramp,flexed in boththe so writing left- that and the hand right-handers, writing should is be not observed the smeared position from as ofboth the wrist pen dorsal and moves and individual palmar from left to right.aspects.fingers However, is Additional highly in both variable observation left- during and right-handers, fromwriting. above To fullythe the writing visualize position surface the of posture wrist will enable and of all individual fingersbetter visualization during fingers writing is of highly wrist flexion or extension. Inspection from the front allows identification of proximal arm and limb variablewhen during evaluating writing. writer’s To fullycramp, visualize the writing the hand posture should of allbe observed fingers during from both writing dorsal when and palmar evaluating girdleaspects. position. Additional It is observationimportant to from check above for forearm the writing pronation surface and will supination enable better as well visualization as wrist and of writer’s cramp, the writing hand should be observed from both dorsal and palmar aspects. Additional fingerwrist flexion deviation. or extension. Inspection from the front allows identification of proximal arm and limb observationgirdleDuring position. from examination, above It is theimportant writing muscle to surface checkselection for will forearmcan enable be aided pronation better by visualization the and examiner supination of applying wrist as well flexion pressure as wrist or extension. thatand Inspectioncountersfinger fromdeviation. the the apparent front allows dystonic identification movement. ofFor proximal example, arm in a and patient limb where girdle there position. is concern It is important that to checkpronation forDuring forearm is contributingexamination, pronation tomuscle dyst andonic supination selection disability, can as thebe well aidedexaminer as wrist by thecan and examinerapply finger pressure deviation.applying in the pressure antagonist that Duringdirectioncounters examination, theof apparentsupination dystonic musclewhile movement.the selection patient can Forwrites beexam aidedorple, performs in by a thepatient examinerthe wheredystonic-eliciting there applying is concern pressureactivity. that that countersImprovementpronation the apparent is contributing with counter-pressure dystonic to dyst movement.onic indicates disability, For likely the example, involvementexaminer in can a patientof apply the agonist pressure where muscle. therein the isantagonist concern that pronationdirectionWhenever is contributingof supination possible, to musicianswhile dystonic the disability,shouldpatient bewrites theevaluated examineror performs playing can the applytheir dystonic-eliciting instrument pressure inusing the activity. antagonistmusic directionselectedImprovement of supination to provoke with whilecounter-pressure the dystonia. the patient Musicians indicates writes and or likely performs othe involvementrs with the occupational dystonic-eliciting of the agonist hand muscle. dystonia activity. should Improvement be askedWhenever about their possible, usual musiciansor intended should upper be limb evaluated position playing when playingtheir instrument as approaches using tomusic the with counter-pressure indicates likely involvement of the agonist muscle. instrumentselected to provokeand technique the dystonia. vary widely. Musicians As andwell othe as appreciatingrs with occupational what the hand intended dystonia or should“normal” be Whenever possible, musicians should be evaluated playing their instrument using music selected asked about their usual or intended upper limb position when playing as approaches to the to provokeinstrument the dystonia.and technique Musicians vary widely. and othersAs well with as appreciating occupational what hand the dystoniaintended shouldor “normal” be asked about their usual or intended upper limb position when playing as approaches to the instrument and technique vary widely. As well as appreciating what the intended or “normal” posture is for Toxins 2018, 10, 20 6 of 14 performing the affected activity, it is helpful for the practitioner to be knowledgeable about commonly Toxins 2018, 10, 20 6 of 13 affected muscles for different types of FHD. In writer’s cramp, flexion dystonia is more common thanposture extension is for [31 performing]. In musicians, the affected the activity, intricacy it is demanded helpful for the of thepractitioner hand or to fingersbe knowledgeable influences the dystonicabout pattern. commonly In affected pianists, muscles higher for technical different demandtypes of FHD. is usually In writer’s on thecramp, right flexion hand dystonia compared is to the left,more so common dystonic than flexion extension of the [31]. right In 4th musicians, and 5th the fingers intricacy is disproportionately demanded of the hand seen. or In fingers violinists, the higherinfluences technical the dystonic demand pattern. is on theIn pianists, fingers ofhigh theer left technical hand, whichdemand is is hence usually more on frequentlythe right hand affected compared to the left, so dystonic flexion of the right 4th and 5th fingers is disproportionately seen. In by dystonia [32]. violinists, the higher technical demand is on the fingers of the left hand, which is hence more Close communication during examination is critical. Because a writing hand normally has flexed frequently affected by dystonia [32]. fingers, itClose can be communication difficult for an during examiner examination to appreciate is critical. superimposed Because a writing dystonic hand finger normally flexion. has flexed However, the patientfingers, may it can report be difficult a “death for grip” an examiner on the pen. to appreciate In musicians superimposed especially, dystonic careful discussionfinger flexion. of hand and fingerHowever, involvement the patient can may avoid report misunderstanding. a “death grip” on Thethe pen. neurology In musicians literature especially, and pianists careful often numberdiscussion the fingers of hand 1 through and finger 5, startinginvolvement with can the avoid thumb. misunderstanding. However, violinists The neurology do not use literature the thumb of theand left pianists hand often on the number strings the and fingers therefore 1 through number 5, starting their with fingers the thumb. 1 through However, 4, starting violinists with do the indexnot finger. use the Thus, thumb the of index the left finger hand would on the be string calleds and digit therefore “2” by number a pianist their but fingers would 1 bethrough digit “1”4, for a violinist.starting with the index finger. Thus, the index finger would be called digit “2” by a pianist but would be digit “1” for a violinist. Examination should also include observation of the performance of other activities that might Examination should also include observation of the performance of other activities that might elicit dystonia without confounds, such as holding a pen or playing an instrument. A simple five-finger elicit dystonia without confounds, such as holding a pen or playing an instrument. A simple five- tappingfinger exercise tapping can exercise bring can out bring dystonic out dystonic posturing posturing in some in patientssome patients with with FHD FHD (Figure (Figure3). 3).

Figure 3. Dystonic finger extension on attempted sequential finger tapping. Figure 3. Dystonic finger extension on attempted sequential finger tapping. Mirror movements, in which involuntary dystonic posturing of the affected limb is evoked by Mirrorperformance movements, of tasks by in the which uninvolved involuntary contralateral dystonic limb, is posturing present in ofabout the 50% affected of those limb withis focal evoked by performancehand dystonia. of When tasks present, by the mirror uninvolved movement contralateral can demonstrate limb, involved is present muscles in about unmasked 50% of by those withthe focal presence hand of dystonia. compensatory When movements present, [33–35], mirror which movement can aid can selection demonstrate of muscles involved for injection muscles unmasked(Figure by 4). the presence of compensatory movements [33–35], which can aid selection of muscles Injection often proceeds based on the history and physical examination and understanding of for injection (Figure4). which muscles contribute to particular action at upper extremity joints. While it is important to Injection often proceeds based on the history and physical examination and understanding of evaluate carefully and document the likely involved muscles, it is not necessary to inject all muscles whichcontributing muscles contribute to the abnormal to particular posture. Injection action of at the upper primary extremity muscles joints. involved While in the itdystonia is important may to evaluatebe adequate carefully to and achieve document significant the likelybenefit. involved Muscle muscles,selection itis isthen not refined necessary over to the inject course all muscles of contributingsubsequent to the injection abnormal sessions posture. based Injectionon patient of response the primary and satisfaction. muscles involved in the dystonia may be adequateAccurate to achieve targeting significant of upper benefit. extremity Muscle muscles selection is also is the then key refined to successful over injection. the course The of position subsequent injectionand sessionsdepth of basedmuscles on varies patient greatly response in individual and satisfaction.s and may change over time and with repeated Accurateinjection. One targeting also needs of upper to consid extremityer normal muscles anatomic is also variants, the key such to successfulas the presence injection. or absence The position of and depthpalmaris of longus. muscles Needle varies placement greatly inbased individuals on anatom andic landmarks may change has been over shown time to and be inaccurate with repeated [36], especially when targeted to specific finger fascicles of compound muscles such as flexor injection. One also needs to consider normal anatomic variants, such as the presence or absence of digitorum superficialis or profundus. A localization technique to assure that the injection is given palmaris longus. Needle placement based on anatomic landmarks has been shown to be inaccurate [36], accurately into the selected muscle, such as electromyography (EMG), electrical stimulation or especiallyultrasound, when is targeted recommended to specific for upper finger extremity fascicles injections. of compound muscles such as flexor digitorum superficialis or profundus. A localization technique to assure that the injection is given accurately into the selected muscle, such as electromyography (EMG), electrical stimulation or ultrasound, is recommended for upper extremity injections. Toxins 2018, 10, 20 7 of 14 Toxins 2018, 10, 20 7 of 13

Figure 4. Mirror dystonia of the dominant hand when writing with a non-dominant hand. Figure 4. Mirror dystonia of the dominant hand when writing with a non-dominant hand. 2.1. Ancillary Techniques for Muscle Selection for Upper Limb Dystonia 2.1. Ancillary Techniques for Muscle Selection for Upper Limb Dystonia When the response to injection is unsatisfactory or if physical examination alone seems Wheninsufficient the response to identify to muscle injection involvement, is unsatisfactory ancillary or testing if physical may be examination helpful. alone seems insufficient to identify muscle involvement, ancillary testing may be helpful. 2.2. Muscle Afferent Block with Lidocaine 2.2. MuscleEarly Afferent reports Block on the with pathophysiology Lidocaine of focal hand dystonia observed that dystonic symptoms Earlycould be reports elicited on by the vibration pathophysiology to the palm or of flexor focal forearm hand dystonia tendons, presumably observed that mediated dystonic by muscle symptoms couldafferents. be elicited The by dystonic vibration movements to the palm were oralleviated flexor forearm by local tendons,injection of presumably lidocaine for mediated as long as by24 muscleh, attributed to lidocaine’s blockade of alpha1 and gamma afferents. While intramuscular lidocaine can afferents. The dystonic movements were alleviated by local injection of lidocaine for as long as 24 h, relieve dystonia [37–40], it is of limited therapeutic value for dystonia as the benefit is short-lasting. attributed to lidocaine’s blockade of alpha1 and gamma afferents. While intramuscular lidocaine can The quick onset (within 5–15 min) and short duration of action, however, make lidocaine potentially relievehelpful dystonia in selecting [37–40 ],muscles it is of for limited injection. therapeutic A muscle value possibly for dystoniainvolved in as the the dystonia benefit isand short-lasting. under The quickconsideration onset (within for botulinum 5–15 min) toxin and treatment short duration can be injected of action, with however, lidocaine make at a lidocainedose that blocks potentially helpfulmuscle in selecting afferents musclesbut not alpha for injection.motor neurons. A muscle Improvement possibly in involveddystonia over in the the dystonia hour following and under considerationlidocaine forinstallation botulinum implicates toxin treatment that muscle’s can be involvement injected with in lidocaine the dystonia at a dose andthat indicates blocks its muscle afferentsappropriateness but not alpha for toxin motor injection. neurons. Improvement in dystonia over the hour following lidocaine installation implicates that muscle’s involvement in the dystonia and indicates its appropriateness for 2.3. Surface and Fine Wire Electromyography (EMG) toxin injection. Dystonia is characterized electromyographically by prolonged contraction of muscles, co- 2.3. Surfacecontraction and Fineof agonist/antagonist Wire Electromyography pairs, and (EMG) recruitment of muscles not normally involved in an activity [41]. EMG can therefore be helpful in understanding which muscles may be involved in the Dystonia is characterized electromyographically by prolonged contraction of muscles, dystonia, although dystonic and compensatory actions may be difficult to differentiate by EMG. co-contractionWhen deep ofmuscles agonist/antagonist not amenable to pairs, direct andvisual recruitmentization are implicated of muscles in notdystonic normally activity, involved wire in an activityEMG may [41 ].be EMG of particular can therefore use [42]. be In helpfulthis techniqu in understandinge, thin wires that which are Teflon muscles coated may except be involvedfor the in the dystonia,barbed tip although are threaded dystonic through and a needle compensatory (Figure 5). actions may be difficult to differentiate by EMG. When deep muscles not amenable to direct visualization are implicated in dystonic activity, wire EMG may be of particular use [42]. In this technique, thin wires that are Teflon coated except for the barbed tip are threaded through a needle (Figure5).

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Figure 5. Needle threaded with hooked wires. Figure 5. Needle threaded with hooked wires. The needle with wires is Figureinserted 5. Needleinto the threaded muscle withselected hooked for wires.study. The needle is then carefully Thewithdrawn, needle leaving with wires the wires is inserted embedded into in the the muscle muscle selected(Figure 6). for study. The needle is then carefully The needle with wires is inserted into the muscle selected for study. The needle is then carefully withdrawn,withdrawn, leaving leaving the the wires wires embedded embedded in in the the musclemuscle (Figure 6).6).

Figure 6. Wire electrode in place in the muscle. Figure 6. Wire electrode in place in the muscle. Once in place, the wireFigure is barely 6. Wire felt electrodeby the patient, in place who in the can muscle. then perform dystonic and non- dystonic eliciting activities while the EMG is recorded. With a multichannel machine, wires can be Once in place, the wire is barely felt by the patient, who can then perform dystonic and non- placed in several muscles, including agonist/antagonist pairs or groups of muscles and activity Oncedystonic in eliciting place, theactivities wire while is barely the EMG felt is by recorded. the patient, With a whomultichannel can then machine, perform wires dystonic can be and recorded simultaneously. Overactivity of a muscle or contraction with an activity, during which it is placed in several muscles, including agonist/antagonist pairs or groups of muscles and activity non-dystonicusually silent, eliciting suggests activities that the while muscle the is EMG dystonic is recorded. and should With be injected. a multichannel machine, wires can be placedrecorded in several simultaneously. muscles, Overactivity including of agonist/antagonist a muscle or contraction pairs with or an groups activity, of during muscles which and it activity is usually silent, suggests that the muscle is dystonic and should be injected. recorded2.4. Imaging simultaneously. Overactivity of a muscle or contraction with an activity, during which it is usually2.4.silent, ImagingUltrasound suggests or thatother the muscle muscle imaging is dystonic may anddemon shouldstrate behypertrophy injected. in dystonic muscles. However, muscle imaging has not been shown to be helpful in selecting muscles for injection. 2.4. ImagingUltrasound or other muscle imaging may demonstrate hypertrophy in dystonic muscles. However, muscle imaging has not been shown to be helpful in selecting muscles for injection. Ultrasound3. Muscle Selection or other for muscle Lower imaging Limb Dystonia may demonstrate hypertrophy in dystonic muscles. However, muscle3. Muscle imagingThe lower Selection has limb not isfor been commonly Lower shown Limb involved to Dystonia be helpful in many in generalized selecting musclesdystonias for including injection. DYT1 and DYT5 (dopa-responsive dystonia (DRD)) as well as in dystonias secondary to other disorders, such as The lower limb is commonly involved in many generalized dystonias including DYT1 and DYT5 3. MuscleParkinson’s Selection Disease, for stroke, Lower or Limb cerebral Dystonia palsy. Adult-onset, focal lower limb dystonia is less common (dopa-responsive dystonia (DRD)) as well as in dystonias secondary to other disorders, such as [43–45]. Focal leg dystonia is more common in women than men and typically of middle age onset TheParkinson’s lower Disease, limb is stroke, commonly or cerebral involved palsy. inAdult-onset, many generalized focal lower dystoniaslimb dystonia including is less common DYT1 and [44]. Similar to upper limb dystonia, lower limb dystonia can be task-specific; for example, cases have [43–45]. Focal leg dystonia is more common in women than men and typically of middle age onset DYT5been (dopa-responsive reported of leg dystonia dystonia only (DRD)) when walking as well down as in steps dystonias [46]. The secondary most common to othertask-specific disorders, [44]. Similar to upper limb dystonia, lower limb dystonia can be task-specific; for example, cases have suchfocal as Parkinson’s lower extremity Disease, dystonia stroke, is “runner’s” or cerebral dystonia palsy. [47]. Adult-onset, focal lower limb dystonia is been reported of leg dystonia only when walking down steps [46]. The most common task-specific less commonAs with [43– other45]. Focaldystonias, leg dystonia lower limb is dystonia more common may be ininitially women task-specific, than men for and example, typically present of middle focal lower extremity dystonia is “runner’s” dystonia [47]. age onsetonly during [44]. Similar running. to The upper task-specificity limb dystonia, can be lower lost over limb time dystonia and other can actions, be task-specific; including walking, for example, As with other dystonias, lower limb dystonia may be initially task-specific, for example, present casescan have be affected. been reported Dystonic of postures leg dystonia in the leg only frequently when walking involve foot down inversion, steps [often46]. Thewith mosttoe flexion common only during running. The task-specificity can be lost over time and other actions, including walking, or extension. There may also be knee and/or hip flexion or extension. Of note is that gait may improve task-specificcan be affected. focal lower Dystonic extremity postures dystonia in the leg is frequently “runner’s” involve dystonia foot inversion, [47]. often with toe flexion or normalize on walking backwards. Asor extension. with other There dystonias, may also lower be knee limb and/or dystonia hip flexion may or be extension. initially task-specific,Of note is that gait for may example, improve present only duringor normalize running. on walking The task-specificity backwards. can be lost over time and other actions, including walking, can be affected. Dystonic postures in the leg frequently involve foot inversion, often with toe flexion or extension. There may also be knee and/or hip flexion or extension. Of note is that gait may improve or normalize on walking backwards. Toxins 2018, 10, 20 9 of 14

3.1. Treatment of Lower Limb Dystonia Because the leg is commonly affected in DRD and since leg dystonia can be a presenting symptom of Parkinson’s Disease, patients should receive a trial of l-dopa. Other medications, such as anticholinergics, often offer only minor beneﬁt and may be associated with signiﬁcant adverse effects at the doses required. Phenol neurolysis can be used in selected patients [48]. For most, however, the treatment of choice is botulinum toxin.

3.2. Muscle Selection for Lower Limb Botulinum Toxin Injection As with injections for upper limb dystonia, appropriate selection of lower limb muscles for injection is mandatory for successful treatment. The medical history will provide information on possible preceding trauma. The patient should be asked to describe the movements and the actions that precipitate dystonic contraction. A history of diurnal ﬂuctuation may suggest dopa-responsive dystonia. Physical examination can help to rule out Parkinsonian syndromes. The gait examination follows. The patient should be examined walking, both with and without shoes. The shoes can also be checked, as abnormal wear patterns of the sole and upper shoe may provide clues as to nature and direction of postural distortions. Stress gaits, such as walking on the toes or heels, may bring out additional dystonic posturing. Patients should be asked to walk backwards; normalization of gait on walking backwards demonstrates the task speciﬁcity of the dystonia. Runners should be observed while running in addition to walking. If the patient has sensory tricks or gestes antagonists that help, they should be displayed. In evaluating patients with lower extremity dystonia, the practitioner should have an understanding of the normal gait cycle and of functional anatomy so that abnormal patterns can be appreciated (Table2).

Table 2. Muscles of lower extremity; primary muscles are in bold.

Hip Flexion Extension iliopsoas Gluteus maximus rectus femoris hamstrings sartorius Adduction Abduction pectineus Gluteus maximus Adductor longus Gluteus medius Adductor magnus Gluteus minimus Adductor brevis Tensor fascia lata gracilis Obturator internus

Knee Flexion Extension hamstrings quadriceps popliteus gastrocnemius gracilis sartorius Ankle Dorsiﬂexion Plantar Flexion Tibialis anterior Gastrocnemius EDL Soleus EHL plantaris Peroneus tertius FHL FDL Toxins 2018, 10, 20 10 of 14

Table 2. Cont.

Ankle Inversion Eversion Tibialis posterior fibularis/peroneus longus Tibialis anterior fibularis/peroneus brevis FHL fibularis/peroneus tertius Hallucis Flexion Extension Toxins 2018, 10, 20 10 of 13 FHL EHL FHL fibularis/peroneusEHB tertius ToesHallucis Flexion Extension Flexion FHL Extension EHL FDL EDL EHB FDB Toes Flexion Quadratus plantae Extension FDL EDL EDL: extensor digitorum longus; EHB: extensor hallucis brevis; EHL: extensor hallucis longus; FDB: flexor digitorum FDB brevis; FDL: flexor digitorum longus; FHL: flexor hallucis longus. Quadratus plantae EDL: extensor digitorum longus; EHB: extensor hallucis brevis; EHL: extensor hallucis longus; FDB: 3.3. Ancillary Techniquesflexor digitorum for brevis; Muscle FDL: Selection flexor digi fortorum Lower longus; Limb FHL: Dystonia flexor hallucis longus.

As with3.3. Ancillary upperlimb Techniques dystonia, for Muscle lidocaine Selection afferent for Lower blockLimb Dystonia and surface and/or fine wire EMG may be helpful in identifying dystonic muscles in the lower limb. Walking is a stereotyped activity, with As with upper limb dystonia, lidocaine afferent block and surface and/or fine wire EMG may be identifiable phases and established patterns of phasic coordination of muscle agonist and antagonist helpful in identifying dystonic muscles in the lower limb. Walking is a stereotyped activity, with activationidentifiable at each stage. phases Formal and established gait analysis patterns includes of phasic monitoring coordination gait of muscle kinematics agonist and and muscleantagonist activity by surfaceactivation or wire at EMG, each stage. and Formal often gait with analysis video includes motion monitoring capture duringgait kinematics performance and muscle of activity various set walking tasks.by surface A formal or wire gaitEMG, analysis and often may with be video helpful motion in capture characterizing during perf howormance the patternof various of set muscle contractionwalking in a patienttasks. A formal with dystoniagait analysis differs may be from helpful standard in characterizing gait norms, how includingthe pattern of identification muscle contraction in a patient with dystonia differs from standard gait norms, including identification of of muscles contracting during phases of gait when they should be silent and co-contraction of muscles contracting during phases of gait when they should be silent and co-contraction of agonist/antagonistagonist/antagonist pairs [ 49pairs]. As [49]. well As well as part as part of of muscle muscle selection, selection, motion motion analysis analysis may may be useful be useful when when repeated afterrepeated treatment after treatment to assess to assess gait responsegait response to injectionto injection (Figure (Figure7 7).).

Figure 7. Cont.

Toxins 2018, 10, 20 11 of 14 Toxins 2018, 10, 20 11 of 13

Figure 7.FigureGait 7. analysis Gait analysis in patients in patients with with focalfocal dystonia, dystonia, before before and andafter botulinum after botulinum toxin injection. toxin ( injection.A) (A) self-selectedself-selected pace pace walking walking before before injection injection shows shows lim limitedited right right knee flexion knee flexion in swing in phase swing of gait phase and of gait limited right ankle plantar flexion at toe off; (B) self-selected pace walking before injection: and limited right ankle plantar flexion at toe off; (B) self-selected pace walking before injection: Electromyography (EMG) shows abnormal out of phase activity in right gastrocnemius during pre- Electromyographyswing and in (EMG) quadriceps shows during abnormal stance outand ofswing, phase with activity abnormal in compensatory right gastrocnemius activity in during pre-swinghamstrings; and in quadriceps(C) self-selected during pace walking stance andafter swing,injection withshows abnormalimproved right compensatory knee and plantar activity in hamstrings;flexion; (C )(D self-selected) self-selected pacepace walking walking after after injection: injection EMG shows shows improvedreduced activity right in knee quadriceps and plantar flexion; (followingD) self-selected injection of pace rectus walking femoris and after in injection:compensatory EMG activity shows in hamstrings. reduced activity in quadriceps following injection of rectus femoris and in compensatory activity in hamstrings. 4. Conclusions

4. ConclusionsCorrect identification of muscles involved in dystonia and selection for injection is especially critical for successful outcome in treating upper and lower extremity dystonia with botulinum toxin Correctinjection. identification Selection of muscles of muscles is not involvedstraightforward in dystonia in the upper and extremity selection due for to injectionthe complexity is especially of critical forforearm, successful hand and outcome finger skilled in treating movement upper and and the lowernumber extremity of muscles dystoniathat can possibly with botulinum contribute toxin injection.to Selection those movements. of muscles Evaluation is not straightforward of lower extremity in thedystonia upper is extremityaided by gait due analysis to the complexityand the of availability of normative gait data. Careful physical examination and evaluation at rest, with forearm, hand and finger skilled movement and the number of muscles that can possibly contribute to activities directly evoking the dystonia, with mirror movements and with other tasks, are the those movements.mainstays of Evaluation initial muscle of lower selection. extremity Observation dystonia of response is aided byto toxins gait analysis over time and allows the availability the of normativepractitioner gait data. to adjust Careful and refine physical muscle examination selection and anddoses evaluation to optimize atbotulinum rest, with toxin activities treatment directly evokingfor the dystonia. dystonia, with mirror movements and with other tasks, are the mainstays of initial muscle selection. Observation of response to toxins over time allows the practitioner to adjust and refine Acknowledgments: This paper was supported in its entirety by the National Institutes of Health (NIH) muscle selectionIntramural andResearch doses Programs to optimize of the National botulinum Institute toxin of Neurological treatment Disorders for dystonia. and Stroke and Department of Rehabilitation Medicine, Warren Grant Magnusen Clinical Center, Bethesda, MD, USA. Acknowledgments: This paper was supported in its entirety by the National Institutes of Health (NIH) IntramuralConflicts Research of Interest: Programs The of authors the National declare no Institute conflict of of interest. Neurological Disorders and Stroke and Department of Rehabilitation Medicine, Warren Grant Magnusen Clinical Center, Bethesda, MD, USA. References Conflicts of Interest: The authors declare no conflict of interest. 1. Albanese, A.; Bhatia, K.; Bressman, S.B.; DeLong, M.R.; Fahn, S.; Fung, V.S.C.; Hallett, M.; Jankovic, J.; Jinnah, H.A.; Klein, C.; et al. Phenomenology and classification of dystonia: a consensus update. Mov. References Disord. 2013, 28, 863–873. 1. Albanese, A.; Bhatia, K.; Bressman, S.B.; DeLong, M.R.; Fahn, S.; Fung, V.S.C.; Hallett, M.; Jankovic, J.; Jinnah, H.A.; Klein, C.; et al. Phenomenology and classification of dystonia: a consensus update. Mov. Disord. 2013, 28, 863–873. [CrossRef][PubMed] 2. Sheehy, M.P.; Rothwell, J.C.; Marsden, C.D. Writer’s cramp. Adv. Neurol. 1988, 50, 457–472. [PubMed] Toxins 2018, 10, 20 12 of 14

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