Treatment of Focal Hand Dystonia: Current Status 2021 PDF

Neurological Sciences https://doi.org/10.1007/s10072-021-05432-7 REVIEW ARTICLE Treatment of focal hand dystonia: current status Navnika Gupta1 · Sanjay Pandey2 Received: 26 April 2021 / Accepted: 23 June 2021 © Fondazione Società Italiana di Neurologia 2021 Abstract Background Focal hand dy...

Neurological Sciences https://doi.org/10.1007/s10072-021-05432-7 REVIEW ARTICLE Treatment of focal hand dystonia: current status Navnika Gupta1 · Sanjay Pandey2 Received: 26 April 2021 / Accepted: 23 June 2021 © Fondazione Società Italiana di Neurologia 2021 Abstract Background Focal hand dystonia (FHD) is usually adult-onset focal dystonia that can be associated with marked occupational and functional disability leading to reduced quality of life. Methods Relevant studies on treatment options for FHD, their limitations, and current recommendations were reviewed using the PubMed search until March 31, 2021. Besides, the reference lists of the retrieved publications were manually searched to explore other relevant studies. Results and conclusion Currently, botulinum toxin has the best evidence for treatment of FHD, and 20–90% of patients experience symptomatic improvement. However, its benefit is often limited by the reduction of muscle tonus acting on the muscle spindle. Different surgical modalities that have been used to treat focal hand dystonia include lesional surgery, deep brain stimulation, and magnetic resonance–guided focused ultrasound thalamotomy. Recent studies exploring the role of behavioral techniques, sensorimotor training, and neuromodulation for the treatment of focal hand dystonia have reported good outcomes, but larger studies are required before implementing these interventions in practice. Keywords Hand dystonia · Botulinum toxin · Lesional surgery · DBS · Neurorehabilitation · Neuromodulation Introduction are writer’s cramp and musician’s dystonia. Other examples are typist’s cramp, shoemaker’s dystonia, tailor’s dystonia, Dystonia is characterized by sustained or intermittent mus- hairdresser’s cramp, golfer’s yips, etc. Over time, the cle contractions that cause abnormal repetitive movements, dystonia may stay task specific or it may lose this specificity. postures, or both, and dystonic movements can be patterned, FHD can cause the motor and psychosocial impairment twisting, or tremulous. Dystonia is classified as child- and lead to significant occupational disability. Hence, it war- hood, adolescent, and adult onset. A common type of rants timely recognition and treatment. Here, we will review adult-onset dystonia is focal dystonia that involves a single and discuss the treatment of FHD. body region. Different types of adult-onset focal dysto- nias described in the literature are blepharospasm, cervi- cal dystonia, cranial dystonia, and limb dystonia. Focal Search strategy hand dystonia (FHD) is a form of upper limb dystonia that is usually task specific at onset and is associated with repeti- A literature search was done on PubMed for articles pub- tive utilization of limb for a particular task for long periods lished until March 31, 2021, with the search terms “Treat-. It is identified by the involved task and, accordingly, ment of hand dystonia,” “Treatment of Writer’s Cramp,” given multiple names of which the most recognized forms “Treatment of Upper Limb Dystonia,” “Treatment of Focal Hand Dystonia,” and “Treatment of Musician’s Dystonia” Table 1. The inclusion criteria were randomized controlled * Sanjay Pandey trials, open-label trials, retrospective trials, case series, [email protected] review articles, systematic review, and meta-analysis pub- 1 University of Nebraska Medical Center, Omaha, NE, USA lished in the English language Fig. 1. The articles of rel- 2 Department of Neurology, Govind Ballabh Pant evance were identified after the literature search. Postgraduate Institute of Medical Education and Research, New Delhi 110002, India 13 Vol.:(0123456789)  Neurological Sciences Table 1  Research string: PubMed search (on March 31, 2021) results medications were not effective and they were associ- Search term used Number ated with side effects. Lang et al. examined the efficacy of articles of treatment with intravenous atropine, benztropine, and retrieved chlorpheniramine in patients with focal dystonia. Five Treatment of hand dystonia 648 patients in their cohort had writer’s cramp. No signifi- Treatment of writer’s cramp 2790 cant benefit was noticed with these medications. Studies Treatment of upper limb dystonia 560 on patients with musician’s dystonia have reported some Treatment of focal hand dystonia 218 benefits with trihexyphenidyl [5, 6]. The results of these Treatment of musician’s dystonia 88 studies indicate that there is a limited benefit with oral medications in focal hand dystonia and hence, it has a lim- ited role in treatment. These are mostly used as an adjunct to other treatments such as botulinum toxin. Pharmacological treatment of FHD Botulinum toxin Oral medications Cohen and colleagues put forth the seminal paper on the Oral medications like trihexyphenidyl, benztropine, treatment of FHD with botulinum toxin injection (BTX) chlorpheniramine, atropine, levodopa, and baclofen have in 1989. Before that, hand dystonia was considered a been tried for the treatment of FHD [3–6] Sheehy and functional disorder for which psychotherapies were tried colleagues prescribed levodopa, anticholinergics, ben- with no benefit. Multiple studies thereafter reported the zodiazepines, antipsychotics, anti-epileptics, and tricy- efficacy of BTX in the treatment of FHD and it is still the clic anti-depressants in their patients. Benzhexol had most widely accepted treatment for FHD [5, 7, 11–27]. With some beneficial effects in six patients. However, other a few exceptions, botulinum toxin type A (from here on, referred to as BTX-A) is the most common toxin type used Fig. 1  Search strategy for the systematic review 13 Neurological Sciences for the treatment of FHD and this review will focus on the supraspinatus, supinator, and triceps are also targeted for the treatment with this toxin type. In this section, we will review treatment of focal hand dystonia. the salient features of BTX-A in the treatment of FHD. Dose of toxin used Clinical evaluation and practical considerations The dose of BTX-A used varies over a wide range of Muscle localization for treatment with BTX 2.5–160 U (OnabotulinumtoxinA/IncobotulinumtoxinA) [5, 7, 11–27]. Lower doses are used for the first session and A good history and clinical examination are essential for they are gradually increased over subsequent treatment ses- identifying the correct muscle to give BTX injection. A sions until the desired effect is achieved. A mean total dose complete neurological examination should be performed of 40–80 U (OnabotulinumtoxinA/IncobotulinumtoxinA) is to rule out other pathologies. When examining, attention effective for most patients [5, 7, 11–27]. Factors influenc- should be paid to activities that precipitate the dystonia. In ing the dose are target muscle, muscle mass, and treatment patients with musician dystonia, playing the instrument can duration. provoke dystonia. Similarly, patients with other forms of occupational dystonia should be encouraged to perform the task to bring out the dystonia. Mirror movements seen Injection of toxin in the muscle in about 50% of patients with FHD can invoke compensatory movements that can unmask the involved muscles and aid in After muscle identification, a focal injection of BTX-A is muscle selection for injection. given to the muscle. EMG guidance can be helpful when Target muscles can be identified by either clinical exam- giving injections, particularly when injecting deeper muscles ination alone or in conjunction with electromyography and/or specific muscle fibers in the case of long tendons of (EMG) which helps determine the type of muscle activity the hand. Ultrasonography-guided injections ± EMG (bursts, spasms), the agonist–antagonist pattern of activity can be useful when injecting specific muscles for the treat- (co-contraction, alternating), and the degree of localization ment of FHD. Ideally, the toxin should be injected into of the cramps (≥ 1 muscle). Other techniques used for the endplate as it works only there. However, since the muscle localization are electrical stimulation and ultrasound toxin diffuses to the adjacent muscle fascicles, injections are [8–10]. usually given in the middle of the muscle belly rather than Studies have examined the role of techniques such as the endplate [7, 10]. local stimulation with cannula and electrical motor point stimulation (EMPS) for muscle selection [8, 9] Geenen and Treatment outcomes with botulinum toxin colleagues reported that local stimulation with a cannula for muscle identification was non-inferior to EMG. Another Subjective and objective measures are used to assess treat- study looked at the role of electrical stimulation and reported ment outcomes with BTX-A in patients with FHD [5, 7, good outcomes with this technique. The authors reported 11–27]. Earlier studies used subjective outcome measures that this technique had advantages such as decreased cost to assess the treatment response. Later studies used various due to reduction in dose of BTX and increased accuracy of objective measures to assess the treatment outcomes. targeting as the weakness was limited to the injected muscle Subjective improvement reported by patients is the most with sparing of the neighboring muscles. common outcome measure used in studies evaluating the efficacy of BTX-A in patients with FHD. Different stud- Muscles targeted for injection ies have shown that 20–90% of patients with FHD improve with BTX-A Table 2 [5, 7, 11–27]. The response rate ranged The muscles targeted for injection are the flexors, extensors, between 50 and 80% in most of the studies [5, 7, 11–27]. or a combination of both Fig. 2a, b [5, 7, 11–27]. The com- The main benefits experienced by patients are reduction in monly injected flexor muscles are flexor digitorum super- excessive muscle tone and contraction. However, not all ficialis, flexor digitorum profundus, flexor carpi ulnaris, patients experience the same level of improvement. Patients flexor pollicis longus, and flexor carpi radialis [5, 7, 11–27]. with musician’s dystonia generally have insufficient benefit Among extensor muscles, the commonly injected muscles than patients with other forms of focal hand dystonia [5, 25, are extensor digitorum communis, extensor carpi ulnaris, 27]. One plausible explanation for this insufficient benefit is extensor carpi radialis, extensor pollicis longus, and exten- that patients with musician’s dystonia are unable to perform sor indicis proprius [5, 7, 11–27]. Intrinsic muscles of the intricate hand movements due to loss of coordination that is hand can be injected to provide symptomatic relief. Proxi- not corrected by BTX-A [5, 25, 27]. This also explains why mal muscles like deltoid, pronator quadratus, pronator teres, patients with musician’s dystonia do not continue BTX-A 13  Neurological Sciences Fig. 2  Muscles commonly injected in focal hand dystonia a patients. a Flexor group of muscles; b extensor group of muscles b treatments in the long-term as suggested by data from vari- toxin or placebo injections [14, 19]. Wissel et al. devel- ous studies [5, 25, 27]. oped a new scale, Writer’s Cramp Assessment Scale Patients can have a good response from one treatment (WCRS), for objective evaluation of writer’s cramp. session but the benefit obtained from individual injections in The authors reported that there was a significant decrease a given session can vary [7, 12, 17]. The response between in writing movement (part A) and writing speed (part B) treatment sessions can vary and may decrease over subse- scores after treatment with BTX-A compared to baseline quent sessions compared to the first treatment session. Fac- (p < 0.001 and < 0.05, respectively). They also performed tors that can contribute to the decrement in response include computer-based writing speed analysis and noted a sig- disease progression, alteration in dystonia following BTX-A nificant increase in writing speed after treatment with injections, and higher patient expectations. BTX-A (p < 0.05). There was moderate to a substantial There is no universal scale for objective measurement. inter-rater agreement between the blinded raters on most Different studies included in this review have used meth- items. However, this scale has not been used widely in ods like writing speed, a number of errors made while other studies. A Movement Disorder Society task force writing, muscle strength testing, and physician’s review reviewed the existing scales for task-specific dystonia and of videotapes for objective assessment [14, 16, 19]. How- concluded that these scales need further assessment as ever, none of these methods have been standardized or none of them had been studied to be valid, reliable, and validated in multiple studies. Another concern is the pres- sensitive to change. ence of a subjective component with some of the methods The most common adverse effect associated with BTX-A like physician review of videotapes [14, 19]. In two of the is a focal weakness of the injected and neighboring muscles randomized trials where this method was used, there was [5, 7, 11–27]. The second most common adverse effect is no significant difference in performance with botulinum pain at the injection site. Other reported adverse effects are 13  Table 2  Studies reporting botulinum toxin treatment in patients with focal hand dystonia Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Neurological Sciences Open-label trial 19 46/7 Dystonic writer’s EI (2); EPL (5); The maximum Subjective func- NA Weakness of (C) cramp: 12 APL (4); EDC cumulative dose tional improve- injected muscles. Simple writer’s (5); FDI (2); of BTX-A in one ment: 16/19 Two patients cramp: 4 FPL (10); FPB series of injec- patients (84.2%) developed Simple piano (1); FDS (15); tions was 160 U. Major improve- asymptomatic player’s cramp: 1 FDP (8); FCR Effective total ment: 13 antibodies against Dystonic non- (5); FCU (6); doses varied Mild improve- botulinum toxin localized hand- ECR (3); ECU between 17.5 ment: 3 type A manifested writing: 1 (1); AP (1); OP and 140 U No/minimal by inability to Simple non-local- (1) improvement: 3 respond to further ized handwrit- injections ing: 1 Simple localized clarinet play- ing: 1 Prospective open 28 42.3/7.9 Focal hand dysto- Most common site Mean muscle dose 17/22 (77%) NA Focal hand weak- trial (C) nia: 28 of injection was of BTX-A was patients with ness: 14/22 right forearm 66.9 U. Mean writer’s cramp flexors. Injec- cumulative dose had at least tions were also in a patient was moderate given in hand 231.6 U improvement extensors noted on a global rating scale used in this study Open-label trial 12 43/9 Simple writer’s FDP (7); FPL (4); During the first Subjective NA Five patients had (C) cramp: 3 EIP (2); EPL (2); session, finger improvement: focal weakness Dystonic writer’s ECU (3); FCU flexor or exten- 11/12 (91.67%) of the target or cramp: 9 (3); FCR (1) sor received Significant neighboring 40–60 U BTX-A improvement: muscles and wrist flexor 7/12 (58.3%) or extensor Moderate received 80–120 improvement: U 4/12 (33.33%) No improvement: 1/12 (8.3%) 13  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects 13 mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Open-label trial 25 36.80/5.88 Writer’s cramp: 25 Forearm muscles 40–80 U of Definite improve- NA 7 patients (33.3%): (C) BTX-A given ment in hand- Transient finger in 2–4 divided writing: 14/21 drop: 5 (23.8%) doses (66.7%) Easily fatigued arm: Minimal improve- 2 (9.5%) ment: 4/21 (19.0%) No improvement: 3/21 (14.3%) Prospective 10 47/NA Writer’s cramp: 9 FCR (2); FCU (4); Usual doses of BTX: Review of ran- Focal weakness: placebo-con- Barber’s cramp: 1 FDS (6); EIP BTX-A were 5 Subjective domly ordered 53% injections of trolled blinded (2); PT (1); EDC to 10, 10 to 20, improvement— videotapes: BTX, 13% injec- study (C) (5); FDP (2); and 20 to 40 U low dose: 7/10, 59% patients tions of placebo EPL (1); ECR per muscle middle dose: improved with Muscle stiffness/ (2); ECU (2); 10/10, high BTX and 38% pain: 10% injec- Sup (1) dose: 9/10 improved with tions Substantial placebo. There Malaise, mus- improvement— was no statisti- cle twitching, low dose: 3/10, cal difference. paresthesia, middle dose: Similar results nausea: < 10% 3/10, high dose: obtained on injections 6/10 handwriting Worsening—low analysis dose: 1/10, high dose: 1/10 Placebo: Subjective improvement: 1/10 Substantial improvement: 1/10 Worsening: 1/10 Neurological Sciences  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Neurological Sciences Long-term pro- 30 46/8 Hand dystonia: Flexors (27) Mean total dose of Peak effect: mild NA Focal hand weak- spective trial of 30; some had Extensors (16) BTX-A per treat- to moderate ness: 24/30 BTX treatment other movement ment session: improvement patients (C) disorders 85 U Local rash and pain Mean dose in a in one patient flexor muscle: each 69.6 U Mean dose in an extensor muscle: 62.4 U Randomized 20 41.75/5.15 Writer’s cramp: 20 FDS, FDP, FCR, Dose of BTX-A Definite improve- Speed and Focal muscle weak- double-blind FCU, FPL, ED, was 25–50 U in ment in writing: accuracy of pen ness: 1 placebo-con- ECU, PT, PQ different muscles 4/20 (20%) control: trolled study based on previ- Slight improve- Significant 20 patients ous experience ment in writing: improvement received both 2/20 (10%) after BTX and BTX and normal No change in no significant saline (B) writing: 13/20 change with (65%) placebo Worse writing: Speed of 1/20 Gibson maze No changes with completion: placebo 9/20 patients improved with BTX and no change with placebo 13  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects 13 mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Open-label study 53 44/5 Writer’s cramp: 32 Muscles in order The initial dose Excellent Focal hand weak- (C) Typist’s cramp: 2 of frequency of of BTX-A was response: 22/53 ness: Musician’s cramp: injection: 2.5–20 U per Moderate 94% patients expe- 19 FDS, FPL, FCU, muscle depend- response: 9/53 rienced with at FDP, FCR, EPL, ing on muscle Mild response: least one session EDC, ECU, size and extent 12/53 Other: ECR, APL, EIP, of dystonia. The Minimal benefit: Pain, bruising Tri, PT, FPB, mean dose of 4/53 at injection EPB, Del, AP BTX-A in a ses- No benefit: 6/53 site, atrophy of sion was 26 U No correlation injected muscle between dose injected and extent and dura- tion of benefit NA 12 39/NA UL dystonia Forearm flexors The mean dose Subjective NA Focal muscle present during (12) (FCR, FCU, of BTX-A was improvement: weakness: 10/12 writing: 5 FDP, FDS, PT, 49.5 U 9/12 (74.9%) (83.33%) Dystonic cramp: 3 FPL) Improvement in Writer’s cramp: 4 Forearm extensors writing: 11/12 (6) (ECR, ECU, (91.5%) EDC, EIP) Improvement in other activities: 6/12 (49.9%) Neurological Sciences  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Neurological Sciences Double-blind trial 10 49.4/8.5 Writer’s cramp: 6 FCR (2), APL (1), Dose of BTX-A Patient’s response Muscle strength: Focal muscle weak- BTX or placebo Stenographer’s EPL (1), FDS used: 5–20 U (BTX): Weakness—BTX: ness: 8/10 injections given cramp: 2 (6), FPL (3), 9/10 improved 8, placebo: 1, in a double-blind Musician’s cramp: FCU (1), FDP (90%)—major: none: 1 fashion and 2 (1), EDC (2) 4, moderate: 5, Writer’s cramp randomly (B) no response: 1 (6)—4 wrote Patient’s response faster with (placebo): BTX-A and 2 4/10 improved with placebo; (40%)—major: less errors with 1, minimal: 3, BTX-A no response: 6 Stenographer’s Physician’s cramp (2): no review of videos effect of BTX-A (BTX): or placebo Subjective posi- tive impression: 5 Subjective nega- tive impression: 2 Discordant impressions: 3 Physician’s review of videos (other): Subjective posi- tive impression: 3 Subjective nega- tive impression: 4 Discordant: 3 Open-label pro- UL dystonia: 107 51.7/NA Focal hand dys- Most frequently Average dose Efficacy: 83.5% 30.1% patients spective analysis Number of focal tonia treated arm mus- of BTX-A for in focal hand with dystonia had (C) hand dystonia Musician’s cramp cles (in order): 50–80% efficacy dystonia transient weak- not known Primary wrist flex- was 7.3 U ness of injected ors and exten- or neighboring sors, FDS, EI muscles 13  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects 13 mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) NA 31 NA/12.3 Simple writer’s Most commonly Mean dose of Subjective WCRS part A Focal weakness of cramp: 15 injected muscles: BTX-A injected response: > 20% and B: injected muscle: Dystonic writer’s FCU (57), FCR per session was improvement in The mean sub- 27/31 patients cramp: 16 (30), FDS (49), 133.2 U 25/31 patients score for part A FPL (28), ECU (18 had 20% was 9.1 at base- (32) to < 60% and 7 line and 6.6 after had 60–100% BTX treatment improvement) (p < 0.001) Performed objec- The mean sub- tive analysis of score for part B improvement was 1.1 at base- with writer’s line and 0.8 after cramp rating BTX treatment scale (WCRS) (p < 0.05) and computer- Moderate or based writing substantial inter- speed analysis rater agreement WCRS useful to for most items assess severity between the 4 and treatment blinded raters response in Computer-based patients with writing speed writer’s cramp analysis: speed Computer-based of pen move- analysis showed ments signifi- a significant cantly increased increase in writ- in patients after ing speed treatment NA 16 35.75/3.64 Writer’s cramp NA BTX-A used Significant NA Asymptomatic improvement weakness in all in abnormal and finger weak- posture, ease ness in 4 of writing, and speed of writing An improvement of ≥ 50% was observed after 13 treatment sessions Neurological Sciences  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Neurological Sciences Retrospective 14 NA Writer’s cramp: 14 NA Mean BTX-A dose 8/14 (57%) NA Development of chart analysis was 77.4 U patients had primary and sec- (C) sustained benefit ondary resistance at 2 years 5/9 (56%) patients had sustained benefit at 5 years NA 47 46.1/7.6 Writer’s cramp: 44 Most frequently BTX-A dose was Subjective benefit: On BFM NA Primary writing injected muscles: 40–160 U 73% patients scale, sever- tremor: 3 FCU, FCR, PT, Patients reported ity decreased FPL, FDP, ECR, 47% functional from 2.8 to 1.8 EPL, Del, Sup, improvement in post-treatment EIP, FDS, Lev, writing and disabil- Supr, PQ, EDC ity decreased from 1.9 to 1.1 post-treatment (p < 0.0001 for both) Retrospective 84 45.9/10.6 Complex musi- The muscle group Average total dose Subjective NA Weakness: 98% chart review (C) cian’s dystonia most frequently of BTX-A per improvement: Excessive weak- with spread of injected was the treatment was 58/84 musicians ness: 56% dystonia to other forearm flexors 126.9 U at the (69%) tasks: 17 in 52 patients initial visit and Long-term benefit Localized musi- (93%) 112.2 U at the in performance cian’s hand last visit ability: 30/84 dystonia: 65 musicians (36%) No response/wors- ening: 26/84 NA 144; 68 with focal 42/5.1 Musician’s dysto- Frequency of Average dose of 35/68 (51.47%) NA NA hand dystonia nia: 144 injected muscles: BTX-A per mus- improved after had BTX (bowed string FDS (70%), cle group was BTX players: 21, FDP (70%), 112 U in upper 23 patients keyboard instru- FCR (18%), arm and shoul- discontinued mentalists: 40, FPL (10%), ED der muscles, 38 treatment due plucked instru- (10%), EI (10%), U in forearm to insufficient ments: 29) PI (7%) extensors, 65 U benefit in forearm flex- ors, and 26 U in hand muscles 13  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects 13 mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Double-blind 39 Placebo: Placebo: Most commonly BTX-A: mean Primary outcome: Secondary Treatment-related randomized BTX-A: 20 45.63/9.13 Simple writer’s injected muscle total dose of 14/20 patients outcomes: adverse effects: placebo-con- Placebo: 19 BTX-A: cramp: 6 was FPL fol- BTX-A was 102 (70%) in BTX significant hand weakness trolled trial 47.60/7.38 Complex writer’s lowed by FDP U at 1st treat- group wished improvement and pain at injec- Trial duration: cramp: 13 and EIP ment session to continue was observed tion site 12 weeks BTX-A: and 75 U at 2nd treatment versus on WCRS part Self-reported hand Patient follow-up: Simple writer’s session. The 6/19 patients A and writ- weakness: 1 year (B) cramp: 7 mean total dose (31.6%) in pla- ing speed with Placebo: 2 Complex writer’s for both sessions cebo group BTX-A treat- BTX-A: 18 cramp: 13 was 178 U Secondary ment Observed weak- Placebo: mean outcomes: ness: total dose of significant Placebo: 1 placebo was improvement BTX-A: 15 equal in volume observed on to 82 U at 1st VAS handwrit- treatment ses- ing and SSS sion and 142 with BTX-A U at 2nd. The treatment. No mean total dose significant dif- for both sessions ference on FSS was 224 U Six patients in BTX-A group did not wish to continue treat- ment due to: Absence of response (1), weakness (5) Follow-up at 1 year: 20/39 (51%) patients were under treatment Neurological Sciences  Table 2  (continued) Study Type of study Number of Mean age at Type of dystonia Muscle injected Dose of botuli- Subjective out- Objective out- Complications/ (grade of recom- patients with hand presentation/mean (number of num toxin used in comes comes/outcomes adverse effects mendation) dystonia disease duration patients receiving studies on clinical rating (years) injection in the scales muscle) Neurological Sciences Retrospective 20 46.6/9.5 Focal hand dysto- Involved muscles: The average 11/20 (55%) NA 9/20 patients chart review (C) nia: 20 forearm flexors BTX-A dose patients had reported mild Writing: 9 (18), extensors was 46.4 U. The mild average weakness Mixed: 5 (16), intrinsic patients received benefit Typing: 1 hand muscles a higher mean There was a Musician: 5 (9), pronators or dose at the end trend toward (piano: 2, guitar: supinators (6), of follow-up larger benefit 1, drums: 1, proximal arm or period compared in women. The trumpet: 1) shoulder (4) to the initial benefit was treatment (49.9 higher with the vs. 31.0 U) last injection compared to the initial AP, adductor pollicis; APL, abductor pollicis longus; BFM scale, Burke–Fahn–Marsden scale; BTX-A, botulinum toxin type A; Del, deltoid; ECR, extensor carpi radialis; ECU, extensor carpi ulnaris; EDC, extensor digitorum communis; EI/EI P, extensor indicis (proprius); EPL, extensor pollicis longus; FCR, flexor carpi radialis; FCU, flexor carpi ulnaris; FDI, first dorsal interos- seous; FDP, flexor digitorum profundus; FDS, flexor digitorum superficialis; FPB, flexor pollicis brevis; FPL, flexor pollicis longus; FSS, Functional Status Scale; Lev, levator scapulae; OP, opponens pollicis; PI, palmaris interosseous; PT, pronator teres; PQ, pronator quadrates; SSS, Symptom Severity Scale; Sup, supinator; Supr, supraspinatus; Tri, triceps; U, international units; VAS, Visual Analog Scale; WCRS, Writer’s Cramp Rating Scale 13  Neurological Sciences paresthesia, local rash, atrophy of injected muscle, and the were similar at 57 and 56%, respectively. The emergence of development of secondary resistance [7, 14, 15, 17, 23]. primary and secondary resistance was the most common rea- son for treatment discontinuation in patients with focal dys- Predictors of outcome tonia. In the present study, patients with focal dystonia had the highest incidence of primary and secondary resistance. Certain factors are predictive of outcome in patients with One factor that can influence the development of secondary FHD treated with BTX-A. resistance is decreased response to BTX-A in central motor Factors predictive of improvement are older age, absence areas. The presence of sensorimotor dysfunction in FHD as of dystonic tremor, certain patterns of dystonia (pronation- well as the effectiveness of neuromodulation and neurore- flexion), and muscle selection based on dystonia pattern habilitation techniques is evidence in support of this theory. (wrist and finger flexors associated with better response) Another study looking at 10-year outcomes of treating. Factors predictive of poor response are the presence writer’s cramp with BTX-A reported good efficacy and tol- of dystonic tremor, elements of poor motor control, pres- erance in the long term with the recovery of normal writing ence of secondary dystonia, and progressive disease [24, in 46%, partial benefit in 10%, failure in 21%, and loss to 29]. Factors like age at dystonia onset, family history of dys- follow-up after the first injection in 23% of patients. tonia or tremor, toxin dose, presence of mirror dystonia, and Lungu and colleagues examined outcomes of BTX-A the number of involved muscle groups did not influence the therapy for FHD at 10 years or greater in a retrospective outcome in studies [17, 24, 27, 29]. study. They reported that 11/20 patients experienced Different studies have reported different results regard- at least mild benefit. Most patients tolerated the discom- ing the role of gender and duration of disease as predictors fort associated with injections and none of them developed of outcome [17, 24]. In certain studies, women had better immunity for the duration of follow-up. They compared outcomes as they needed lower doses of BTX-A to achieve this cohort with those who received treatment for less than moderate to excellent outcomes and had a longer duration of 10 years and the most common reason for discontinuation in a benefit than men [17, 27]. In other studies, gender did not the latter was an insufficient benefit and a higher proportion influence outcome. One study reported that duration of of them were professional musicians. dystonia before BTX-A treatment did not influence outcome while another one reported that longer duration was associ- Evidence for botulinum toxin in the treatment ated with poor outcome [17, 29]. of focal hand dystonia Some patients respond to BTX-A during the initial ses- sions but do not respond subsequently. Few of them have The American Academy of Neurology (AAN) and the Euro- been shown to have anti-botulinum toxin type A antibodies pean Federation of Neurological Societies (EFNS) have pub- that explain the loss of response and hence, the presence of lished recommendations for the treatment of FHD [30, 31]. antibodies is used as a predictor of loss of response. There have been four double-blind randomized con- trolled trials that have examined the efficacy of BTX-A Long‑term efficacy and safety of BTX‑A in the treatment of FHD (one class I and three class II) [14, 16, 19, 26]. Three studies randomized the patients Studies looking at long-term treatment efficacy and safety to receive two sets of treatment each where they received of BTX-A for FHD have reported that 9.34–56% of patients BTX-A in one set and placebo in the other set in a random continued to receive treatment on longer follow-up [5, 17, manner [14, 16, 19]. Two studies had patients predomi- 23, 24, 26, 27, 29]. This suggests that BTX-A is safe for nantly with writer’s cramp and the third study had patients patients with FHD in the long term. with various forms of FHD [14, 16, 19]. Also, 60–90% of Karp et al. examined the efficacy of BTX-A in their patients improved subjectively with BTX-A. In two stud- cohort of 37 patients over 2 years or greater and reported ies, blinded physicians reviewed the videotapes of the that 13 patients (35.2%) continued to receive the injections patients receiving either form of treatment and there was for a mean of 3 years. Twenty-four patients (64.8%) no significant difference between those receiving BTX-A discontinued treatment due to multiple reasons including and placebo [14, 19]. On objective tests of handwriting inadequate benefit, loss of response, improvement in dys- analysis, writing speed, and writing errors, there was sig- tonia, the expense of toxin, and inaccessibility of treatment nificant improvement with BTX-A compared to placebo provider. [14, 16, 19]. In a fourth trial, the investigators enrolled 40 Hsiung and colleagues examined the efficacy of BTX-A patients with writer’s cramp and randomized 20 patients in the treatment of various movement disorders over 10 years each to either BTX-A or placebo with intention to treat. The number of patients with writer’s cramp reporting Seventy percent of patients who received BTX-A sustained benefit with BTX-A at 2-year and 5-year intervals treatment wished to continue treatment versus 31.6% of 13 Neurological Sciences those receiving placebo. Patients who received BTX-A had Deep brain stimulation better results on objective testing with significant improve- ment on WCRS Part A and in writing speed. Certain groups have performed thalamic Vo complex DBS Most patients in these studies had writer’s cramp and a and reported similar results as thalamotomy suggesting handful of patients had other forms of FHD [14, 16, 19, that this procedure can be considered in patients with FHD 26]. Hence, it seems that BTX-A is probably efficacious in [38, 40, 48]. Fukaya and colleagues performed thalamic writer’s cramp but the same cannot be said with certainty Vo complex and globus pallidus interna (GPi) DBS in one regarding other forms of FHD due to the small sample size. of their patients and reported that thalamic DBS was supe- Studies enrolling patients with other forms of dystonia will rior to GPi DBS. be required to answer the question of the efficacy of BTX-A in all forms of FHD. Besides randomized controlled trials, open-label studies, Long‑term outcomes of surgical procedures prospective placebo-controlled studies, and retrospective studies have examined the role of BTX-A in the treatment Favorable long-term outcomes have been reported with of focal hand dystonia [7, 11–13, 15, 17, 18, 20–25, 27]. both procedures. Studies comparing these procedures Based on these studies, there is level III evidence and grade head-to-head are lacking. Hence, it is hard to determine C recommendation for BTX-A in treatment of focal hand which procedure is better. dystonia. Groups in favor of lesional surgery argue that most Based on the available evidence, AAN gives a level B rec- patients with focal dystonia are young (in the mid-30 s) ommendation for BTX-A in the treatment of FHD suggest- and require long-term management for which thalamotomy ing that it is probably effective for this disorder EFNS is a better option [37, 53] Some of the other reasons for gives level A recommendation for BTX-A in treatment of favoring thalamotomy over DBS are hardware-associated writer’s cramp and level B recommendation for other forms complications (infections, battery malfunctions, lead of FHD. migration, and lead fracture), physiological and psycho- logical burden associated with device implantation, higher cost of DBS, and the need for long-term follow-up in cent- Lesional surgery and deep brain stimulation in FHD ers specializing in DBS. Disadvantages of thalamotomy are a higher rate of complications such as transient or per- Lesional surgery and deep brain stimulation (DBS) are sur- manent dysarthria and motor deficits [36, 41, 43, 44, 46, gical options reserved for patients with medically refractory 53]. Intraoperative test lesions and adequate expertise in FHD. performing surgery can reduce the complication rates. Traditionally, it was thought that patients requiring bilateral procedures (e.g., bilateral FHD) should undergo Lesional surgery bilateral DBS placement instead of bilateral thalamotomy due to its high complication rate (possible severe pseudob- In published studies, the most common lesional surgery ulbar palsy). However, recent studies have examined is stereotactic ventral oralis complex (Voc) thalamotomy the role of bilateral thalamotomy in essential tremor, and Table 3 [32–53]. The Voc refers to the complex of ven- suggested that it is feasible and safe in carefully selected tral oralis anterior (Voa) and ventral oralis posterior (Vop) patient populations [54–56]. nuclei. The fibers of the cortico-pallido-thalamo-cortico cir- Advantages of DBS are the ability to control the lead cuit and cortico-cerebello-thalamo-cortico circuit pass via parameters and lower incidence of postsurgical neuro- these nuclei. It has been suggested that lesion of these fib- logical deficits. DBS was previously thought to be a ers results in improvement of dystonia. One of the recently reversible procedure. However, recent studies have sug- published studies provided class IV evidence for ventro- gested that stopping DBS stimulation suddenly can pre- oral thalamotomy for patients with task-specific FHD. cipitate a medication-refractory malignant parkinsonian The ventral intermediate nucleus has been targeted in some crisis, or dystonic crisis, and have proposed a new diag- studies, but the sample size of these studies is too small to nosis of “DBS withdrawal syndrome.” [57–60]. suggest if this target is as beneficial as the Voc [33, 34]. Pal- lidotomy has been performed in patients with FHD due to its beneficial effects in patients with generalized dystonia. Newer surgical techniques like magnetic resonance–guided focused ultrasound (MRgFUS)–thalamotomy are being explored for the treatment of FHD. 13  Table 3  Studies reporting lesional surgery and deep brain stimulation in patients with focal hand dystonia Study Number of patients Age at presentation Disease duration Type of dystonia Surgical technique Outcomes Complications/adverse effects (mean) (years) (mean) 13 (years) 1 (M) 60 4 Tremulous writer’s cramp Stereotactic VL thalam- Writing was normal at None reported otomy 3-month follow-up 1 (M) 39 16 Writer’s cramp Stereotactic thalamotomy Patient had initial improve- Relapsed 6 weeks later to (likely Vim) ment preoperative stage 3 Writer’s cramp Stereotactic thalamotomy (likely Vim) 1 (F) 23 5 Writer’s cramp Stereotactic Voa and Vop Patient was able to write Thalamic hemorrhage caus- thalamotomy 7 days following surgery. ing upper motor neuron Improvement was type left facial palsy unchanged 6 months fol- lowing surgery 8 (5 M, 3 F) 26–40 (32.1) 3–6 (4) Writer’s cramp Stereotactic Voc thalam- All patients had immediate One patient had partial otomy postoperative improve- recurrence of symptoms ment of dystonia with and underwent second sustained effect dur- thalamotomy 5 months ing follow-up period after the initial surgery with (3–29 months) except in satisfactory results. Other one case complications were air embolism during surgery, transient paresis, and dys- esthesia 1 (1 M) 33 Since childhood Writer’s cramp Stereotactic Voa–Vop com- Improvement in dystonia No complications reported plex thalamotomy 5 (5 M) 26–73 (46.6) 2–25 (11.8) Writer’s cramp Thalamic Vo/Vim DBS Improvement in dystonia in No complications reported GPi DBS all five cases (Lead was implanted in both GPI and Vo/Vim in one patient with superior outcomes with thalamic stimulation) 4 (4 M) 16–68 (35.5) 16–68 (23.75) Focal hand dystonia: 4 Stereotactic Voc thalam- All patients had improve- CT of 1 patient immediately (All patients had DYT1 otomy ment in dystonia following after surgery showed small dystonia) the thalamotomy. One high density in the L thala- patient developed mild mus, suggesting lesional dystonia of both hands bleeding. The patient had after 12 years mild tingling sense in the L leg, which resolved 1 month later Neurological Sciences  Table 3  (continued) Study Number of patients Age at presentation Disease duration Type of dystonia Surgical technique Outcomes Complications/adverse effects (mean) (years) (mean) (years) 1 (1 F) 36 Focal hand dystonia Thalamic Vo complex DBS Remarkable improvement in No post-surgical complica- Neurological Sciences (writer’s cramp) writing tions reported (Preoperative BFMDR scale was 4 and post-op scale was 1) 15 (10 M, 5 F) (41.5) 2–29 (8.3) Musician’s dystonia (10 gui- Stereotactic Vo thalam- All patients except 1 showed 1 patient had weakness in tarists, 3 pianists, 1 flutist, otomy remarkable improvement right lower limb after and 1 violinist) immediately after surgery. surgery but recovered to The mean preoperative an extent as to have no TMDS score was 2.7 and difficulty with daily life the mean final postopera- activities tive score was 4.6 4/10 had transient dysarthria 2 (2 M) 23 (M) Patient 1—5 years Writer’s cramp Stereotactic Vo thalam- Symptoms improved imme- No post-surgical complica- 62 (M) Patient 2—10 years otomy diately following the sur- tions reported gery. For patient 1, WCRS score improved from 5 pre-op to 0 post-op. For patient 2, WCRS score improved from 7 pre-op to 0 post-op 1 (M) 35 – Watchmaker’s dystonia Stereotactic thalamotomy Dystonia improved follow- Mild pyramidal signs that ing surgery. Pre-op Arm subsequently improved Dystonia Disability score was 60 and post-op score was 100 4 (4 M) 32–61 (41.5) 3–6 (4.25) Hairdresser’s dystonia Stereotactic Vo thalam- Patients 1 and 4 had marked Patients 1 and 4 had no surgi- otomy improvement in symptoms cal complications. Patient with no recurrence on 2 developed transient mild follow-up. Patients 2 and dysarthria following the 3 had recurrence of symp- second surgery. Patient 3 toms within 3 months had permanent mild dysar- of surgery and patient 2 thria following the surgery underwent second thalam- otomy with little effect 13  Table 3  (continued) Study Number of patients Age at presentation Disease duration Type of dystonia Surgical technique Outcomes Complications/adverse effects (mean) (years) (mean) 13 (years) 1 (1 F) 19 2 Writer’s cramp Stereotactic GPi pal- Patient underwent L stereo- Transient dysarthria fol- lidotomy tactic thalamotomy with lowing 2nd surgery that recurrence of symptoms resolved after 2 weeks. after 3 months. She With recurrence of writer’s underwent a repeat L cramp 4 months after sec- stereotacti