Effectiveness of repeated treatment with botulinum toxin type A across different conditions.
Key Words: muscle tone, dystonia, spasticity, cerebral palsy
Botulinum toxin type A (BoNTA) is a focal, injectable therapeutic that is important in the treatment of certain conditions of increased or aberrant muscular activity, such as focal dystonias, focal spasticity, glabellar lines, and some urologic and gastrointestinal disorders. (1,2) Botulinum toxin type A has also been used for the treatment of disorders that are not strictly neuromuscular, such as headache and musculoskeletal pain, (3,4) and is an established treatment for focal hyperhidrosis. (5)
Botulinum toxin type A acts by inhibiting the release of acetylcholine from neuromuscular and autonomic cholinergic fibers in the local region of injection. (6-8) These actions form the basis for its effects in neuromuscular conditions and hypersecretory disorders. However, recent evidence also suggests that botulinum toxin type A inhibits the release of selected neuropeptides, (9,10) which has been suggested as a possible mechanism for its effects on headache/migraine and musculoskeletal pain. (10,11)
Treatment with botulinum toxin type A typically produces temporary and reversible clinical effects. This temporary action allows treatment to be individualized for each patient based on clinical need (eg, adjustments in doses and/or injection sites). Studies have shown that repeated treatments are usually necessary to maintain benefit in chronic conditions.
Over the years, botulinum toxin type A has proven to be an extremely useful long-term treatment for focal dystonias, providing consistent benefit to the majority of patients following repeated injections. (12-14) Long-term studies of botulinum toxin type A treatment for adult spasticity, cerebral palsy, and glabellar lines are just beginning to appear in the literature. (2,15,16) As botulinum toxin type A gains importance as a treatment for these and other chronic conditions, it is critical to determine its long-term effectiveness to provide a basis for the long-term expectations and plans of patients, practitioners, and payer organizations. This review examines the literature on repeated botulinum toxin type A injections across different disorders and conditions.
The following search terms were used to identify clinical studies from the MEDLINE, EMBase, Biosis, SciSearch, JICST, and Pascal databases: botulinum toxin type A or BOTOX. Abstracts and non-English language studies were excluded. From this list, original research articles were identified in which patients received multiple botulinum toxin type A injections and the authors either summarized or presented data on the duration or efficacy of repeated injections. A number of long-term or repeated treatment studies were excluded because data were not presented, or were not separated, by treatment. (17-33) Several other studies were excluded because they used outcome measures that were not classifiable as clinical efficacy or duration measures. (34-37) Articles that examined the disposition of patients treated with botulinum toxin type A over time but did not include efficacy or duration data were grouped and considered separately.
Although several different formulations of botulinum neurotoxins are available in various countries, each has a unique clinical profile and dosing requirements and is non-interchangeable with the others. (38) For this reason, we have confined our review to a single botulinum toxin type A preparation (BOTOX[TM]; Allergan), which has been examined in a large number of published studies; doses refer specifically to this product.
Studies with Data on Repeated Treatments
A total of 44 original research studies were identified in the literature that included data on the duration or efficacy of repeated injections of botulinum toxin type A. In all of these studies, the benefits of repeated botulinum toxin type A treatments were sustained or increased over the follow-up period (Table 1). In approximately half of these studies (21 of 44), statistics were used to determine whether efficacy or duration changed over time (Table 1). The definition of efficacy varied by study and condition but remained consistent over time within any given report. Most studies defined duration as the interval between treatments (Table 2). Doses were constant or did not change significantly over time in 22 of the 44 studies (Table 1). Seventeen additional studies did not report doses over time. Doses increased over time in 4 of the studies. (44,58,64,67) One additional study (53) listed doses that appeared to initially increase then slightly decrease over time. One of the studies that reported consistent doses over time for two subgroups of patients reported a decrease followed by an increase over time for one other subgroup of patients. (56)
Seven of the studies reviewed here reported a statistically significant increase in the efficacy or duration of botulinum toxin type A over time. (2,3,15,16,44,63,68) Doses remained constant in all of these studies, except one in which the lower dose was associated with an increase in duration (44) and another that did not report doses over time. (3) In several other studies, the authors noted a trend toward decreased (43) or increased (50) duration that was not statistically significant. In several additional studies, our examination of the data suggested a trend toward enhanced improvement, but the authors did not offer this interpretation. (66,76)
The studies followed patients for varying time periods ranging from a few treatments to more than 10 years of treatment, and spanned 16 different conditions (Table 1). Seventeen studies followed patients (or a subgroup of patients) for more than an average of 4 treatments, and most of these (12 of 17; 71%) included patients with dystonias or hemifacial spasm (Table 1). However, several studies that followed patients for 6 treatments or more included individuals with adult spasticity, spastic cerebral palsy, and chronic tension-type headache. (3,15,16) Although most of the studies included 50 patients or fewer, 15 followed more than 100 patients and 6 followed more than 200 patients over the course of repeated treatments (Table 1).
The studies could be generally grouped into 2 categories. In the first type, patients in the study had received varying numbers of treatments and thus different numbers of patients were included at each time point in the analysis of long-term effects. The reasons for this variability in N values at each time point included inter-individual variations in duration, patients discontinuing the study, patient accrual, patients lost to follow up, no further need for treatments, or other factors (Table 1). For instance, many of the studies were reviews of all patients at a single clinic or prospective studies of consecutive patients who had received BoNTA treatment for a given condition (see patient sample column in Table 1). At the time of analysis, patients had been treated for different lengths of time and this is reflected in the different numbers of patients at the different time points. The second type of study involved the assessment of the same subgroup of patients after multiple treatments (Table 1). Some studies in the first category analyzed the data for a subgroup of patients who had all received the same number of treatments (Table 1). (12,39,51,52,59,60,63) Still other studies recruited patients to specific inclusion/exclusion criteria (Table 1). Many studies did not report how they selected patients for inclusion in the study (Table 1).
Studies of Patient Disposition
Five studies were identified that followed the disposition of patients treated with botulinum toxin type A to determine whether or not they continued treatment over time (Table 3). (77-81) Results of these studies indicate that the majority of patients with blepharospasm, cervical dystonia, Meige syndrome, and hemifacial spasm continued botulinum toxin type A treatment--some up to 11 years or until death of unrelated causes (Table 3). In contrast, the single study of patients with focal hand dystonia found that most patients discontinued treatment over the course of 2 years. (81)
Discussion and Implications
All of the 44 studies reviewed here that examined the effects of repeated botulinum toxin type A treatments found sustained or enhanced improvement over the follow-up period, which ranged from a few treatments to more than 10 years of treatment. The consistent benefits were not due to increasing doses over time, as the majority of studies found no significant change in doses, although 17 of the studies did not report whether doses were consistent over time. The results of these studies spanned 16 different conditions, suggesting that the continued benefit with repeated injections is widely applicable. The consistent benefits of botulinum toxin type A are particularly well documented for hemifacial spasm and the craniocervical dystonias, and are buttressed by studies of patient disposition over time. Spastic cerebral palsy and adult spasticity were also well represented in this review, with studies documenting consistent or enhanced benefits from approximately 4 to 6 treatments with botulinum toxin type A.
An exception to the consistent improvement observed across most of the conditions may be in the treatment of focal hand dystonias. We found only one study that followed writer's cramp patients over multiple treatments. (81) In this study, 24 of the 37 patients discontinued botulinum toxin type A treatment over time, with reasons for discontinuation cited as no benefit (n = 5), inadequate improvement in hand performance (n = 7), loss of response (n = 4), dystonia no longer a problem (n = 3), and other reasons (n = 5).
Although several studies of patients with achalasia met the inclusion criteria for this review, achalasia is clearly different from the other conditions studied here in that many patients require only a single treatment over the course of 2 years. (70,72) Thus, data are reported in the achalasia studies as the numbers of patients who underwent multiple treatments to control their symptoms instead of mean scores for efficacy or duration, as is the case for the other conditions.
Enhanced Benefit with Repeated Treatments
Seven of the studies reviewed here found a significant enhancement in patient response over the course of repeated treatments. There are several possible explanations for these findings. Carryover effects from the previous injection are possible, as many patients return for reinjection before their symptoms return to baseline. The remaining subclinical amount of muscle relaxation may add to the relaxation produced by the next injection, enhancing its apparent effect. This explanation may be tenable for subtle enhancements in efficacy but seems unlikely to account for a progressive increase in benefit with each treatment (16,63) or the large increases in duration reported in an adult spasticity study. (15)
Another possible explanation that applies particularly to functional outcome measures is that the patient may adapt to reduced muscle tone over the course of injections and, as a result, may perform better on functional tests. This may be the case in cerebral palsy patients, for whom cumulative functional improvements have been reported in two studies. (16,63) In studies of children, improvements over time are confounded with biologic development and thus cannot be unequivocally attributed to the treatment, particularly in the absence of a parallel control cohort. However, another study found that patients with cerebral palsy who were treated with modalities other than surgery or botulinum toxin did not show spontaneous improvement in equinus deformity over seven years. (82) In Garcia Ruiz et al, (16) physical therapy remained constant over the time studied, but Balkrishnan et al (63) did not include physical therapy in their analysis.
Yet another possible explanation for the enhanced benefits over time is that botulinum toxin type A may indirectly alter sensory feedback to the central nervous system. (83-86) In preclinical studies, local injection of botulinum toxin type A has been found to reduce afferent discharge of muscle spindles, indicating a modulatory effect on sensory feedback. (87) Indirect support for the sensory feedback hypothesis comes from a study of cervical dystonia patients who showed electromyographic changes in the contralateral, uninjected sternocleidomastoid following repeated treatments, but not after a single treatment. (36) However, none of the studies reviewed here reported enhanced benefits in cervical dystonia patients, although we cannot rule out such benefits for a subgroup of patients or subtle effects that were not detected on the broad rating scales (eg, 5-point Likert-type scales) used in most of the studies.
In addition to the potential explanations for enhanced benefit that have already been offered, a psychological/learned component to the enhanced benefits cannot be ruled out in the absence of placebo controls, which none of the studies included.
Implications for Clinically Relevant Neutralizing Antibody Formation
The results of this review further suggest that neutralizing antibody formation is not a clinical issue for most patients undergoing long-term treatment with the preparation of botulinum toxin type A studied here. We base this suggestion on the continued response reported in all of the studies, in addition to the high percentage of patients who remain on treatment in observational studies. Neutralizing antibody formation is often associated with decreasing efficacy, and higher doses are needed to maintain benefit. (88) That we did not find decreasing efficacy or higher doses in most studies suggests a relative lack of clinically significant neutralizing antibody formation. In one of the few studies that actually tested for neutralizing antibodies, only 1 of 207 patients was found to be positive for neutralizing antibodies. (66) The patient had received 4 injections of botulinum toxin type A. The low rate of neutralizing antibody formation is supported by those of an ongoing multicenter study of patients with cervical dystonia who have received up to 9 treatments with BoNTA. (89) In this study, 99.5% of 1,036 serum samples from 326 patients have tested negative for neutralizing antibodies, 0.1% have tested positive, and 0.4% have given inconclusive results.
Each type of study used to examine the consistency of botulinum toxin type A effects has particular advantages and disadvantages. Many of the studies included the analysis of different patient numbers at each treatment session. Some of these studies included all patients who presented at a single clinic with a given disorder and thus the results are not limited to a selected subgroup that elected to stay with treatment over the long term (ie, self-selection bias). Other studies recruited a group of patients to participate, some of whom discontinued for a variety of reasons, potentially biasing the analysis toward those who elected to stay with the treatment. In neither case is it possible to conclude that the patients with the fewest treatments would respond the same way as those who received the most treatments. For instance, in some cases, the decreasing patient numbers at each treatment were due to differential need for retreatment (5,66) or continuing accrual into the study (Table 1). Thus, we cannot predict whether patients who have received only a few treatments would respond similarly to those for whom longer-term treatment data are available.
In contrast, following a subgroup of patients over successive treatment sessions permits conclusions about the consistency of benefits in that particular subgroup. However, these conclusions may not be generalized to others with this disorder due to self-selection bias, need for more frequent treatments in the subgroup with a high number of treatments, or other reasons.
Analysis of the treatment history or disposition of all patients may assume that patients would only consistently return for retreatment if they were deriving continued benefit. Such studies do not allow conclusions about whether duration or efficacy remains constant over time, but permit assessment of whether patients remain on long-term treatment in actual clinical practice, which provides information about the broad group of patients who qualify for and receive botulinum toxin type A treatment for a given condition.
It is difficult to overstate the importance of long-term patient responsiveness to botulinum neurotoxin therapy. Treatment failure has both health and financial costs. Additional physician visits and trials of other treatments can be frustrating and expensive. Surgery is invasive and, for some indications, irreversible. Moreover, patients may not experience as great a benefit from the alternate therapy or may experience more adverse effects. (90) For instance, the incidence of treatment-related adverse events in a recent controlled trial of botulinum toxin type A for the treatment of focal spasticity in adults was 18.8% (n = 64) compared with 17.7% (n = 62) in the placebo group. (91) In a recent open label trial of tizanidine, a drug approved by the FDA for spasticity, 89% of patients experienced at least one adverse event that was deemed possibly related to treatment, including 62% with somnolence and 32% with dizziness. (92) Although studies with lower and higher adverse event rates can be cited for both drugs, the low rate and localized nature of adverse events with botulinum toxin type A are evident throughout the literature. (93)
Well-designed follow-up studies are important to evaluate the potentially enhanced benefits from successive botulinum injections and their effect on patient quality of life and treatment satisfaction (including factors of convenience, cost, and adverse effects). In some conditions, it may be possible to identify a subgroup of patients who are likely to receive enhanced benefit from repeated treatments, which may then affect treatment decisions.
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Artists who seek perfection in everything are those who cannot attain it in anything. --Gustave Flaubert
Mark Forrest Gordon, MD, and Rich Barron, MS
From North Shore-Long Island Jewish Health Systems, New Hyde Park, NY, and Allergan, Inc., Irvine, CA.
Reprint requests to Rich Barron, MS, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612. Email: Barron_Rich@Allergan.com
Mr. Rich Barron is an employee of Allergan Inc. (the makers of BOTOX[R]) and receives corporate stock as part of his employee compensation. Dr. MF Gordon has served as an investigator in Allergan-sponsored trials. He has received research grants, consultant fees (advisory boards), and speaker fees from Allergan, Inc.
Accepted February 3, 2006.
RELATED ARTICLE: Key Points
* Forty-four original research articles reporting on 16 different conditions were identified that included data on the duration or efficacy of multiple treatments with botulinum toxin type A.
* All of the 44 studies found sustained or enhanced improvement in efficacy and/or duration over the follow-up period, which ranged from a few treatments to more than 10 years.
* Seven studies reported a statistically significant increase in the efficacy or duration of botulinum toxin type A over time.
* Results suggest that continued benefit with repeated botulinum toxin type A treatment is widely reported in the literature.
Table 1. Summary of studies that examined efficacy and/or duration of repeated BoNTA treatments Patient Condition Reference sample (a) Patients (N) (b) BL 39 1,2 168; 25 discontin (subgroup of 12 > 14 txs) BL, HFS, MeS 40 1 22 BL 41 4 77 BL, OMD 42 4 101; 12 discontin BL, HFS, MeS 12 2,4 232 (subgroup of 50: [greater than or equal to]8 txs) BL, HFS 43 2 32 (same) BL, HFS 44 2 27 (same) BL 45 2 115 BL, MeS 46 1,2 76 (subgroup of 11: 5 txs) BL, HFS 47 1 28 (same) BL, HFS 48 4 31 (BL) 20 (HFS) HFS 49 2 (but 4 65 (same) clinics) HFS 50 4 17; 2 discontin HFS 51 1,2 65; 14 discontin (subgroup of 12: 9 txs) HFS 52 1,2 137 (subgroups of 20: 3txs; 11: 4txs) CD 53 1 232; 27 discontin CD, BL 14 2 157 (same) CD 54 3 84 CD 55 2 60 (same) HFS, facial and 56 2 235; 109 discontin (f) limb dystonias SD 57 1,2 102 (subgroup of 12: 6 txs) SD 58 1,2 178 (subgroup of 21: 4-5 txs) SD 59,60 1,2 42; 6 discontin (subgroup of 11: 5 txs) SD 61 4 10 (same) SD 62 1 91 CP 63 3 180; 17 discontin CP 64 3 207; 86 discontin (g) CP 16 3 8 (same 12 mos) 5 (same 24 mos) SPAST 65 3 14 SPAST 15 3 34 (6 discontin) SPAST 66 3 111 (23 discontin) MFP 67 Case 2 (same) reports ACH 68 3 20 ACH 69 3 37 ACH 70 1 57 (7 discontin) ACH 71 1 23 ACH 72 1 30 DES 73 3 9 TESF 74 3 23; 2 discontin CTTH 3 3 30 (same) HH (ax) 5 3 207 (33 discontin) HH (ax) 75 3 12 Glab lines 2 3 405 (subgroup of 258: 3 txs) Detruss 76 3 40 (same) overactiv Condition No. of treatments Outcome assessed BL 1 to 41 (mean 7.5) Efficacy Duration BL, HFS, MeS 1 to 9 Duration BL Mean 2.5 Efficacy Duration BL, OMD [greater than or equal to] 3 Duration BL, HFS, MeS 1 to 18 (mean 4.5) Efficacy Duration BL, HFS 12 Duration BL, HFS 4 to 6 years Duration Dose BL 3 to 8 years Duration BL, MeS 1 to 6 (mean 2.9) Duration BL, HFS [greater than or equal to]6 Duration Dose BL, HFS 1 to 5 Duration HFS 10 years Efficacy Duration HFS 1 to 5 Duration HFS 9 Efficacy Duration HFS Mean 1.7 Duration CD Mean 2.5 (3 months to 4 years) Dose Duration CD, BL [greater than or equal to]5 Efficacy Duration CD 1 to 6 (Mean 2.7) Dose Efficacy Duration CD 4 Dose Duration HFS, facial and [greater than or equal to]2 years Efficacy limb dystonias Dose SD Up to 2 years Efficacy SD 2 to 10 Efficacy Duration Dose SD 1 to 7 Quality of life SD 3 Efficacy Duration SD 1 to 3 Efficacy CP Mean 4; exact value NS Function Efficacy CP Mean 1.5 years Duration Efficacy Dose CP 6 Efficacy SPAST 1 to 3 Efficacy SPAST [greater than or equal to] 6 Efficacy Duration Dose SPAST Up to 4 Efficacy MFP 2 Efficacy Daily activity ACH 1 to 5 (Mean 2.5) Duration ACH 1 or 2 Efficacy ACH 1 to 3 Efficacy ACH 1 or 2 Efficacy ACH 1 to 3 Efficacy DES 1 or 2 Efficacy TESF 1 to 3 Efficacy CTTH 6 Efficacy HH (ax) 1 to 3 Efficacy HH (ax) 2 to 4 Duration Glab lines Up to 3 Efficacy Detruss Mean 3.4 Efficacy overactiv Response with repeated Condition treatments Statistics (c) Doses over time BL Sustained N Not reported Sustained BL, HFS, MeS Sustained N Same BL Sustained N Not reported BL, OMD Sustained N Not reported (but authors stated decrease) BL, HFS, MeS Sustained N Not change Sustained BL, HFS Sustained Y Dose stable after (nonsignificant first few txs decrease) BL, HFS BL low dose Y Dose increased if increased response deemed HFS sustained HFS, inadequate BL increased BL Sustained Y No change in dose/ duration relationship (d) BL, MeS Sustained Y Same BL, HFS Sustained Y Nonsignificant increase BL, HFS Sustained N Not reported, implied similar HFS Sustained Y No change HFS Nonsignificant Y Not reported increase HFS Sustained Y Not reported HFS Sustained Y Not reported CD Sustained N Appeared to slightly increase then decrease CD, BL Sustained N No change CD Sustained (e) N No change CD Sustained Y Not reported HFS, facial and Sustained Y CD, HFS no change limb dystonias (NS increase); BL dec then inc SD Sustained N Not reported SD Sustained Y Inc if less than optimal response SD Sustained Y Not reported SD Sustained (g) Y Not reported SD Sustained N Not reported CP Increased Y (WeeFIM) Not reported CP Sustained (h) N Increased Sustained Increased (h) CP Increased Y Same SPAST Sustained N Same SPAST Sustained Y No change Increased Sustained SPAST Sustained or N No change increased MFP Increased N Doses increased 50 to 150 U ACH Increased Y Same ACH 35 responded to 1 N Same or 2 txs ACH Sustained N Same ACH 19 responded to 1 N Not reported or 2 txs ACH 23 responded to 1 N Same to 3 txs DES Sustained N Same TESF 20 responded to 1 N Not reported or 2 txs CTTH Sustained to Y Not reported increased HH (ax) Sustained N Same HH (ax) Sustained (i) N Same Glab lines Increased Y Same Detruss Sustained Y Same overactiv (a) 1=all patients who received BoNTA for a given disorder at a single clinic; 2=subgroup of patients at a single clinic who received a specified number of treatments with BoNTA for a given disorder; 3=recruited sample that met specific inclusion/exclusion criteria; 4=not specified (many of these appeared to include all or consecutive patients at a single clinic but this was not specifically stated). (b) Number of patients enrolled in the study and discontinuation rate, if reported. (c) Comparing treatments over time. (d) Doses over time examined as duration-dosage quotient weeks/unit. (e) Efficacy, dose, and duration were generally sustained from treatments 3 to 6; treatments 1 and 2 tended to show slightly higher efficacy scores and/or durations, but trends were not statistically analyzed and patient numbers at each injection ranged from 6 to 84. (f) Reasons for discontinuation: primary resistance (n = 22), surgery (n = 21), secondary resistance (n = 18), lost to follow up (n = 17), practicality (eg, patient moved; n = 17), remission (n = 8), death due to causes not related to treatment (n = 3), adverse events (n = 3). (g) Patient-rated efficacy varied over the postinjection course and the timing of improvement was not the same for all of the treatments, although the overall duration was not statistically different between treatments. (h) Reasons for discontinuation: reasons unrelated to treatment (n = 47), lack of efficacy (n = 39), not evaluable (n = 4); duration appeared to be sustained through treatment 8, although the number of patients decreased from 207 at treatment 1 to 31 at treatment 8; too few patients had >8 treatments to draw any conclusions and no statistics were calculated on these data. (i) Durations between treatments 2-3 and 3-4 appeared to be comparable (means 158.7 and 141.3 days). The duration was longer for the first injection (mean 205.7 days); however, this value represents all patients in the study, even those who did not need further injections. Statistics were not calculated on these data. ACH, achalasia; ax, axillary; BL, blepharospasm; CD, cervical dystonia; CP, cerebral palsy; CTTH, chronic tension-type headache; Detruss overactiv, detrussor overactivity (neurogenic); dec, decrease; inc, increase; DES, diffuse esophageal spasm; discontin, discontinued; Glab, glabellar; HA, headache; HFS, hemifacial spasm; HH, hyperhidrosis; LD, laryngeal dystonia; MeS, Meige syndrome; MYO, myokymia; NS, not specified; OMD, oromandibular dystonia; SD, spasmodic dysphonia; STRAB, strabismus; SPAST, spasticity; TESF, tracheoesophageal speech failure; tx, treatment; Same, same exact dose used at each treatment; No change, no significant change in doses over treatments; MFP, myofascial face pain. Table 2. Assessment methods used in the various studies (a) Assessment Method Studies Duration: time 15,41,43-47,49,52,55,61,64,75 between treatments Duration: not 12,40,42,48,50,68 specified Efficacy: Likert-type 2,3,12,14,39,44,46,49,51,58,61,69,70,71-73 symptom rating scales Efficacy: Disease- 14,54,65,66 specific clinical scales Function or quality 5,16,59,60,63,64,66 of life scales Other Time to disabling symptoms (39) Patient--rated (diary) duration of benefit (56) Vocal recordings (57) Vocal fold movement (58) Translaryngeal airflow, other mechanical variables (62) Patient report--no scale (67) Speech fluency (74) 50% decrease in sweating (5) Urodynamics, incontinence (76) Spasm--free period (51) Duration of any improvement (14,53) Time to patient-reported worsening (54) Days with positive voice ratings (58) (a) Some studies used more than one method. Table 3. Studies that examined BoNTA patient disposition over time Condition Reference N No. of treatments Outcome assessed BL, MeS 77 228 Up to 11 years Continuation (a) BL, HFS, 78 50 Mean 10.4 Natural history MeS HFS 79 108 1 to 24 Natural history CD 80 133 [greater than or equal to] Continuation 6 years Focal hand 81 37 Up to 6 years Continuation dystonia Condition Results with repeated treatments BL, MeS 202 were still treated with BoNTA, 18 did not seek futher txs, 5 remission, 3 surgery BL, HFS, 26 returned for txs, 3 no response, 3 went into remission, MeS 6 treated until death (unrelated to tx), 6 received repeated txs at other centers, 5 lost to follow up, I had only 1 tx HFS At a median of 30 months follow up, 55 patients still receiving injections, 10 failed to respond, 4 stopped treatment for other reasons, 5 in remission after 1 to 6 injections, 4 treated until they died of causes unrelated to injections, 8 received repeated injections at other centers, 22 lost to follow up CD 104 continued treatment and 29 stopped; 1/3 reported the first injection was most helpful, 1/3 felt all were similarly effective Focal hand 24 patients followed for 2 years discontinued treatment dystonia (a) The number of patients who continued BoNTA therapy. BL, blepharospasm; CD, cervical dystonia; HFS, hemifacial spasm; MeS, Meige syndrome; tx,treatment