Abstract
Introduction
Patients receiving onabotulinumtoxinA treatment for chronic migraine (CM) may have coexisting diseases warranting multi-indication use of onabotulinumtoxinA. However, data on safety and treatment patterns for concomitant treatment of CM and other diseases are limited.
Methods
SYNCHRONIZE was a phase 4, multicenter, retrospective study that explored the safety of onabotulinumtoxinA treatment for ≥ 2 therapeutic (non-aesthetic) indications within 3 months. The observation period of interest was approximately 6 months before and 24 months after receiving treatment for the second indication. The primary outcome was treatment-emergent adverse events (TEAEs) occurring within 6 months. Results are reported descriptively and stratified by treatment indications. This analysis focuses on patients treated for CM and ≥ 1 other onabotulinumtoxinA indication.
Results
A total of 183 patients had CM and ≥ 1 other onabotulinumtoxinA indication (CM + cervical dystonia [CD], n = 121; CM + oromandibular dystonia [OD] ± blepharospasm [BS], n = 17; CM + BS or hemifacial spasm [HS], n = 13; CM + CD + other movement disorders [MD], n = 11; CM + spasticity [SP] or focal dystonia [FD], n = 10; CM + hyperhidrosis [HH] ± other MD, n = 5; CM + overactive bladder [OAB] or neurogenic detrusor overactivity [NDO], n = 4; CM + other MD, n = 2). The 3-month mean cumulative onabotulinumtoxinA dose ranged from 163.4 U (CM + OD ± BS) to 396.2 U (CM + SP or FD), and most patients received treatment for their first and subsequent indications within 24 h. The proportion of patients with ≥ 1 TEAE in the 6 months post-index was 23.5% overall, with the most common being neck pain (6.6%), headache (4.9%), migraine (4.9%), and brow ptosis (2.2%). There were no TEAEs consistent with distant spread of toxin and no discontinuations due to adverse events.
Conclusion
TEAEs associated with onabotulinumtoxinA treatment in adults with CM and ≥ 1 coexisting disease within 3 months were generally consistent with the known safety profiles for the individual onabotulinumtoxinA indications. There were no new safety signals observed for up to 6 months after multi-indication treatment.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40122-026-00816-z.
Keywords: Botulinum toxins, Type A, Cervical dystonia, Headache, Migraine disorders, Muscle spasticity, Torticollis, Urinary bladder, Overactive
Plain Language Summary
OnabotulinumtoxinA is used to treat chronic migraine and other diseases that may occur in the same patient, including dystonias and overactive bladder. The safety of using onabotulinumtoxinA for treating multiple diseases is unclear. The SYNCHRONIZE study examined patients receiving onabotulinumtoxinA for chronic migraine and at least one other disease within 3 months to evaluate safety. A total of 183 patients were observed for approximately 6 months before and up to 24 months after receiving treatment for a second disease, including movement disorders (e.g., cervical or oromandibular dystonia, blepharospasm) and other diseases (e.g., hyperhidrosis, overactive bladder). Most patients received treatment for both diseases within 24 hours. Overall, 23.5% of patients had at least one side effect; the most common were neck pain (6.6%), headache (4.9%), and migraine (4.9%). The safety reported for onabotulinumtoxinA for treating chronic migraine plus one or more diseases was consistent with the known safety of onabotulinumtoxinA when treating a single indication.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40122-026-00816-z.
Key Summary Points
| Why carry out this study? |
| Patients receiving onabotulinumtoxinA treatment for chronic migraine (CM) may have coexisting diseases that are also treated with onabotulinumtoxinA. |
| Data on safety and treatment patterns for concomitant treatment of CM and other diseases are limited, often leading to delayed treatment because of safety concerns and/or payor restrictions. |
| This study was conducted to assess the real-world safety of onabotulinumtoxinA for the preventive treatment of CM and treatment of ≥ 1 frequently co-occurring disease. |
| What was learned from the study? |
| Adverse events associated with onabotulinumtoxinA treatment of adults with CM and at least one other indication within 3 months were consistent with the known safety profiles for the individual onabotulinumtoxinA indications, with no new safety signals observed up to 6 months after multi-indication treatment. |
| The findings of this study may provide guidance that could help remove barriers to care for patients with both CM and other onabotulinumtoxinA treatment indication(s). |
Introduction
Migraine is a debilitating neurological disease affecting more than one billion people worldwide [1]. Chronic migraine (CM, defined as ≥ 15 monthly headache days, 8 of which are migraine days) [2] is a particularly disabling disease, associated with more severe disability and greater health care utilization than episodic migraine (< 15 monthly headache days) [3–5].
The prevalence of many comorbidities in people with migraine has been shown to be associated with the number and frequency of attacks [6, 7]. The existence of pathophysiological features that are common to both migraine and certain coexisting neurological diseases, including non-migraine pain disorders, movement disorders (MDs), and some forms of bladder dysfunction, is thought to increase the potential for these diseases to co-occur [8–10]. For example, migraine has been associated with diseases such as neck pain and overactive bladder, and some individuals with MDs such as temporomandibular joint disorder (TMD), dystonia, and dyskinesia also experience headache [10–16]. OnabotulinumtoxinA is an injectable botulinum toxin formulation that was first approved by the US Food and Drug Administration (FDA) in 1989 for the treatment of blepharospasm and strabismus and is now approved for a total of 12 therapeutic indications, including CM [17, 18]. The safety and effectiveness of onabotulinumtoxinA for the preventive treatment of CM are well established across multiple clinical trials and real-world studies [19–24].
Given the frequent co-occurrence of migraine with other diseases, some patients receiving onabotulinumtoxinA treatment for CM may have coexisting diseases that are also treated with onabotulinumtoxinA, leading to multi-indication use [25–29]. Although the current onabotulinumtoxinA prescribing information states that adult patients being treated for one or more indications should not receive more than 400 U in a 3-month period [17], higher doses of onabotulinumtoxinA are commonly used in clinical practice [30]. However, few studies have evaluated the safety of concomitant indication use and cumulative doses of onabotulinumtoxinA that may exceed the approved total cumulative dose [30, 31]. In the absence of such data, health care professionals may delay onabotulinumtoxinA treatment for concomitant indications because of safety concerns, potentially affecting patient outcomes. Moreover, payor restrictions for multiple treatments can also delay care [30, 31]. To inform clinical decision-making, additional analyses are required to determine the safety of onabotulinumtoxinA treatment when used for more than one indication—particularly for CM, which is one of the most common diseases treated with onabotulinumtoxinA [32, 33].
A retrospective, observational, real-world study (SYNCHRONIZE) was conducted to assess the safety of onabotulinumtoxinA in patients treated for ≥ 2 therapeutic indications within a 3-month period [33]. The objective of this subanalysis was to assess the real-world safety of onabotulinumtoxinA for the preventive treatment of CM and treatment of ≥ 1 frequently co-occurring disease in the SYNCHRONIZE population.
Methods
Study Design
SYNCHRONIZE was a phase 4, multicenter, retrospective chart review using deidentified medical records from electronic health records (EHRs) collected from 10 clinical sites in the USA from January 2010 through January 2022. A detailed description of the methodology of this study can be found in the primary publication for SYNCHRONIZE [33]. Briefly, data were collected retrospectively from EHRs for up to approximately 24 months from the index date, defined as the date the patient met study inclusion criteria (i.e., the date of the initial onabotulinumtoxinA treatment for a second therapeutic indication) (Fig. 1). These analyses focus on the first exposure period, which was defined by the dates of the initial onabotulinumtoxinA treatments for the first and second indications and includes the up to 90-day pre-index period during which the first qualifying onabotulinumtoxinA treatment occurred. Subsequent onabotulinumtoxinA treatments occurring within 3 months of the first onabotulinumtoxinA treatment and for a different therapeutic indication from the first and second indications were considered a third treatment indication and as part of the primary exposure period.
Fig. 1.
SYNCHRONIZE study design. OnabotA onabotulinumtoxinA, TEAE treatment-emergent adverse event. aIndex date is defined as the date the patient met study inclusion criteria. bBrow, frontalis, or extensor digitorum brevis test
Study sites were identified using a feasibility assessment conducted via an electronic qualification questionnaire to confirm that sites had a sufficient population of eligible patients. Data collected from charts could include treatments for multiple therapeutic indications with onabotulinumtoxinA at the same visit or at separate visits. The SYNCHRONIZE study was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki principles consistent with good clinical practice and all applicable regulatory requirements. Informed consent was not required because no identifiable patient information was obtained. All study-related documents were approved by independent ethics committees and IRBs at each of the following sites in the USA: EvergreenHealth Multiple Sclerosis Center Kirkland, Kirkland, WA (approved June 21, 2021); Lucetta, LLC/Grace Forde, Lake Success, NY (approved January 26, 2022); Swedish Neuroscience Institute MS Center, Seattle, WA (approved April 19, 2022); Kansas Institute of Research, Overland Park, KS (approved January 23, 2022); Neuroscience Group, Neenah, WI (approved February 3, 2022); Neurology and Pain Specialty Center, Aliso Viejo, CA (approved January 27, 2022); Diamond Headache Clinic Chicago, IL (approved January 21, 2022); Rush University Medical Center, Chicago, IL (approved January 1, 2022); NYU Langone Health, New York, NY (approved February 19, 2022); and Rancho Research Institute, Rancho Los Amigos National Rehabilitation Center, Downey, CA (approved February 27, 2022).
Study Population
Patients aged ≥ 18 years at the index date who were treated with onabotulinumtoxinA for CM and ≥ 1 additional therapeutic indication within a 3-month period were included in this analysis. Eligible patients were required to have available medical record data for the baseline period (6 months prior to the index date) and at least one follow-up visit after the index date. Patients who were participating in a clinical trial for any onabotulinumtoxinA indication or receiving botulinum toxins other than onabotulinumtoxinA for approximately 6 months prior to the index date or at any point during the data collection period were excluded.
Study Variables
Baseline patient demographic and clinical characteristics were collected for 6 months prior to and including the index date, including age, sex, race/ethnicity, comorbidities, concomitant medications, whether onabotulinumtoxinA treatments were provided by same or different providers, use of a caregiver, and distance traveled for onabotulinumtoxinA treatment appointments. Comorbidities were defined as any other disease state documented in the medical record; data was limited to what was in the EHRs and may not have included comorbidities documented outside of the medical record that was accessed. All therapeutic indications for onabotulinumtoxinA, including off-label indications, were documented for approximately 24 months after the patient’s first onabotulinumtoxinA treatment that occurred within 3 months of treatment for another indication.
The primary outcome of interest was treatment-emergent adverse events (TEAEs) occurring within 6 months following the index date of the primary exposure period. An adverse event (AE) was considered any unfavorable and unintended sign, symptom, or disease temporally associated with onabotulinumtoxinA treatment, regardless of causality. The secondary outcome of interest was the proportion of patients with lack of effect of onabotulinumtoxinA (as documented by a brow, frontalis, or extensor digitorum brevis test), which may indicate immunoresistance [34].
Statistical Analysis
As a result of the observational nature of this study, inferential statistical analyses were not performed. Results are reported descriptively and stratified by treatment indication group (TIG). For further analysis, results were stratified by treatment area (i.e., CM + face/neck/head ± other areas vs CM + other areas) to assess safety outcomes when onabotulinumtoxinA treatments were administered to nearby or overlapping muscles. Categorical variables were reported using frequency and percentage distributions; continuous variables were reported using means and standard deviations (SDs). Continuous and discrete variables were also categorized into ranges and are described using frequency and percentage distributions. Analyses were conducted using R version 4.4.0 or greater (The R Foundation for Statistical Computing, Vienna, Austria, 2025 [https://www.R-project.org/]).
Results
Baseline Demographic and Clinical Characteristics
A total of 279 patients who were treated with onabotulinumtoxinA for at least two different therapeutic indications within 3 months during the study period met study criteria; of these, 183 had CM as a treatment indication during the primary exposure period (CM + cervical dystonia [CD], n = 121; CM + oromandibular dystonia [OD] ± blepharospasm [BS], n = 17; CM + BS or hemifacial spasm [HS], n = 13; CM + CD + other MDs, n = 11; CM + spasticity [SP] or focal dystonia [FD], n = 10; CM + hyperhidrosis [HH] ± other MD, n = 5; CM + overactive bladder [OAB] or neurogenic detrusor overactivity [NDO], n = 4; CM + other MD, n = 2) (Fig. 2). The mean age ranged from 38.8 years (CM + HH ± other MD) to 53.0 years (CM + OAB/NDO), and more than 80% of patients overall were female (Table 1). No patient had documented nonresponse via a clinical objective measurement, and no patient had documented discontinuation because of lack of effect. Of the 279 patients included in SYNCHRONIZE, 5 discontinued onabotulinumtoxinA treatment. In the 183 patients with CM and ≥ 1 additional therapeutic indication included in the current analyses, 3 patients discontinued. The reasons for discontinuation (n = 1 each) were patient rejected future treatments (CM + CD), physician determined treatment is no longer necessary (CM + SP), and pregnancy (CM + SP) (Supplementary Table). Among patients with available race/ethnicity information, the majority were identified as white and non-Hispanic. Most patients (89.1%) received their qualifying onabotulinumtoxinA treatments from the same provider, and 32.8% overall traveled ≥ 20 miles for treatment (CM + CD, 48/183 [39.7%]; CM + OD ± BS, 2/17 [11.8%]; CM + BS or HS, 2/13 [15.4%]; CM + CD + other MD, 3/11 [27.3%]; CM + SP or FD, 4/10 [40.0%]; CM + HH ± other MD, 0/5 [0%]; CM + OAB/NDO, 1/4 [25.0%]; CM + other MD, 0/2 [0%]). Concomitant medications used at baseline included preventive and acute headache medications, muscle relaxers or antispasmodics, and antidepressants (Table 2). Besides migraine, the most common comorbidities at baseline were anxiety, significant pain conditions, and depression.
Fig. 2.
Detailed distribution of patients across treatment indication groups. BS blepharospasm, CD cervical dystonia, CM chronic migraine, FD focal dystonia, HH hyperhidrosis, HS hemifacial spasm, NDO neurogenic detrusor overactivity, OAB overactive bladder, OD oromandibular dystonia, SP spasticity. aIncludes CM + hyperhidrosis (n = 4) and CM + hyperhidrosis + oromandibular dystonia (n = 1). bIncludes CM + gastroparesis (n = 1) and CM + neck and jaw pain (n = 1)
Table 1.
Baseline demographic characteristics by treatment indication group
| Characteristic | Overall | CM + CD | CM + OD ± BS | CM + BS or HS | CM + CD + other MD | CM + SP or FD | CM + HH ± other MD | CM + OAB/NDO | CM + other MD |
|---|---|---|---|---|---|---|---|---|---|
| (N = 183) | (n = 121) | (n = 17) | (n = 13) | (n = 11) | (n = 10) | (n = 5) | (n = 4) | (n = 2) | |
| Age, mean (SD), years | 46.3 (12.3) | 46.2 (12.5) | 44.9 (11.0) | 48.8 (10.4) | 47.7 (12.7) | 46.5 (11.0) | 38.8 (17.7) | 53.0 (17.6) | 46.5 (13.4) |
| Female sex, n (%) | 152 (83.1) | 100 (82.6) | 14 (82.4) | 12 (92.3) | 9 (81.8) | 7 (70.0) | 5 (100) | 4 (100) | 1 (50.0) |
| Race, n (%) | |||||||||
| White | 100 (54.6) | 73 (60.3) | 1 (5.9) | 6 (46.2) | 1 (9.1) | 10 (100) | 3 (60.0) | 4 (100) | 2 (100) |
| Black/African/Caribbean | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Native Hawaiian or Pacific Islander | 1 (0.5) | 1 (0.8) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Other | 1 (0.5) | 1 (0.8) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Data not available | 81 (44.3) | 46 (38.0) | 16 (94.1) | 7 (53.8) | 10 (90.9) | 0 | 2 (40.0) | 0 | 0 |
| Ethnicity, n (%) | |||||||||
| Hispanic or Latinx | 7 (3.8) | 3 (2.5) | 0 | 2 (15.4) | 0 | 1 (10.0) | 0 | 1 (25.0) | 0 |
| Not Hispanic or Latinx | 82 (44.8) | 61 (50.4) | 1 (5.9) | 5 (38.5) | 1 (9.1) | 9 (90.0) | 2 (40.0) | 3 (75.0) | 0 |
| Data not available | 94 (51.4) | 57 (47.1) | 16 (94.1) | 6 (46.2) | 10 (90.9) | 0 | 3 (60.0) | 0 | 2 (100) |
| Use of caregiver, n (%) | |||||||||
| Yes | 5 (2.7) | 0 | 1 (5.9) | 0 | 1 (9.1) | 3 (30.0) | 0 | 0 | 0 |
| No | 176 (96.2) | 120 (99.2) | 16 (94.1) | 13 (100) | 10 (90.9) | 6 (60.0) | 5 (100) | 4 (100) | 2 (100) |
| Data not available | 2 (1.1) | 1 (0.8) | 0 | 0 | 0 | 1 (10.0) | 0 | 0 | 0 |
| Provider(s) of onabotA treatments for first and subsequent indication(s), n (%) | |||||||||
| Same provider | 163 (89.1) | 114 (94.2) | 17 (100) | 10 (76.9) | 11 (100) | 6 (60.0) | 4 (80.0) | 0 | 1 (50.0) |
| Different providers | 19 (10.4) | 7 (5.8) | 0 | 3 (23.1) | 0 | 4 (40.0) | 1 (20.0) | 3 (75.0) | 1 (50.0) |
| Data not available | 1 (0.5) | 0 | 0 | 0 | 0 | 0 | 0 | 1 (25.0) | 0 |
| Distance traveled to treatment, n (%), miles | |||||||||
| < 10 | 59 (32.2) | 35 (28.9) | 11 (64.7) | 4 (30.8) | 5 (45.5) | 1 (10.0) | 2 (40.0) | 1 (25.0) | 0 |
| ≥ 10 to < 20 | 33 (18.0) | 23 (19.0) | 2 (11.8) | 1 (7.7) | 3 (27.3) | 1 (10.0) | 2 (40.0) | 1 (25.0) | 0 |
| ≥ 20 | 60 (32.8) | 48 (39.7) | 2 (11.8) | 2 (15.4) | 3 (27.3) | 4 (40.0) | 0 | 1 (25.0) | 0 |
| Data not available | 31 (16.9) | 15 (12.4) | 2 (11.8) | 6 (46.2) | 0 | 4 (40.0) | 1 (20.0) | 1 (25.0) | 2 (100) |
The table excludes treatment indication groups that had only 1 patient (CM + neck and jaw pain; CM + HH + OD)
BS blepharospasm, CD cervical dystonia, CM chronic migraine, FD focal dystonia, HH hyperhidrosis, HS hemifacial spasm, MD movement disorder, NDO neurogenic detrusor overactivity, OAB overactive bladder, OD oromandibular dystonia, SP spasticity
Table 2.
Baseline clinical characteristics by treatment indication group
| Characteristic | Overall | CM + CD | CM + OD ± BS | CM + BS or HS | CM + CD + other MD | CM + SP or FD | CM + HH ± other MD | CM + OAB/NDO | CM + other MD |
|---|---|---|---|---|---|---|---|---|---|
| (n = 183) | (n = 121) | (n = 17) | (n = 13) | (n = 11) | (n = 10) | (n = 5) | (n = 4) | (n = 2) | |
| Baseline concomitant medications, n (%) | |||||||||
| Preventive headache medications | 57 (31.1) | 37 (30.6) | 7 (41.2) | 6 (46.2) | 1 (9.1) | 4 (40.0) | 0 | 1 (25.0) | 1 (50.0) |
| Acute headache medications | 57 (31.1) | 41 (33.9) | 6 (35.3) | 6 (46.2) | 1 (9.1) | 3 (30.0) | 0 | 0 | 0 |
| Muscle relaxers or antispasmodics | 41 (22.4) | 31 (25.6) | 0 | 5 (38.5) | 2 (18.2) | 3 (30.0) | 0 | 0 | 0 |
| Antidepressants | 41 (22.4) | 31 (25.6) | 2 (11.8) | 4 (30.8) | 2 (18.2) | 0 | 1 (20.0) | 0 | 1 (50.0) |
| Anxiolytics | 13 (7.1) | 12 (9.9) | 1 (5.9) | 0 | 0 | 0 | 0 | 0 | 0 |
| Pain medications | 7 (3.8) | 5 (4.1) | 0 | 0 | 1 (9.1) | 1 (10.0) | 0 | 0 | 0 |
| Antiemetic medications | 10 (5.5) | 9 (7.4) | 0 | 0 | 1 (9.1) | 0 | 0 | 0 | 0 |
| Oral urinary incontinence medications | 3 (1.6) | 1 (0.8) | 0 | 0 | 0 | 0 | 0 | 2 (50.0) | 0 |
| Baseline comorbidities, n (%)a | |||||||||
| Migraine | 142 (77.6) | 89 (73.6) | 16 (94.1) | 11 (84.6) | 11 (100) | 8 (80.0) | 4 (80.0) | 2 (50.0) | 1 (50.0) |
| Anxiety | 54 (29.5) | 30 (24.8) | 10 (58.8) | 3 (23.1) | 5 (45.5) | 4 (40.0) | 1 (20.0) | 0 | 1 (50.0) |
| Depression | 48 (26.2) | 28 (23.1) | 5 (29.4) | 6 (46.2) | 4 (36.4) | 3 (30.0) | 0 | 1 (25.0) | 1 (50.0) |
| Significant pain condition | 42 (23.0) | 23 (19.0) | 8 (47.1) | 1 (7.7) | 9 (81.8) | 0 | 0 | 1 (25.0) | 0 |
| Insomnia or sleep disorder | 28 (15.3) | 15 (12.4) | 7 (41.2) | 1 (7.7) | 3 (27.3) | 2 (20.0) | 0 | 0 | 0 |
| Bruxism | 11 (6.0) | 3 (2.5) | 4 (23.5) | 0 | 3 (27.3) | 0 | 0 | 0 | 1 (50.0) |
| Fibromyalgia | 9 (4.9) | 5 (4.1) | 3 (17.6) | 0 | 1 (9.1) | 0 | 0 | 0 | 0 |
| TMJD | 7 (3.8) | 2 (1.7) | 3 (17.6) | 0 | 1 (9.1) | 1 (10.0) | 0 | 0 | 0 |
| Traumatic brain injury | 6 (3.3) | 3 (2.5) | 1 (5.9) | 0 | 1 (9.1) | 1 (10.0) | 0 | 0 | 0 |
| Bipolar disorder | 3 (1.6) | 2 (1.7) | 0 | 0 | 1 (9.1) | 0 | 0 | 0 | 0 |
BS blepharospasm, CD cervical dystonia, CM chronic migraine, FD focal dystonia, HH hyperhidrosis, HS hemifacial spasm, MD movement disorder, NDO neurogenic detrusor overactivity, OAB overactive bladder, OD oromandibular dystonia, SP spasticity, TMJD temporomandibular joint disorder
aComorbidities reported for > 1 patient are shown
Treatment Utilization
The mean (SD) 3-month cumulative onabotulinumtoxinA dose administered was 270.5 (101.2) U overall, ranging from 163.4 (37.0) U for CM + OD ± BS to 396.2 (148.4) U for CM + SP or FD (Fig. 3). The most common dose category was ≥ 200 to < 400 U overall (113/183 [61.7%]) and also for patients with CM + CD (87/121 [71.9%]), CM + CD + other MD (7/11 [63.6%]), CM + HH ± other MD (4/5 [80.0%]), and CM + OAB/NDO (4/4 [100%]). The dose varied across the other TIGs (Table 3).
Fig. 3.
Mean cumulative 3-month onabotulinumtoxinA dose in the primary exposure period by treatment indication group. CD cervical dystonia, CM chronic migraine, NDO neurogenic detrusor overactivity, OAB overactive bladder, onabotA onabotulinumtoxinA, SD standard deviation
Table 3.
Distribution of patients across 3-month cumulative onabotulinumtoxinA doses and treatment intervals
| Number | 3-month cumulative onabotA dose | Treatment interval | ||||||
|---|---|---|---|---|---|---|---|---|
| < 200 U | ≥ 200 to < 400 U | ≥ 400 to < 600 U | ≥ 600 to < 800 U | ≤ 24 h | > 24 h to 13 days | ≥ 14 days | ||
| Overall, n (%) | 183 | 51 (27.9) | 113 (61.7) | 16 (8.7) | 3 (1.6) | 114 (62.3) | 16 (8.7) | 53 (29.0) |
| CM + CD | 121 | 20 (16.5) | 87 (71.9) | 13 (10.7) | 1 (0.8) | 70 (57.9) | 11 (9.1) | 40 (33.1) |
| CM + OD ± BS | 17 | 15 (88.2) | 2 (11.8) | 0 | 0 | 17 (100) | 0 | 0 |
| CM + BS or HS | 13 | 9 (69.2) | 4 (30.8) | 0 | 0 | 10 (76.9) | 1 (7.7) | 2 (15.4) |
| CM + CD + other MD | 11 | 4 (36.4) | 7 (63.6) | 0 | 0 | 11 (100) | 0 | 0 |
| CM + SP or FD | 10 | 1 (10.0) | 4 (40.0) | 3 (30.0) | 2 (20.0) | 3 (30.0) | 1 (10.0) | 6 (60.0) |
| CM + HH ± other MD | 5 | 1 (20.0) | 4 (80.0) | 0 | 0 | 2 (40.0) | 1 (20.0) | 2 (40.0) |
| CM + OAB/NDO | 4 | 0 | 4 (100) | 0 | 0 | 0 | 1 (25.0) | 3 (75.0) |
| CM + other MD | 2 | 1 (50.0) | 1 (50.0) | 0 | 0 | 1 (50.0) | 1 (50.0) | 0 |
BS blepharospasm, CD cervical dystonia, CM chronic migraine, FD focal dystonia, HH hyperhidrosis, HS hemifacial spasm, MD movement disorder, NDO neurogenic detrusor overactivity, OAB overactive bladder, OD oromandibular dystonia, onabotA onabotulinumtoxinA, SP spasticity
During the primary exposure period, most patients (114/183, 62.3%) had a treatment interval of ≤ 24 h between treatments for multiple indications (Table 3). Most patients with CM + CD, CM + BS or HS, CM + CD + other MD, or CM + OD ± BS had a treatment interval of ≤ 24 h, whereas most patients with CM + OAB/NDO or CM + SP or FD had a treatment interval of ≥ 14 days. This difference may be reflective of receiving treatment from different providers; however, small populations limit interpretation.
Safety Outcomes
The proportions of patients with at least one TEAE in the 6 months following the index date were 43/183 (23.5%) overall, ranging from 0/2 [0%] for CM + other MD to 6/11 [54.5%] for CM + CD + other MD (Table 4). The most commonly reported TEAEs were neck pain (12 patients total: CM + CD, 10/121 [8.3%]; CM + OD ± BS, 2/17 [11.8%]), headache (9 patients total: CM + CD, 6/121 [5.0%]; CM + OD ± BS, 2/17 [11.8%]; CM + CD + other MD, 1/11 [9.1%]), migraine (9 patients total: CM + CD, 6/121 [5.0%]; CM + OD ± BS, 1/17 [5.9%]; CM + BS or HS, 1/13 [7.7%]; CM + CD + other MD, 1/11 [9.1%]), and brow ptosis (4 patients total: CM + CD, 3/121 [2.5%]; CM + OD ± BS, 1/17 [5.9%]). TEAE prevalence was highest among the < 200 U onabotulinumtoxinA dose group (43.1%), and there was no apparent trend between an onabotulinumtoxinA dose and TEAE occurrence (Table 5).
Table 4.
Overview of TEAEs by treatment indication group
| TEAE, n (%) | Overall | CM + CD | CM + OD ± BS | CM + BS or HS | CM + CD + other MD | CM + SP or FD | CM + HH ± other MD | CM + OAB/NDO | CM + other MD |
|---|---|---|---|---|---|---|---|---|---|
| (N = 183) | (n = 121) | (n = 17) | (n = 13) | (n = 11) | (n = 10) | (n = 5) | (n = 4) | (n = 2) | |
| ≥ 1 TEAE within 6 months post-index | 43 (23.5) | 23 (19.0) | 4 (23.5) | 5 (38.5) | 6 (54.5) | 3 (30.0) | 1 (20.0) | 1 (25.0) | 0 |
| Specific TEAE within 6 months post-indexa | |||||||||
| Neck pain | 12 (6.6) | 10 (8.3) | 2 (11.8) | 0 | 0 | 0 | 0 | 0 | 0 |
| Headache | 9 (4.9) | 6 (5.0) | 2 (11.8) | 0 | 1 (9.1) | 0 | 0 | 0 | 0 |
| Migraine | 9 (4.9) | 6 (5.0) | 1 (5.9) | 1 (7.7) | 1 (9.1) | 0 | 0 | 0 | 0 |
| Brow ptosis | 4 (2.2) | 3 (2.5) | 1 (5.9) | 0 | 0 | 0 | 0 | 0 | 0 |
| Muscular weakness | 4 (2.2) | 3 (2.5) | 0 | 1 (7.7) | 0 | 0 | 0 | 0 | 0 |
| Injection-site pain | 3 (1.6) | 0 | 1 (5.9) | 0 | 2 (18.2) | 0 | 0 | 0 | 0 |
| Pain in extremity | 3 (1.6) | 1 (0.8) | 1 (5.9) | 1 (7.7) | 0 | 0 | 0 | 0 | 0 |
| Chest pain | 2 (1.1) | 0 | 0 | 1 (7.7) | 1 (9.1) | 0 | 0 | 0 | 0 |
| Dysphagia | 2 (1.1) | 1 (0.8) | 0 | 0 | 1 (9.1) | 0 | 0 | 0 | 0 |
| Facial asymmetry | 2 (1.1) | 1 (0.8) | 0 | 0 | 0 | 0 | 1 (20.0) | 0 | 0 |
| Hypoesthesia | 2 (1.1) | 0 | 2 (11.8) | 0 | 0 | 0 | 0 | 0 | 0 |
| Injury | 2 (1.1) | 2 (1.7) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Mastication disorder | 2 (1.1) | 1 (0.8) | 1 (5.9) | 0 | 0 | 0 | 0 | 0 | 0 |
| Urinary tract infection | 2 (1.1) | 0 | 0 | 0 | 0 | 1 (10.0) | 0 | 1 (25.0) | 0 |
BS blepharospasm, CD cervical dystonia, CM chronic migraine, FD focal dystonia, HH hyperhidrosis, HS hemifacial spasm, MD movement disorder, NDO neurogenic detrusor overactivity, OAB overactive bladder, OD oromandibular dystonia, SP spasticity, TEAE treatment-emergent adverse event
aTEAEs reported for > 1 patient are shown
Table 5.
Overview of TEAEs by 3-month cumulative onabotulinumtoxinA dose
| TEAE, n (%) | < 200 U | ≥ 200 to < 400 U | ≥ 400 to < 600 U | ≥ 600 to < 800 U |
|---|---|---|---|---|
| (n = 51) | (n = 113) | (n = 16) | (n = 3) | |
| ≥ 1 TEAE within 6 months post-index | 22 (43.1) | 15 (13.3) | 5 (31.3) | 1 (33.3) |
| Specific TEAE within 6 months post-indexa | ||||
| Neck pain | 8 (15.7) | 4 (3.5) | 0 | 0 |
| Headache | 3 (5.9) | 6 (5.3) | 0 | 0 |
| Migraine | 5 (9.8) | 3 (2.7) | 1 (6.3) | 0 |
| Muscular weakness | 4 (7.8) | 0 | 0 | 0 |
| Brow ptosis | 3 (5.9) | 1 (0.9) | 0 | 0 |
| Pain in extremity | 3 (5.9) | 0 | 0 | 0 |
| Chest pain | 1 (2.0) | 1 (0.9) | 0 | 0 |
| Dysphagia | 1 (2.0) | 1 (0.9) | 0 | 0 |
| Facial asymmetry | 2 (3.9) | 0 | 0 | 0 |
| Hypoesthesia | 1 (2.0) | 1 (0.9) | 0 | 0 |
| Injection-site pain | 3 (5.9) | 0 | 0 | 0 |
| Injury | 0 | 1 (0.9) | 1 (6.3) | 0 |
| Mastication disorder | 1 (2.0) | 1 (0.9) | 0 | 0 |
| Urinary tract infection | 0 | 1 (0.9) | 1 (6.3) | 0 |
TEAE treatment-emergent adverse event
aTEAEs reported for > 1 patient are shown
TEAE incidence by onabotulinumtoxinA treatment interval is shown in Fig. 4. Among all patients with CM indications, the proportion with at least one TEAE within 6 months post index was 34/114 (29.8%) for those with a treatment interval of ≤ 24 h, 2/16 (12.5%) for > 24 h to 13 days, and 7/53 (13.2%) for ≥ 14 days. TEAE prevalence among patients with indications of CM + CD or CM + OD ± BS was higher for those with a treatment interval ≤ 24 h (27.1% [19/70] and 23.5% [4/17], respectively) compared with longer intervals (CM + CD: 9.1% [1/11] for > 24 h to 13 days, 7.5% [3/40] for ≥ 14 days; CM + OD ± BS: no TEAEs reported for other treatment intervals). For the other TIGs, there was no apparent trend between dose interval and TEAE occurrence. Notably, the small populations of some TIGs may limit making comparisons with larger TIGs.
Fig. 4.
Incidence of ≥ 1 TEAEs by onabotulinumtoxinA treatment intervals in the primary exposure period by treatment indication group. a Overall, CM + CD, CM + OD ± BS, CM + BS or HS, and CM + CD + other movement disorders. b CM + SP or FD, CM + HH ± other movement disorders, CM + OAB/NDO, and CM + other movement disorders. N = total number of patients within each treatment interval; n = number of patients with ≥ 1 TEAE within each treatment interval. BS blepharospasm, CD cervical dystonia, CM chronic migraine, FD focal dystonia, HH hyperhidrosis, HS hemifacial spasm, OAB overactive bladder, OD oromandibular dystonia, NDO neurogenic detrusor overactivity, TEAE treatment-emergent adverse event
No reported TEAEs were considered to indicate distant spread of toxin, and there were no discontinuations due to adverse events or lack of effect. There was no documentation of lack of effect via a clinical objective measurement such as the brow, frontalis, or extensor digitorum test.
Safety Outcomes Examined by Treatment Area
During the primary observation period, most patients received treatment for CM and another indication in the face/neck/head area; 164 had onabotulinumtoxinA treatment indications categorized as CM + face/neck/head ± other areas (including CM and one of the following indications or indication combinations: CD, BS, HS, OD, and neck and jaw pain), and 19 had treatment indications categorized as CM + other areas (including CM and one of the following indications: gastroparesis, HH, OAB/NDO, and SP or FD) (Table 6). The mean (SD) cumulative onabotulinumtoxinA dose was 262.3 (95.5) U for CM + face/neck/head ± other areas and 340.9 (123.0) U for CM + other areas. The most common TEAEs reported among patients with CM + face/neck/head ± other areas were consistent with the known safety profiles for the individual indications treated: neck pain (11/164 [6.7%]), headache and migraine (9/164 [5.5%] for each), and brow ptosis and muscular weakness (4/164 [2.4%] for each). The only TEAE reported among ≥ 2 patients with CM + other areas was symptomatic urinary tract infection (2/19 [10.5%]).
Table 6.
Overview of cumulative 3-month onabotulinumtoxinA dose and TEAEs by treatment area
| CM + face/neck/heada ± other areas | CM + other areasb | |
|---|---|---|
| (n = 164) | (n = 19) | |
| Cumulative onabotA dose, U, mean (SD) | 262.3 (95.5) | 340.9 (123.0) |
| Specific TEAE within 6 m post-index, n (%)c | ||
| Neck pain | 12 (7.3) | 0 |
| Headache | 9 (5.5) | 0 |
| Migraine | 9 (5.5) | 0 |
| Brow ptosis | 4 (2.4) | 0 |
| Muscular weakness | 4 (2.4) | 0 |
| Injection-site pain | 3 (1.8) | 0 |
| Pain in extremity | 3 (1.8) | 0 |
| Dysphagia | 2 (1.2) | 0 |
| Urinary tract infection, symptomatic | 0 | 2 (10.5) |
| Facial asymmetry | 2 (1.2) | 0 |
| Chest pain | 2 (1.2) | 0 |
| Injury | 2 (1.2) | 0 |
| Mastication disorder | 2 (1.2) | 0 |
| Hypoesthesia | 2 (1.2) | 0 |
CD cervical dystonia, CM chronic migraine, NDO neurogenic detrusor overactivity, OAB overactive bladder, onabotA onabotulinumtoxinA, TEAE treatment-emergent adverse event
aCM + face/neck/head indications include CM plus the following: CD, blepharospasm or hemifacial spasm, CD + other movement disorder, oromandibular dystonia ± blepharospasm, neck and jaw pain, hyperhidrosis + oromandibular dystonia, blepharospasm + hyperhidrosis + oromandibular dystonia, and oromandibular dystonia + other dystonia
bCM + other area indications include CM plus the following: gastroparesis, hyperhidrosis, OAB/NDO, and spasticity or focal dystonia
cTEAEs reported for > 1 patient are shown
Discussion
In clinical practice, onabotulinumtoxinA is commonly administered for multiple indications in a single treatment cycle. Data on safety, treatment interval, and dosing for treating multiple indications are limited, as are data on cumulative doses surpassing the approved total cumulative dose indicated by the current prescribing information (400 U within a 3-month period) [17, 30]. This may lead to delays in treatment due to safety concerns and/or payor coverage [30, 31]. To help address common questions regarding onabotulinumtoxinA dosing in multi-indication patients, this real-world, retrospective study demonstrated that there were no new safety signals when treating patients with CM and ≥ 1 coexisting disease with onabotulinumtoxinA. Reported TEAEs were consistent with those for the indications being treated, none were consistent with distant spread of toxin, and there were no discontinuations due to TEAEs. Notably, higher doses (> 400 U per 3 months) were not associated with increased TEAEs.
In previous clinical studies, common TEAEs reported during individual treatment of CM and CD with onabotulinumtoxinA have included neck pain and headache [21, 35]. Results from the present study are consistent with these findings. Overall, 43 of 183 (23.5%) patients reported at least one TEAE during the 6 months following the index date. The most common TEAEs—neck pain (12/183 [6.6%]), headache (9/183 [4.9%]), and migraine (9/183 [4.9%])—were reported only among patients with CM + CD, CM + OD (oromandibular dystonia) ± BS (blepharospasm), CM + CD + other MD, or CM + BS or HS (hemifacial spasm) indications and at rates comparable with those previously reported for individual treatment of CM or CD with onabotulinumtoxinA [17]. As both CM and CD are associated with neck pain and headache [11, 36], it is plausible that these TEAEs may be related to the underlying diseases rather than to onabotulinumtoxinA treatment itself; however, it is not possible to determine causality from this study.
When analyzed by treatment interval, TEAE incidence for treatment intervals of ≤ 24 h was higher compared with longer intervals (i.e., > 24 h to 13 days or ≥ 14 days) only among patients treated for CM + CD, CM + OD ± BS, CM + CD + other MD, or CM + HH + other MD. The majority of patients with these indications were treated within 24 h, with none or a limited number treated at a longer interval. Interpretability of TEAE incidence by treatment interval is, therefore, limited by the inconsistent patient distribution across treatment intervals. There was no association between incidence of TEAEs and treatment intervals for the other indication combination groups; however, concomitant treatment of other indications typically occurred at longer treatment intervals. Importantly, when safety outcomes were analyzed by treatment area, TEAEs were consistent with those for the individual indications even among participants who had adjacent muscles treated (i.e., those with CM and other face/neck/head indications). In this group, the most frequently reported TEAEs were neck pain (6.7%), headache and migraine (5.5% each), and brow ptosis and muscular weakness (2.4% each). Some payors may limit reimbursement for multi-indication treatment with onabotulinumtoxinA on the same day or within a certain time frame, which may delay patient care and necessitate multiple trips to the provider’s office [30, 31]. Given that many patients in this study received multi-indication onabotulinumtoxinA treatments from the same provider and traveled long distances (e.g., ≥ 20 miles) for treatment, these data may provide guidance that could mitigate the travel burden and help remove barriers to care for those with CM and another onabotulinumtoxinA treatment indication(s).
Treatment of CM and CD with onabotulinumtoxinA may involve the injection of adjacent or overlapping muscle groups, raising the question of whether concomitant treatment of these diseases could reduce the total number of units necessary to achieve a therapeutic effect or increase the potential for TEAEs. In this study, nearly 90% of patients had treatment indications for CM and another indication in the face, neck, or head. For CM + CD, the most common treatment indication captured, the mean 3-month cumulative onabotulinumtoxinA dose was 270.5 U. In comparison, a previous analysis of registry data for more than 1000 US patients with CD indicated that the mean total onabotulinumtoxinA dose received at their first treatment (for CD alone) ranged from 136.6 to 218.3 U, depending on patient-reported pain level and previous treatment status [37]. Given that the recommended total onabotulinumtoxinA dose for treating CM is 155 U [17], these findings suggest that the total dose received by patients concomitantly treated for CM and CD in SYNCHRONIZE was lower than it would have been if treatments had been administered at studied doses separately. Specific injection approaches were not captured in this analysis so it is unknown if additional injection sites for CM (up to 195 U) were used. It is feasible that strategic targeting of onabotulinumtoxinA to overlapping muscle groups to treat multiple indications could have resulted in a more efficient dosing approach, potentially lowering the risk of adverse safety outcomes. Notably, TEAEs in this study were generally consistent with the known safety profile of onabotulinumtoxinA for the individual indications treated. Taken together with existing evidence from small studies indicating that onabotulinumtoxinA treatment of CD reduces migraine frequency and that treatment of CM and CD at the same visit can effectively and safely control symptoms of both diseases [25, 38], these results suggest that further exploration of synergistic treatment of CM and CD may be warranted. This may be particularly impactful given the high incidence of CD with CM and the substantial health care burden experienced by patients with both diagnoses [28, 29].
In these analyses, there was no documentation of lack of effect of onabotulinumtoxinA using a clinical objective measurement or lack of effect as a reason for discontinuation. A previous meta-analysis of global registration studies reported that antibodies directed toward onabotulinumtoxinA occurred at a rate of 0.5% across all indications [39]. Using the lowest effective dose of onabotulinumtoxinA at the longest possible period between injections can potentially reduce the risk of antibody formation [17]. Although the development of antibodies to onabotulinumtoxinA was not specifically assessed in this analysis, this study showed no new safety concerns for concurrent treatment of multiple coexisting diseases.
To our knowledge, SYNCHRONIZE is the largest investigation to date of real-world safety outcomes among adults treated with onabotulinumtoxinA for more than one therapeutic indication within a 3-month interval, and the present analysis is the largest to examine concomitant treatment of CM and other indications with onabotulinumtoxinA. However, this study has some limitations that should be noted, including its observational nature, which limits the conclusions that can be made; additional confirmatory research is required. There was no documentation of lack of effect for onabotulinumtoxinA via a clinical objective measurement, so it is not possible to determine whether this reflects an absence of occurrence or a lack of reporting. It is unknown if it can be inferred that there was no suspected immunogenicity to warrant testing or if the site did not have the means to readily test for suspected immunogenicity. As a result of the retrospective nature of this study, patients did not receive serum immunogenicity testing. Furthermore, this analysis also does not have a comparator control group (i.e., patients receiving onabotulinumtoxinA for a single indication or within-label dose). Second, retrospective studies of safety follow-up data are limited to information that is reported in patient charts, as opposed to using a standardized TEAE-reporting methodology. This limitation may have negatively affected the results that were observed and limits the potential for determining whether the observed TEAEs are related to onabotulinumtoxinA treatment or the underlying conditions. Similarly, any onabotulinumtoxinA treatments administered outside of the electronic medical record system may not be reflected in this dataset. Finally, it is unclear whether the predominance of patients with CM + CD indications in the study population was due to the high prevalence of co-occurrence of these diseases or because clinical sites treating CM in addition to a more diverse subset of other indications were not included. The potential selection bias associated with the sites having a high level of patients with CM + CD may have affected the results that were observed. Other subgroups were considerably smaller in size which limits comparability between indication groups.
Conclusion
OnabotulinumtoxinA demonstrated a consistent safety profile, with no new safety signals observed in adults treated concomitantly for the preventive treatment of CM and at least one other treatment indication within a 3-month period. The most common TEAEs occurred at frequencies similar to or lower than those previously reported for treatment of the individual indications, and there were no apparent correlations between TEAEs and onabotulinumtoxinA dosage or indications treated. Some patients traveled a long distance to receive treatment, highlighting the potential burden of treating multiple indications on separate days.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
AbbVie and the authors thank all the study investigators and patients who participated in this study. The authors also thank Krystal Anson Spenta for her contributions to the study.
Medical Writing, Editorial, and Other Assistance
Medical writing support was provided by Peloton Advantage, LLC, an OPEN Health company, and was funded by AbbVie.
Author Contributions
Study design: Andrew M. Blumenfeld. Study investigator: Andrew M. Blumenfeld. Data analysis: Marc Schwartz. Data interpretation: All authors. Manuscript review and revisions: All authors. Final approval of manuscript: All authors.
Funding
AbbVie funded this study and contributed to the study design, the collection, analysis, and interpretation of data, and the review and approval of the final manuscript for publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. AbbVie funded the journal’s Rapid Service fee.
Data Availability
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, synopses, or statistical analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Use Agreement (DUA). Data requests can be submitted at any time after approval in the USA and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home.”
Declarations
Conflict of Interest
Andrew M. Blumenfeld has served on advisory boards for, consulted for, and/or been a speaker or contributing author for AbbVie, Aeon, Alder, Allergan, Amgen, Axon, Axsome, Bausch Health, Biohaven, Equinox, Ipsen, Lilly, Lundbeck, Novartis, Pfizer, Revance, Teva, Theranica, and Zosano. He has received grant support from AbbVie, Amgen, and Lundbeck. He owns stock options for Aeon, Axon, and Haven. He is an Editorial Board member of Pain and Therapy; he was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Christopher Rhyne has no conflicts to disclose. Kenneth Martinez has received personal compensation for serving as a consultant for Merz and Revance. The institution of KM has received compensation for him serving as a consultant for Abbott, AbbVie, Amgen/Novartis, and Biohaven and on a speakers bureau for AbbVie and Merz. The institution of Kenneth Martinez has received research support from AbbVie, Boston Scientific, and Medtronic. Atul Patel is a consultant for AbbVie, Ipsen, and Revance; a speaker for AbbVie and Ipsen; and has received research grant support from AbbVie and Ipsen. Kim Becker Ifantides, Ritu Singh, Irina Yushmanova, and Simona Battucci are employees of AbbVie and may hold AbbVie stock. Marc Schwartz has served as a biostatistical consultant for Allergan, an AbbVie company. Grace Forde has received compensation from AbbVie for serving as a speaker.
Ethical Approval
The SYNCHRONIZE study was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki principles consistent with good clinical practice and all applicable regulatory requirements. Informed consent was not required because no identifiable patient information was obtained. All study-related documents were approved by independent ethics committees and IRBs at each of the following sites in the USA: EvergreenHealth Multiple Sclerosis Center Kirkland, Kirkland, WA (approved June 21, 2021); Lucetta, LLC/Grace Forde, Lake Success, NY (approved January 26, 2022); Swedish Neuroscience Institute MS Center, Seattle, WA (approved April 19, 2022); Kansas Institute of Research, Overland Park, KS (approved January 23, 2022); Neuroscience Group, Neenah, WI (approved February 3, 2022); Neurology and Pain Specialty Center, Aliso Viejo, CA (approved January 27, 2022); Diamond Headache Clinic Chicago, IL (approved January 21, 2022); Rush University Medical Center, Chicago, IL (approved January 1, 2022); NYU Langone Health, New York, NY (approved February 19, 2022); and Rancho Research Institute, Rancho Los Amigos National Rehabilitation Center, Downey, CA (approved February 27, 2022).
Footnotes
Prior Presentation: This work was presented in part at the American Academy of Neurology Annual Meeting, April 22–27, 2023, Boston, Massachusetts, USA, and virtual; and the International Congress of Parkinson’s Disease and Movement Disorders, August 27–31, 2023, Copenhagen, Denmark.
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