Use of Botulinum Toxin in Parkinson's Disease PDF

Parkinsonism and Related Disorders 59 (2019) 57–64 Contents lists available at ScienceDirect Parkinsonism and Relate...

Parkinsonism and Related Disorders 59 (2019) 57–64 Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis Use of botulinum toxin in Parkinson's disease T ∗ Angeline Jocson , Mark Lew Division of Movement Disorders, Department of Neurology, Keck/University of Southern California School of Medicine, Los Angeles, CA, USA A R T I C LE I N FO A B S T R A C T Keywords: Botulinum toxin has emerged as an important therapeutic intervention within the realm of movement disorders, Botulinum toxin especially for focal and generalized dystonias. Botulinum toxin has additionally been used for a variety of Parkinson's disease symptoms associated with parkinsonism. In this review, we will specifically evaluate use of botulinum toxin in idiopathic Parkinson's disease. We will discuss symptoms including sialorrhea, limb, dystonia, tremor, dyski- nesias, freezing of gait, camptocormia, pisa syndrome, urinary dysfunction, constipation, dysphagia, eyelid opening apraxia, and blepharospasm. 1. Introduction Lagalla et al. enrolled 32 PD patients in a double-blind, randomized, placebo-controlled trial studying onabotulinum toxin. Each patient re- Botulinum toxins, produced by the non-aerobic Clostridia bacteria, ceived 50 units of onabotulinum toxin to each parotid gland versus inhibit the release of acetylcholine from the presynaptic terminal by placebo. Outcomes assessed included visual analogue scales for affecting SNARE and SNAP proteins. Four different preparations are drooling frequency and patient embarrassment, UPDRS ADL subscores currently FDA approved in the U.S.A. including onabotulinum toxin A for drooling and dysphagia, and saliva production by weight. There (Botox), incobotulinum toxin A (Xeomin), rimabotulinum toxin B were significant improvements between baseline and 1 month. 37% of (Myobloc), and abobotulinum toxin A (Dysport). Botulinum toxin was toxin treated patients had UPDRS salivation score less than 2 (moderate first used for the treatment of focal and segmental dystonias including excessive saliva, minimal drooling) versus 6% in the placebo group. blepharospasm and cranial-cervical dystonias in the 1980s. Botulinum Saliva production weights improved on average from 2.7 g to 1.3 g in toxin has been used for aspects of parkinsonism including tremor, sia- the treatment group. lorrhea, camptocormia, overactive bladder and pain. The 2016 AAN Mancini et al. included 20 parkinsonian patients (14 PD, 6 MSA) in guidelines cite Level A evidence for a variety of toxins for use in cervical a double-blind, randomized, placebo-controlled trial studying abobo- dystonia, upper and lower limb spasticity and chronic migraine. There tulinum toxin. Each patient receiving toxin was injected under ultra- is level B evidence for blepharospasm. In this review, we will spe- sound guidance with about 145 units in each parotid and about 80 units cifically discuss the use of botulinum toxin in idiopathic Parkinson's in each submandibular gland. There was a significant reduction in disease (PD). Drooling Severity Scores at 1 week with benefit lasting on average about one month. 2. Sialorrhea In studies for cervical dystonia, botulinum toxin type B was often noted to be associated with a high incidence of dry mouth as a side Sialorrhea is observed in 40–80% of patients with advanced PD. effect. The heavy chain of the B toxin has an increased affinity for se- Swallowing dysfunction with oropharyngeal dysphagia from bradyki- cretory gland cholinergic acceptors. Multiple studies have demon- nesia can contribute to drooling in addition to severe hypomimia and strated benefit of B toxin on sialorrhea. Dashtipour et al. published a stooped posture. Certain medications such as cholinesterase inhibitors literature review including 6 studies using BoNT-B for sialorrhea, with and atypical antipsychotics used for cognition and psychosis can ag- dosing between 1500 and 4000 units. All studies demonstrated a sta- gravate drooling. Pooling of saliva poses a risk of aspiration and in- tistically significant benefit compared to placebo. A multicenter, fection. Use of anticholinergics is often limited by intolerable side ef- double-blind RCT of 54 PD patients treated with botulinum toxin B fects. Botulinum toxin injections have been shown to improve demonstrated significant improvement in Drooling Frequency and sialorrhea in PD patients. A common side effect of botulinum toxin Severity Scores and salivary flow rate across three treatment groups injections is dry mouth. with dosing ranging from 1500 to 3500 units [5,6]. ∗ Corresponding author. E-mail address: [email protected] (A. Jocson). https://doi.org/10.1016/j.parkreldis.2018.12.002 Received 15 August 2018; Received in revised form 2 December 2018; Accepted 7 December 2018 1353-8020/ © 2018 Elsevier Ltd. All rights reserved. A. Jocson, M. Lew Parkinsonism and Related Disorders 59 (2019) 57–64 Recently, incobotulinum toxin A was studied for sialorrhea in a Dystonia (BFMD) scale score. Following botulinum toxin injections, all small randomized, double-blind, placebo-controlled, cross-over study of six patients were able to walk briskly and had significant improvement 10 PD patients. In this study, there was no significant change in saliva in pain scores. Five of 6 patients had an improvement in BFMD scores production by weight or with Drooling Frequency and Severity scores. by 2 points while one patient had improvement from a score of 4 to 0. Dosing for this study was 20 units per parotid and 30 units per sub- Dosing ranged from 250 to 400 units; injection pattern varied de- mandibular gland. As compared to other studies, this study used pending on patient presentation. lower dosing of toxin which may have affected efficacy. Additionally, As noted in the above studies, pain is often significantly improved there may have been additional benefit if the parotid glands were in- following botulinum toxin injections for dystonia. One retrospective jected in addition to targeting the submandibular glands. study of 160 parkinsonian patients noted that 50.6% had received in- In general, treatment of sialorrhea with botulinum toxin appears jections with an indication of pain; of these, 77.6% was dystonic in safe and efficacious. Most frequently, this involves injections in both nature versus 22.4% musculoskeletal. Subjective CGI scores were used parotid and submandibular glands. Dry mouth can be a common side as the primary assessment. Of the 117 PD patients included, 81% noted effect of salivary gland injections with botulinum toxin, but is rarely subjective benefits (CGI score +1 or greater) for pain, with 53.4% problematic in patients with baseline sialorrhea. rating pain as very much improved. As a treatment for limb dystonia, botulinum toxin can significantly 3. Limb dystonia improve pain as well as dystonic posturing. A consensus of the above studies suggests that pain was more consistently improved with toxin Dystonia has been reported to affect 30% of PD patients and 60% of therapy, and functional improvement was variable but possible. those with onset younger than 40 years old. Most commonly, dystonia can affect the feet as an off phenomenon. 4. Tremor Pachetti et al. treated 30 PD patients with painful foot dystonia in an open label study with botulinum toxin under EMG guidance. Unlike other cardinal Parkinson's symptoms, tremor may be more Approximately 40 IU of onabotulinum toxin was injected per muscle refractory to standard pharmacologic treatments such as levodopa. group, divided in two sites, based on foot posture. Muscles included the Other medications for tremor including anticholinergics and amanta- tibialis posterior, tibialis anterior, gastrocnemius, flexor digitorum dine are more commonly associated with side effects such as cognitive longus, and extensor hallucis longus; the median dose was 70 IU per dysfunction. Botulinum toxin has not been widely adopted for patient. All patients noted improvement in pain within 10 days, and no Parkinson's tremor treatment. In prior studies looking at patients with local or distant side effects were noted. 21/30 patients had no pain for 4 ET or PD, onabotulinum toxin treatment was limited by weakness in months with decreased intensity of dystonic spasm. 7/30 patients with 30–70% of patients. Some of this may be attributed to rigid protocols in “on” foot dystonia noted improvement in foot posture with walking. regards to fixed dosing and predetermined injection sites. Rieu et al. enrolled 46 PD patients with prolonged (> 1 h per day) Rahimi et al. studied 28 PD patients in an open label study of in- unilateral or bilateral toe plantarflexion in a randomized, double-blind, cobotulinum toxin for rest tremor. Their goal was to use kinematic placebo-controlled trial comparing EMG-guided incobotulinum toxin guidance to target more active muscles to individualize injections; injections of flexor digitorum longus (FDL), flexor digitorum brevis doses varied from 75 to 390 units per patient. Commonly injected (FDB) and placebo. In those receiving toxin, 100IU was injected into muscles were flexor carpi ulnaris, extensor carpi ulnaris, pronator teres, either FDL or FDB as the first site based on randomization, and placebo pronator quadratus, flexor carpi radialis, extensor carpi radialis, and was injected into the second site. Placebo patients received two placebo supinator. The injection patterns varied by treatment period depending injections into FDL and FDB. Patients received two sets of injections upon kinematic guidance. There was a significant reduction in UPDRS three months apart. Injections targeted the more severely affected side rest tremor (baseline 2.7 versus 2.0 and 2.1 at weeks 16 and 32, if bilateral foot dystonia was present. The Clinical Global Impression of p = 0.014) and Fahn-Tolosa-Marin tremor severity scores; no sig- Change, the primary variable, was significantly improved in the in- nificant change in UPDRS action tremor. However, 57% had 3rd digit cobotulinum toxin group (3.14 at 6 weeks, 2.90 at 18 weeks; weakness, and 25% had decreased grip strength. Most patients de- p = 0.039). There was a significant reduction in pain, dystonia severity, scribed this as slight to mild, though 21% withdrew from the study due and the Burke-Fahn-Marsden lower limb score in the incobotulinum to weakness. toxin group compared to baseline scores; however, there was no sig- Mittal et al. described 30 PD pts with moderate-severe tremor en- nificant difference when compared with the placebo group. This lack of rolled in a randomized, double-blind, placebo-controlled crossover significance was postulated to be secondary to low sample size and study. The injection pattern was customized based on the clinical fea- limited injection sites. tures of each patient's tremor and administered under EMG guidance. Patients with more persistent abnormal striatal limb deformities, The most commonly injected muscles, having been injected in 60% or such as striatal hand or foot, have also been treated with botulinum more patients, were the lumbricals, flexor carpi radialis, flexor digi- toxin. Giladi described 2 PD patients with both on and off striatal toe torum superficialis, flexor carpi ulnaris, pronator, biceps, triceps, ex- with 80–90% improvement with 50–70 units of onabotulinum toxin; tensor carpi radialis, and extensor digitorum. Each patient received EHL weakness was present but without significant gait impairment about 7–12 injections, with a total of 85–110 units per patient. When. undergoing incobotulinum toxin injections, the UPDRS rest tremor Dystonic clenched fist can be seen as a rare late complication of PD score, the primary outcome, decreased from an average of 3 points to with associated loss of function, pain and poor palm hygiene. 0–1 points at weeks 4 and 8. Grip strength was not statistically sig- Abobotulinum toxin has been used as treatment of dystonic fist. One nificantly different between the placebo and treatment groups. Two open-label study of 14 patients, 7 with idiopathic PD, noted muscle patients in the toxin group had moderate to severe weakness that was relaxation in all patients treated with toxin and mild-moderate posture interfering compared to one in the placebo group. Eight additional improvement and pain relief in 5 PD patients. Three moderately to patients experienced weakness after incobotulinum toxin treatment severely affected patients were able to gain mild functional benefit which was either not perceived by the patient or subtle and non-in-. terfering. One open-label study looked at 6 PD patients who developed painful There is a case series of 3 PD patients with jaw tremor treated with foot dystonia following deep brain stimulation surgery. All patients abobotulinum toxin. The patients received 60–200 units, divided into either required assistance with walking or were unable to stand in- each masseter; one patient had additional injections in the mentalis. All dependently. The primary outcome was the Burke Fahn Marsden patients had improvement of tremor at follow-up with benefit lasting 58 A. Jocson, M. Lew Parkinsonism and Related Disorders 59 (2019) 57–64 up to 3–4 months. No side effects were noted in this cohort. botulinum toxin into each tensor fascia latae. Eight of 11 patients had a In patients with poorly controlled PD limb tremor, botulinum toxin significant decline in freezing of gait scores. Time up and go scores injections can be considered, but can be limited by weakness as a side showed a decline in 6 patients, increase in 3 patients and was un- effect even with individualized injection patterns. changed in 1 patient; this was not significant at week 4. CGI scores were significantly improved with 6 patients noting moderate to marked im- 5. Dyskinesias provement. These studies of freezing of gait demonstrated inconsistent benefit Levodopa-induced dyskinesias can affect 45–85% of patients within with botulinum toxin. Additionally, these studies were limited by small a few years of starting treatment with L-dopa. Dyskinesias can occur sample sizes. The more recent 2016 study showed more promising re- both at peak-dose and with wearing off of levodopa effect. Aside from sults with tensor fascia latae injections, but larger controlled studies are titrating levodopa dosing to address dyskinesias, the main pharmaco- still needed. logic option for the treatment of dyskinesias is amantadine which can be associated with possible cognitive and other anticholinergic-like side 7. Camptocormia effects. Treatment of dyskinesias with botulinum toxin has not been ex- Camptocormia occurs in 3–7% of patients with Parkinson's disease. tensively studied. Espay et al. enrolled 12 PD patients with bothersome This involuntary axial flexion occurs while upright and can increase cervical-predominant levodopa-induced dyskinesias in a randomized, while walking. Many use a degree of flexion of at least 45° of the double-blind, placebo-controlled crossover trial. However, the study thoracolumbar spine to define camptocormia. Muscles postulated was prematurely terminated due to study concerns with excessive neck to contribute to camptocormia include the abdominal external and in- weakness. The primary outcome was change in the Goetz dyskinesia ternal obliques for the upper subtype and the rectus abdominus and rating scale (GDRS) score. Those that did receive treatment with bo- iliopsoas for the lower subtype. Camptocormia has a variable response tulinum toxin did note improvement in GDRS scores for resting but not with dopaminergic therapies and deep brain stimulation. Botulinum action-induced dyskinesias. toxin use has been studied due to the theory that camptocormia may be Thus far, there has not been sufficient data to support botulinum a form of axial dystonia. The tendency to resolve when supine, when toxin injections for effective treatment of cervical dyskinesias. leaning against a support, or when wearing a backpack can be sug- gestive of a sensory trick. 6. Freezing of gait Azher and Jankovic described 9 PD patients treated with botulinum toxin A injected into the rectus abdominus for camptocormia; four In the later stage of Parkinson's disease, about 40–60% of patients patients had improvement lasting eight weeks. Fietzek et al. de- can experience freezing of gait. The pathophysiology is poorly under- scribed 10 patients treated with US-guided Incobotulinum toxin A in- stood. It is postulated that this may be a dystonic manifestation with jections to the iliopsoas or rectus abdominus with a mean of 210 units. dis-synchronized contractions of agonist and antagonist muscles in the In this group, there was no significant improvement in camptocormia lower extremities. Freezing of gait is considered to be unresponsive to. Van Coelln et al. treated 3 PD and 1 MSA patients with 500–1500 medical therapy with dopaminergics. units of Abobotulinum toxin A to each side of the iliopsoas. Two pa- In 1997, Giladi et al. first reported an improvement in freezing of tients had worsened posture, and 2 had subtle improvement. gait in a PD patient injected with botulinum toxin for foot dystonia. In Variable results in the above small studies may be related to difficult 2001, the Giladi group described a cohort of 10 parkinsonian patients, 7 access of muscles for injection versus appropriateness of muscle selec- of whom had idiopathic PD, who were injected with botulinum toxin in tion. The above series did not include abdominal oblique injections. an open label study for freezing of gait (FoG). Patients received a total Additionally, sample sizes and dosing may not be adequate in the above of 100–300 units with one injection into the soleus, the lateral gastro- mentioned papers to come to conclusions of therapeutic intervention cnemius, and the medial gastrocnemius; additional muscles were in- with toxins. This additionally suggests complexity of this syndrome and cluded if foot dystonia was present. Five patients received bilateral central control of abnormal posture that is difficult to treat with any injections, and the remaining 5 had unilateral injections. Seven of 10 form of therapy. patients had some improvement in FoG, while 4 patients reported marked improvement. The mean duration of benefit was 6 weeks. 8. Pisa syndrome Gurevich et al. published a follow-up randomized, double-blind, placebo controlled study with 11 PD patients with FoG. Six patients Pisa syndrome (PS) is observed in about 10% of patients with received 150 units of onabotulinum toxin divided evenly in the soleus Parkinson's disease and presents with lateral trunk flexion. Similar to and lateral and medial heads of the gastrocnemius, and 5 patients re- camptocormia, this tends to improve in a supine position, and has ceived saline. Improvement was only noted in the saline group at week limited improvement with dopaminergic therapy. 16; there was no significant improvement in the toxin group according Tassorelli and colleagues enrolled 26 PD patients with PS in a ran- to UPDRS ADL, UPDRS motor, subjective CGI-C or Freezing of Gait domized, placebo-controlled trial of incobotulinum toxin for PS. Questionnaire scores. Three patients in the toxin group and 2 patients in Patients also had a four week rehabilitation program following injec- the saline group complained of leg weakness, though this was not de- tions. All patients were screened with an EMG protocol assessing ab- tectable on clinical exam. Two patients in the toxin group had increased dominal, paravertebral and iliopsoas muscles in supine and upright fall frequency while 1 patient had decreased frequency. positions. Up to six sites for injection were selected if there was in- Fernandez et al. studied the use of rimabotulinum toxin for FoG in a voluntary tonic activity longer than 500 ms. Patients were randomized double-blind, placebo controlled trial. Nine patients received 5000 to placebo, with 4–6 injections of saline, versus incobotulinum toxin units divided into 4 sites in the gastrocnemius-soleus complex in the injections, ranging from 50 to 200 IU per patient. Lateral trunk in- predominantly affected leg; 5 patients received placebo. In the B toxin clination was significantly reduced versus baseline in the toxin treat- group, 1 patient was “much improved,” 2 were “minimally improved,” ment group following the rehabilitation period as well as at 3 month 2 were “minimally worse,” and 4 patients were unchanged according to follow-up. As compared to the group's prior study looking at re- CGI scores. There was no significant change in UPDRS II/III scores, habilitation alone, there were additional improvements in pain in- Visual Analogue Scale, or Webster Step-Seconds scores. tensity, UPDRS score, camptocormia and trunk range of motion in the A more recent study by Vastik and colleagues in 2016 enrolled 11 toxin group. PD patients with FoG in an open label trial. Patients received 50 units of Artusi et al. described 15 patients undergoing onabotulinum toxin 59 A. Jocson, M. Lew Parkinsonism and Related Disorders 59 (2019) 57–64 injections for PS with greater than 10° of lateral flexion; 2 patients were 10. Constipation excluded who were undergoing concomitant rehabilitation. Patients underwent T1-weighted axial MRI to assess atrophy of paraspinal and Gastrointestinal dysfunction is one of the most common non-motor non-paraspinal axial muscles. Patients were injected under ultrasound symptoms in PD. Defecatory dysfunction is five times more common in and EMG guidance if pathological muscular hyperactivity was noted on Parkinson's disease as compared to the general population, with about EMG on standing in addition to absence of atrophy on MRI. Dosing 60% of patients affected. Constipation in Parkinson's disease may have ranged from 50 to 75 units per paraspinal muscle and 25–50 units per contributions both from slow transit as well as outlet obstruction. non-paraspinal muscle, with an average dose of 151.9 ± 53.5 units. The Outlet obstruction has been attributed to focal dystonia of the pelvic responder rate was 84.6% with average improvement of lateral flexion floor with failure of puborectalis relaxation or paradoxical contraction. by 40% and pain/discomfort improving about 52%. There are two open-label studies using onabotulinum toxin for There are few studies assessing botulinum toxin injections for Pisa prominent outlet-type constipation. Both studies used 100 units of bo- syndrome. However, the studies currently published suggest possible tulinum toxin injected into two sites in the puborectalis muscle under efficacy in their small cohorts. Larger, multi-center randomized clinical transrectal ultrasound guidance. In the Albanese et al. study, mano- trials are needed to determine definitive efficacy of toxin injections for metry, defecography and EMG were utilized before and after treatment. Pisa syndrome. Anal tone during straining and anorectal angle were improved at 1 month. In the Cadeddu et al. study, patients were assessed by manometry and defecography. At 1 and 2 months, pressure with 9. Urinary dysfunction straining was reduced and anorectal angle improved. Ten of eighteen patients subjectively improved in 2 months, with five patients having Genitourinary symptoms including nocturia, frequency, urgency resolution of their symptoms at 1 month. Of the eight non-responders, and incontinence are common in PD patients. Lower urinary tract higher dosing of 200 units was used with four patients noting symp- symptom prevalence ranges from 27 to 64% of patients. Neurogenic tomatic improvement. In these studies, there were no noted side overactive bladder is the most common presentation for PD patients, effects reported. likely related to altered nigrostriatal signaling to the pontine micturi- Further studies are necessary to study the efficacy of botulinum tion center through the periaqueductal gray. This is also often com- toxin injections for constipation; however, the small studies currently pounded by age-associated idiopathic overactive bladder and benign published demonstrate possible benefit. prostatic hypertrophy. Medications such as anticholinergic agents are frequently poorly tolerated. Onabotulinum toxin has been in use for 11. Dysphagia urinary dysfunction in patients with spinal cord injuries and multiple sclerosis [24,25]. Dysphagia occurs in more than 50% of PD patients. All phases of Anderson et al. enrolled 20 patients in an open-label study for pa- swallowing can be affected. Hyperactivity can be noted at the upper tients with PD with neurogenic bladder and incontinence with no im- esophageal sphincter which can result in aspiration. Botulinum toxin provement on antimuscarinics. Each patient received 100 units of has been used in patients noted to have absence of cricopharyngeal onabotulinum toxin injected into 10–20 submucosal intra-detrusor inhibition. Restivo et al. described 4 PD patients injected with abobo- bladder sites within the lower hemisphere of the bladder, with 2–3 sites tulinum toxin A, 30 units per cricopharyngeal muscle. All four patients being in the trigone. King's Health Questionnaire part III (bladder) noted improvement in swallowing within 48 h, supported by improve- scores decreased significantly at months 1 and 3 post-treatment. Three- ment on videofluoroscopic and EMG studies. Benefits lasted 16–20 day voiding diaries and American Urological Association (AUS) symp- weeks. toms scores showed a decrease in mean incontinence scores by at least A later open-label study of 34 patients with clinical dysphagia in- 50% in the six months following treatment. 57% of patients had mod- cluded 7 patients with PD; 15 units of onabotulinum toxin were injected erately to markedly improved symptoms. Two patients required alpha- into one cricopharyngeal muscle. Only 2 of 7 patients with PD had blocking agents to assist bladder emptying, but no patients required improvement by Dysphagia Severity Score. It was postulated that PD catheterization. patients may have more issues with pharyngeal delay time in addition Vurture et al. described 24 PD patients analyzed in a retrospective to absent cricopharyngeal inhibition. In contrast, 6 of 9 PSP and 4 of 4 study after receiving intradetrusor injections of onabotulinum toxin. All MSA-P patients improved, suggesting more prominent cricopharyngeal patients were refractory or intolerant to anticholinergics and/or mir- hyperactivity. Neither study noted significant side effects with the abegron. Each patient received 5 units injected into 20 sites throughout above dosing. the bladder wall and trigone. A second set of injections totaling Botulinum toxin injections may be more beneficial for atypical 100–200 units was offered for those with partial or complete inefficacy. parkinsonian syndromes with prominent cricopharyngeal hyper- In this cohort, 79.2% of patients endorsed improved overactive bladder activity, as compared to idiopathic Parkinson's disease but further study symptoms, with 29.1% having complete resolution of incontinence. is needed. Most patients did not require pads after treatment, compared to median daily pad use of three prior to treatment. Two patients experienced 12. Eyelid opening apraxia and blepharospasm worsened symptoms after the first treatment, but noted clinical im- provement with repeat injections of 100 units. The complication rate Apraxia of lid opening (ALO), the intermittent ability to open the was higher in this cohort with 25% of patients developing urinary tract eyes without orbicularis oculi contraction, can be seen in parkinsonian infections and 12.5% requiring catheterization for high post-void re- disorders, more commonly atypical syndromes. This can be associated siduals. At 17-month follow-up, 45.8% of patients were continuing to with frontalis contraction. Botulinum toxin has been shown to be ef- receive injections versus 37.5% on medications alone and 8.3% un- fective in patients with blepharospasm in conjunction with ALO as well dergoing sacral neuromodulation. as isolated ALO. Botulinum toxin is approved for treatment of neurogenic bladder There is a case report of use of botulinum toxin in a 73 year old symptoms. In PD patients specifically, there can be improvements in patient with PD with ALO. Twenty units total was injected in two sites overactive bladder. Patients should be made aware of possible side ef- close to the lash line to target the pretarsal orbicularis oculi. This pa- fects in regards to urinary retention and infection risk. tient experienced significant improvement in visual function, lasting 2–3 months. One retrospective study included 64 patients with primary and 60 A. Jocson, M. Lew Parkinsonism and Related Disorders 59 (2019) 57–64 secondary blepharospasm, treated with either Onabotulinum toxin A or beneficial for symptoms including cervical dystonia, laryngeal dystonia, Rimabotulinum toxin B. Of the secondary patients, 12 patients had PD, oromandibular dystonia and hyperhidrosis. 8 of whom had developed blepharospasm following deep brain stimu- lation. There was comparable duration and magnitude of benefit noted 14. Summary between groups. There is insufficient evidence currently to conclude efficacy on use Botulinum toxin appears efficacious for the treatment of sialorrhea, of botulinum toxin for ALO. As with injections for blepharospasm, focal limb dystonia and blepharospasm. Use of botulinum toxin for common side effects of ALO can include ptosis. tremor and overactive bladder may be considered if standard phar- macologic treatments are ineffective; preliminary data for outlet-ob- 13. Other uses struction constipation is promising. There is limited data to support the use of botulinum toxin for camptocormia, freezing of gait, levodopa- Based on non-Parkinson's literature, botulinum toxin may be induced dyskinesias, apraxia of lid opening and dysphagia. Appendix Study Type of Study Toxin Type Total Patients Dosing Units EMG Outcome Results Adverse US Measures* Events** Sialorrhea Lagalla et al, 20- Double-blind, Onabotulinum 32 total 50 units per parotid No VAS-D Improved VAS scores 1 mild, tran- 06 randomized, toxin A 16 toxin gland VAS-FD (p < 0.0001-0.01) sient swal- placebo-con- 16 placebo VAS-SD Improved ADL-drooling lowing diffi- trolled trial UPDRS II (p < 0.0001) culty Patient satisfac- 88% satisfaction tion Decreased saliva weight at 1 Dental roll month (p < 0.0001) weights Mancini et al, 2- Double-blind, Abobotulinum 20 total (14 PD, 146.25 units per US DFSS Improved drooling score at 1 None reported 003 randomized, toxin A 6 MSA) parotid gland week (p=0.005), average benefit placebo-con- 10 toxin 78.75 units per sub- 1 month trolled trial 10 placebo mandibular gland Chinnapongse et- Double-blind, Rimabotulinum 54 total 500, 1000, or 1500 No Safety Improved drooling score at 4 and 4 dry mouth al, 2012 randomized, toxin B 14 1500 units per parotid gland DFSS 8 weeks in all toxin groups 1 breath odor 1 placebo-con- 12 2500 units 250 units per sub- CGI-C (p < 0.05) change in saliva trolled trial 13 3500 units mandibular gland PGI-C Decreased salivary rates in all 1 tongue 15 placebo UPDRS II groups (p < 0.02, p < 0.0033) coating Salivary flow rate Improved CGI, PGI and UPDRS II 1 trismus scores 1 dysguesia Narayanaswami Double-blind, Incobotulinum 10 total 20 units per parotid No Salivary weight No significant change in salivary 1 difficulty et al, 2016 [- randomized, toxin A gland DFSS weight or secondary outcome chewing and 7] placebo-con- 30 units per sub- UPDRS II measures tongue control trolled cross- mandibular gland UPDRS III 1 viscous saliva over study Limb Dystonia Pachetti et al, 1- Open-label Onabotulinum 30 with painful 40-100 units total, EMG McGill pain ques- 30/30 improved pain (p=0.024) None reported 995 toxin A ‘off’ foot dys- median 70 units tionnaire 21/30 with no pain for 4 months tonia 40 units per injected Subjective re- 7/30 improved ‘on’ dystonia with muscle, chosen by sponse walking foot posture Rieu et al, 2017 Double-blind, Incobotulinum 45 total with 100 units in either No CGI-C Moderate improvement CGI-C at 9 falls (2 in randomized, toxin A dystonic toe flexor digitorum BFMD score 6 and 18 weeks (p=0.039) placebo group) placebo-con- plantarflexion longus or brevis VAS Significant improvement in pain 1 transient loss trolled parallel 13 FDL PDQ39 (p < 0.001, p=0.002), severity sensation study 16 FDB (p < 0.001, p= < 0.001) and 16 placebo BFM score (p=0.026, p=0.001) at 6 and 18 weeks in toxin group compared to baseline scores; no significant difference compared to placebo group Giladi et al, 1994 Case series Onabotulinum 2 with striatal 50-70 units in ex- No Subjective re- 80-90% subjective and objective Moderate EHL toxin A toe tensor hallucis sponse improvement weakness longus Cordivari et al, Case series Abobotulinum 14 total with 220-1200 units total EMG Assessed muscle 14/14 mild-moderate posture None reported 2001 toxin A dystonic in varying injection relaxation, pain, improvement clenched fist (7 sites posture, function 4/7 PD patients with functional PD, 3 CBD, 4 improvement CRPS) 5/7 PD patients with improved pain Gupta et al, 2106 Case series Onabotulinum 6 total with foot 250-400 units total EMG BFMD score 6/6 able to walk independently None reported toxin A dystonia im- in varying injection VAS 6/6 with significant pain im- pairing gait fol- sites UPDRS leg scores provement lowing deep TUG 5/6 with 2 point BFMD improve- brain stimula- 6MWT ment tion Gait velocity and 1/6 with 4 point BFMD improve- cadence ment GAS 61 A. Jocson, M. Lew Parkinsonism and Related Disorders 59 (2019) 57–64 Bruno et al, 2016 Retrospective Onabotulinum 160 total (117 100-600 units total EMG CGI-C 81% of PD patients with im- 4 transient chart review toxin A (96%) PD, 14 PSP, 16 in varying injection provement in CGI score > =1 weakness Incobotulinum MSA, 6 CBS, 7 sites, for pain (50.6% for pain toxin A (4%) NOS) with his- patients) 53.4% of PD patients rated pain tory of dystonia ‘very much improved’ injections Tremor Rahimi et al, 20- Open-label Incobotulinum 28 total with 75-390 units total in EMG UPDRS III 20-21 UPDRS item 20 (rest tremor se- 57% 3rd digit 15 toxin A limb rest tremor varying injection FTM scale verity) significantly reduced at 16 weakness sites based on kine- Likert scale and 32 weeks (p=0.006, 25% decreased matic tremor mea- p=0.014) grip strength surements No significant difference UPDRS item 21 (action tremor severity) FTM tremor severity significantly reduced at week 6 (p=0.024) Mittal et al, 2017 Double-blind, Incobotulinum 30 total with 85-110 units total EMG UPDRS III 20-21 UPDRS item 20 and 21 scores 16 decreased randomized, toxin A limb rest tremor across 7-12 varying NIHCGC tremor significantly decreased at 4 and 8 grip (6 in pla- placebo-con- injection sites severity score weeks (p < 0.001, p=0.01) cebo group) trolled cross- PDQL Significant improvement in 3 moderate-se- over study PGI-C NIHCGC (p < 0.001) and PGIC vere weakness Ergometer (p < 0.001) (1 in placebo strength No significant difference in PDQL group) or grip strength Schneider et al, Case series Abobotulinum 3 total with jaw 60-200 units total EMG Subjective re- 3/3 improvement at 4 and 9 None reported 2006 toxin A tremor divided into each sponse weeks post-injection masseter; 1 patient including mentalis Dyskinesias Espay et al, 2011 Double-blind, Onabotulinum 12 total with 200 units total EMG GDRS score Study prematurely terminated 2 head drop randomized, toxin A cervical dyski- 25 units in each CGI-C due to safety concerns with moderate placebo-con- nesias sternocleidomastoid UPDRS IV 32-34 Improvement in resting but not dysphagia trolled cross- 50 units in each action-induced dyskinesias over study splenius capitis, di- vided 25 units in each tra- pezius Freezing of Gait Giladi et al, 2001 Cross-sectional Onabotulinum 10 total (7 PD, 1 100-300u total in EMG CGI-C 7/10 with some improvement 1 transient leg study toxin A vascular parkin- one or both gastro- 4/10 with marked improvement, weakness sonism, 1 Parkin cnemius and soleus, mean of 6 weeks gene, 1 gait dis- +/- tibialis pos- 2/7 with no effect order NOS) terior, +/-extensor hallucis longus Gurevich et al, 2- Double-blind, Onabotulinum 11 total 300 units total EMG UPDRS II No improvement in the toxin 5 leg weakness 007 randomized, toxin A 6 toxin 50 units in the lateral FOG-Q group (2 in placebo placebo-con- 5 placebo and medial heads of CGI-C Significant increase in fall fre- group), not trolled trial each gastrocnemius quency in the toxin group clinically de- 50 units in each so- (p < 0.05) tectable leus 2 increased fall frequency Fernandez et al, Double-blind, Rimabotulinum 14 total 5000 units divided in No UPDRS II No significant differences be- 2 dry mouth 2014 randomized, toxin B 9 toxin four sites in the gas- UPDRS III tween groups 1 increased fes- placebo-con- 5 placebo trocnemius-soleus VAS tination trolled trial complex in more af- CGI-C fected leg Modified Webster Step-Seconds test Vastik et al, 2016 Open-label Botulinum toxin 11 50 units in each EMG FOG-Q 8/11 with improved FOG-Q None reported A tensor fascia latae TUG scores (p < 0.001) UPDRS Significant improvement CGI Hoehn and Yahr scores (p < 0.005) CGI fMRI No significant change in TUG Camptocormia Azher et al, 2005 Case series Onabotulinum 16 total (11 PD) 300-600 units in the No UPDRS 4/9 with marked improvement None reported toxin A 9 PD with toxin rectus abdominis 3/9 with no improvement Fietzek et al, 20- Open-label Incobotulinum 10 100-300 units in US Goal attainment No noted improvement 2 sore muscles 09 toxin A either the rectus ab- Change in posture dominis or iliopsoas UPDRS III based on hip or TUG lower trunk flexion Van Coelln et al, Case series Abobotulinum 4 total (3 PD, 1 500-1500 units in US Change in posture 2 subtle-mild benefit 1 injection site 2008 toxin A MSA-P) each side of the 1 slight worsened posture pruritis iliopsoas 1 significantly worsened 3 mild hip flexion weak- ness 1 moderate hip flexion weak- ness impacting ADLs Pisa Syndrome 26 total EMG None reported 62 A. 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Lew Parkinsonism and Related Disorders 59 (2019) 57–64 Tassorelli et al, Double-blind, Incobotulinum 50-200 units total in Lateral and ante- Lateral and anterior trunk flexion 2014 randomized, toxin A varying sites in ab- rior flexion and improved in toxin group placebo-con- dominal, paraver- range of motion (p=0.044, p=0.001) trolled trial tebral or iliopsoas UPDRS III Improvements in pain, UPDRS, muscles FIM and FIM (p=0.001, p=0.001, VAS p=0.001) Artusi et al, 2018 Open-label Onabotulinum 15 152 units total mean EMG Change in posture 84.6% responder rate None reported toxin A dose US VAS Significant improvement of 50-75 units per flexion (p < 0.001) and pain paraspinal muscle (p < 0.001) 25-50 per non-para- spinal muscle Urinary Dysfunction Anderson et al, Open-label Onabotulinum 20 100 units in 10-20 No KHQ Improvement in KHQ bladder 2 required 2014 toxin A submucosal intrade- AUA symptom symptoms at 1 and 3 months alpha-blocking trusor sites score (p < 0.02) agents for 3-day voiding Improved diary and AUA scores bladder emp- diary (p < 0.05, p=0.006) tying Post-void resi- Decreased incontinence episodes duals (p < 0.05) Urodynamics 57% with moderate to marked improvement Vurture et al, 20- Open-label Onabotulinum 24 100 units in 20 sites No Overactive 79.2% improved 25% UTIs 18 toxin A in the bladder wall bladder symptoms 29.1% resolved incontinence 12.5% required and trigone Post-void resi- (< 0.001) catheterization duals Pad use decreased from 3 to 0 Change in urgency (p=0.016) Pad use Constipation Albanese et al, 2- Open-label Onabotulinum 10 100 units in the US Manometry Reduced tone during straining None reported 003 toxin A puborectalis muscle Defecography (p=0.00001) EMG Anorectal angle increased (p=0.0004) Cadeddu et al, 2- Open-label Onabotulinum 18 100 units in two sites US Manometry Symptomatic improvement at 1 None reported 005 toxin A of the puborectalis Defecography and 2 months in 8 and 10 patients muscle (p=0.002, p=0.0003) 5 with resolved symptoms at 1 month Straining pressure reduced (p=0.00001) Anorectal angle increased (p=0.00001) Dysphagia Restivo et al, 20- Case series Abobotulinum 4 30 units per crico- EMG Clinical exam 4/4 with improvement through None reported 02 toxin A pharyngeal muscle EMG week 20 Videofluoroscopy Alfonsi et al, 20- Open-label Onabotulinum 34 total (7PD, 9 15 units in one cri- EMG DSS Improvement in dysphagia None reported 10 toxin A PSP, 4 MSA-P, 1 copharyngeal muscle EMG (p < 0.001), but only 2/7 PD MSA-C, 2 MS, 10 patients improved versus 6/9 PSP stroke, 1 ataxia and 4/4 MSA-P patients telangiectasia) Apraxia of Lid Opening Lepore et al, 19- Case report Onabotulinum 1 20 units in pretarsal No Subjective re- Improved visual function for 2-3 None reported 95 toxin A orbicularis oculi sponse months Clinical exam Martinez-Ramire- Retrospective Onabotulinum 64 total (41 pri- 39.3-57.2 units in No Duration of ben- Similar efficacy for primary and 8 Bruising z et al, 2014 chart review toxin A mary, 23 sec- varying injection efit secondary blepharospasm 3 Dry eyes Rimabotulinum ondary blephar- sites Peak dose im- (p=0.88) 3 Ptosis toxin B ospasm with 12 provement 1 Redness PD) 4 Diplopia 1 Pain * Assessments: Visual Analogue Scale (VAS), Unified Parkinson’s Disease Rating Scale (UPDRS), Drooling Frequency and Severity Scale (DFSS), Clinical Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), Burke-Fahn-Marsden Dystonia (BFMD), Parkinson’s Disease Questionnaire-39 (PDQ-39), Timed Up and Go (TUG), 6 Minute Walk Test (6MWT), Goal Attainment Scale (GAS), Fahn-Tolosa-Marin (FTM), NIH Collaborative Genetic Criteria (NIHCGC), Parkinson’s Disease Quality of Life (PDQL), Goetz Dyskinesia Rating Scale (GDRS), Freezing of Gait Questionnaire (FOG-Q). 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