Keywords

Introduction

Botulinum neurotoxin (BoNT) is an exotoxin produced by Clostridium botulinum and is the most potent biological toxin [105]. Although the various BoNT products contain only 0.44–5 ng/vial, the estimated lethal dose is 0.09–0.15 μg when BoNT is injected intravenously and 70 μg when ingested; 39.2 g sufficient to eradicate humankind [33]. In addition to the well-defined seven BoNT serotypes (BoNT/A-G), a new mosaic toxin type termed BoNT/HA (also known as BoNT FA or H) was reported [103, 263]. All BoNTs act by inhibiting acetylcholine release at the nerve terminals of striatal and smooth muscles, and exocrine glands, but they also act on other neurotransmitters including adenosine triphosphate, substance P, and calcitonin gene-related peptide and may downregulate sensory receptors, such as transient receptor potential cation channel subfamily V member 1 (TRPV1). The latter mechanism is important in the analgesic’s effects of BoNT.

BoNT acts as a zinc proteinase by cleaving neuronal vesicle-associated proteins, collectively called the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, thereby preventing the docking and fusion of the vesicles with the presynaptic membrane and thus preventing the release (exocytosis) of acetylcholine into the nerve terminal [142]. Various BoNT serotypes work differently and the sites of cleavage of SNARE complex vary between serotypes. BoNT serotype A, C, and E cleave SNAP-25 (synaptosome-associated protein of 25 kd) while serotypes B, D, F, and G cleave synaptobrevin, also known as VAMP (vesicle-associated membrane protein) [263]. Due to this cleavage, acetylcholine is unable to leave the nerve terminal to initiate contraction in the postsynaptic muscle, resulting in chemodenervation [103]. Of the eight serotypes, only BoNT types A and B are approved for clinical use in the United States. There are three formulations of BoNT type A used in clinical practice in the United States, namely, onabotulinumtoxinA (Botox®), abobotulinumtoxinA (Dysport®), and incobotulinumtoxinA (Xeomin®). BoNT-type B classified as rimabotulinumtoxinB (Myobloc®) is the other neurotoxin available for clinical use in the United States.

In 1977, Dr. Allen Scott first injected BoNT in a patient with strabismus. In October 1981, Dr. Joseph Jankovic first injected a patient with blepharospasm with BoNT, and this was followed by a double-blind controlled study of BoNT in cranial-cervical dystonia including cervical dystonia (CD) and blepharospasm. In 1989, onabotulinumtoxinA (Botox) was the first BoNT product approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and cranial nerve VII disorders including hemifacial spasms [105]. Since then, it has been widely adopted for several additional indications in neurology, urology, dermatology, gastroenterology, and pain management/neuro-rehabilitation. BoNT is most frequently used for the treatment of various conditions that involve abnormal, excessive, inappropriate exaggerated muscle contraction, and pain, but its use is expanding to many new and different indications [105].

The duration of benefits from BoNT injections last for about 3–4 months, after which there is a loss of inhibitory effect, likely due to sprouting of new terminals, and eventual loss of effect at the original nerve terminal [193]. Side effects from BoNT vary depending on the area injected and adjacent non-target muscles or glands to which the toxin could spread, resulting in undesired effects such as ptosis, dry eyes with eyelid injections, dysphagia, especially following anterior neck injections, neck weakness, particularly with posterior neck injections, facial asymmetry with injections for hemifacial spasm or facial dystonia, and weakness in the hands with forearm injections for hand dystonia or tremor. In addition to local side effects, about 14% of treatment visits are associated with transient flu-like symptoms [13, 77]. BoNT should be avoided in patients with neuromuscular disorders and motor neuron disease and pregnant or lactating women, although there is no evidence of teratogenicity associated with BoNT therapy [25]. Although EMG, ultrasound, and kinematic guidance can be used for localization, no muscle targeting technique has yet proven to be superior [159, 215, 268].

Neurology

Tremor

The role of BoNT has been studied in different tremor conditions with good success, but BoNT is not yet FDA approved for these tremor indications and its use is off label. Several studies have provided evidence of beneficial effects of BoNT in the treatment of various tremors [148,149,150, 159].

(a) Dystonic tremor

Dystonic head and neck tremors could be present in patients with CD, voice tremor in spasmodic dysphonia, and dystonic hand tremors in patients with focal dystonia of the upper extremity such as organic writer’s cramp, musician’s dystonia, and other task-specific tremors. Primary dystonia patients are more likely to have tremor than patients with secondary dystonia including tardive dystonia [169]. Hand tremor has been reported in patients with dystonia affecting other parts of their body and reported the prevalence of postural or kinetic tremor in these patients to range from 14% to 86% [169].

In a retrospective chart review on 91 patients with medically refractory hand tremor treated with botulinum toxin, 31 patients had dystonic tremor. The majority of patients noted a benefit with BoNT injections in the forearm flexor muscles [159]. Other studies have confirmed the efficacy of BoNT in the treatment of essential (ET) and dystonic tremors [104, 148, 159].

(b) Task-specific tremor

Primary writing tremor (PWT) is a type of task-specific movement disorder where tremor occurs predominantly or exclusively while writing. This shares features with ET and dystonia [219, 246]. The lack of adequate response to typical medications used to treat ET like primidone and propranolol, presence of mirror movements typically seen in patients with dystonia, makes this more closely related to dystonia than to ET. PWT causes significant inconvenience to patients in occupations that demand a great deal of writing or enjoy writing as a hobby. Several studies have examined the effects of BoNT on PWT. There are two case series and a case report, which showed beneficial effects of BoNT in this condition [11, 172, 219]. In one of the case series, four out of five patients noted a significant and sustained improvement in tremor during the course of BoNT treatment. In this study, 10–12 units of BoNT/A was injected into flexor carpi radialis, extensor carpi radialis and ulnaris, abductor pollicis longus and extensor digitorum communis [172]. In a case report of a 64-year-old man, retired postal worker, 12.5 units of BoNT type A was injected into flexor carpi radialis under EMG guidance. This resulted in a 75% improvement in the symptoms that sustained for 3 months [219].

(c) Essential tremor

BoNT has been studied in patients with ET resulting in hand tremor, voice tremor, and head tremor. There is a paucity of large trials looking at the efficacy of BoNT for tremors, but BoNT has been used for selected patients who are refractory to medications prior to consideration of more invasive strategies like deep brain stimulation (DBS). The mechanism of BoNT is thought to be from the relaxation of involved muscle groups, or due to altered peripheral or central mechanisms [131].

For ET involving the hands, there were small studies looking at injection of flexor and extensor muscles. These were limited due to side effects of hand weakness noted particularly with extensor muscle injections [109]. In one open label study which enrolled 26 tremor patients of whom 14 had ET, there was significant improvement in the tremor and disability scores of ET patients [234]. Five of the fourteen patients reported moderate-to-marked subjective improvement in functional abilities after BoNT. However, the average reduction in tremor amplitude was less than 25% and the degree of tremor amplitude reduction correlated with patients’ subjective impression about tremor benefit [234]. There are a few other open label trials evaluating the efficacy of BoNT in ET hand tremor which have shown significant improvement in tremor subjectively [167, 185, 204] and some using objective tremor [203, 204].

In 1996, Jankovic et al. reported the first randomized double-blind placebo-controlled study to evaluate the effect of BoNT injections in patients with ET hand tremor. Twenty-five patients with moderate–to-severe hand tremor were injected with BoNT, and there was significant improvement in tremor noted on tremor severity rating scales and on accelerometry measurements. Fifty units of BoNT was injected into wrist flexors and extensors with repeat injections in 4 weeks. There was mild and transient weakness of finger and wrist extensors attributed to injections of the extensor carpi radialis and ulnaris muscles [110]. Subsequently, another randomized placebo-controlled study was done involving 133 patients who were injected in the flexors and extensors in two parallel groups of low- and high-dose injections. There was significant improvement in postural tremor in both groups, but there was more weakness in the group injected with higher dose BoNT. There were no major changes in measures of motor tasks and functional disability, possibly due to weakness that resulted after the injections [27]. In a retrospective chart review done in patients with medically refractory tremor, of 53 patients with ET affecting their hands who received BoNT injections, the majority noted improvement in their tremor [159]. As a result of troublesome weakness-associated extensor muscle injections, many investigators tend to avoid injecting these muscles in patients with ET-related hand tremor, but the selection of the muscles and dosage must be individualized [114]. Another randomized double-blind placebo-controlled crossover trial evaluated the efficacy of BoNT in 33 ET patients with hand tremor, with injections customized to individual patients’ tremor quality. Between 80 and 120 U of incobotulinumtoxinA was injected between 8 and 14 muscles in the hand and forearm of individual patients. There was significant improvement in Fahn Tolosa Marin tremor rating scales at 4 and 8 weeks. There was no significant hand weakness, but mild weakness was observed in 50% of patients receiving BoNT injections [150].

In ET patients with voice tremor, a minority of patients experience tremor benefit from BoNT injections into the vocal cords. Breathiness of voice is a common side effect seen with BoNT injection into the vocal cord. In a study which included 34 patients, 16 noted improvement in their voice tremor after BoNT injections into thyroarytenoid muscle [222]. In another study, EMG-guided injections were performed depending on the type of tremor, with thyroarytenoid injections performed for horizontal tremor, and strap muscle injections for vertical laryngeal tremor. For mixed tremor type, injections were performed based on the tremor type that was dominant/more severe. If both vertical and horizontal tremors were equally severe, strap muscles were injected first with thyroartytenoid injection done 2 weeks later. Starting doses of 1 unit was injected into the thyroarytenoid muscle with higher doses less than 10 units used for strap muscles and other adjacent neck muscles injected in this study. All 16 patients who received injections in this series had tremor benefit from BoNT; hoarseness was the only side effect observed, mostly following injections to the thyroarytenoid muscle [93]. Another small open label crossover study looked into BoNT injection into vocalis muscle either unilaterally or bilaterally. This was a small study in 10 patients with essential voice tremor, with EMG guided injections of 15 units into the left vocalis (unilaterally) with cross over to the bilateral vocalis injection arm (2.5 units into each vocalis) of the study after 16 or 18 weeks or vice versa. Only 3 of the 10 patients had objective reduction in voice tremor with bilateral injections and 2 of 9 patients who received unilateral injection. Breathiness and reduced vocal effort were seen, but 8 of the 10 patients chose to get re-injected at the end of the study [255]. In 15 patients with ET resulting in voice tremor, BoNT was injected into thyroarytenoid or into the cricothyroid or thyrohoid muscles; there was significant improvement in voice tremor based on subjective evaluation and also based on perceptual evaluation of recorded speech samples [97]. There is a small study by Ludlow et al. in 1989, another study by Brin et al. in 1992 and a case report by Warrick et al. in 2000, all of which showed efficacy of BoNT in the treatment of voice tremor. A prospective randomized trial over 6 weeks involving 13 ET patients with voice tremor showed that there was improvement in voice tremor in all patients over the observed period with dysphagia and breathiness being the most common side effects [3]. Based on these studies, an evidence-based review suggested level 1 recommendation for the use of BoNT in ET affecting the voice [179].

About 30–40% of ET patients with head tremor do not respond well to medications. There was one small double-blind placebo-controlled trial by Pahwa et al. in 1995 assessing BoNT in 10 patients with head tremor. In this study, 40 units were injected into bilateral sternocleidomastoid muscles and 60 units into bilateral splenius capiti muscles, with subsequent crossover into the placebo group. There was over mild-to-moderate improvement in 50% of the patients compared to 10% improvement noted in the placebo group [168]. Transient, non-disabling, neck weakness is the most common side effect observed with this pattern of injection. Several patients with essential tremor also have concomitant CD and dystonic tremor affecting their head. BoNT appears to work better for dystonic head tremors than for ET associated head tremor [130].

In a study involving 43 patients of which 13 had head tremor due to ET without dystonic component, and the remaining had head tremor secondary to CD, BoNT was injected into neck muscles with dosing individualized based on neck position and visible and palpable tremor oscillation. A mean dose of 400 units of abobotulinumtoxinA was split between the two splenius capiti muscles in patients with ET head tremor. There was significant improvement in tremor, based on accelerometry analysis in both groups of patients with head tremor from ET and from CD [259]. In a study involving 51 patients with disabling tremor, 8 of whom had ET related head tremor, there was significant improvement in tremor with BoNT injections [109].

(d) Parkinson-associated rest tremor

The rest tremor in Parkinson’s disease (PD) tends to be responsive to levodopa, but in some patients there is insufficient tremor control or side effects with medication titration which limits tremor control. In these patients, BoNT could be used for better tremor control with muscle selection individualized based on the nature of the tremor depending on the predominant movement (flexion-extension, pronation supination or ulnar-radial deviation type), and the predominant joint involved (finger tremor, wrist tremor or elbow tremor) [160].

In a randomized double-blind placebo-controlled cross-over study, 30 patients received BoNT injections into the hand and forearm muscles. Patients were injected customized to their tremor rather than a standard protocol. Between 2.5 and 20 units of BoNT/A was injected in different muscles, including lumbricals, flexor carpi radialis, flexor carpi ulnaris, flexor digitorum superficialis, pronator, biceps, triceps, extensor carpi radialis, extensor carpi ulnaris, extensor digitorum, flexor pollicis brevis, flexor digitorum profundus, abductor pollicis brevis, brachioradialis, supinator, and opponens pollicis. There was a significant improvement in the tremor on tremor severity scale and improvement in patients’ impression of change and an improved ability to do activities at home, without much weakness as side effect [149].

In an open label study, 28 patients were injected with BoNT for PD tremor using kinematic measures to personalize muscle selection for injection. There was significant decrease in Unified Parkinson’s Disease Rating Scale (UPDRS) rest tremor scores and Fahn-Tolosa-Marin tremor severity scores. Ten patients experienced mild weakness which did not affect activities of daily living [187, 203]. In another 3-month open label study in 7 patients with PD-related upper-limb tremor, with kinematic assessment of tremor done pre and post injections, there was significant improvement in kinematic assessments of static and functional tasks at 2 and 3 months. There was also significant improvement in the UPDRS tremor scores and spiral drawings [186]. In another open label study in 26 patients, 12 of whom had PD; there was over 50% reduction in tremor in 2 patients and moderate-to-marked subjective improvement in functional benefit in 5 patients after BoNT injections. However, the average tremor reduction was less than 25% by quantitative measures [234]. In a prospective study in 187 patients with tremor, 15 patients with tremor due to Parkinson’s disease, BoNT injections were done under EMG guidance with booster injections given if needed for optimum tremor control. In this study, there was an average BoNT efficacy of 35.7% for PD tremor. There was marked subjective improvement in tremor along with significant reduction in tremor amplitude of over 50% in 2 of 15 patients with PD tremor [185].

(e) Jaw tremor

Jaw tremor could be seen as part of the tremor spectrum in patients with ET, dystonic tremor, PD, task specific tremor and also in other neurologic conditions such as hereditary geniospasm. Patients with jaw tremor as part of ET typically have more widespread severe tremor and a long history of having ET. There is some thought that jaw tremor may be a marker of subsequent development of PD in these patients [132]. Jaw tremor is more common in PD than in ET patients, with prevalence in ET estimated to be between 7.5% and 18% [96]. Jaw tremor could also be a dystonic tremor in the setting of dystonia. In patients with bothersome jaw tremor, refractory to medical therapy, BoNT should be considered as a therapeutic option.

In a case report about a woman with position specific jaw tremor, likely dystonic in nature, where there was improvement in tremor after BoNT injections [228]. In a case series of 7 patients with jaw tremor in the setting of dystonia, one patient had BoNT injection for jaw tremor and noted improvement in the tremor. Others in this series did not receive injection and received oral medications with inadequate benefit [206].

In a pilot study involving three patients with jaw tremor due to PD, who were injected with onabotulinumtoxinA, there was significant improvement in jaw tremor in all 3 patients at 4 and 9 weeks post injection. Between 30 and 100 units of abobotulinumtoxinA was injected in the masseter bilaterally with mentalis muscle included in one of the patients. There were no side effects including no dry mouth [207].

(f) Holmes tremor

Holmes tremor, also called rubral, mesencephalic, or thalamic tremor, is a slow (2–5 Hz tremor), high-amplitude tremor, present at rest, worse with action. This often occurs after lesions affecting the thalamus, brainstem, or cerebellum. Usual etiology of the lesion includes vascular lesions, demyelinating disorders, head trauma, AV malformations, or neoplasms [63, 188].

A case report of a 29-year-old male patient with Holmes tremor after pontine hemorrhage describes marked improvement in tremor after BoNT injection. BoNT was injected into the 2nd, 3rd, 4th flexor digitorum superficialis and 40 units in the extensor pollicis longus using ultrasound guidance. There was sustained improvement at the 4- and 9-week follow-up. There was some improvement noted in the activities of daily living [4].

(g) Cerebellar tremor

Lesions in the deep cerebellar nuclei (dentate, globose, or emboliform) or in the brachium conjunctivum (superior cerebellar peduncle), which contains fibers crossing over to the contralateral ventrolateral thalamus, could result in a cerebellar intention tremor. These deep cerebellar lesions cause intension tremor on the ipsilateral extremity. This is often an irregular 3–5 Hz tremor, affecting proximal more than distal muscle groups [63].

A retrospective analysis about the effect of BoNT on cerebellar tremor in 14 patients before and 1 month after injections, showed that there was improvement in tremor after BoNT injection into the agonist muscles alone. Antagonist muscles were avoided to prevent limb weakness. However, in this study, in addition to patients with cerebellar tremor from stroke, multiple sclerosis, and spinocerebellar ataxia, some ET patients were also included [243].

A small pilot study looked at the effect of BoNT in five patients with cerebellar tremor from multiple sclerosis and found no significant improvement in tremor with BoNT injection, but there was a trend toward improvement on some of the tremor ratings. Two of these five patients were injected again 2 months from first injection. There was worsening of pre-existing weakness that limited the use of BoNT in these patients [41].

(h) Palatal myoclonus (tremor)

Palatal myoclonus or tremor could either be primary/essential palatal myoclonus or secondary due to lesions in the Guillian-Mollaret triangle or the dentato-rubro-olivary network. Essential palatal myoclonus is due to repetitive contraction of the tensor veli palatini muscle, innervated by the trigeminal nerve, which results in rhythmic opening of the eustachian tube. Secondary palatal myoclonus is due to contraction of the levator veli palatini and results in repetitive palatal elevation [12]. This ear clicking and palatal myoclonus could be bothersome and distracting to patients.

There are several case reports which show efficacy of BoNT in palatal myoclonus [45, 49, 129, 214, 252]. BoNT is injected trans-palatal into the aponeurosis of the tensor veli palatini muscle.

In a case series of five patients with palatal myoclonus who received BoNT injections, four reported complete resolution of symptoms. One patient reported transient dysphagia and weak voice. BoNT was injected into the soft palate at the posteromedial aspect of maxillary tuberosity, where tensor veli palitini and levator veli palitini insert. Starting doses between 5 and 15 units of abobotulinumtoxinA were used in this study [178].

Other Parkinsonian Disorders

There are many symptoms experienced by patients with PD that may be amenable to BoNT therapy including blepharospasm, anterocollis, camptocormia, foot dystonia, hand and jaw tremor, sialorrhea, seborrhea, overactive bladder, and constipation [32, 104, 106, 111]. In addition to utilizing BoNT in the treatment of PD-related symptoms, there is emerging research on the role of BoNT in the central nervous system that may have relevance to the treatment of neurodegenerative disorders such as PD. For example BoNT/B when injected in the brains of animal models has been shown to block the transynaptic transmission of alpha-synuclein [164].

Freezing of gait (FoG)

There have been several studies suggesting the use of BoNT in FoG, but the results have been inconsistent [271]. This initially came about after a patient who received BoNT for off dystonia in the foot reported improvement in FoG [82, 84]. This was studied further in a pilot study of ten PD patients with FoG where three patients reported marked improvement in FoG, while two had no benefit, and one patient who was injected in a blinded manner had no improvement with saline injections and marked improvement after BoNT injection in calf muscles. Between 100 and 300 units of onabotulinumtoxinA was injected into the lateral and medial heads of gastrocnemius and into the soleus in this study. One or both legs were injected [83]. In another study involving 20 patients with PD of whom 10 had FoG, there was improvement in FoG after BoNT injection into the tensor fascia latae. Eight of the ten patients had significant improvement in FoG scores [240]. However, in a prospective double-blind placebo-controlled trial testing this concept further in 11 patients, 6 patients received 150 units of onabotulinumtoxinA injections and 5 received saline injections into the calves of both legs. There was no significant improvement in FoG in either group with leg weakness and falls, resulting in early termination of the study [92].

In a study involving 14 PD patients with FoG, 9 were injected with 5000 units of rimabotulinumtoxinB into the gastrocnemius-soleus complex of the predominantly affected leg. Five patients received placebo. There was marked improvement in symptoms in one patient, minimal improvement in two patients, unchanged symptoms in nine patients, and two patients with minimal worsening of symptoms. No significant differences in UPDRS scores between treatment and placebo groups were found [69].

Levodopa-induced Dyskinesia

Levodopa-induced dyskinesia (LID) occurs in over 90% of patients treated with levodopa for over 15 years, although the prevalence varies from study to study. Peak dose dyskinesia is the most common form of LID, followed by wearing off dystonia, both of which could benefit from BoNT injections as a treatment option [244]. In a randomized double-blind crossover study of 12 patients with medication refractory levodopa-induced cervical dyskinesia, 200 units of BoNT was injected in the neck muscles (bilateral sternocleidomastoid, splenius capitis, trapezius). Of these 12 patients, 8 were randomized and only 4 completed the study before it was voluntarily terminated due to safety concerns, predominantly due to excessive neck weakness. There was a trend towards reduced On time with LID in the BoNT group compared to baseline, and reduced dyskinesia on self-reported dyskinesia and pain related to dyskinesia [65]. There are other studies demonstrating the utility of BoNT in the treatment of various forms of LID [106].

Axial Dystonia (anterocollis, camptocormia, Pisa syndrome)

See section “Dystonia“

Constipation: see section “Gastroenterology”

Hyperhidrosis: see section “Autonomic Disorders”

Dystonia

Dystonia is a movement disorder characterized by sustained or intermittent muscle contraction, resulting in abnormal repetitive movements, posture or both [5]. Dystonic movements are often patterned, initiated, or worsened with voluntary action and associated with overflow activation of involved muscles. Dystonia can be classified based on several factors including the age of onset, body distribution, temporal pattern, and also based on associated symptoms as part of a systemic condition. Dystonia could also be classified based on etiology. Based on body distribution, dystonia could be classified as focal, segmental, hemidystonia, multifocal, and generalized dystonia [5]. BoNT has become the mainstay treatment for focal and segmental dystonia. Muscle selection and adequate dosing are also important factors to determine efficacy, as in other dystonic conditions. BoNT has been noted to be an effective and safe treatment option for long term use [116].

(a) Blepharospasm and apraxia of eyelid opening

Blepharospasm is a type of focal cranial dystonia resulting in repetitive involuntary forceful eyelid closure, often associated with dystonia of other adjacent areas like neck, jaw, and facial muscles. Since BoNT was approved by the FDA in 1989, for the treatment of blepharospasm, this has become the mainstay of treatment for this form of focal dystonia [245]. Based on 2016 Practice Guidelines from the American Academy of Neurology [217], onabotulinumtoxinA and incobotulinumtoxinA have level B evidence (probably effective) and abobotulinumtoxinA has level C evidence (possibly effective) for use in the treatment of blepharospasm. OnabotulinumtoxinA and incobotulinumtoxinA are FDA approved in the United States for the treatment of blepharospasm; abobotulinumtoxinA is approved for the treatment of blepharospasm in Europe.

A randomized, double-blind, placebo-controlled multicenter trial evaluated the safety and efficacy of incobotulinumtoxinA in 109 patients in a 2:1 ratio for treatment to placebo, and found a significant difference in the Jankovic Rating Scale (JRS) in favor of the BoNT group [107]. There was also clinically relevant improvement in symptoms and in functional impairment assessed using the Blepharospasm Disability Index (BSDI) and patient and physicians’ global assessments. Ptosis and dry eyes were the few noted adverse effects.

There have been randomized, double-blind studies and split face studies (injecting different BoNT products to either side of the face) comparing different BoNT products which did not find significant difference between these toxins for use in blepharospasm [217]. A randomized double-blind trial compared incobotulinumtoxinA (Xeomin®) to onabotulinumtoxinA (Botox®) in patients with blepharospasm. Both BoNT products reduced scores on JRS, BSDI, and Patient Global Assessment (PGA) scales with no significant difference between the two products but with a tendency toward greater improvement with onabotulinumtoxinA [249]. Similarly, there are studies comparing incobotulinumtoxinA (Xeomin®) to onabotulinumtoxinA (Botox®) [192] and abobotulinumtoxinA (Dysport®) to onabotulinumtoxin A (Botox®) [162] with no significant difference in benefits seen between the two products.

Studies evaluating the long-term use of BoNT in patients with blepharospasm noted that the benefits persist for several decades of treatment [40, 217, 237]. A study in 128 patients who were receiving abobotulinumtoxinA or onabotulinumtoxinA had maintained benefit at 15 years [18, 189].

Frowning as a result of frontal dystonia, in the absence of blepharospasm, could also be treated using BoNT. A case series on two patients who had facial frowning reported an improvement in symptoms after BoNT injections. Corrugator and nasalis were the main muscles injected in these patients with improvement in facial frowning [99]. We have also used BoNT in the treatment of levodopa-induced dyskinesia, manifested by repetitive frontalis contractions [106].

Apraxia of eyelid opening

Apraxia of eyelid opening refers to the inability to open the eyelid in the absence of paralysis, sensory loss, or other disorders affecting language or alertness. This is often seen co-existing in patients with blepharospasm, Parkinson’s disease, atypical parkinsonian syndromes, especially in progressive supranuclear palsy (PSP). The mechanism of “apraxia of eyelid opening” is not well understood, but it is probably not a true apraxia and more likely related to a dystonia phenomenon, inhibition of levator palpebrae, or other mechanisms [61].

Smaller studies have shown improvement in apraxia of eyelid opening after BoNT injections, especially if associated with blepharospasm. Injection of the pretarsal portion of the orbicularis oculi seems to be critical to help with apraxia of eyelid opening [102]. There have been several case reports on the benefit of BoNT in apraxia of eyelid opening [68, 126, 180].

One study noted benefits of BoNT in 32 patients with apraxia of lid opening, of which 3 patients had primary apraxia of eyelid opening, 20 with associated blepharospasm, 7 with PSP, and 2 with dystonic parkinsonian syndrome. Injections to the junction of preseptal and pretarsal portion of palpebral orbicularis oculi yielded best results. 83% of patients had improvement in symptoms after BoNT injections on a rating scale administered pre-and post-BoNT injections [119].

Another study looked into the effect of BoNT in 10 patients with apraxia of eyelid opening, where 8 of 10 had improvement in eyelid opening after BoNT injections. Between 20 and 30 units were used per eye injected at two sites at the junction of orbital and preseptal orbicularis oculi, compared to 10–20 units injected at one site at the middle of the upper lid close to the eyelash line. Injection of BoNT close to the pretarsal portion of orbicularis oculi resulted in improvement whereas injections to the preseptal and orbital portions did not yield the same benefit [53].

Ten patients with apraxia of eyelid opening associated with blepharospasm had BoNT injections and the lid opening parameters were compared to normal eyelid opening parameters obtained from 12 healthy control subjects. There was improvement in all lid opening measurements after BoNT injections [73].

(b) Cervical dystonia

Cervical dystonia (CD) is the most common isolated focal dystonia affecting the muscles of the neck and shoulders. BoNT is the first line treatment of CD. There are several good-quality studies that show the benefit of BoNT in CD. The 2008 American Academy of Neurology (AAN) evidence-based review identified 7 Class I studies showing the effect of BoNT in CD [215]. These have been listed and described briefly in Table 4.1.

Table 4.1 Evidence-based review of the use of BoNT
Full size table

The 2016 AAN Practice Guideline Update reviewed the evidence and listed level A (effective) evidence for the use of abobotulinumtoxinA and rimabotulinumtoxinB in patients with CD and level B (probably effective) evidence for the use of onabotulinumtoxinA and incobotulinumtoxinA in CD. These are based on 15 randomized double-blind clinical trials, listed in Table 4.1. All the formulations are approved for use in CD in the US [217].

Although anterocollis is often excluded from clinical trials of CD, some patients benefit from BoNT injections into the anterior scalene muscles, sternocleidomastoid muscles, and submental complex [106].

(c) Camptocormia

Camptocormia refers to an abnormal forward flexion in the thoracolumbar region, of more than 45°, apparent while standing or walking, but resolves in supine position. This is seen in PD patients with longer disease duration and severity, estimated to have prevalence between 3% and 17% in PD patients [59, 256].

In a case series studying 16 patients with camptocormia from different etiology, 9 patients were injected with BoNT for camptocormia. Between 300 and 600 units of onabotulinumtoxinA was injected in the rectus abdominus muscle. Of these 9 patients, 4 had marked improvement in symptoms lasting for about 3 months [10].

An open label study in 10 patients with camptocormia looked into the effect of ultrasound-guided injection of 100–300 units of incobotulinumtoxinA injected into either the rectus abdominus muscle or iliopsoas muscle based on whether the flexion was at the hip or lower trunk. There was no significant improvement in posture with these injections [72].

A case series of 4 patients with camptocormia, due to PD in 3 patients and one patient with MSA-P, evaluated changes in camptocormia after injecting 500–1500 units of abobotulinumtoxin A to bilateral iliopsoas using ultrasound guidance. There was subtle improvement in two patients, worsening of posture in one, and marked worsening in one patient. At the highest doses, all patients complained of mild hip weakness [247].

Another study in two patients where 300 units of BoNT was injected in the rectus abdominis with CT guidance showed no improvement in symptoms after BoNT injection [42].

A case report of a single patient with camptocormia, who had insufficient benefit in trunk posture and pain after rectus abdominis injection, was injected with 200 units of onabotulinumtoxinA in the external oblique on one side and rectus abdominis on the other side. This led to an improvement in trunk posture and improvement in pain. This patient had a partial resection of rectus abdominis on one side for breast cancer reconstruction surgery [257]. This was based on the observation in a previous study where injection of lidocaine into external oblique muscles in patients with camptocormia resulted in an improvement in posture and pain in 8 of 12 patients [75].

(d) Pisa syndrome

Pisa syndrome refers to the marked lateral flexion of the trunk, of more than 10°, improves with lying down, and with passive manipulation. This is estimated to have a prevalence of about 8% in PD patients with longer disease duration [59], and in patients with atypical parkinsonian syndromes.

In a randomized placebo-controlled trial involving 26 patients, 13 patients received BoNT injections while the remaining 13 received saline injections for camptocormia. Between 50 and 200 units of incobotulinumtoxinA was injected using EMG guidance into iliopsoas, rectus abdominis, thoracic, or lumbar paravertebral muscles. There was significant improvement in trunk posture in the patients injected with BoNT and also in pain and range of motion [229].

In an open label pilot study of the effect of BoNT in Pisa syndrome, 13 of 15 patients initially enrolled completed follow-up assessments, and of these, 11 patients had at least 40% improvement in posture, and all patients had improvement in pain/discomfort. Between 50 and 75 units of onabotulinumtoxinA was injected into the paraspinal muscles under ultrasound or EMG guidance, and between 25 and 50 units injected in the non-paraspinal muscles with pathologic hyperactivity on EMG [9].

Hemifacial Spasm (HFS)

HFS is characterized by unilateral, involuntary clonic contraction of muscles innervated by the seventh cranial nerve. This is often due to an aberrant vascular loop compressing the exiting nerve root [262]. Secondary HFS could occur when seventh cranial nerve is damaged due to tumor, infection, Bell’s palsy, or demyelinating causes. HFS is primary in 79% patients and secondary in 21% [116].

There is level C (possibly effective) recommendation for the use of BoNT in HFS. The evidence for the use of BoNT is not optimal but the initial open label studies showed significant degree of benefit and this has discouraged larger controlled studies for this condition [215]. However, BoNT has become the mainstay first-line treatment for HFS and both primary and secondary HFS respond well to BoNT injection [116]. Pretarsal injections have been noted to be more beneficial to help the eyelid spasms in HFS than preseptal injections [31].

An open trial studied the effects of BoNT in 101 patients with HFS. Of 144 treatments, 98.6% had significant improvement in symptoms. This study initially started as a double-blind study with 8 patients randomized to receive BoNT and 4 patients in the placebo arm received saline injections. Due to the benefits noted with BoNT, the remaining patients were studied in an open trial and all patients treated with BoNT received benefit after the first injection for HFS. Patients with suboptimal benefit received repeat injections 7–10 days after the first round of BoNT [175]. This practice is generally discouraged due to concern for immunoresistance with injections repeated less than 3 weeks apart [17]. Dry eye, facial weakness, and ptosis were the adverse effects noted.

A prospective, placebo-controlled blinded study in 11 patients with HFS showed subjective improvement in 79% and objective improvement in 84% after BoNT injections [265].

In a single-blinded randomized parallel group study comparing two BoNT products, onabotulinumtoxinA (Botox®) and abobotulinumtoxinA (Dysport®) were studied in 49 patients with HFS. Similar improvement was noted with the two BoNT products with a slightly higher number of patients needing booster injections with Dysport® than with Botox®. A conversion ratio of 4:1 was used for Dysport®: Botox® to estimate an equivalent potency [205]. In a study of BoNT in blepharospasm and HFS, 28 patients with HFS had improvement in symptoms with the injection of BoNT to pretarsal orbicularis oculi [31]. In a retrospective chart, review of 32 patients injected with BoNT for blepharospasm and HFS, 11 patients had HFS. There was improvement in symptoms with BoNT injections, and these persisted with repeat treatments over the course of 10 years. A slightly higher dose was needed for similar benefits over time [1].

Synkinesis

Aberrant regeneration of the facial nerve after facial nerve injury or paralysis from a variety of etiologies could result in abnormal movement of facial muscles called synkinesis. The involved muscles could include eyelid and upper or lower facial muscles. BoNT can treat these abnormal movements to restore facial symmetry in these patients.

A double-blind multicenter placebo-controlled trial evaluated the use of BoNT in 30 patients with synkinesis and an additional 6 patients in an open label pilot study design. Etiology of facial paralysis for patients in this study included chronic Bell’s palsy in 20 patients, post-acoustic neuroma surgery in 4 patients, Ramsey-Hunt syndrome in 4 patients and one patient after mastoiditis and another after meningioma resection. BoNT/A injected to the synkinetic side suppressed the degree of abnormal movements associated with different facial movements in both study designs. In the double-blind placebo-controlled study, 15 patients received BoNT injections and were compared to 15 patients who received placebo. In this study, there was reduction in the synkinetic movements based on videotape and blinded physician examination and improvement in quality of life, vision, social interaction, and self-perception of facial asymmetry [21].

Another study compared onabotulinumtoxinA to abobotulinumtoxinA in facial synkinesis by injecting BoNT to the non-paralyzed side of the face using a dose conversion ratio of 1:3, which is the most commonly used conversion ratio. After randomization, 25 patients received onabotulinumtoxinA and 30 patients received abobotulinumtoxinA with doses individualized to the patients. Both toxins showed an improvement in facial asymmetry after injections using subjective and objective assessments. Facial symmetry was assessed subjectively by independent evaluation by two plastic surgeons on a four-point scale, and objective evaluation included Clinical Score for Facial Palsy and Facial Disability index [57].

A randomized placebo-controlled trial in 20 patients with facial palsy followed by synkinesis evaluated the effects of BoNT in these patients. Ten were randomized to receive BoNT followed by neuromuscular retraining therapy (NMRT), which is an exercise program to improve synkinesis, compared to 10 patients who received NMRT alone. There was significant improvement in synkinesis in the BoNT group compared to placebo [46, 152].

Another randomized single-blind three-arm comparison clinical trial compared three different BoNT types, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA, in 28 patients with facial synkinesis. Of these, 6 patients were enrolled multiple times. Of a total of 38 treatment visits, 15 were onabotulinumtoxinA, 13 abobotulinumtoxinA, and 10 incobotulinumtoxinA injection visits. There was no significant difference in SAQ score improvement between the three toxin groups, implying similar efficacy of these toxins for facial synkinesis up to 4 weeks. At 4 weeks, incobotulinumtoxinA had less effect on SAQ scores compared to onabotulinumtoxinA, probably due to shorter duration of action. Higher doses may be needed to allow for longer duration of benefit when using incobotulinumtoxinA for facial synkinesis [231].

In addition to these randomized clinical trials, there are multiple other open label studies showing benefits of BoNT in synkinesis.

A prospective cohort study in 23 patients who received BoNT injections for facial synkinesis showed improvement in synkinesis after injections. Some of these patients got injections to the buccinator muscle, which is thought to be a symptomatic muscle in synkinesis. Although all patients who received BoNT injections had improved synkinesis, patients who received injections to the buccinator had greater improvement in post-injection scores and greater difference between the pre- and post-injection scores on the Synkinesis Assessment Questionnaire (SAQ). Buccinator injections were performed, using EMG guidance, below the dentate line in the buccal mucosa anterior to the level of Stenson’s duct [176].

Another prospective cohort study in 99 patients with facial synkinesis who received BoNT injections showed that there was significant improvement in synkinesis after BoNT injections. Bell’s palsy and facial paralysis after resection of vestibular schwannoma were the main etiology preceding facial synkinesis in these patients. A group of 6 muscles including corrugator, orbicularis oculi superioris, orbicularis oculi inferioris, risorius, mentalis, and platysma were injected in these patients. SAQ was used to assess symptoms pre and post injections. Higher doses of BoNT injections resulted in increased improvement in SAQ scores [212].

In a cohort of 51 patients who received BoNT injections, SAQ was administered pre and post injections. There was significant improvement in SAQ scores and improvement in scores for every question on the SAQ post onabotulinumtoxinA injection compared to the pre scores [158].

Orofacial and Oromandibular Dystonia

Orofacial/oromandibular dystonia (OMD) refers to dystonic contraction of the facial muscles along with pharyngeal, laryngeal, and masticatory muscles [116]. This could accompany dystonia in the neck as part of cranial cervical dystonia. There are numerous case reports and case series describing the benefit of BoNT in OMD, but there is paucity of well-designed, placebo-controlled trials [144, 151]. Jaw closing dystonia with or without bruxism tends to be more responsive to BoNT than jaw opening dystonia [218, 226]. In a double-blind, placebo-controlled trial of 23 patients with sleep bruxism treated with BoNT/A injections into masseter and temporalis (60 and 40 units each, respectively) or placebo, the clinical global impression and the visual analog scale favored the BoNT/A group [166].

A prospective, longitudinal, observational case series evaluated 30 patients with focal facial dystonia pre and post BoNT injections using Abnormal Involuntary Movement Scale (AIMS). BoNT doses between 3 and 100 units were used (mean dose 27.4 units). There was improvement in the AIMS score and the percentage of improvement depended on the dose injected, the area affected, and the etiology. However, among patients with facial dystonia, this study included 11 patients with HFS and 7 patients with facial paralysis, all inappropriately listed under the facial dystonia class [197].

In a large prospective open label study looking at the safety and efficacy of BoNT in OMD, 162 patients with OMD had Botox® injections in either the masseter or the submental complex or both muscle groups. Jaw closing dystonia was the most common type in this study and the majority had primary/idiopathic dystonia. 110 of the 162 patients had a global improvement of ≥3 on a scale where 4 means complete resolution/marked improvement of symptoms [226].

A cross-sectional survey of 23 patients, 5 with OMD, showed that patients with OMD had benefits noted on the Glasgow Benefit Inventory (GBI). This questionnaire evaluates quality of life after otolaryngologic interventions, in this case, BoNT for spasmodic dysphonia and OMD. The benefit was less than what was noted in patients with spasmodic dysphonia (SD), but there was not a significant difference between the groups. All patients with SD and OMD noticed benefits after BoNT injections [20].

Another similar study in 12 patients with jaw opening OMD, using GBI scores pre and post BoNT injections showed a significant improvement in quality of life after BoNT injections. Doses of 40 units or more were injected into the lateral pterygoid muscles bilaterally with an additional midline injection of 10 units into the submental complex for patients with suboptimal benefit despite dose increase to the lateral pterygoid muscles. There was significant reduction in the GBI scores after BoNT injections. There were no major adverse effects [36].

Neuro-rehabilitation: Spasticity

BoNT has level A evidence of efficacy in patients with upper- and lower-limb spasticity [105]. There are several reports which show a significant reduction in post-stroke spasticity in patients receiving BoNT. There is also improved pain with reduced spasticity in these patients. However, a meta-analysis of six studies reported no significant improvement in functional status or change in disability after BoNT injections. However, there was a trend toward reduced spasticity-related pain [194]. The AAN Practice Update in 2016 and a meta-analysis by Sun et al. in 2019 lists several randomized placebo-controlled trials which show the efficacy and safety of BoNT in patients with upper- and lower-limb spasticity [217, 223]. Some of these studies, along with a brief description, are listed in Table 4.1. BoNT injections in patients with spasticity should occur in conjunction with aggressive neurorehabilitation for improved functional status and reduced disability in this patient population.

Tics

There are not many studies providing good-quality evidence for this indication, but BoNT injections continue to be a strategy that is considered when tics are at danger of causing secondary complications or if there are isolated simple tics affecting one body segment which is not responding well to medications [131, 230]. For example, with whiplash tics, which are forceful and repetitive, there is a risk of cervical myelopathy and cord injury if left untreated or inadequately treated. With forceful repetitive eye blinking tics, there could be functional blindness, which could limit driving or potentially result in harmful situations. BoNT injections into the vocal cords have been found to be very effective in the treatment of troublesome phonic tics, including coprolalia [122]. There are reports on the efficacy of BoNT in reducing tic frequency and severity, and this is also thought to reduce the premonitory urge associated with both motor and phonic tics. A small randomized double-blind placebo-controlled cross-over study involving 18 patients with tics, noted a significant improvement in tic frequency and the urge leading up to the tic. However, this study interestingly noted that the patients did not appreciate any improvement in their tics. This discrepancy between the lack of adequate benefit noted by the patients and significant tic reduction observed by the examiner was thought to be due to presence of other tics in muscle groups that were not injected [141].

A Cochrane review which looked into the utility of BoNT for the treatment of motor and phonic tics was able to only find one study that met their selection criteria [170]. This is the study mentioned above by Marras et al. in 2001. The overall beneficial effect of BoNT was deemed to be uncertain by the Cochrane review [170].

There are other small open label studies where there has been improved patient-reported tic control after BoNT injection. In an open label study of BoNT in 35 patients with tics, 29 patients reported an improvement in tics after BoNT injections, and 21 of 25 patients with a premonitory urge noted an improvement in this urge after BoNT injections [122].

Autonomic Disorders

(a) Sialorrhea

Sialorrhea may accompany several neurological disorders including PD, atypical parkinsonian conditions, amyotrophic lateral sclerosis (ALS), and cerebral palsy. Sialorrhea results in social embarrassment for the patient and family members and in addition could result in tissue breakdown where saliva pools in the neck or result in fungal infections from drooling and constant moisture. BoNT works by inhibiting acetylcholine release at the parasympathetic ganglion, thereby reducing saliva secretion [100]. In these patients, drooling is often thought to be due to decreased swallowing more than due to overproduction of saliva [157].

There are several randomized controlled trials showing efficacy of BoNT in sialorrhea [123, 179, 221]. Injections are typically done in the parotid gland and submandibular glands, with benefits lasting between 3 and 6 months, with injections repeated for benefit maintenance. Both BoNT type A and B could be used for injections with benefit in sialorrhea [214].

Over 50% patients with ALS have problems with sialorrhea and trouble handling the secretions. Trouble swallowing saliva due to bulbar involvement contributes to this symptom. About 20% patients have sialorrhea despite the use of anticholinergics or have side effects limiting the use of oral medications. A systematic review of five small studies in 28 patients showed positive benefit of BoNT on sialorrhea in this patient population [221]. This review included 5 small studies, two of which showed reduction in sialorrhea after BoNT-A injection [80, 258], one study showed no change in the number of tissue papers used and no subjective effect on sialorrhea [210], another showed some improvement based on QoL questions in 5 patients [138], and the last included study showed 30% reduction in daily tissue use and improvement in drooling impact score in over half the patients with bulbar ALS [241].

Between 40% and 80% patients with PD have sialorrhea. BoNT is thought to probably be safe and effective for treating drooling in patients with PD [157]. Oropharyngeal dysphagia due to bradykinesia is thought to cause sialorrhea. A double-blind placebo-controlled trial of the use of BoNT in sialorrhea in 32 PD patients showed that there was significant improvement in sialorrhea when assessed a month after injecting 50 units of BoNT in each parotid when compared to placebo [123]. Another double-blind study involving 20 parkinsonian patients, 14 with PD and 6 with multiple system atrophy (MSA), showed significant improvement in sialorrhea starting a week after injecting 145 units of BoNT in bilateral parotid glands and 80 units in each submandibular gland [136]. Another double-blind placebo-controlled trial in 54 patients also showed improved salivation after BoNT injection [37]. A list of double-blind placebo-controlled trials evaluating the use of BoNT in patients with sialorrhea has been listed in Table 4.1.

BoNT has been studied for sialorrhea from other etiology as well. In pediatric population with neurologic impairment, Dohar, J retrospectively looked at the effect of BoNT for sialorrhea in a long-term study which showed persistent benefit of BoNT over time in 112 children over the study period of 9 years [58].

(b) Hyperhidrosis

Sweating abnormalities could be seen in patients with PD with prevalence as high as 60%. Injection of BoNT is thought to work by inhibiting acetylcholine at the parasympathetic nerve terminals [250]. The use of BoNT in these patients is based on studies done on patients with essential hyperhidrosis.

Primary focal hyperhidrosis is a disorder of excessive sweating which could be localized to the axilla, palms, soles, or forehead. Based on the 2008 AAN review, BoNT is established to be safe and effective in axillary hyperhidrosis and is probably safe and effective for use in patients with palmar hyperhidrosis [157]. A list of randomized controlled trials that led to these recommendations is briefly described in Table 4.1.

Otolaryngology

BoNT is the preferred treatment for laryngeal dystonia/spasmodic dysphonia (SD), a form of focal dystonia affecting the larynx and vocal cords resulting in a strained effortful voice or irregular, interrupted speech during spasms of vocal cords [198]. There are three main different subtypes are adductor SD, abductor SD, and mixed SD. Abductor SD is characterized by a breathy voice and breaks in speech due to inappropriate glottal opening during speech. The posterior cricoarytenoid muscles are the main muscles involved in abductor SD. In Adductor SD, there is a strained quality to the voice and speech interruptions due to excessive glottal closure [213]. Injection of BoNT into thyroarytenoid muscle improves the symptoms of adductor spasmodic dysphonia [153]. In a survey of 70 physicians who inject patients with SD, where they collectively injected over 4000 patients with SD over the prior year. In this survey, the physicians self-reported that the majority used EMG to inject the thyroarytenoid or throarytenoid-lateral cricoarytenoid muscle complex or for adductor SD via transcricothyroid membrane approach. A substantial majority (87%) preferred to start with bilateral injections. For abductor SD, 92% targeted the posterior cricoarytenoid muscle alone, 31 physicians (51%) preferred the anterior transcricoid injection approach, and 67% used EMG guidance for the injections [213].

A prospective, observational study in 30 patients with laryngeal dystonia (LD), with or without accompanying jaw dystonia, evaluated the effect of BoNT in patients with LD using oromandibular dystonia questionnaire-25 (OMDQ-25). This study noted a significant reduction in the OMDQ-25 scores after BoNT injections at 4 and 8 weeks post injection. No major adverse effects were observed. A consistent, measurable improvement in quality of life was noted after BoNT injections in LD patients with the injection of genioglossus and other muscles in the oromandibular region [155].

A cross-sectional survey of 23 patients, 18 with SD and 5 with OMD, showed that patients with SD had significant benefit in symptoms noted after BoNT injections when quantified on the Glasgow Benefit Inventory. The benefit was higher in the SD group than patients with OMD [20].

The dose of BoNT required for adductor spasmodic dysphonia typically tends to reduce over time. A retrospective chart review in the charts of 44 patients who were on BoNT treatment for adductor Spasmodic Dysphonia showed that over time, patients received less BoNT doses over a course of 10 years with maintained benefit [22]. Similar results were noted by another study where the BoNT doses required reduced over time when patients were observed for a 20-year period. Unilateral or bilateral thyroarytenoid muscles were injected in these patients [153].

A retrospective study of 8 patients with adductor SD as part of Meige syndrome, who received BoNT injections under EMG guidance had clinically relevant improvement noted after injections [177].

A retrospective chart review in 32 patients with adductor spasmodic dysphonia, who received EMG-guided intracordal BoNT injections, were performed. Doses of BoNT injected ranged from 2.74 U to 3.85 U, with mean dose of 3.64 U. There was significant improvement in voice quality after 1 month and this stabilized after 3 months [139].

Urology

Overactive bladder affects 12–17% of the general population at some point in life, of which about a third experience urge incontinence [161]. BoNT chemodenervation is the third-line treatment for overactive bladder (OAB) in patients that have refractory symptoms despite behavioral and pharmacologic treatment [224].

Mechanism of action for the benefit is thought to be secondary to blockage of synaptic release of acetylcholine, resulting in paralysis of detrusor muscle, and relaxation and improvement in symptoms of overactive bladder. There is, however, increasing evidence that BoNT has effects on afferent nerve terminals as well. There is now high-quality evidence for the efficacious use of BoNT in detrusor overactivity. Effects from BoNT last about 8–11 months before injections have to be repeated [171]. Urinary retention is a possible adverse effect, and patients may need to self-catheterize for urinary retention, if this happens.

In an open label study in 20 PD patients with overactive bladder, 100 units of onabotulinumtoxinA was injected into submucosal intradetrusor. This resulted in improved bladder symptoms at 1 and 3 months, and 50% decreased incontinence episodes over 6 months. 57% had moderate to marked improvement [7].

In another open label study of onabotulinumtoxinA in 24 PD patients with OAB, 100 units of onabotulinumtoxinA was injected into bladder wall and trigone. In this study, 79.2% patients had improved symptoms of OAB at 4 weeks, and 29.1% had resolution of urge incontinence [248].

A large randomized placebo-controlled clinical trial in 557 patients with OAB, 280 of who received BoNT injections for urge incontinence refractory to anticholinergic medications, about 65% of BoNT-treated patients had improvement in symptoms. The rate of urinary retention in these patients was 5.4% [161].

In a prospective randomized single-blinded trial in 21 female patients with OAB who had failed first-line and second-line therapies, abobotulinumtoxinA was injected at two doses of 300 U and 500 U. Intravesical injections were done at 30 sites, avoiding the trigone. At 12 weeks, there was significant improvement in 91% patients in both groups. Patients were better or much better in 70% patients who received 300 U and in 88.9% patients who received 500 U BoNT injections at 12 weeks; and in 50% who received 300 U and in 100% at 500 U at 24 weeks. Intravesical injections of 500 U improved quality of life and symptoms for longer periods of time than 300 U [51].

There are several other trials which demonstrated the benefits of BoNT for overactive bladder, some of which are listed in Table 4.1.

BoNT has also been used to treat interstitial cystitis (IC)/bladder painful syndrome. Several randomized controlled trials (RCT) have evaluated the efficacy of BoNT in IC, some of which have been described briefly in Table 4.1.

Gastroenterology

(a) Esophageal motility disorders

BoNT has been used for the treatment of spastic esophageal motility disorders and achalasia. BoNT provides short-term symptom relief in patients who are considered high risk for more invasive surgical treatment options like myotomy or esophageal dilatation [239]. BoNT is considered less efficacious than the surgical alternatives [190] but could be considered in high-risk surgical candidates. About 70–90% of patients notice improvement in symptoms within a month of injection; but over half requires repeat injections within 6–24 months [239].

There are several randomized controlled trials that evaluated the benefits of BoNT in achalasia. A meta-analysis that evaluated this deemed that there were better remission rate and reduced relapse rate in patients that received pneumatic dilatation when compared to BoNT injections [253]. Several of these RCTs are included in Table 4.1.

In patients with nonachalasia spastic dysmotility disorders, BoNT may improve dysphagia symptoms, based on small retrospective studies [220].

(b) Anal fissure

Anal fissure is a linear ulceration in the anal canal, affecting especially young adults, resulting in pain and bleeding after defecation. Chronic anal fissure is a fissure that persists after 4–12 weeks of treatment. BoNT injection into the internal anal sphincter or intersphincteric groove is a minimally invasive procedure that results in symptom release, often for 3 months. Flatus (18%) and fecal incontinence (5% of patients) are possible side effects with less of a risk of fecal incontinence when compared to the other surgical interventions including lateral internal sphincterotomy (LIS), which is first-line surgery for medically refractory anal fissure [15]. Three meta-analysis showed that LIS is superior to BoNT for anal fissure, but there is less of a risk of fecal incontinence with BoNT injections compared to LIS [15]. In a retrospective observational study of 128 patients treated with BoNT over 5 years, 46.6% of patients had complete response, 23.9% had partial response, and 29.5% were refractory. Complete response was defined by symptomatic improvement along with anal fissure healing, while partial response including symptomatic improvement without fissure healing and refractory patients had neither symptomatic improvement or fissure resolution [15]. Reported dosages of BoNT vary between 20 and 100 units injected into the internal anal sphincter, under the anal fissure, on both sides of the fissure, or circumferential injections, with no one method deemed superior to another [15, 86, 251].

A meta-analysis identified six randomized controlled trials evaluating the effect of BoNT in chronic anal fissure which showed that BoNT has fewer side effects than topical nitrates, but there is no difference in fissure healing or recurrence [202]. These studies are briefly described in Table 4.1.

(c) Internal anal sphincter achalasia

Internal anal sphincter achalasia is a condition similar to Hirschsprung disease but with ganglion cells preserved. BoNT has been studied in this condition. A meta-analysis that looked at 16 prospective and retrospective studies deemed posterior myectomy to be a more efficacious procedure than interspincteric BoNT in patients with internal anal sphincter achalasia [74].

(d) Constipation

There are a few open label studies looking into the utility of BoNT for constipation [111]. In an open label involving 10 patients, onabotulinum toxin A was injected into the puborectalis muscle; there was reduced rectal tone while straining [6]. In another study involving 18 patients, where 100 units of onabotulinum toxin A was injected at two sites on the puborectalis muscle, there was subjective symptomatic improvement in 10 patients at 2 months and in 8 patients at 1 month post injection. There was also a significant reduction in the straining pressure [30].

(e) Gastroparesis

Pyloric sphincter dysfunction could result in delayed gastric emptying and lead to idiopathic and diabetic gastroparesis; and relaxation of this using BoNT has been postulated to improve gastroparesis. There are some case reports and case series on the use of BoNT for gastroparesis.

In a case series of two patients with PD who had gastroparesis diagnosed by gastroenterologist via gastric emptying study (GES), both received 100 U of BoNT into the pyloric sphincter via endoscopy and was followed for 4–8 weeks. The first patient had complete resolution of abdominal discomfort and nausea at 5 weeks and a repeat GES was “within normal limits.” The second patient had complete resolution of nausea and abdominal discomfort after 2 months from injection and repeat GES was normal [81].

In another case series of ten patients with idiopathic gastroparesis not responding to medications, 80–100 U of BoNT was injected into the pyloric sphincter. There was significant improvement in mean solid gastric retention 4 weeks after injections and significant improvement in symptoms as well after BoNT injections [147].

In a case series of six patients with diabetic gastroparesis and an abnormal solid phase gastric emptying study, injection of 100 U of BoNT into the pyloric sphincter improved symptoms. There was mean improvement of 55% in subjective symptoms by 2 weeks, with improvement maintained at 6 weeks [67].

Pain Medicine

BoNT has been found to have an effect on many peripheral and central mechanisms of pain and has been studied in multiple conditions associated with pain [142]. At the peripheral nerve endings, BoNT inhibits the secretion of pain modulators like substance P, calcitonin gene–related peptide (CGRP), glutamate from nerve endings, and dorsal root ganglion; reduces local inflammation at the nerve endings; and is also thought to potentially have a regenerative effect on injured nerves [142, 174]. Currently, chronic migraine is the only FDA-approved pain condition for which BoNT is approved. BoNT is also approved for use in spasticity and could help relieve spasticity-related pain. BoNT has also been observed to reduce pain associated with dystonia. BoNT has been studied in painful temporomandibular disorders in several RCTs, but the level of evidence was low and insufficient to support the use of BoNT for this condition. However, BoNT was well tolerated without significant increase in adverse effects [135]. BoNT is being studied for use in neuropathic pain conditions and considered effective in the treatment of conditions including post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, and intractable neuropathic pain [174]. There are smaller studies showing a beneficial role of BoNT in occipital neuralgia, carpal tunnel syndrome, phantom limb pain, and some randomized controlled trials showing a beneficial role of BoNT in spinal cord injury–related neuropathic pain and central post-stroke pain [174]. The possible role for BoNT in pain management is being increasingly recognized and studied. Evidence for a few of these indications is briefly discussed below. Other pain conditions will be discussed in further detail in a separate chapter.

(a) Trigeminal neuralgia

A randomized double-blind placebo-controlled trial in 84 patients who received submucosal and intradermal injections of BoNT/A at two doses of 25 U and 75 U showed that patients had reduced pain, with patient reports of being “much improved” or “very much improved.” The response rate was 70.4% for the 25 U group and 86.2% for 75 U group, significantly higher than the placebo group at 32.1% [270].

In another randomized double-blind placebo-controlled trial in 42 patients who received intradermal and/or submucosal injections of BoNT/A compared to placebo, there was significant improvement in pain intensity and pain attacks at week 1. There were significantly more responders in the BoNT injection group (68.18%) than in placebo group (15%) [260].

Another randomized double-blind placebo-controlled trial in 36 patients compared patients who received placebo to patients who received subcutaneous injections of BoNT in the affected area, along with an additional intramuscular injection of 10 U BoNT or placebo in the ipsilateral masseter of patients with involvement of the third branch of the trigeminal nerve. Three months after injection, there was significant improvement in the visual analog scale (VAS) of pain in the BoNT group when compared to placebo [272].

(b) Post-herpetic neuralgia

In a randomized double-blind placebo-controlled trial in 60 patients who received BoNT, lidocaine, or placebo in the affected dermatome. Doses less than 200 U of BoNT/A were used based on individualized patient dosing. There was significant decrease in pain scores at week 1 and at 3 months compared to the lidocaine and placebo groups [261].

In another randomized double-blind placebo-controlled parallel group trial in 30 patients who received BoNT vs placebo, 13 patients had over 50% reduction in VAS score [8].

(c) Diabetic neuropathy

In a randomized double-blind placebo-controlled trial in 40 patients, 20 of whom received intradermal injections on the dorsum of the foot (total of 12 sites with 8–10 u per site), there was a reduction in neuropathic pain score compared to placebo [78].

In another randomized double-blind placebo-controlled crossover trial in 18 patients who received intradermal injections (4 U per site, 50 U per foot) of BoNT vs placebo, 44.4% had a reduction in VAS scores within 3 months with no similar response in the placebo group [266].