Botulinum Toxin

Number: 0113

Policy

1. OnabotulinumtoxinA (Botox Brand of Botulinum Toxin Type A)

   Aetna considers onabotulinumtoxinA (Botox) medically necessary for any of the following conditions:

   1. Esotropia, horizontal strabismus with deviations of less than 50 prism diopters, vertical strabismus, or persistent cranial nerve VI palsies of 1 month duration or longer (including gaze palsies accompanying diseases, such as neuromyelitis optica and Schilder's disease), as an alternative to surgery, or previous failed surgery, when interference with normal visual system development is likely to occur and when spontaneous recovery is unlikely.

      Note: Strabismus repair is considered cosmetic in adults with uncorrected congenital strabismus and no binocular fusion.

   2. Blepharospasm, characterized by intermittent or sustained closure of the eyelids caused by involuntary contractions of the orbicularis oculi muscle, including blepharospasm associated with dystonia and benign essential blepharospasm.
   3. Post-facial (7th cranial) nerve palsy synkinesis (hemifacial spasms), characterized by sudden, unilateral, synchronous contractions of muscles innervated by the facial nerve.
   4. Laryngeal spasm.
   5. Cervical dystonia (spasmodic torticollis) of moderate or greater severity when all of the following criteria are met:  
       
      
      1. There are clonic and/or tonic involuntary contractions of multiple neck muscles (e.g., sternocleidomastoid, splenius, trapezius and/or posterior cervical muscles); and
      2. There is sustained head torsion and/or tilt with limited range of motion in the neck; and
      3. The duration of the condition is greater than 6 months; and
      4. Alternative causes of the member’s symptoms have been considered and ruled out, including chronic neuroleptic treatment, contractures, or other neuromuscular disorders.

   6. Focal hand dystonias (i.e., organic writers cramp), when both of the following criteria are met:

      1. Documentation that abnormal muscle tone is causing persistent pain and/or interfering with functional ability, and
      2. Documented failure on conservative medical therapy

   7. Focal dystonias, including:

      1. Adductor laryngeal dystonia;
      2. Focal dystonias in corticobasilar degeneration;
      3. Jaw-closing oromandibular dystonia, characterized by dystonic movements involving the jaw, tongue, and lower facial muscles;
      4. Lingual dystonia;
      5. Symptomatic torsion dystonia (but not lumbar torsion dystonia).

   8. Limb spasticity, including:

      • Equinus varus deformity or other lower limb spasticity in children with cerebral palsy in the absence of significantly fixed deformity;
      • Hereditary spastic paraplegia;
      • Limb spasticity due to multiple sclerosis;
      • Limb spasticity due to other demyelinating diseases of the central nervous system (including adductor spasticity and pain control in children undergoing adductor-lengthening surgery as well as children with upper extremity spasticity);
      • Spastic hemiplegia, such as due to stroke or brain injury.

      When the following criteria are met:

      1. Documentation that abnormal muscle tone is either interfering with functional ability, or is expected to result in joint contracture with future growth, and
      2. Documented failure to standard medical treatments, and
      3. Surgical intervention is considered to be the last option, and
      4. Treatment is being requested to enhance function or allow additional therapeutic modalities to be employed

   9. Esophageal achalasia (e.g., Nutcracker esophagus), for individuals who have any of the following:

      • Are at high risk of complications of pneumatic dilation or surgical myotomy; or
      • Advanced age or limited life expectancy; or
      • Have failed conventional therapy; or
      • Have failed a prior myotomy or dilation; or
      • Have had a previous dilation-induced perforation; or
      • Have a sigmoid-shaped esophagus; or
      • Have an epiphrenic diverticulum or hiatal hernia, both of which increase the risk of dilation-induced perforation.
        
        
   10. Chronic (greater than 2 months) anal fissure unresponsive to conservative therapeutic measures (e.g., nitroglycerin ointment, topical diltiazem cream).

   11. Intractable, disabling focal primary hyperhydrosis (axillae, palms, and soles), when all of the following are met:

       1. Member is unresponsive or unable to tolerate pharmacotherapy prescribed for excessive sweating (e.g., anticholinergics, beta-blockers, or benzodiazepines) if sweating is episodic; and
       2. Significant disruption of professional and/or social life has occurred because of excessive sweating; and
       3. Topical aluminum chloride or other extra-strength antiperspirants are ineffective or result in a severe rash.

   12. Ptyalism/sialorrhea (excessive secretion of saliva, drooling) that meets both of the following criteria:

       1. Refractory to pharmacotherapy (including anticholinergics); and 
       2. Documentation of medically significant complications of sialorrhea, such as chronic skin maceration or infections that cannot be controlled with topical treatments or hygiene.
          
          
   13. Facial myokymia and trismus associated with post-radiation myokymia.
   14. Hirschsprung’s disease with internal sphincter achalasia following endorectal pull-through. 
   15. Medically refractory upper extremity tremor that interferes with activities of daily living (ADLs). Additional botulinum toxin injections are considered medically necessary if response to a trial of botulinum toxin enables ADLs or communication.
   16. Neurogenic detrusor (bladder) overactivity or detrusor-sphincter dyssynergia resulting from a spinal cord injury, multiple sclerosis or other neurologic condition when the following criteria are met:
        
       1. Documentation of detrusor overactivity or dyssynergia confirmed by urodynamic testing, and
       2. Documented failure of behavioral therapy, and
       3. Documented failure/intolerance to at least one adequately titrated anticholinergic medication (e.g., oxybutynin, tolterodine, trospium, darifenacin, fesoterodine, solifenacin). 
           
   17. Overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who meet the following criteria:
        
       
       1. Documented failure of behavioral therapy, and
       2. Documented failure/intolerance to at least three adequately titrated prescription overactive bladder medications (e.g., oxybutynin (Ditropan), trospium (Sanctura), tolterodine (Detrol), darifenacin (Enablex), fesoterodine (Toviaz), mirabegron (Myrbetriq), solifenacin (Vesicare), duloxetine (Cymbalta)) or two adequately titrated prescription overactive bladder medications and an OTC bladder medication (oxybutynin transdermal patch (Oxytrol for Women).
          

          OnabotulinumtoxinA when used in the treatment of urinary incontinence is contraindicated and considered experimental and investigational for the following:

       • In persons with acute urinary tract infections and/or acute urinary retention;
       • When used without prophylactic antibiotics (aminoglycosides should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment);
       • When onabotulinumtoxinA is given in combination with other anticholinergic agents
          
   18. Frey's syndrome (gustatory sweating).
   19. Orofacial tardive dyskinesia when conventional therapies had been tried and failed (e.g., benzodiazepines, clozapine, and tetrabenazine).
   20. Migraines -- for prevention of chronic (more than 14 days per month with headaches lasting 4 hours a day or longer) migraine headaches (see appendix for diagnostic criteria) in adults who have tried and failed trials of at least 3 medications selected from at least two classes of migraine headache prophylaxis medications of at least 2 months (60 days) duration for each medication:
        
       
       1. Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (e.g., losartan, valsartan, lisinopril);
       2. Anti-depressants (e.g., amitriptyline, clomipramine, doxepin, mirtazapine, nortryptiline, protriptyline);
       3. Anti-epileptic drugs (e.g., divalproex, gabapentin, topiramate, valproic acid);
       4. Beta blockers (e.g., atenolol, metoprolol, nadolol, propranolol, timolol);
       5. Calcium channel blockers (e.g., diltiazem, nifedipine, nimodipine, verapamil).

       Botulinum toxin is considered experimental and investigational for migraines that do not meet the above-listed criteria. 

       Note: If members do not respond to a course of treatment (usually lasts for 12 weeks), treatment should be discontinued. 

       Note: Continuing treatment with botulinum toxin injection for ongoing prevention of chronic migraine headaches is considered medically necessary when:

       • Migraine headache frequency was reduced by at least 7 days per month (when compared to pre-treatment average) by the end of the initial trial; or
       • Migraine headache duration was reduced by at least 100 total hours per month (when compared to the pre-treatment average) by the end of the initial trial.
         
         
   21. Painful bruxism.
   22. Palatal myoclonus with disabling symptoms (e.g., objective, intrusive clicking tinnitus)
   23. Individuals with persistent symptoms of first bite syndrome and who have failed analgesics, antidepressants, and gabapentin
   24. Indiviuals with cricopharyngeal dysfunction who are not candidates for surgery or endoscopic balloon dilation
   25. Post-parotidectomy sialocele when conservative management (e.g., antibiotics, pressure dressings, and serial percutaneous needle aspiration) has failed.

2. RimabotulinumtoxinB (Myobloc Brand of Botulinum Toxin Type B)

   Aetna considers rimabotuninumtoxinB (Myobloc) medically necessary for the treatment of any of the following conditions:

   1. Individuals with cervical dystonia (spasmodic torticollis) of moderate or greater severity when the following criteria are met:

      1. Alternative causes of the member’s symptoms have been considered and ruled out, including chronic neuroleptic treatment, contractures; or other neuromuscular disorders ; and
      2. There is sustained head torsion and/or tilt with limited range of motion in the neck; and
      3. The duration of the condition is greater than 6 months; and
      4. There are clonic and/or tonic involuntary contractions of multiple neck muscles (e.g., sternocleidomastoid, splenius, trapezius and/or posterior cervical muscles.

   2. Ptyalism/sialorrhea (excessive secretion of saliva, drooling) that meets the following criteria:

      1. Refractory to pharmacotherapy (including anticholinergics); and
      2. Documentation of medically significant complications of sialorrhea, such as chronic skin maceration or infections that cannot be controlled with topical treatments or hygiene.

   3. Intractable, disabling focal primary hyperhydrosis (axillae, palms, and soles), when all of the following are met:

      1. Member is unresponsive or unable to tolerate pharmacotherapy prescribed for excessive sweating (e.g., anticholinergics, beta-blockers, or benzodiazepines) if sweating is episodic; and
      2. Significant disruption of professional and/or social life has occurred because of excessive sweating; and
      3. Topical aluminum chloride or other extra-strength antiperspirants are ineffective or result in a severe rash.

3. AbobotulinumtoxinA (Dysport Brand of Botulinum Toxin Type A)

   Aetna considers abobotulinumtoxin A (Dysport) medically necessary for the treatment of any of the following indications:

   1. Blepharospasm, characterized by intermittent or sustained closure of the eyelids caused by involuntary contractions of the orbicularis oculi muscle, including blepharospasm associated with dystonia and benign essential blepharospasm.

   2. Cervical dystonia, (spasmodic torticollis) of moderate or greater severity when all of the following criteria are met:

      1. Alternative causes of the member’s symptoms have been considered and ruled out, including chronic neuroleptic treatment, contractures, or other neuromuscular disorders; and
      2. There is sustained head torsion and/or tilt with limited range of motion in the neck; and
      3. The duration of the condition is greater than 6 months; and
      4. There are clonic and/or tonic involuntary contractions of multiple neck muscles (e.g., sternocleidomastoid, splenius, trapezius and/or posterior cervical muscles).

   3. Limb spasticity, including:

      1. Equinus varus deformity or other limb spasticity in children with cerebral palsy in the absense of significant fixed deformity;
      2. Hereditary spastic paraplegia;
      3. Limb spasticity due to multiple sclerosis;
      4. Limb spasticity due to other demyelinating diseases of the central nervous system (including adductor spasticity and pain control in children undergoing adductor-lengthening surgery as well as children with upper extremity spasticity);
      5. Spastic hemiplegia, such as due to stroke or brain injury.

      When the following criteria are met:

      1. Documentation that abnormal muscle tone is either interfering with functional ability, or is expected to result in joint contracture with future growth, and 
      2. Documented failure to standard medical treatments, and
      3. Surgical intervention is considered to be the last option, and
      4. Treatment is being requested to enhance function or allow additional therapeutic modalities to be employed.

4. IncobotulinumtoxinA (Xeomin Brand of Botulinum Toxin Type A)

   Aetna considers incobotulinumtoxinA (Xeomin) medically necessary for the treatment of any of the following indications:

   1. Blepharospasm, characterized by intermittent or sustained closure of the eyelids caused by involuntary contractions of the orbicularis oculi muscle, including blepharospasm associated with dystonia and benign essential blepharospasm.
   2. Cervical dystonia, (spasmodic torticollis) of moderate or greater severity when all of the following criteria are met:
       
      
      1. Alternative causes of the member’s symptoms have been considered and ruled out, including chronic neuroleptic treatment, contractures, or other neuromuscular disorders; and
      2. There is sustained head torsion and/or tilt with limited range of motion in the neck; and
      3. The duration of the condition is greater than 6 months; and
      4. There are clonic and/or tonic involuntary contractions of multiple neck muscles (e.g., sternocleidomastoid, splenius, trapezius and/or posterior cervical muscles).
         
         
   3. Ptyalism/sialorrhea (excessive secretion of saliva, drooling) that meets both of the following criteria:
      
      
      1. Refractory to pharmacotherapy (including anticholinergics); and 
      2. Documentation of medically significant complications of sialorrhea, such as chronic skin maceration or infections that cannot be controlled with topical treatments or hygiene.
         

   4. Spasticity of the upper limb in adults.

5. EMG Guidance
   
   The use of EMG guidance of botulinum toxin injections is considered medically necessary for strabismus, cervical dystonia and limb spasticity. The use of EMG guidance for botulinum toxin injections for the treatment of hyperhydrosis, blepharospasm, bladder dysfunction, and migraines is considered experimental and investigational.
   
   

6. Experimental and Investigational Indications

   Aetna considers botulinum toxin (types A or type B) experimental and investigational for all other indications, including any of the following conditions:

   • Airway obstruction in persons with bilateral vocal fold motor impairment; or
   • Anal sphincter dysfunction; or
   • Animus (pelvic floor dyssynergia); or
   • Aspiration pneumonia in neurologically impaired children; or
   • Atrial fibrillation; or
   • Bell’s palsy; or
   • Benign prostatic hypertrophy; or
   • Biliary dyskinesia; or
   • Bladder exstrophy; or
   • Bladder pain syndrome; or
   • Brachial plexus injury (also known as brachial palsy in newborns and Erb's palsy); or
   • Carpal tunnel syndrome; or
   • Cervicalgia; or
   • Chronic constipation; or
   • Chronic exertional compartment syndrome; or
   • Chronic low back pain or discogenic pain; or
   • Chronic neck pain; or
   • Chronic pelvic pain; or
   • Chronic quadratus lumborum strain; or
   • Clenched fist syndrome; or
   • Clubfoot; or
   • Complex regional pain syndrome; or
   • Congenital hypertonia; or
   • Contracture of hip secondary to Legg-Perthe-Calves disease; or
   • Cranial/facial pain of unknown etiology; or
   • Cricopharyngeal/oropharyngeal dysphagia; or
   • Depression; or
   • Duane syndrome with lateral muscle weakness; or
   • Dyspareunia; or
   • Dsyphagia; or
   • Endometriosis; or
   • Episodic (non-chronic) migraine; or
   • Esophageal stricture; or
   • Eustachian tube dysfunction; or
   • Excessive gingival display (gummy smile); or
   • Fecal incontinence; or
   • Fibromyalgia; or
   • Fibromyositis; or
   • Focal lower limb dystonia; or
   • Forced eyelid closure syndrome; or
   • Gastroparesis; or
   • Graves ophthalmopathy; or
   • Gustatory sweating; or
   • Head and voice tremor; or 
   • Headache including cervicogenic, cluster, or tension-type or chronic daily headache, episodic migraine, hemicrania continua; or
   • Hyperactive and hypertrophic frontalis muscles from chronic compensatory brow elevation, or
   • Hyper-lacrimation; or
   • Hypertrophic scars; or
   • Injection of the pylorus during esophago-gastrectomy; or
   • Interstitial cystitis; or
   • Irritable colon; or
   • Intra-operative relaxation of the anal sphincter during hemorrhoidectomy; or
   • Keratoconjunctivitis; or
   • Knee flexion contracture; or
   • Knee osteoarthritis; or
   • Knee pain: or
   • Lateral epicondylitis (tennis elbow); or
   • Lumbar dystonia; or
   • Lumbar spasticity, or
   • Lumbar torsion dystonia; or
   • Masseter hypertrophy; or
   • Meralgia paresthetica; or
   • Morton neuroma; or
   • Motor tics; or
   • Myofascial pain; or
   • Neuropathic pain (including complex regional pain syndrome, diabetic neuropathy, post-herpetic neuralgia, occipital neuralgia, post-traumatic neuralgia, pudendal neuralgia, and trigeminal neuralgia); or
   • Notalgia paresthetica; or
   • Nystagmus; or
   • Obesity; or
   • Obturator internus syndrome; or
   • Osteo-articular joint pain; or 
   • Pain control in breast reconstruction with tissue expanders; or
   • Pain from muscle trigger points; or
   • Painful cramps; or
   • Painful scars; or
   • Paradoxical vocal cord motion in asthmatics; or
   • Parkinson's disease; or
   • Parotitis; or
   • Puberphonia; or
   • Pelvic floor tension myalgia (also known as coccygodynia, diaphragma pelvis spastica, levator ani syndrome, levator spasm syndrome, spastic and pelvic floor syndrome), or
   • Phantom limb pain; or
   • Phonic tics; or
   • Piriformis syndrome; or
   • Popliteal artery entrapment syndrome; or
   • Post-hemorrhoidectomy pain; or
   • Post-concussion headaches; or
   • Post-traumatic headaches, or
   • Pylorospasm; or
   • Quivering chin syndrome, or
   • Raynaud's phenomenon/Raynaud's scleroderma; or
   • Reduction of mucin secretion; or
   • Reduction of muscle tension after hamstring avulsion repair; or
   • Restless legs syndrome; or 
   • Restrictive strabismus (a type of ocular misalignment with limitation of motility caused by intrinsic or extrinsic mechanical forces); or
   • Schwalbe-Ziehen-Oppenheim disease; or
   • Secondary strabismus caused by prior surgical over-recession of the antagonist muscle; or
   • Shoulder pain; or
   • Sciatica; or
   • Scoliosis; or
   • Soto's syndrome; or
   • Spasm of the pectoralis muscle after breast reconstruction; or
   • Sphincter of Oddi dysfunction (chronic biliary pain); or
   • Spina bifida; or
   • Stiff person syndrome; or
   • Stuttering; or
   • Temporomandibular joint disorders; or
   • Tendon contracture; or
   • Testicular pain (cremasteric synkinesia); or
   • Thoracic outlet syndrome; or 
   • Tinnitus; or
   • Tourette's syndrome; or
   • Treatment of complications associated with breast implants for mammoplasty; or
   • Treatment of facial scars or mastectomy scars; or
   • Ulcers; or
   • Vaginismus; or
   • Ventral hernia; or
   • Vocal cord paralysis (see CPB 0253 - Vocal Cord Paralysis/Insufficiency Treatments); or
   • Vulvodynia; or
   • Whiplash-related disorders

7. Cosmetic Indications

   Aetna considers botulinum toxin cosmetic for the following indications:

   • Aging neck; or
   • Blepharoplasty (eyelid lift); or
   • Canthal rhytide; or
   • Crow's feet; or
   • Cutaneous scar (facial wounds); or
   • Deep forehead lines; or
   • Deep nasolabial folds; or
   • Glabellar lines; or
   • Hyperkinetic facial lines; or
   • Wrinkles, frown lines.
      

8. Neutralizing Antibodies to Botulinum Toxin

   Aetna considers testing for neutralizing antibodies to botulinum toxin experimental and investigational.

Background

Local injections of onabotulinumtoxinA (Botox) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of strabismus, essential blepharospasm, and hemifacial spasm.  In patients with congenital strabismus who have compromised or absent binocular vision, treatment is cosmetic as ocular realignment is not capable of restoring binocular vision.

Clinical studies indicate that Botox can also provide symptomatic relief in a variety of other conditions characterized by involuntary spasm of certain muscle groups, notably in cervical dystonia (spasmodic torticollis) and spasmodic dysphonia.  Ninety percent of spasmodic torticollis patients show some improvement of pain relief, head position, and disability, and botulinum toxin is now the treatment of choice for this condition.  Botox has been shown to result in normal or near normal voice in patients with adductor type (strained or strangled voice) laryngeal dystonia and to be of considerable benefit in patients with abductor type (breathy, whispery voice) laryngeal dystonia.

The American Academy of Neurology (AAN)'s assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that while botulinum neurotoxin is probably effective for the treatment of adductor type laryngeal dystonia, there is insufficient evidence to support a conclusion of effectiveness for botulinum neurotoxin in patients with abductor type of laryngeal dystonia.  The assessment also stated that while many clinicians utilize electromyographic targeting for laryngeal injections, the utility of this technique is not established in comparative trials.

Botox has been evaluated in various spastic disorders.  Botox can be used to reduce spasticity or excessive muscular contractions to relieve pain; to assist in posturing and walking; to allow better range of motion; to permit better physical therapy; and to reduce severe spasm in order to provide adequate perineal hygiene. 

Botox has been shown to improve gait patterns in patients with cerebral palsy with progressive dynamic equinovarus or equinovalgus foot deformities.  Treatment of children with cerebral palsy during the early years when functional skills in walking are being developed improves the outcome and may help to avoid surgery for contracture and bony torsion.  In multiple sclerosis, Botox can relieve contractions of thigh adductors that interfere with sitting, positioning, cleaning, and urethral catheterization.

Moore et al (2008) examined the durability of effect of Botox in spasticity in cerebral palsy. The investigators stated that the controlled evidence favoring Botox in the treatment for spasticity in cerebral palsy (CP) is based on short-term studies.  These researchers conducted a randomized, double-blind, placebo-controlled, parallel-group study of Botox for leg spasticity in 64 children with CP.  For 2 years, the children received trial injections of up to 30 mu/kg every 3 months if clinically indicated.  For the primary endpoints of Gross Motor Function Measure (GMFM) and Pediatric Evaluation of Disability Index (PEDI) scaled scores at 2 years (trough rather than peak effect), there were no differences between the mean change scores of each group.  For the GMFM total score, the 95 % confidence interval (CI) of -4.81 to 1.90 excluded a 5-point difference in either direction, and a 2-point benefit with 95 % CI.  There were no differences in adverse events.  The authors concluded that there was no evidence of cumulative or persisting benefit from repeated Botox at the injection cycle troughs at 1 year or 2 years.  The dose was not enough to change spasticity measures and thus GMFM in this heterogeneous group.  Ceiling effects in GMFM and PEDI may have reduced responsiveness.  This finding does not deny the value, individually, of single injection cycles or prove that repeating them is unhelpful.  In this regard, Botox therapy can be viewed in the same light as other temporary measures to relieve spasticity, such as oral or intra-thecal agents: there is no evidence of continuing benefit if the treatment ceases.  The study provided long-term, fully controlled adverse event data and has not revealed any long-term adverse effects.

Treatment with Botox has been shown to be safe and effective in the jaw-closing variant of oromandibular dystonia.  Injections of Botox into the masseter, temporalis, and internal pterygoid muscles result in reduction in the oromandibular and lingual spasms and an improvement in chewing and speech.  Symptoms are reduced in about 70 % of patients, and treatment may prevent dental complications and temporomandibular joint dysfunction.  Treatment with Botox has been shown to be safe and effective for writer's cramp (local and segmental limb dystonia).  This dystonia can be incapacitating and has been exceptionally resistant to treatment with oral medications.  Other occupational cramps, such as musician’s cramp, respond less well to injections as they require very sophisticated neuromuscular performance.

The AAN's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Naumann et al, 2008) stated that while many clinicians advocate electromyography or nerve stimulation guidance to optimize needle localization for injection, further data are needed to establish this recommendation.

Botox has also been shown to be effective in the treatment of achalasia.  Two-thirds of patients with this condition respond within 6 months and effectiveness lasts on an average of a little over 1 year for an initial treatment, although shorter and longer duration have been reported.  There is some question whether Botox treatments are as good as or better than conventional therapy, pneumatic dilation, or myotomy.

Botox has been shown to be a promising alternative to sphincterotomy in patients with chronic anal fissures.

Some autonomic disorders resulting in hypersecretion of glands such as hyperhydrosis and sialism (ptyalism) respond well to Botox.

An early randomized controlled single-center study that found benefits of onabotulinumtoxinA in the treatment of migraine; however, no firm conclusions could be drawn from this early study because of the marginal statistical significance of the results, the lack of an expected dose-response relationship, and the lack of a valid scientific explanation for treatment effects.  In a randomized double-blind, vehicle-controlled study, 123 subjects with a history of 2 to 8 moderate-to-severe migraine attacks per month were randomized to receive single administration of placebo vehicle or onabotulinumtoxinA 25 or 75 U, injected into multiple sites of pericranial muscles at the same visit.  Study subjects were assessed at 1, 2 and 3 months.  For the 25-U onabotulinumtoxinA group, reduction in migraine frequency barely reached statistical significance (p = 0.46) at the 3-month assessment, but did not reach statistical significance at the 1- or 2-month assessments.  The 75-U botulinum toxin group had no statistically significant reduction in migraine frequency at any assessment (Silberstein et al, 2000).  A commentary on this study (Bandolier, 2001) noted that, because of significant flaws in the design of the study by Silberstein et al, "[t]he trial would score 2 out of a possible 5 points on a common quality scoring scale in which trials scoring 2 or less may be subject to bias."   The commentary also noted the marginal statistical significance of results and the lack of an expected dose-response relationship.  "The simple fact is that with one or two patients giving different responses, this would have been declared a negative trial.  It does not inspire confidence, especially as this is the only randomised controlled trial for this intervention in this indication and the quality of reporting allows for the possibility of bias, as well as it being financed by the manufacturer."  These results need to be replicated in a longer-term, multi-center randomized clinical study before conclusions about the effectiveness of botulinum toxin in migraine can be drawn.

A subsequent randomized controlled clinical trial found no benefit to onabotulinumtoxinA in preventing migraine headaches (Evers et al, 2004).  Researchers evaluated 60 migraine patients for a 3-month period; participants received injections of either a high or low dose of botulinum toxin or placebo in muscles in the neck and/or forehead.  During the course of the study, “migraine frequency was halved” for 30 % of the participants in the botulinum toxin groups and for 25 % of those in the placebo group.  Researchers also found that there were “no significant differences” among the three groups regarding the number of days participants had the migraine or the amount of drugs needed to treat the headaches.  The researchers concluded that their findings “did not support the hypothesis that [Botox] is [an] effective…treatment [for] migraines.”  

A study by Dodick et al (2005) presented a secondary analysis of data from a randomized controlled clinical trial of botulinum toxin A in the treatment of chronic daily headache, examining outcomes for a subgroup of subjects who were not receiving prophylactic medications.  This was a secondary analysis of data from a study in which the overall cohort had no significant benefit from botulinum toxin (Mathew et al, 2005).  In addition, the largest study of botulinum toxin for chronic daily headache showed no overall benefit (Silberstein et al, 2005) (see below).  These inconsistent results among studies lead the AAN to conclude that there is insufficient evidence to support or refute a benefit of botulinum toxin for chronic daily headache (Naumann et al, 2008).

In a phase II clinical trial (n = 702), Silberstein et al (2005) assessed the safety and effectiveness of 3 different doses of onabotulinumtoxinA as prophylactic treatment of chronic daily headache (CDH).  Eligible patients were injected with Botox at 225 U, 150 U, 75 U, or placebo and returned for additional masked treatments at day 90 and day 180.  Patients were assessed every 30 days for 9 months.  The primary efficacy end point was the mean change from baseline in the frequency of headache-free days at day 180 for the placebo non-responder group.  The primary efficacy end point was not met.  Mean improvements from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 headache-free days per month were observed in the placebo non-responder group treated with Botox at 225 U, 150 U, 75 U, or placebo, respectively (p = 0.44).  An a priori-defined analysis of headache frequency revealed that Botox at 225 U or 150 U had significantly greater least squares mean changes from baseline than placebo at day 240 (-8.4, -8.6, and -6.4, respectively; p = 0.03 analysis of covariance).  Only 27 of 702 patients (3.8 %) withdrew from the study because of adverse events, which generally were transient and mild to moderate.  These investigators concluded that although the primary efficacy end point was not met, all groups responded to treatment.  The 225 U and 150 U groups experienced a greater decrease in headache frequency than the placebo group at day 240.  The placebo response was higher than expected.  The authors stated that onabotulinumtoxinA was safe and well-tolerated.  The authors noted that further study of Botox prophylactic treatment of CDH appears warranted.  The findings of this study were in agreement with those of Mathews et al (2005).  A review in Clinical Evidence (Silver, 2005) concluded that botulinum toxin for chronic tension-type headache was “likely to be ineffective or harmful.”

An assessment on use of botulinum toxin in pain associated with neuromuscular disorders, prepared for the Minnesota Health Technology Advisory Committee (2001), concluded that there is insufficient evidence to support the use of botulinum toxin in the treatment of migraine.  A review of the literature on treatments for migraine concluded that "botulinum toxin A ha[s] recently been suggested to be effective [for treatment of migraine]; however, at present, there are insufficient rigorous and reliable controlled data on these drugs for them to be indicated for such use" (Krymchantowski et al, 2002).  A structured evidence review by the BlueCross BlueShield Association Technology Evaluation Center (2002) concluded “The available evidence does not permit conclusions regarding the prophylactic or abortive effect of [botulinum toxin A] or any other botulinum toxin type on chronic primary headache syndromes”, including migraine, chronic tension, and cluster headache syndromes.  The BlueCross BlueShield Association Technology Evaluation Center reevaluated the use of botulinum toxin for primary headache disorders (BCBSA, 2004) and concluded that this does not meet the TEC criteria.

The AAN's assessment on the use of botulinum neurotoxin in the treatment of autonomic disorders and pain (Naumann et al, 2008) stated that botulinum neurotoxin is probably ineffective in episodic migraine and chronic tension-type headache.  Also, there is currently no consistent evidence or strong evidence to allow drawing conclusions on the effectiveness of botulinum neurotoxin in chronic daily headache.  The assessment also noted that the evidence for botulinum neurotoxin in gustatory sweating is suboptimal.

In a meta-analysis, Shuhendler et al (2009) evaluated the effectiveness of botulinum toxin type A in lowering the frequency of migraine headaches in patients with episodic migraines.  A total of 1,601 patients with a history of episodic migraine headaches classified as those experiencing headaches fewer than 15 times/month over a 3-month period were included in the analysis.  PubMed, Google Scholar, and the Cochrane Library were searched from inception to October 2007 in order to locate randomized, double-blind, placebo-controlled trials that compared the effectiveness of peri-cranial botulinum toxin A injections with placebo in the prevention of migraines in patients with a history of episodic migraine headaches.  The primary outcome of interest was change from baseline to end point in migraine frequency (number of migraines/month).  A random effects model was used to combine study results, and the standardized mean difference (Cohen's d) in migraine frequency between the placebo and botulinum toxin A groups was reported.  Effect sizes (d) less than 0.2 were considered small.  Quality assessment was performed by using the Downs and Black scale.  Eight randomized, double-blind, placebo-controlled clinical trials (1,601 patients) presented a quantitative assessment of the effectiveness of botulinum toxin A versus placebo.  The overall treatment effect size of botulinum toxin A over placebo for 30, 60, and 90 days after injection was d -0.06 (95 % CI: - 0.14 to 0.03, z = 1.33, p = 0.18), d -0.05 (95 % CI: -0.14 to 0.03, z = 1.22, p = 0.22), and d -0.05 (95 % CI: -0.13 to 0.04, z = 1.07, p = 0.28), respectively.  Even after controlling for a high placebo effect, and after dose stratification, no significant effect of botulinum toxin A in reducing migraine frequency/month was seen over placebo.  The authors concluded that botulinum toxin A for the prophylactic treatment of episodic migraine headaches was not significantly different from placebo, both from a clinical and statistical perspective.

Magalhaes et al (2010) compared the effects of Botox with those of amitriptyline on the treatment of chronic daily migraines.  Chronic migraine sufferers were randomized into 2 groups and treated with 25 or 50 mg/day of amitriptyline or 250 U of Botox.  A reduction of at least 50 % in the number of pain episodes, in the intensity of pain, and in the number of drug doses for pain and reports of improvement by the patient or by the examiner were the main end points.  A total of 72 subjects were enrolled in the study.  A reduction of at least 50 % in the number of days of pain was recorded in 67.8 % of the patients in the Botox group and 72 % (n = 23) of the patients in the amitriptyline group (p = 0.78; risk ratio [RR] = 0.94; CI: 0.11 to 8).  The reduction in the intensity of pain, as assessed using the visual analog scale (VAS), was 50 % in the Botox group and 55.6 % in the amitriptyline group (p = 0.79; RR = 1.11; CI:  0.32 to 3.8).  The reduction in the number of pain drug doses was 77 % for the Botox group and 71 % for the amitriptyline group (p = 0.76; RR = 0.92; CI: 0.45 to 1.88).  The authors concluded that Botox was as effective as amitriptyline for the prophylactic treatment of chronic daily migraines.

Aurora and colleagues (2010) evaluated the safety, effectiveness, and tolerability of Botox as headache prophylaxis in adults with chronic migraine.  The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase III study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase.  Subjects were randomized (1:1) to injections every 12 weeks of Botox (155 U to 195 U; n = 341) or placebo (n = 338) (2 cycles).  The primary end point was mean change from baseline in headache episode frequency at week 24.  No significant between-group difference for Botox versus placebo was observed for the primary end point, headache episodes (-5.2 versus -5.3; p = 0.344).  Large within-group decreases from baseline were observed for all efficacy variables.  Significant between-group differences for Botox were observed for the secondary end points, headache days (p = 0.006) and migraine days (p = 0.002).  Botox was safe and well-tolerated, with few treatment-related adverse events.  Few subjects discontinued due to adverse events.  The authors concluded that there was no between-group difference for the primary end point, headache episodes.  However, significant reductions from baseline were observed for Botox for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

Dodick et al (2010) evaluated the efficacy, safety, and tolerability of Botox as headache prophylaxis in adults with chronic migraine.  The 2 multi-center, pivotal trials in the PREEMPT clinical program each included a 24-week randomized, double-blind phase followed by a 32-week open-label phase.  Qualified patients were randomized (1:1) to Botox (155 U to 195 U) or placebo injections every 12 weeks.  Study visits occurred every 4 weeks.  These studies were identical in design (e.g., inclusion/exclusion criteria, randomization, visits, double-blind phase, open-label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints.  Thus, the pre-defined pooling of the results was justified and performed to provide a complete overview of between-group differences in efficacy, safety, and tolerability that may not have been evident in individual studies.  The primary end point for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks.  Secondary end points were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (greater than or equal to 60) Headache Impact Test-6 score at week 24.  A total of 1,384 adults were randomized to Botox (n = 688) or placebo (n = 696).  Pooled analyses demonstrated a decrease from baseline in mean frequency of headache days, with statistically significant between-group differences favoring Botox over placebo at week 24 (-8.4 versus -6.6; p < 0.001) and at all other time points.  Significant differences favoring Botox were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes.  Adverse events occurred in 62.4 % of Botox patients and 51.7 % of placebo patients.  Most patients reported adverse events that were mild-to-moderate in severity and few discontinued (Botox, 3.8 %; placebo, 1.2 %) due to adverse events.  No unexpected treatment-related adverse events were identified.  The authors concluded that the pooled PREEMPT results demonstrate that Botox is an effective prophylactic treatment for chronic migraine.  Botox (onabotulinumtoxinA) resulted in significant improvements compared with placebo in multiple headache symptom measures, and significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life.  Repeat treatments with Botox were safe and well-tolerated.

Cady (2010) stated that Botox has been studied as a migraine preventive in numerous clinical trials and in a variety of sub-populations with migraine.  Overall, results from the clinical trials are mixed.  However, the largest and most recent parallel studies (n = 1,330) conducted on subjects with chronic migraine achieved statistically significant efficacy on numerous end points including the primary end point of reduction of headache days.  The author reviewed several clinical studies using Botox in migraine prevention and highlighted some of the inherent difficulties defining study end points and outcomes that are relevant to clinician, patients, and regulatory agencies.  The author concluded that clinical trials utilizing Botox as a preventive therapy for migraine has revealed mixed results.  In part this reflects the inherent difficulties in study design such as defining different sub-populations of migraine sufferers and trial end points that are meaningful to patient populations.  Recent studies of subjects with chronic migraine appear to have positive results.  If confirmed this would be the first preventive medication indicated specifically for chronic migraine.

In October 2010, the FDA approved Botox injection (onabotulinumtoxinA) to prevent headaches in adult patients with chronic migraine (more than 14 days per month with headaches lasting 4 hours a day or longer).  To treat chronic migraines, Botox is given approximately every 12 weeks as multiple injections -- a total of 31 injections into 7 specific head and neck sites for a total of 155 U per treatment session.  Botox has not been shown to work for the treatment of migraine headaches that occur 14 days or less per month, or for other forms of headache.  The most common adverse reactions reported by patients being treated for chronic migraine were neck pain and headache.

On behalf of the AAN, Silberstein et al (2012) provided updated evidence-based recommendations for the preventive treatment of migraine headache.  The clinical question addressed was: What pharmacologic therapies are proven effective for migraine prevention?  The authors analyzed published studies from June 1999 to May 2009 using a structured review process to classify the evidence relative to the efficacy of various medications available in the United States for migraine prevention.  The author panel reviewed 284 abstracts, which ultimately yielded 29 Class I or Class II articles that were reviewed.  Divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A).  Frovatriptan is effective for prevention of menstrual migraine (Level A).  Lamotrigine is ineffective for migraine prevention (Level A).

An UpToDate review on “Chronic migraine” (Garza and Schwedt, 2013) lists amitriptyline, beta blockers (metoprolol, propranolol, and timolol), topiramate as well as valproic acid and its derivatives as first-line agents for the treatment of chronic migraines. 

Delayed-release capsule of valproic acid, immediate-release topiramate, propranolol (excluding Innopran XL) and timolol are FDA-approved for migraine prophylaxis.

Botox has been shown to reduce muscle tone and increase range of movement in upper extremity spasticity or in spastic foot drop after stroke.  However, whether this translates into functional improvement has yet to be substantiated.

The value of Botox in treating conditions other than those listed above is under investigation.

Unit dosing of onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and rimabotulinumtoxinB (Myobloc) or other botulinum toxin serotypes are not interchangeable.  According to the FDA, "[u]nits of biologic activity of Botox cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other assay method."

If concomitant neuromuscular disorders, such as myasthenia gravis and certain myopathies exist, Botox may be harmful.  Thus, diagnosis is crucial before undertaking botulinum toxin type A injections.

Botox is not indicated in patients receiving aminoglycosides, which may interfere with neuromuscular transmission.

The AAN's assessment on the use of botulinum neurotoxin in the treatment of spasticity (Simpson et al, 2008a) recommended botulinum neurotoxin as a treatment option to reduce muscle tone and improve passive function in adults with spasticity.  The assessment also recommended botulinum neurotoxin for equinus varus deformity in children with cerebral palsy, adductor spasticity and pain control in children undergoing adductor-lengthening surgery, and children with upper extremity spasticity.  Furthermore, the assessment stated that there is insufficient evidence to recommend an optimum technique for muscle localization at the time of injection.  It noted that further studies on injection methodology including the use of electromyographic guidance, ultrasonography, and electrical stimulation are needed to optimize treatment technique.

The AAN's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that the role of electromyography has not been established for cervical dystonia.  It also stated that while a few patients in one Class II study suggested that botulinum neurotoxin may be effective for lower extremity dystonia, the data are inadequate to provide a recommendation.

A randomized controlled clinical trial (n = 16) demonstrated significant reductions in sialorrhea without compromising dysphagia in persons with Parkinson’s disease and problematic sialorrhea (Ondo et al, 2004).

According to a systematic review of the evidence for botulinum toxin for essential tremor (Ferreira and Sampaio, 2003), there is evidence of short-term reduction of tremor but no consistent improvement in disability and function.  The review noted that botulinum toxin injections cause hand weakness, resulting in a "trade off" between benefits and harms.  The review concluded that "RCTs [randomized controlled clinical trials] comparing botulinum A toxin-haemagglutinin complex versus placebo found short term improvement of clinical rating scales, but no consistent improvement of motor task performance or functional disability.  Hand weakness, which is dose dependent and transient, is a frequent adverse effect."  The AAN (Zesiewicz et al, 2005) has stated that botulinum toxin A injections for limb, head, and voice tremor associated with essential tremor may be considered in medically refractory cases.  This recommendation was categorized as Level C, given the limited strength of the available evidence.  The AAN concluded that “[t]he effect of botulinum toxin A [botulinum toxin A] on limb tremor in ET [essential tremor] is modest and is associated with dose-dependent hand weakness.  botulinum toxin A may reduce head tremor and voice tremor associated with ET, but data are limited. When used to treat voice tremor, botulinum toxin A may cause breathiness, hoarseness, and swallowing difficulties.” These conclusions were unchanged with subsequent update of the AAN guidelines on ET (Zesiewicz et al, 2011); there were no additional trials published since the previous guideline and rated better than Class IV that examined the efficacy and safety of botulinum toxin for ET. 

The AAN's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that botulinum neurotoxin should be considered a treatment option for essential hand tremor in those patients who fail treatment with oral agents.  On the other hand, there is insufficient evidence to draw a conclusion on the use of botulinum neurotoxin in the treatment of head and voice tremor.

The evidence of botulinum toxin in the treatment of piriformis syndrome is limited to a small, controlled short-term study and a small pilot cross-over study reporting on the impact of botulinum toxin on pain, but not on disability and function (Fishman et al, 2002; Childers et al, 2002).  In addition, the placebo-controlled study had a significant drop-out rate.  The existence of piriformis syndrome as a clinical entity is controversial (NHS, 2002).

Several studies have tested the effects of pyloric injection of botulinum toxin in patients with diabetic and idiopathic gastroparesis (Parkman et al, 2004).  These studies have all been unblinded with small numbers of patients from single centers and have observed mild improvements in gastric emptying and modest reductions in symptoms for several months.  Moreover, the American Gastroenterological Association (2004) has concluded that double-blind controlled studies are needed to support the efficacy of this treatment (Parkman et al, 2004).

1. it was a retrospective study,
2. the lack of a validated symptom questionnaire or a visual analog scale before for pre- and post-injection estimation of improvement,
3. subjects were not prescribed a standardized diet and/or medication regimen for gastroparesis following Botox injection,
4. a high number of patients (n = 27) were lost to follow-up that may have influenced the response rate, and
5. issues with experimental design -- selection bias as well as recall bias.

Ezzeddine et al (2002) reported their findings of pyloric injection of Botox for the treatment of diabetic gastroparesis.  A total of 6 patients with diabetic gastroparesis and an abnormal solid phase gastric emptying study underwent upper endoscopy during which 100 units of Botox were injected into the pyloric sphincter.  Gastric emptying studies were obtained at 48 hours and 6 weeks after injection.  Patients were questioned about symptoms of gastroparesis, and a symptom score was obtained at baseline and at 2 weeks and 6 weeks after injection.  There was a mean improvement in the subjective symptom score at 2 weeks of 55 % (range of 14 to 80 %).  This improvement was maintained at 6 weeks.  There was a 52 % improvement in gastric emptying at 2 and 6 weeks.  The authors concluded that pyloric injection of Botox can improve symptoms and gastric emptying in patients with diabetic gastroparesis.  They stated that further evaluation of pyloric injection of Botox as a treatment for diabetic gastroparesis is warranted.

Gupta and Rao (2002) noted that well-designed, prospective, double-blinded, placebo-controlled studies are needed to establish the role of Botox in selected patients with diabetic gastroparesis.

Yeh and Triadafilopoulos (2006) reviewed injection therapies for non-bleeding disorders of the gastrointestinal tract.  With regards to the use of Botox for the treatment of gastroparesis, the authors noted that data from a randomized, sham-controlled study are needed to draw firm conclusion on the utility of this treatment.

Reddymasu et al (2007) examined the use of endoscopic pyloric injection of Botox in the treatment of patients with post vagotomy gastroparesis (n = 11).  The authors concluded that this approach appears to be safe; but randomized trials are needed.

Friedenberg and colleagues (2008) noted that observational data suggest that intra-pyloric injection of Botox reduces symptoms and accelerates gastric emptying in idiopathic and diabetic gastroparesis. These researchers examined if Botox would improve symptoms to a significantly greater extent than placebo.  An additional objective was to ascertain if there is an acceleration of gastric emptying after injection.  A single-institution, randomized, double-blind, placebo-controlled study was carried out.  Eligible patients had a Gastroparesis Cardinal Symptom Index score greater than or equal to 27 with randomization to intra-pyloric botulinum toxin, 200 U, or saline placebo.  Re-assessment of symptoms and repeat gastric emptying scan at 1-month follow-up were done.  A total of 32 patients were randomized to botulinum toxin (n = 16) and placebo (n = 16).  At 1-month follow-up, 37.5 % randomized to Botox and 56.3 % randomized to placebo achieved improvement as defined by this study.  There were no identifiable clinical predictors of response.  The Botox group reported improvement in gastric emptying; however, this was not superior to placebo.  No serious adverse events were attributable to Botox.  The authors concluded that intra-pyloric injection of Botox improves gastric emptying in patients with gastroparesis, although this benefit was not superior to placebo at 1 month.  Also, in comparison to placebo, symptoms do not improve significantly by 1 month after injection.  These investigators stated that they could not recommend Botox for widespread use in the treatment of delayed gastric emptying until more data are available.

There is insufficient evidence to support the use of botulinum toxin for treatment of constipation.  Lembo and Camilleri (2003) do not recommend botulinum injection for the management of patients with chronic constipation.  Furthermore, Talley (2004) stated that a novel approach for the management of chronic constipation is injection of Botox into the puborectalis muscle of patients with pelvic floor dysfunction.  However, there is insufficient evidence to support the effectiveness of this approach.

Botulinum toxin is currently being studied for the management of patients with lower urinary tract dysfunctions such as detrusor-sphincter dyssynergia and detrusor overactivity.  Botulinum toxin is injected into the external urethral sphincter to treat detrusor sphincter dyssynergia, while intra-detrusal injections of botulinum toxin is employed in treating detrusor overactivity and symptoms of the overactive bladder (OAB).  In a single treatment, randomized, placebo-controlled study (n = 59), Schurch et al, (2005) found that intramuscular injections of Botox into the detrusor can provide rapid, well-tolerated, clinically significant decreases in the signs and symptoms of urinary incontinence caused by neurogenic detrusor overactivity during a 24-week study period.  These researchers noted that Botox is a potential candidate for the management of neurogenic urinary incontinence.

In a randomized, double-blind, placebo-controlled crossover clinical trial, Ghei and colleagues (2005) examined the safety and effectiveness of rimabotulinumtoxinB for the treatment of OAB.  A total of 20 patients 18 to 80 years old with detrusor over-activity unresponsive to oral anti-muscarinic agents participated in the study.  They were injected with either placebo (20 ml normal saline) or rimabotulinumtoxinB (5,000 IU diluted up to 20 ml) intravesically in a day case setting.  After 6 weeks the treatments were crossed over without washout in line with previous findings.  The primary outcome was the paired difference in change in average voided volumes.  Frequency, incontinence episodes and paired differences in quality of life measured by the King's Health Questionnaire were the secondary outcome measures.  Little carryover was noted in the second arm placebo and the placebo data from both arms were included in analysis.  There were clinically statistically significant paired differences in the change in average voided volume, urinary frequency and episodes of incontinence between active treatment and placebo.  There were similarly significant paired differences in the change in quality of life affecting 5 domains of the King's Health Questionnaire.  These investigators concluded that the findings of this study provided evidence of the efficacy of rimabotuoinumtoxnB in the treatment of OAB.  Autonomic side effects were observed in 4 patients.  Moreover, they noted that the short duration of action will presumably limit the use to patients who have experienced tachyphylaxis with Botox.

In an editorial that accompanied the study by Ghei et al Chancellor (2005) stated that “one undesirable feature of the study was that the hypothesis was tested on a mixed population of patients (patients with mixed etiologies of detrusor overactivity, 3 neurogenic and 17 nonneurogenic with detrusor overactivity).  This limits the generalizability of the findings.  The authors made a strong argument why a crossover design was appropriate and their data were valid.  However, since almost all studies have shown that botulinum toxin A has a duration of efficacy of approximately 6 months, most experts in the field would still question the merit of a crossover at 6 weeks as not all the patients returned to pre-injection clinical and urodynamic values done at 6 weeks.  Most experts would submit that a washout period after the crossover may have been appropriate.  Since there are limited experiences with botulinum toxin-B in the bladder, assessment of duration of response would be valuable”.  Chancellor was surprised how short the duration of effectiveness attained by rimabotulinumtoxinB was.  Moreover, it is unclear how useful rimabotulinumtoxinB will be in urology since there are suggestions that rimabotulinumtoxinB has a more systemic effect that Botox.

In a multi-center, randomized, placebo-controlled trial (n = 86), Gallien et al (2005) assessed the safety and effectiveness of Botox in the treatment of detrusor sphincter dyssynergia in patients with multiple sclerosis (MS).  Individuals with chronic urinary retention were included if they had post-voiding residual urine volume between 100 and 500 ml.  They received a single transperineal injection of either Botox (100 U) or placebo in the sphincter and also 5 mg slow release alfuzosin twice-daily over 4 months.  Main endpoint was post-voiding residual urine volume assessed 1 month after injection.  Follow-up duration was 4 months.  The study was stopped after the 4th analysis (placebo = 41, Botox = 45).  At inclusion, there was no significant difference between groups whichever variable was considered.  Mean (standard deviation) post-voiding residual urine volume was 217 (96) and 220 (99) ml in placebo and Botox groups, respectively.  One month later, post-voiding residual urine volume was 206 (145) and 186 (158) ml (p = 0.45) in placebo and Botox groups, respectively.  However, compared to placebo, Botox significantly increased voiding volume (+54 %, p = 0.02) and reduced pre-micturition (-29 %, p = 0.02) and maximal (-21 %, p = 0.02) detrusor pressures.  Other secondary urodynamic endpoints and tolerance were similar in the 2 groups.  These investigators concluded that in MS patients with detrusor sphincter dyssynergia, a single injection of Botox (100 U) does not decrease post-voiding residual urine volume.  Also, De Laet and Wyndaele (2005) noted that generalized side effects after Botox injection for voiding disorders are rare but they can be very disabling for patients with spinal cord injury.  Although no long-term side effects are reported so far, urologists should be aware that these effects of Botox injections are unknown.

The AAN's assessment on the use of botulinum neurotoxin in the treatment of autonomic disorders and pain (Naumann et al, 2008) reported that botulinum neurotoxin is safe and effective for the treatment of neurogenic detrusor over-activity in adults.  On the other hand, data on the use of botulinum neurotoxin for detrusor-sphincter dyssynergia (DSD) are conflicting.  The AAN concluded that botulinum neurotoxin is probably safe and effective for the treatment of DSD in patients with spinal cord injury and should be considered for use in these patients.  However, it does not provide significant benefit for the treatment of DSD in patients with MS.

Other than detrusor-sphincter dyssynergia after spinal cord injury, the role of botulinum toxin in the treatment of lower urinary tract dysfunctions has yet to be established.  Sahai et al (2005) stated that application of botulinum toxin in the lower urinary tract has produced promising results in treating lower urinary tract dysfunction, which needs further evaluation with randomized, placebo-controlled trials.  This is in agreement with the observations of Schurch and Corcos (2005) as well as Grise et al (2005).  Schurch and Corcos noted that Botox appears to be a reasonable alternative to surgery in the management of intractable OAB in children.  However, studies of the delivery method, site of injection, dose and long-term follow-up are needed to confirm the good safety profile/clinical benefit of this new, minimally invasive approach.  In a review on the use and mechanism of botulinum toxin in the treatment of OAB, Grise and colleagues stated that further studies remain necessary regarding the dosage of Botox, selection of patients, combination with anti-cholinergic treatment, as well as effects of repeated injections.

The Vanderbilt Evidence-based Practice Center systematically reviewed evidence on treatment of OAB, UI, and related symptoms (Hartmann et al, 2009).  These investigators focused on prevalence and incidence, treatment outcomes, comparisons of treatments, modifiers of outcomes, and costs.  They searched PubMed, MEDLINE, EMBASE, and CINAHL.  They included studies published in English from January 1966 to October 2008; excluded studies with fewer than 50 participants, fewer than 75 % women, or lack of relevance to OAB.  Of 232 included publications, 20 were good quality, 145 were fair, and 67 poor.  These researchers calculated weighted averages of outcome effects and conducted a mixed-effects meta-analysis to investigate outcomes of pharmacological treatments across studies.  Overactive bladder affects more than 10 to 15 % of adult women, with 5 to 10 % experiencing UI monthly or more often.  Six available medications are effective in short-term studies: estimates from meta-analysis models suggest extended release forms (taken once-daily) reduce UI by 1.78 (95 % CI: 1.61 to 1.94) episodes per day, and voids by 2.24 (95 % CI: 2.03 to 2.46) per day.  Immediate release forms (taken twice or more a day) reduce UI by 1.46 (95 % CI: 1.28 to 1.64), and voids by 2.17 (95 % CI: 1.81 to 2.54).  As context, placebo reduces UI episodes by 1.08 (95 % CI: 0.86 to 1.30), and voids by 1.48 (95 % CI: 1.19 to 1.71) per day.  No one drug was definitively superior to others, including comparison of newer more selective agents to older anti-muscarinics.  Current evidence is insufficient to guide choice of other therapies including sacral neuromodulation, instillation of oxybutynin, and injections of botulinum toxin.  Acupuncture was the sole complementary and alternative medicine treatment, among reflexology and hypnosis, with early evidence of benefit.  The strength of the evidence is insufficient to fully inform choice of these treatments.  Select behavioral interventions were associated with symptom improvements comparable to medications.  Limited evidence suggests no clear benefit from adding behavioral interventions at the time of initiation of pharmacological treatment.  The authors concluded that OAB and associated symptoms are common.  Treatment effects are modest.  Quality of life and treatment satisfaction measures suggest such improvements can be important to women.  The amount of high quality literature available is meager for helping guide women's choices.  Gaps include weak or absent data about long-term follow-up, poorly characterized and potentially concerning harms, information about best choices to minimize side effects, and study of how combinations of approaches may best be used.  This is problematic since the condition is chronic and a single treatment modality is unlikely to fully resolve symptoms for most women.

Brubaker et al (2008) compared 200 U intradetrusor botulinum toxin A versus placebo in women with refractory idiopathic urge incontinence (UI).  This institutional review board approved, multi-center registered trial randomized women with refractory UI, detrusor overactivity incontinence and 6 or greater UI episodes in 3 days to botulinum toxin A or placebo at a 2:1 ratio.  Refractory was defined as inadequate symptom control after 2 or more attempts at pharmacotherapy and 1 or more other first line therapies for detrusor overactivity incontinence.  The primary outcome measure was time to failure, as evidenced by a Patient Global Impression of Improvement score of 4 or greater at least 2 months after injection, or changes in treatment (initiation or increase) at any time after injection.  Safety data, including increased post-void residual volume, defined as more than 200 ml irrespective of symptoms, was obtained at specified time points.  Approximately 60 % of the women who received botulinum toxin A had a clinical response based on the Patient Global Impression of Improvement.  The median duration of their responses was 373 days, significantly longer than the 62 days or less for placebo (p < 0.0001).  In the botulinum toxin A group increased post-void residual urine (12 of 28 women or 43 %) and urinary tract infection in those with increased post-void residual urine (9 of 12 or 75 %) exceeded expected ranges.  Further injections were stopped after 43 patients were randomized, including 28 to botulinum toxin A and 15 to placebo.  The authors concluded that local injection of 200 U botulinum toxin A was an effective and durable treatment for refractory over-active bladder (OAB).  However, a transient post-void residual urine increase was experienced in 43 % of patients.  The authors noted that botulinum toxin A for idiopathic over-active bladder is still under investigation.

Chuang et al (2003) stated that botulinum toxin type A treatment inhibits afferent-nerve-mediated bladder contraction.  This analgesic effect may expand the application of botulinum toxin type A in the localized genitourinary tract pain syndrome, such as interstitial cystitis and prostatodynia.  The authors concluded that application of botulinum toxin type A is a promising treatment for lower urinary tract dysfunction with profound basic and clinical implications.  Chancellor and Yoshimura (2004) noted that among the potentially effective new treatment modalities for interstitial cystitis currently under investigation are suplatast tosilate, resiniferatoxin, botulinum toxin, and gene therapy to modulate the pain response.

There is insufficient evidence to support the use of botulinum toxin for interstitial cystitis.  Kuo (2005) evaluated the clinical effectiveness of sub-urothelial injection of botulinum toxin A in patients with chronic interstitial cystitis (n = 10).  Eight women and 2 men with chronic interstitial cystitis who had failed conventional treatments were enrolled in this study.  In 5 patients, 100 units of botulinum toxin A was injected sub-urothelially into 20 sites, and an additional 100 units was injected into the trigone in the other 5 patients.  Therapeutic outcome including functional bladder capacity, number of daily urinations, bladder pain, and urodynamic changes were compared between baseline and 3 months after treatment.  In 2 patients bladder pain and urinary frequency were improved 3 months after treatment.  Mild difficulty in urination was reported by 7 patients.  Functional bladder capacity recorded in a voiding diary was significantly increased (155 +/- 26.3 versus 77 +/- 27.1 ml, p < 0.001), and the frequency of daily urinations (18 +/- 7.7 versus 24.2 +/- 10.3, p = 0.025) and the pain score (2.4 +/- 1.6 versus 3.2 +/- 1.1, p = 0.003) were mildly but significantly reduced after treatment.  Only the cystometric capacity improved significantly (287 +/- 115 versus 210 +/- 63.8 ml, p = 0.05) in urodynamic results.  Trigonal injection had no therapeutic effect on symptom or urodynamic improvement.  No adverse effect was reported.  The author concluded that the clinical result of sub-urothelial botulinum toxin A injection was disappointing.  None of the patients was symptom-free and only a limited improvement in bladder capacity and pain score was achieved in 2 patients.

Toft and Nording (2006) reviewed the recently published literature on intravesical therapy strategies in painful bladder syndrome/interstitial cystitis.  Bladder irrigation with different agents has been used during years in an attempt to treat painful bladder syndrome/interstitial cystitis.  The 'traditional' agent for glycosaminoglycan substitution is hyaluronic acid.  Often used are heparin and dimethyl sulfoxide, the actions of which are not quite clear but supposedly on an anti-inflammatory basis.  Other agents for intravesical treatment are Bacillus Calmette-Guerin vaccine and botulinum toxin, and some recent studies have pointed to resiniferatoxin and RDP58.  The authors concluded that painful bladder syndrome/interstitial cystitis persists as a challenging syndrome in urology.  Intravesical instillation therapy has basically not changed during the last few years, although some studies have disconfirmed some regimens.  Intensive research may hopefully result in more effective treatments in the future.

Botulinum toxin has been studied as a treatment for flexion contractures.  Shah et al (2005) described the development of a flexion contracture in a patient with Parkinson's disease after total knee arthroplasty.  This contracture was successfully treated with manipulation under anesthesia and injections of botulinum toxin A into the hamstring and gastrocnemius muscles, in conjunction with a static progressive extension orthosis and rigorous physical therapy.  This was a case study; and the clinical benefit of botulinum toxin, if any, is confounded by the multiple therapies used in this patient.

There is little evidence to support the use of botulinum toxin for tinnitus.  In a prospective, double-blinded study, Stidham et al (2005) assessed the potential benefit botulinum toxin A in the treatment of tinnitus.  A total of 30 patients with tinnitus were randomly placed into 1 of 2 treatment arms.  Patients either received botulinum toxin A (20 to 50 U) or saline injection at the first treatment, and the opposite treatment 4 months later.  Prospective data including tinnitus matching test, tinnitus handicap inventory (THI), tinnitus rating scale (TRS), and patient questionnaires were obtained over a 4-month period after each injection.  A total of 26 patients completed both injections and follow-up and were included in data analysis.  After botulinum toxin A, subjective tinnitus changes included 7 patients improved, 3 worsened, and 16 unchanged.  Following placebo, 2 patients were improved, 7 worsened, and 17 unchanged.  Comparison of the treatment and placebo groups was statistically significant (p < 0.005) when including better, worse, and same effects.  A significant decrease in THI scores between pre-treatment and 4 month post-botulinum toxin A injection (p = 0.0422) was recorded.  None of the other comparisons of pre-treatment to 1 month, or pre-treatment to 4 months were significantly different.  This study found improvement in THI scores and patient subjective results after botulinum toxin- A injection compared with placebo, suggesting a possible benefit of botulinum toxin- A in tinnitus management.  The authors noted that larger studies need to be completed to further evaluate potential benefits of botulinum toxin- A in treatment of this difficult problem.

1. half the patients received 50 U of botulinum toxin- A, and
2. the remainder received normal saline solution. 

The intramuscular injections were performed 5 cm distal to the maximum point of tenderness at the lateral epicondyle, in line with the middle of the wrist.  The 2 solutions used for the injections were identical in appearance and temperature.  The results of a quality-of-life assessment with the Short Form-12 (SF-12), the pain score on a VAS, and the grip strength measured with a validated Jamar dynamometer were recorded before and 3 months after the injection.  Three months following the injections, there was no significant difference between the 2 groups with regard to grip strength, pain, or quality of life.   The authors reported that with the numbers studied, they failed to find a significant difference between the 2 groups.  Therefore, they concluded that there is no evidence of a benefit from botulinum toxin injection in the treatment of chronic tennis elbow.

A number of studies have evaluated the effectiveness of botulinum toxin in the treatment of back and neck pain.  However, there is currently insufficient scientific evidence of the effectiveness of botulinum toxin in the treatment of back pain.  Two early small double blind studies (Foster et al, 2000; Foster et al, 2001) of botulinum toxin for back pain were published, one involving 28 patients, and another involving 31 patients.  However, both of these studies were small and from a single investigator, raising questions about the generalization of the findings.  In addition, both of the studies were short term, with no comparisons to other treatments for back pain. 

The AAN's assessment on the use of botulinum neurotoxin in the treatment of autonomic disorders and pain (Naumann et al, 2008) found that botulinum neurotoxin is possibly effective for the treatment of chronic predominantly unilateral low back pain.  This was based on a single Class II study.  The authors stated that the evaluation and treatment of low back pain (LBP) is complicated by its diverse potential causes.  In most clinical settings, it is difficult to diagnose the precise origin of pain.  This creates challenges in study design, especially in the selection of homogeneous subject populations.  The assessment also noted that there is insufficient evidence to support the effectiveness of botulinum neurotoxin in hyper-lacrimation.

In a review of the evidence for non-surgical interventional therapies for LBP for the American Pain Society, Chou and colleagues (2009) concluded that there is insufficient (poor) evidence from randomized controlled trials (conflicting trials, sparse and lower quality data, or no randomized trials) to reliably evaluate botulinum toxin injection.

There is limited evidence for the use of botulinum toxin in chronic pelvic pain.  In a double-blind, randomized, placebo- controlled trial (n = 60), Abbott et al (2006) examined if botulinum toxin A is more effective than placebo at reducing pain and pelvic floor pressure in women with chronic pelvic pain and pelvic floor muscle spasm.  Subjects had chronic pelvic pain of more than 2 years duration and evidence of pelvic floor muscle spasm.  Thirty women had 80 units of botulinum toxin A injected into the pelvic floor muscles, and 30 women received saline.  Dysmenorrhea, dyspareunia, dyschezia, and non-menstrual pelvic pain were assessed by VAS at baseline and then monthly for 6 months.  Pelvic floor pressures were measured by vaginal manometry.  There was significant change from baseline in the botulinum toxin-A group for dyspareunia (VAS score 66 versus 12; chi2 = 25.78, p < 0.001) and non-menstrual pelvic pain (VAS score 51 versus 22; chi2 = 16.98, p = 0.009).  In the placebo group only dyspareunia was significantly reduced from baseline (64 versus 27; chi2 = 2.98, p = 0.043).  There was a significant reduction in pelvic floor pressure (centimeters of water) in the botulinum toxin- A group from baseline (49 versus 32; chi2 = 39.53, p < 0.001), with the placebo group also having lower pelvic floor muscle pressures (44 versus 39; chi2 = 19.85, p = 0.003). The authors concluded that objective reduction of pelvic floor spasm reduces some types of pelvic pain. Injection of botulinum toxin- A reduces pressure in the pelvic floor muscles more than placebo; it may be a useful agent in women with pelvic floor muscle spasm and chronic pelvic pain who do not respond to conservative physical therapy.  There were no significant inter-group differences reported in this study between botulinum toxin A and placebo for pain scores.  These investigators noted that more research in this area is essential to further define this tool in the treatment of chronic pelvic pain.

There is insufficient evidence for the use of botulinum toxin in motor or phonic tics. Awaard (1999) reported that the combination of baclofen/botulinum toxin type A are very effective, safe, and reliable in the treatment of tics/Tourette's syndrome.  The author opined that it is worthwhile considering this treatment approach in patients with tics/Tourette's syndrome in order to reduce or avoid the side effects of other medications.  Moreover, the author concluded that further studies are needed.

Marras et al (2001) discussed the use of botulinum toxin for simple motor tics (n = 18).  The authors concluded that botulinum toxin reduced treated tic frequency and the urge associated with the treated tic.  Despite these changes, patients did not report an overall benefit from the treatment.

The AAN's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that botulinum neurotoxin is possibly effective for the treatment of motor tics (based on one Class II study).  On the other hand, there is insufficient data to ascertain the effectiveness of botulinum neurotoxin in patients with phonic tics.

Botulinum toxin is the only known treatment for painful dystonia accompanying rare corticobasilar degeneration (CBD).  Dystonia, often accompanied by painful rigidity and fixed contractures, is one of the most disabling features of CBD.  Vanek and Janovic (2001) found that dystonia is a common manifestation of CBD; of 66 patients with CBD, 39 (59.0 %) had dystonia.  The investigators noted that there is no effective treatment for this relentless disorder, except for temporary relief of dystonia and pain, with local botulinum toxin injections.

Botulinum toxin has also been studied for its use in treating brachial plexus injury.  However, there is currently insufficient evidence to support it use for this indication. Heise et al (2005) reported their preliminary experience with the use of botulinum toxin A for the treatment of biceps-triceps muscle co-contraction.  A total of 8 children were treated with 2 to 3 U/Kg of botulinum toxin injected in the triceps (4 patients) and biceps (4 patients) muscle, divided in 2 or 3 sites.  All patients submitted to triceps injections showed a long-lasting improvement of active elbow flexion and none required new injections, after a follow-up of 3 to 18 months.  Three of the patients submitted to biceps injections showed some improvement of elbow extension, but none developed anti-gravitational strength for elbow extension and the effect lasted only 3 to 5 months.  One patient showed no response to triceps injections.  The authors stated that their findings suggested that botulinum toxin can be useful in some children that have persistent disability secondary to obstetrical brachial plexopathy.

DeMatteo et al (2006) noted that following obstetrical brachial plexus injury, infants are unable to learn specific patterns of movement due to the disruption of neural pathways.  Even with successful re-innervation (spontaneously or post-surgical reconstruction), function can be suboptimal due to over-activity in antagonist muscles preventing movement of re-innervated muscles.  Botulinum toxin type A was used to temporarily weaken antagonistic muscles early in the re-innervation process following brachial plexus injury, with the aim of facilitating functional improvement.  These researchers reported a case series of 8 children (5 females, 3 males; mean age of 12.5 months [SD 6.43]; range of 5 to 22 months) with significant muscle imbalances but evidence of re-innervation who were given botulinum toxin A injections into the triceps, pectoralis major, and/or latissimus dorsi muscles.  After a single injection, all parents reported improvement in function.  Active Movement Scale total score changed significantly between pre botulinum toxin A and 1 month (p = 0.014), and 4 months (p = 0.022) post botulinum toxin A injection.  The authors proposed that botulinum toxin A facilitated motor learning through improved voluntary relaxation of antagonist muscles while allowing increased activity in re-innervated muscles.

Price et al (2007) retrospectively reviewed 26 patients who underwent reconstruction of the shoulder for a medial rotation contracture after birth injury of the brachial plexus.  Of these, 13 patients with a mean age of 5.8 years (2.8 to 12.9) received an injection of botulinum toxin A into the pectoralis major as a surgical adjunct.  They were matched with 13 patients with a mean age of 4.0 years (1.9 to 7.2) who underwent an identical operation before the introduction of botulinum toxin therapy to these investigators' unit.  Pre-operatively, there was no significant difference (p = 0.093) in the modified Gilbert shoulder scores for the 2 groups.  Post-operatively, patients who received the botulinum toxin had significantly better Gilbert shoulder scores (p = 0.012) at a mean follow-up of 3 years (1.5 to 9.8).  It appears that botulinum toxin A produces benefits which are sustained beyond the period for which the toxin is recognised to be active.  The authors suggested that by temporarily weakening some of the power of medial rotation, afferent signals to the brain are reduced and cortical recruitment for the injured nerves is improve.

Botulinum toxin has been investigated for use in restless legs syndrome; however, there is insufficient evidence to support its use for this indicaiton.  A small randomized controlled trial found no effect of botulinum toxin on restless leg syndrome; however, this study may have been underpowered to detect clinically significant benefits.  In a double-blind, placebo-controlled, pilot trial (n = 6),  Nahab and colleagues (2008) examined the effects of botulinum toxin A in the treatment of adults with restless legs syndrome (RLS).  Patients were randomized to receive botulinum toxin A or saline, with a maximum dose of 90 mU per leg.  At week 12, patients received the alternate compound with continued monitoring.  These researchers used the IRLS and the Clinical Global Improvement scale (CGI) to assess efficacy (Nahab et al, 2008).  To monitor adverse effects (AEs), patients were asked to rate from 0 (no symptoms) to 10 (severe symptoms) the presence of weakness, pain, swelling, and redness based on the preceding 2 weeks.  Ratings were completed at baseline (weeks 0 and 12), and 2 and 4 weeks post-injections. The primary outcome measure was mean change in IRLS from baseline at 4 weeks post-injection.  Secondary outcomes included mean IRLS change from baseline at 2 weeks post-injection, mean CGI scores at weeks 2 and 4, and reported AEs.  At week 2, placebo-treated patients noted a 5.0 ± 5.1 point improvement on the IRLS versus a 1.0 ± 3.5 point improvement in the botulinum toxin arm (p = 0.06).  At week 4, placebo-treated patients maintained only a 2.7 ± 5.9 point improvement from baseline, whereas botulinum toxin-treated patients showed a 5.0 ± 6.0 point improvement (p = 0.24).  The CGI showed similar findings for the botulinum toxin arm with scores of 4.3 ± 0.8 at week 2 (p = 0.01) and 3.7 ± 1.4 at week 4 (p = 0.74), compared to placebo-arm scores of 2.8 ± 1.2 at week 2 and 3.8 ± 1.7 at week 4.  These researchers compared baseline scores at week 0 and week 12 to assess for any carry-over effect in the botulinum toxin-arm and found no differences (p = 0.55).  Reported AEs were similar between groups, with mean placebo AE scores of 1.5 ± 2.5 at baseline, 3.2 ± 5.4 at week 2, and 5 ± 7.4 at week 4, while botulinum toxin A scores were 1.8 ± 3.3 at baseline, 6.3 ± 7.1 at week 2, and 4.5 ± 5.6 at week 4.  Two patients reported mild weakness following both placebo and botulinum toxin A injections.  This study showed no significant improvement in IRLS and CGI at week 4 for botulinum toxin A.  A statistically significant benefit was noted on the CGI secondary endpoint for the placebo group at week 2.  Adverse events were similar between the groups.  The authors stated that any future studies should be powered to account for the significant placebo response while exploring higher doses without unmasking controls.

A small single-blind randomized controlled trial found a nonsignificant reduction in orofacial tardive dyskinesia with botulinum toxin A.  Slotema and colleagues (2008) stated that orofacial tardive dyskinesia (OTD) is difficult to treat and botulinium toxin A may be an option.  In a single-blind (raters were blind) study (n = 12, duration 33 weeks), OTD was treated with botulinum toxin A in 3 consecutive sessions with increasing dosages.  The severity was measured with the Abnormal Involuntary Movement Scale (AIMS).  Overall, there was a non-significant reduction in the severity of OTD (p = 0.15).  However, in patients with no change in their anti-psychotic medication (n = 8) the reduction was significant (p = 0.035).  After the study, 50 % of the patients preferred to continue the treatment with botulinum toxin A.  The authors concluded that botulinum toxin A was well-tolerated and showed a non-significant improvement for OTD.  They stated that a larger double-blind study is warranted.

An UpToDate review on "Tardive dyskinesia: Prevention and treatment" (Tarsy, 2011) states that "[f]or patients with a diagnosis of TD, additional pharmacologic interventions include the following: Use of benzodiazepines, botulinum toxin injections, tetrabenazine, or anticholinergic drugs to control symptoms of TD.  For patients who have debilitating TD or tardive dystonia not amenable to treatment with botulinum toxin, we suggest treatment with tetrabenazine".  Also, the National Institute of Neurological Disorders and Stroke's "Tardive Dyskinesia Information Page" (NINDS, 2011) states that "[t]reatment is highly individualized.  The first step is generally to stop or minimize the use of the neuroleptic drug, but this can be done only under close supervision of the physician.  However, for patients with a severe underlying condition this may not be a feasible option.  Replacing the neuroleptic drug with substitute drugs may help some individuals.  The only approved drug treatment for tardive dyskinesia is tetrabenazine, which is usually effective but can have side effects that need to be discussed prior to starting therapy.  Other drugs such as benzodiazepines, clozapine, or botulinum toxin injections also may be tried".

Botulinum toxin is being investigated as a treatment for dyspareunia.  Park and Paraiso (2009) stated that refractory dyspareunia presents a challenging therapeutic dilemma.  These researchers presented the case of a woman with defecatory dysfunction and dyspareunia presented with stage 2 prolapse.  She underwent laparoscopic and vaginal pelvic floor reconstruction with excision of endometriosis.  The patient experienced increased dyspareunia and de novo vaginismus post-operatively that were refractory to trigger point injections, physical therapy, and medical and surgical management.  She underwent botulinum toxin type A (BoNT/A) injections into her levator ani muscles, which allowed her to have sexual intercourse again after 2 years of apareunia with no recurrence of pain for 12 months.  The authors concluded that injecting botulinum toxin into the levator ani muscles shows promise for post-operative patients who develop vaginismus and do not respond to conservative therapy.

A pilot study suggests that botulinum toxin may be useful in treating painful diabetic neuropathy.  Yuan et al (2009) noted that diabetic neuropathy is a common complication in diabetes, with patients typically experiencing diverse sensory symptoms including dysesthesias in the feet and usually accompanied by sleep disturbance.  There is still no comprehensive understanding of the underlying biologic processes responsible for diabetic neuropathic pain.  Thus, the current symptomatic therapy remains unsatisfactory.  Recent experimental evidence suggested that botulinum toxin A may not only inhibit the release of acetylcholine at the neuromuscular junctions, but also modulate afferent sensory fiber firing, thereby relieving neuropathic pain.  These investigators performed a double-blind cross-over trial of intradermal botulinum toxin A for diabetic neuropathic pain in 18 patients.  They found significant reduction in VAS of pain by 0.83 +/- 1.11 at 1 week, 2.22 +/- 2.24 at 4 weeks, 2.33 +/- 2.56 at 8 weeks, and 2.53 +/- 2.48 at 12 weeks after injection in the botulinum toxin group, as compared to the respective findings for a placebo group of 0.39 +/- 1.18, -0.11 +/- 2.04, 0.42 +/- 1.62, and 0.53 +/- 1.57 at the same time-points (p < 0.05).  Within the botulinum toxin group, 44.4% of subjects experienced a reduction of VAS greater than or equal to 3 within 3 months after injection, whereas there was no similar response in the placebo group.  At the 4-week post-injection stage, improvement in sleep quality was measured using the Chinese version of the Pittsburgh Sleep Quality Index.  The authors concluded that the findings of this pilot study showed that botulinum toxin type A significantly reduced diabetic neuropathic pain and transiently improved sleep quality.  They stated that further large-scaled study is warranted. In an editorial that accompanied the afore-mentioned study, Apfel (2009) stated that larger, carefully designed, multi-center, clinical trials with longer periods of observation are needed to ascertain the clinical value of botulinum toxin for neuropathic pain.  The author also noted that it will be essential in future studies to examine the effectiveness and tolerability of multiple dosing.

There is insuffience evidence for the use of botulinum toxin for Raynaud's phenomenon. Fregene et al (2009) performed a retrospective chart review on the use of botulinum toxin type A (botulinum toxin A) for the treatment of digital ischemia in patients with Raynaud's phenomenon.  All patients presented with a diagnosis of Raynaud's phenomenon with worsening pain, discoloration, or non-healing wound of the hand.  Patients received botulinum toxin A injections into the peri-neurovascular tissue of the wrist or the distal palm, or along the digit.  Outcomes measured included pain rating, digit color and appearance, transcutaneous oxygen saturation, and healing of chronic ulcers.  A total of 26 patients were treated, with a total of 55 treatment encounters.  Patients were observed for an average of 18 months.  Statistically significant improvements were noted for pain score and digit transcutaneous oxygen saturation measurements after treatment (p < 0.05).  These investigators found smokers and women were more likely to have improved coloration and appearance after injections.  Complications included localized injection-related pain and transient intrinsic muscle weakness.  The authors concluded that botulinum toxin A significantly improves pain and improves healing in Raynaud's patients with few complications.  Botulinum toxin type A was found to be a safe and useful treatment option for vasospastic digital ischemia.  Moreover, the authors stated that none of the studied demographic data was a significant predictor of improved response to botulinum toxin A.  They noted that further investigation is underway to determine the risk factors that respond best to peri-vascular botulinum toxin A therapy.

The drawbacks of this study by Neumeister and colleagues (2009) include

1. this was a non-controlled case series without a placebo group,
2. various confounding factors may be important in the findings, including ambient room temperature, patient core temperature, time of year injected, and
3. small sample size, broad inclusion criteria, as well as lack of a subjective or objective pain scale. 

The authors stated that randomized, controlled, prospective studies are needed to address these issues and to define the true benefits of Botox injections in patients with ischemic digits.

Restivo et al (2006) stated that no specific treatment for oropharyngeal dysphagia related to diabetic neuropathy has been described to date.  Chemical myotomy of the cricopharyngeus (CP) muscle by botulinum toxin A has been effective in reducing or abolishing dysphagia associated with upper esophageal sphincter (UES) hyperactivity of different etiologies.  In the present study, these researchers evaluated the effectiveness of botulinum toxin A injections into the CP muscle in diabetic patients with severe oropharyngeal dysphagia associated with diabetic autonomic and/or somatic peripheral neuropathy.  A total of 12 type-2 diabetic patients with severe dysphagia for both solid and liquid foods associated with autonomic and/or peripheral somatic neuropathy were investigated.  Swallowing function was evaluated by clinical examination, videofluoroscopy (VDF), and simultaneous needle EMG of the CP and pharyngeal inferior constrictor (IC) muscles.  Clinical evaluation using a 4-level dysphagia severity score was performed every other day for the 1st week and thereafter every other week until week 24.  Videofluoroscopy and EMG follow-up were carried out at week 1, 4, 12, 16, 18, and 24 after botulinum toxin A injection.  botulinum toxin A was injected percutaneously into the CP muscle under EMG control.  botulinum toxin A induced the complete recovery of dysphagia in 10 patients and had a significant (p = 0.0001, ANOVA) improvement in 2 patients within 4 +/- 1.1 days (range of 3 to 7).  Clinical improvement was confirmed by VDF and EMG.  The authors concluded that these findings suggested a potential benefit from botulinum toxin A treatment in dysphagia associated with diabetic neuropathy.  They stated that randomized controlled trials (RCTs) are needed to confirm this observation.

In a prospective pilot study, Terre et al (2008) evaluated the effectiveness of botulinum toxin A injection in the CP muscle in patients with neurological dysphagia caused by alteration in the UES opening and with preserved pharyngeal contraction.  A total of 10 patients (7 brain lesions and 3 cervical spinal cord injuries), with a minimum time-lapse of 6 months from neurological lesion to botulinum toxin A injection were included in this study.  Dysfunction of the UES opening and the presence of pharyngeal contraction were diagnosed by VDF and esophageal manometry (EM).  The botulinum toxin A (100 U) injection was guided by endoscopy.  Clinical, VDF, and EM follow-ups were carried out at 3 weeks, 3 and 6 months, and at 1 year post-injection.  Prior to treatment, 6 patients were fed by nasogastric tube.  Videofluoroscopy showed impairment of the UES opening, residue in pyriform sinuses, and aspiration in all cases.  During follow-up, there was a decrease in the number of patients that had aspiration: 3 patients at 1 year.  During swallowing, EM showed a mean UES relaxation of 90 % (range of 74.5 to 100 %), residual pressure 3.2 mmHg (range of 0 to 13 mmHg) and pharyngeal amplitude 52 mmHg (range of 25 to 80 mmHg).  At follow-up, a significant improvement in UES relaxation (98 % [89 to 100 %]) and pharyngeal contraction (97 mmHg [35 to 165 mmHg]) was observed.  At 3 months, 6 patients were eating exclusively by mouth.  The authors concluded that 1 single injection of botulinum toxin A in the UES has long-lasting effectiveness in patients with neurological dysphagia caused by alteration in the UES opening and with pharyngeal contraction.  They stated that nevertheless, a RCT should be done to confirm these results and rule out the effect of potential spontaneous improvement of neurological injury.

There is emerging evidence that injection of the pylorus with botulinum toxin may be an alternative to pyloroplasty or pyloromyotomy for esophagogastrectomy.  Cerfolio et al (2009) performed a retrospective study with a prospective database on patients with esophageal cancer or high-grade dysplasia who underwent Ivor-Lewis esophago-gastrectomy.  All had 1 surgeon and similar stomach tubularization, hand-sewn anastomoses, nasogastric tube duration, and post-operative prokinetic agents.  Outcomes of post-operative gastric emptying, aspiration, and swallowing symptoms were compared.  Between January 1997 and June 2008, there were 221 patients.  Seventy-one patients had a pyloromyotomy, and gastric emptying judged on post-operative day 4 was delayed in 93 % (52 % had any morbidity and 14 % had respiratory morbidity).  Fifty-four patients had no drainage procedure, and gastric emptying was delayed in 96 % (59 % had any morbidity and 22 % had respiratory morbidity).  Twenty-eight patients underwent pyloroplasty, and 96 % had delayed gastric emptying (50 % had any morbidity and 32 % had respiratory morbidity).  Sixty-eight patients had botulinum toxin injection into the pylorus.  Gastric emptying was delayed in only 59 % (p = 0.002, 44 % had any morbidity and 13 % had respiratory morbidity).  Hospital length of stay (p = 0.015) and operative times (p = 0.037) were shorter in the botulinum toxin group.  Follow-up (mean of 40 months) showed symptoms of biliary reflux to be lowest in the botulinum toxin group (p = 0.024).  The authors concluded that injection of the pylorus with botulinum toxin at the time of esophago-gastrectomy is safe and decreases operative time when compared with pyloroplasty or pyloromyotomy.  In addition, it can improve early gastric emptying, decrease respiratory complications, shorten hospital stay, and reduce late bile reflux.  They stated that a prospective multi-institutional RCT is needed.

A pilot study found no significant effect of botulinum toxin on complex regional pain syndrome.  Safarpour and colleagues (2010) examined the effectiveness and tolerability of botulinum toxin A in allodynia of patients with complex regional pain syndrome (CRPS).  A total of 14 patients were studied: 8 were subjects of a randomized, prospective, double-blind, placebo-controlled protocol; 6 were studied prospectively in an open-label protocol.  Patients were rated at baseline and at 3 weeks and 2 months after botulinum toxin A administration.  Ratings included brief pain inventory, McGill pain questionnaire, clinical pain impact questionnaire, quantitative skin sensory test, sleep satisfaction scale, and patient global satisfaction scale.  Botulinum toxin A was injected intradermally and subcutaneously, 5 units/site into the allodynic area (total dose 40 to 200 units).  None of the patients with allodynia showed a significant response following treatment.  The treatment was painful and poorly tolerated.  The authors concluded that intrademal and subcutaneous administration of botulinum toxin A into the allodynic skin of the patients with CRPS failed to improve pain and was poorly-tolerated.

A Cochrane systematic evidence review found that botulinum toxin may have a role in certain types of shoulder pain.  In a Cochrane review, Singh and Fitzgerald (2010) compared the safety and effectiveness of botulinum toxin in comparison to placebo or other treatment options for shoulder pain.  These investigators selected RCTs comparing botulinum toxin with placebo or active treatment in people with shoulder pain.  For continuous measures, they calculated mean difference (MD), and for categorical measures risk ratio (RR) (with 95 % CI).  A total of 6 RCTs with 164 patients were included.  Five RCTs in participants with post-stroke shoulder pain indicated that compared with placebo, a single intramuscular injection of botulinum toxin A significantly reduced pain at 3 to 6 months post-injection (MD -1.2 points, 95 % CI: -2.4 to -0.07; 0 to 10 point scale) but not at 1 month (MD -1.1 points, 95 % CI: -2.9 to 0.7).  Shoulder external rotation was increased at 1 month (MD 9.8 degrees , 95 % CI: 0.2 to 19.4) but not at 3 to 6 months.  Shoulder abduction, external rotation or spasticity did not differ between groups, nor did the number of adverse events (RR 1.46, 95 % CI: 0.6 to 24.3).  One RCT in arthritis-related shoulder pain indicated that botulinum toxin reduced pain severity (MD -2.0, 95 % CI: -3.7 to -0.3; 10 point scale) and shoulder disability with a reduction in Shoulder Pain and Disability Index score (MD -13.4, 95 % CI: -24.9 to -1.9; 100 point scale) when compared with placebo.  Shoulder abduction was improved (MD 13.8 degrees, 95 % CI: 3.2 to 44.0).  Serious adverse events did not differ between groups (RR 0.35, 95 % CI: 0.11 to 1.12).  The authors concluded that these findings should be interpreted with caution due to few studies with small sample sizes and high risk of bias.  Botulinum toxin-A injections seem to reduce pain severity and improve shoulder function and range of motion when compared with placebo in patients with shoulder pain due to spastic hemiplegia or arthritis.  It is unclear if the benefit of pain relief in post-stroke shoulder pain at 3 to 6 months but not at 1 month is due to limitations of the evidence, which includes small sample sizes with imprecise estimates, or a delayed onset of action.  The authors stated that more studies with safety data are needed.

Botulinum toxin is being investigated as a treatment for depression.  Beer (2010) noted that the standard of care for the treatment of depression entails pharmacotherapy with selective serotonin reuptake inhibitors.  Cognitive therapy is typically utilized in addition to a pharmacological intervention.  However, the benefits of the drugs used may be marginal compared with placebo yet the costs associated with their use continue to increase.  One potential treatment for depression utilizes botulinum toxins.  Currently, there is a small body of evidence supporting their use for depression, the potential efficacy and cost effectiveness of this treatment requires more research including head-to-head clinical trials.

In a review on airway mucus function and dysfunction, Fahy and Dickey (2010) listed botulinum neurotoxins as one of the agents in development for reducing mucin secretion.

RimabotulinumtoxinB (Myobloc) was approved by the FDA for symptomatic treatment of patients with cervical dystonia (i.e., spasmodic torticollis) to reduce the severity of abnormal head position and neck associated with cervical dystonia.  RimabotulinumtoxinB is antigenically distinct and has a different mechanism of action than botulinum toxin type A.  Although the U.S. Pharmacopeial Convention (2004) has stated that treatment of spasticity caused by stroke or brain injury is an accepted off-label indication for rimabotulinumtoxinB, based in part on the positive results of an uncontrolled prospective study of rimabotulinumtoxinB (Bradshear et al, 2003), a subsequently published randomized controlled clinical trial by the same investigator group failed to demonstrate a statistically significant effect of rimabotulinumtoxinB (Bradshear et al, 2004), perhaps due to the small size of the study.

Both Botox and Myobloc are neurotoxins produced by fermentation of the bacterium Clostridium botulinum.  They interfere with neuromuscular transmission, temporarily paralyzing the affected muscle.  Clostridium botulinum is a gram-positive, spore-forming obligate anaerobe that is widely distributed in nature and frequently found in soil, marine environments, and agricultural products.  Each strain produces 1 of 8 antigenically distinct toxins designated A through H.  Human disease is caused by types A, B, E, and (rarely) F.  After repeated use of high doses, antibodies can develop in some individuals, making further treatment ineffective indefinitely.  Because of Myobloc’s unique mechanism of action and antigenicity, Myobloc may be effective in patients with cervical dystonia who have developed antibodies to or who have not responded to Botox.

There is evidence to support the use of rimabotulinumB in axillary hyperhidrosis.  Baumann et al (2005) reported on the results of a pilot study of rimabotulinumtoxinB for axillary hyperhidrosis.  Twenty patients were randomly assigned to rimabotulinumtoxinB (n = 15) or to placebo injection (n = 5).  The investigators explained that this trial was initially conceived as a placebo-controlled study; however, owing to the insufficient size of the placebo group (1 placebo subject failed to return for follow-up and 1 responded to placebo injections), the placebo arm of this trial was dropped during data analysis.  The investigators reported a significant difference in subject and physician assessed measures of treatment response at 1 month in the participants receiving Myobloc injections.  Duration of action ranged from 2.2 to 8.1 months (mean of 5.0 months).

Nelson et al (2005) reported on the results of rimabotulinumtoxinB injections in 13 patients with axillary hyperhidrosis.  The investigators reported a significant reduction in hyperhidrosis at 4-week, 8-week, and 12-week follow-up compared to baseline.

Dressler et al (2002) reported on a self-controlled study comparing the efficacy of onabotulinumtoxinA and rimabotulinumtoxinB in persons with bilateral axillary hyperhidrosis.  A total of 19 subjects with axillary hyperhidrosis received rimabotulinumtoxinB in one axilla and onabotulinumtoxinA in the other axilla.  The investigators reported that all subjects except 1 reported excellent improvement in hyperhidrosis in both axillae, and that none of the subjects had residual hyperhidrosis on clinical examination.  The duration of effect was not statistically significantly different between onabotulinumtoxinA and rimabotulinumtoxinB.

Baumann and Halem (2004) reported on a randomized controlled clinical study of rimabotulinumtoxinB in palmar hyperhidrosis.  Twenty persons with hyperhidrosis were randomly assigned to injection with rimabotulinumtoxinB (n = 15) or placebo (n = 5).  The investigators reported a significant difference in treatment response (as determined by participant assessment) between the subjects injected with rimabotulinumtoxinB and placebo.  The duration of cessation of palmar sweating ranged from 2.3 months to 4.9 months, with a mean duration of 3.8 months.  The investigators reported, however, that 18 of 20 participants reported dry mouth/throat, 60 % reported indigestion/heartburn, 60 % reported muscle weakness, and 50 % reported decreased grip strength.  The investigators concluded that rimabotulinumtoxinB was safe and effective in treating bilateral palmar hyperhidrosis.  However, the side effect profile was substantial.

There is conflicting evidence on the use of rimabotulinumtoxinB in spasticity. Gracies, et al. (2014) determined the efficacy and safety of 2 doses of botulinum toxin type B (rimabotulinumtoxinB, BoNT/B) in spastic upper limb muscles. The investigators conducted a randomized, double-blind, placebo-controlled trial with a 3-month follow-up in a sample of 24 adult hemiparetic patients with disabling elbow flexor overactivity after stroke or traumatic brain injury who were referred to a tertiary center. Patients were injected with 10,000U of rimabotulinumtoxinB (fixed 2500U dose into elbow flexors; n=8), 15,000U (5000U into elbow flexors; n =8), or placebo (n=8), into overactive upper limb muscles selected as per investigator's discretion. Outcome measures at 1 month post-injection, active range of elbow extension (goniometry; primary outcome); active upper limb function (Modified Frenchay Scale, MFS); subjective global self-assessment (GSA) of arm pain, stiffness, and function; rapid alternating elbow flexion-extension movement frequency over the maximal range; elbow flexor spasticity grade and angle (Tardieu), and tone (Ashworth). The investigators reported that no adverse effects were associated with either BoNT/B dose. Both doses improved active elbow extension vs placebo (+8.3°, 95%CI [1.1-15.5°], p=0.028, ANCOVA). The high dose of BoNT/B also improved subject-perceived stiffness (p=0.005) and the composite pain, stiffness and function GSA (p=0.017), effects that persisted 3 months from injection. No MFS change was demonstrated although subjects with baseline MFS <70/100 seemed more likely to benefit from BoNT/B. The investigators concluded that, in this short-term study, BoNT/B up to 15,000U into spastic upper limb muscles including elbow flexors, was well tolerated and improved active elbow extension and subject-perceived stiffness.

Bradshear et al (2004) reported on a single-site, double-blind, placebo-controlled randomized trial and open-label study to determine whether botulinum toxin type B (BTX-B) is effective in controlling upper-limb spasticity.  The study included subjects with an Ashworth Scale score of 2 or more at the elbow, wrist, and fingers. Subjects were injected with 10,000 U of BTX-B or placebo at the elbow, wrist, and finger flexors.  Measures recorded at weeks 0, 2, 4, 8, 12, and 16, with a 12-week open-label study included: Ashworth Scale score, a global assessment of change (GAC), adverse events and mouse neutralization antibody testing.  The investigators reported that BTX-B did not decrease muscle tone in the elbow, wrist, or finger flexors at 10,000 U over the 16-week period.  A decrease in Ashworth Scale score for the BTX-B patient group was present at the wrist at week 2 of the double-blind study (p = 0.003) but was not statistically significant at other visits.  In the open-label study, improvement was noted at week 4 for the elbow (p = 0.039), wrist (p = 0.002), finger (p = 0.001), and thumb flexors (p = 0.002).  In the double-blind study, the Physician GAC did not reach significance.  Dry mouth was reported by 8 of 9 BTX-B subjects in the double-blind study.  Mouse neutralization antibodies were negative.  The authors concluded that their study does not show a significant decrease in tone from 10,000 U of BTX-B, and that dry mouth was common. 

The FDA has approved incobotulinumtoxinA (Xeomin, Merz USA), a botulinum toxin type A, for the treatment of adults with cervical dystonia or blepharospasm.  The FDA approval of incobotulinumtoxinA was based on the results of 2 pivotal U.S. clinical trials involving adult patients diagnosed with either cervical dystonia or blepharospasm.

A randomized, double-blind, placebo-controlled study examined the efficacy of incobotulinumtoxinA in 233 patients with cervical dystonia.  Patients were randomized (1:1:1) to receive a single administration of incobotulinumtoxinA 240 Units (n = 81), incobotulinumtoxinA 120 Units (n = 78), or placebo (n = 74).  The primary efficacy endpoint was the change in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score from baseline to week 4 post-injection.  The difference between the incobotulinumtoxinA 240 Unit group and the placebo group in the change of the TWSTRS total score from baseline to week 4 was -9.0 points (95 % CI: -12.0 to -5.9 points).  The difference between the incobotulinumtoxinA 120 Unit group and the placebo group in the change of the TWSTRS total score from baseline to week 4 was -7.5 points (95 % CI: -10.4 to -4.6 points).  Initial inobotulinumtoxinA doses of 120 Units and 240 Units demonstrated no significant difference in effectiveness between the doses.  The efficacy of incobotulinumtoxinA was similar in patients who were botulinum toxin naïve and those who had received botulinum toxin prior to this study.  Examination of age and gender subgroups did not identify differences in response to incobotulinumtoxinA among these subgroups.

Incobotulinumtoxin A has been investigated in a randomized, double-blind, placebo-controlled trial in a total of 109 patients with blepharospasm.  Patients were randomized (2:1) to receive a single administration of incobotulinumtoxinA (n = 75) or placebo (n = 34).  The primary efficacy endpoint was the change in the Jankovic Rating Scale (JRS) Severity subscore from baseline to week 6 post-injection.  The difference between the incobotulinumtoxinA group and the placebo group in the change of the JRS Severity subscore from baseline to week 6 was -1.0 (95 % CI: -1.4 to -0.5) points.  Comparison of the incobotulinumA group to the placebo group was statistically significant at p < 0.001.  Examination of age and gender subgroups did not identify substantial differences in response to incobotulinumtoxinA among these subgroups.

In addition, there is randomized controlled clinical study evidence of the efficacy of incobotulinumtoxinA in the treatment of post-stroke spasticity of the upper limb.  Kanovsky et al (2009) reported on the results of a randomized controlled clinical trial of incobotulinumtoxinA on muscle tone, functional disability, and caregiver burden in patients with post-stroke upper limb spasticity.  The investigators found that incobotulinumtoxinA led to statistically significant improvements in muscle tone and disability and was well-tolerated in patients with poststroke upper limb spasticity.  A total of 148 patients with an Ashworth Scale for Spasticity score (a quantitative measure of hypertonia) of 2 or higher for wrist and finger flexors and at least moderate disability in their principal therapeutic target of the Disability Assessment Scale (a measure of functional impairment) were treated either with incobotulinumtoxinA (median, 320 U) or placebo and followed up for up to 20 weeks.  The investigators reported that a significantly higher proportion of patients treated with incobotulinumtoxinA were responders (improvement of 1 point or more in the Ashworth Scale score), as observed in comparison to placebo 4 weeks after treatment in wrist flexors (odds ratio, 3.97; 95 % CI: 1.9 to 8.3) by intention-to-treat analysis.  For all treated flexor muscle groups, statistically significant odds ratios in favor of incobotulinumtoxinA were observed at week 4 (p < 0.009).  Statistically significant results in favor of incobotulinumtoxinA were observed at all post-injection visits until week 12 in the principal therapeutic target (p < 0.005), in the global assessment of efficacy (p < 0.001), and in some tasks of the Caregiver Burden Scale (p < 0.05).  Similar numbers of patients in each group experienced at least 1 adverse event (incobotulinumtoxinA, n = 21; placebo, n = 20).  The investigators noted that none of the study subjects developed neutralizing antibodies.

In clinical studies of incobotulinumtoxinA for cervical dystonia submitted to the FDA, the most commonly observed adverse reactions were dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain.  In clinical studies of incobotulinumtoxinA for blepharospasm, the most commonly observed adverse reactions were eyelid ptosis, dry eye, dry mouth, diarrhea, headache, visual impairment, dyspnea, nasopharyngitis, and respiratory tract infection.

The potency units of incobotulinumtoxinA are not interchangeable with other preparations of botulinum toxin products.  Therefore, units of biological activity of incobotulinumtoxinA can not be compared to or converted into units of any other botulinum toxin products.  IncobotulinumtoxinA is the only botulinum toxin that does not require refrigeration prior to reconstitution.

Abobotulinumtoxin A (Dysport) is an acetylcholine release inhibitor and a non-depolarizing neuromuscular blocking agent.  It has been shown in European studies to be a safe and effective treatment for cervical dystonia.  In a multi-center, double-blind, randomized, controlled trial, Truong and colleagues (2005) evaluated the safety and effectiveness of Dysport in cervical dystonia patients in the United States.  A total of 80 patients were randomly assigned to receive one treatment with Dysport (500 units) or placebo.  Participants were followed up for 4 to 20 weeks, until they needed further treatment.  They were assessed at baseline and weeks 2, 4, 8, 12, 16, and 20 after treatment.  Dysport was significantly more effective than placebo at weeks 4, 8, and 12 as assessed by the Toronto Western Spasmodic Torticollis Rating Scale (10-point versus 3.8-point reduction in total score, respectively, at week 4; p < or = 0.013).  Of participants in the Dysport group, 38 % showed positive treatment response, compared to 16 % in the placebo group (95 % CI: 0.02 to 0.41).  The median duration of response to Dysport was 18.5 weeks.  Side effects were generally similar in the two treatment groups; only blurred vision and weakness occurred significantly more often with Dysport.  No participants in the Dysport group converted from negative to positive antibodies after treatment.  These results confirmed previous reports that Dysport (500 units) is safe, effective, and well-tolerated in patients with cervical dystonia.

In a prospective, randomized, double-blind, placebo-controlled, dose-ranging study, Bakheit et al (2000) ought to define a safe and effective dose of Dysport for the treatment of upper limb muscle spasticity due to stroke.  Patients received either a placebo or 1 of 3 doses of Dysport (500, 1000, 1,500 units) into 5 muscles of the affected arm.  Effectiveness was assessed periodically by the Modified Ashworth Scale and a battery of functional outcome measures.  A total of 83 patients were recruited, and 82 completed the study.  The 4 study groups were comparable at baseline with respect to their demographic characteristics and severity of spasticity.  All doses of Dysport studied showed a significant reduction from baseline of muscle tone compared with placebo.  However, the effect on functional disability was not statistically significant and was best at a dose of 1,000 units.  There were no statistically significant differences between the groups in the incidence of adverse events.  The authors concluded that these findings suggested that treatment with Dysport reduces muscle tone in patients with post-stroke upper limb spasticity.  Treatment was effective at doses of Dysport of 500, 1000, and 1,500 units.  The optimal dose for treatment of patients with residual voluntary movements in the upper limb appears to be 1,000 units.

Hyman et al (2000) defined a safe and effective dose of Dysport for treating hip adductor spasticity in patients with multiple sclerosis.  Patients with definite or probable multiple sclerosis, and disabling spasticity affecting the hip adductor muscles of both legs, were randomized to one of four treatment groups.  Dysport (500, 1000, or 1,500 units), or placebo was administered by intra-muscular injection to 3 muscles.  Patients were assessed at entry, and 2, 4 (primary analysis time-point), 8, and 12 weeks post-treatment.  A total of 74 patients were recruited.  Treatment groups were generally well- matched at entry.  The primary efficacy variables -- passive hip abduction and distance between the knees -- improved for all groups.  The improvement in distance between the knees for the 1,500-unit group was significantly greater than placebo (p = 0.02).  Spasm frequency was reduced in all groups, but muscle tone was reduced in the Dysport groups only.  Pain was reduced in all groups, but improvements in hygiene scores were evident only in the 1,000-unit and 1,500-unit groups.  Duration of benefit was significantly longer than placebo for all Dysport-treated groups (p < 0.05).  Adverse events were reported by 32/58 (55 %) Dysport-treated patients, and by 10/16 (63 %) placebo patients.  Compared with the 2 lower dose groups, twice as many adverse events were reported by the 1,500-unit group (2.7/patient).  The incidence of muscle weakness was higher for the 1,500-unit group (36 %) than for placebo (6 %).  The response to treatment was considered positive by 2/3 of the patients in the 500-unit group, and by about 50 %  the patients in the other groups.  The authors concluded that Dysport reduced the degree of hip adductor spasticity associated with multiple sclerosis, and this benefit was evident despite the concomitant use of oral anti-spasticity medication and analgesics.  Although evidence for a dose response effect was not statistically significant, there was a clear trend towards greater efficacy and duration of effect with higher doses of Dysport.  Dysport treatment was well-tolerated, with no major side effects seen at doses up to 1,500 units.  The optimal dose for hip adductor spasticity seems to be 500 to 1,000 units, divided between both legs.

In a prospective, multi-center, double-blind, placebo-controlled, dose-ranging study, Pittock et al (2003) evaluated the effects of Dysport in post-stroke calf spasticity.  Dysport was administered at 500, 1,000 or 1,500 units in 234 stroke patients.  They were assessed at 4-week intervals over 12 weeks.  The primary outcome measure, 2-min walking distance and stepping rate increased significantly in each group (p < 0.05, paired test), but there was no significant difference between groups (including placebo).  Following Dysport treatment, there were small but significant (p = 0.0002 to 0.0188) improvements in calf spasticity, limb pain, and a reduction in the use of walking aids, compared to placebo.  Investigators' and patients' assessments of overall benefit suggested an advantage for Dysport over placebo, but this was not significant.  A total of 68 patients reported 130 adverse events, with similar numbers in each group.  The few severe events recorded were not considered to be treatment-related.  The authors concluded that Dysport resulted in a significant reduction in muscle tone, limb pain and dependence on walking aids.  The greatest benefits were in patients receiving Dysport 1,500 units, but 1,000 units also had significant effects.  Dysport 500 units resulted in some improvements.  Since few adverse events were reported, this therapy is considered safe and may be a useful treatment in post-stroke rehabilitation of the leg.

In a phase IV, prospective, one-arm, non-comparative open trial, Tsai et al (2005) investigated the safety and effectiveness of Dysport in patients with idiopathic blepharospasm or hemifacial spasm.  During the treatment period, patients were evaluated at baseline (week 0), week 6, and week 8, 10, or 12.  A total of 32 women and 16 men completed the whole course of the study.  The therapeutic efficacy of Dysport became evident from 1.5 to 15 days (mean +/- SD, 6.1 +/- 2.9 days).  The maximal effect appeared 12.2 +/- 5.0 days later.  Injection of Dysport resulted in amelioration of spasm symptom.  Dysport significantly improved the functions (e.g., reading, watching TV, house work, working, driving and outing alone).  Improvements remained at 12th week following Dysport injection.  The most frequent adverse event was ptosis, which was noted in 9 cases and represented 18.7 % of total patients.  Other adverse events were very mild, although lagophthalmos and dry eyes occurred in some patients, but none manifested any corneal complications.  The authors concluded that Dysport injection appears to be a safe and effective procedure with only by minor, and transit adverse events.

In a large-scale, multi-center, randomized clinical trial, Truong et al (2008) examined the safety and effectiveness of Dysport (40, 80, and 120 units/eye) versus placebo in the treatment of bilateral benign essential blepharospasm (BEB).  The findings of this study supported the high efficacy and good safety profile of Dysport, with improvement in functional impairment, reduction in frequency and intensity of facial spasms, and fewer withdrawals through lack of efficacy in the active treatment group compared with controls.  The best balance of sustained efficacy and favorable safety profile was provided by 80 units of Dysport/eye.

In a prospective, multi-center, randomized, double-blind, placebo-controlled study, Straube et al (2008) examined the effects of peri-cranial injection of Dysport for the treatment of tension-type headache.  Patients received injections of Dysport (total dose of 420 or 210 units) or saline placebo in 18 sites on the head and neck.  Of 125 patients treated, 118 were included in the intention-to-treat dataset.  No significant differences between each verum group and placebo were seen for the primary efficacy parameter -- change in the number of headache-free days at 4 to 8 weeks after injection compared with 4 weeks before injection.  The groups receiving 420 or 210 units of Dysport experienced 2.60 and 2.87 more headache-free days, respectively, compared with 1.93 more headache-free days for the placebo group (p = 0.66 versus 420 units; p = 0.52 versus 210 units).  Treatment with 420 units of Dysport was associated with significant improvements compared with placebo for two secondary efficacy parameters: mean change in headache duration from baseline to weeks 8 to 12 (p < 0.05) and improved global physician and patient assessment scores (p < 0.05).  The authors concluded that further studies should address the possible value of multiple injections with extended observation periods, dose optimization, and whether duration of headache history and number of previous treatments are predictors of patient response.

While several botulinum toxin preparations have been used in the treatment various disorders including cervical dystonia, there is much controversy regarding their respective potencies.  In a Cochrane review on botulinum toxin type A therapy for cervical dystonia, Costa et al (2005) noted that indirect comparisons between trials that used Dysport against placebo and trials that used Botox against placebo showed no significant differences between Dysport and Botox in terms of benefits or adverse events.  On the other hand, Chapman et al (2007) reported differences in adverse event rates between botulinum neurotoxin preparations (Botox, Dysport, and Myobloc), suggesting that use of these products should be based on their individual dosing, efficacy, and safety profiles.  Moreover, Karsai and Raulin (2009) performed a systematic review of published evidence about the unit equivalence of United Kingdom and United States botulinum neurotoxin A formulations.  The review was based on a detailed literature research in all relevant databases (MEDLINE, PubMed, Cochrane Library, specialist textbooks).  The present review supports the recent assumption that dose ratios of less than 3:1 (e.g., 2.5:1 or even 2:1) between Dysport and Botox are probably more suitable.  The authors stated that the current evidence is still insufficient, and further investigation of lower dose ratios is recommended.

1. the treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients, and
2. the temporary improvement in the appearance of moderate-to-severe glabellar lines associated with procerus and corrugator muscle activity in adult patients less than 65 years of age.

In July 2009, the FDA approved the following revisions to the prescribing information of Botox/Botox Cosmetic and Myobloc:

• A boxed warning highlighting the possibility of experiencing potentially life-threatening distant spread of toxin effect from the injection site after local injection.
• A Risk Evaluation and Mitigation Strategy (REMS) that includes a Medication Guide to help patients understand the risks and benefits of botulinum toxin products.
• Changes to the established drug names to reinforce individual potencies and prevent medication errors.  The drug name for Botox is onabotulinumtoxinA, and the drug name for Myobloc is rimabotulinumtoxinB.  The FDA emphasized that the potency units are specific to each botulinum toxin product, and the doses or units of biological activity can not be compared or converted from one product to any other botulinum toxin product.  The new established names are intended to reinforce these differences and the lack of interchangeability among products.

The other botulinum toxin product in this class, abobotulinumtoxinA (Dysport), included the Boxed Warning, REMS, and new established name at the time of approval in April 2009.

The FDA stated that health professionals should consider the following when using botulinum toxin:

• A Boxed Warning has been added to the prescribing information to highlight that botulinum toxin may spread from the area of injection to produce symptoms consistent with botulism.  Symptoms such as unexpected loss of strength or muscle weakness, hoarseness or trouble talking (dysphonia), trouble saying words clearly (dysarthria), loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids may occur. 
• Swallowing and breathing difficulties can be life-threatening and there have been reports of deaths related to the effects of spread of botulinum toxin. 
• Children treated for spasticity are at greatest risk for these symptoms, but symptoms can also occur in adults treated for spasticity and other conditions.
• Cases of toxin spread have occurred at botulinum toxin doses comparable to those used to treat cervical dystonia and at lower doses.
• No definitive serious adverse event reports of distant spread of toxin effect have been associated with dermatologic use of Botox/Botox Cosmetic at approved doses. 
• No definitive serious adverse event reports of distant spread of toxin effect have been associated with Botox for blepharospasm or for strabismus at approved doses. 
• The established drug names of the botulinum products have been changed to emphasize the differing dose to potency ratios of these products.
• Botulinum toxin products are not interchangeable.
• All botulinum toxin products have a Medication Guide; health professionals should urge patients, their families, and caregivers to review it carefully.
• Clinical doses expressed in units are not comparable from one botulinum toxin product to the next.  Units of one product can not be converted into units of another product.

Testing for Neutralizing Antibodies to Botulinum Toxin

Patients who respond to botulinum toxin injections initially but lose the response on subsequent injections may have developed neutralizing antibodies.  According to the prescribing information for Botox, the potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.  In uncontrolled studies, there are individuals who continue to respond to treatment despite the presence of neutralizing antibodies.  Not all patients who became non-responsive to botulinum toxin after an initial period of clinical responsiveness had neutralizing antibodies.

According to Hauser and Wahba (2205), an estimated 5 to 15 % of patients injected serially with 79-11 Botox developed secondary non-responsiveness from the production of neutralizing antibodies.  Risk factors associated with the development of neutralizing antibodies include injection of more than 200 units per session and repeat or booster injections given within 1 month of treatment.  The new BCB 2024 Botox may have a lower potential for neutralizing antibody production because of its decreased protein load, but this is not known.

Some patients injected for cosmetic purposes develop neutralizing antibodies.  When a patient loses his or her response, serum can be tested for neutralizing antibodies, although this rarely is performed outside research settings.  Alternatively, a patient's physiological response can be evaluated with a single injection of 15 units into the frontalis on one side.

Limited information is available as to whether neutralizing antibodies resolve over time and, consequently, whether attempts at re-injection should be made after a prolonged period.  An investigation is underway to determine whether injections of rimabotulinumtoxinB are useful in patients with neutralizing antibodies to botulinum toxin A.  Using the lowest dose of toxin necessary to achieve the desired clinical effect and avoiding re-injection within 1 month appear prudent in an effort to keep antibody formation as low and unlikely as possible.

Dressler and Hallett (2006) stated that in some patients treated with botulinum toxin, antibodies are produced in association with certain treatment parameters, patient characteristics and immunological properties of the botulinum toxin preparation used.  Therapeutic botulinum toxin preparations are comprised of botulinum neurotoxin, non-toxic proteins and excipients.  Antibodies formed against botulinum neurotoxin can block botulinum toxin's biological activity.  The antigenicity of a botulinum toxin preparation depends on the amount of botulinum neurotoxin presented to the immune system.  This amount is determined by the specific biological activity, the relationship between the biological activity and the amount of botulinum neurotoxin contained in the preparation.  For Botox the specific biological activity is 60 MU-EV/ng neurotoxin, for Dysport 100 MU-EV/ng neurotoxin and for Myobloc/NeuroBloc 5 MU-EV/ng neurotoxin.  For Myobloc/NeuroBloc this translates into an antibody-induced therapy failure rate of 44 % in patients treated for cervical dystonia, whereas for botulinum toxin type A preparations this figure is approximately 5 %.  No obvious differences in antigenicity of botulinum toxin type A preparations have been detected thus far.  For the current formulation of Botox, the rate of antibody-induced therapy failure is reportedly less than 1 %.  The authors concluded that to determine the antigenicity of different botulinum toxin preparations in more detail, prospective studies on large series of unbiased patients with sensitive and specific botulinum toxin antibody tests are needed.

On August 24, 2011, the FDA approved botulinum toxin type A (Botox) for treating bladder over-activity (neurogenic bladder) resulting from MS or spinal cord injury.  The drug must be injected into the bladder using cystoscopy, which may require general anesthesia.  It relaxes the bladder muscle, increasing its storage capacity and reducing incontinence.  According to the FDA, treatment benefits last about 9 months.  The approval was based on 2 placebo-controlled clinical studies involving a total of 691 patients.  Both studies showed statistically significant decreases in the weekly frequency of incontinence episodes in the Botox group compared with placebo.  Urinary tract infections and urinary retention were the most common adverse effects in this population.  The latter condition may require self-catheterization to empty the bladder.

In a 6-month follow-up study, Giannantoni et al (2011) examined the effect of intra-detrusor injection of 100 U botulinum toxin type A in patients with Parkinson's disease (PD) and refractory detrusor overactivity.  A total of 8 patients (1 man and 7 women) with PD and detrusor overactivity refractory to anti-cholinergics were injected with 100 U botulinum toxin type A.  Daytime and nighttime urinary frequency, and urinary incontinence episodes were recorded.  Patients also completed a standardized quality of life questionnaire on incontinence and a VAS on the impact of bladder problems on daily life activities, and underwent urodynamic assessment, including pressure flow studies.  Clinical and urodynamic assessment was performed before, and 1, 3 and 6 months after injection.  In all patients 100 U botulinum toxin type A induced decreased daytime and nighttime urinary frequency, a decreased number of urinary incontinence episodes, increased quality of life scores and, as shown by increased maximum cystometric capacity, improved urodynamic findings.  In 2 patients with PD post-void residual urine volume developed.  The authors concluded that intra-detrusor injection of 100 U botulinum toxin type A induced clinical and urodynamic improvement in overactive bladder symptoms that lasted at least 6 months in patients with PD.  Moreover, the authors stated that further studies are needed before botulinum toxin type A can be proposed as treatment for men with PD.

Ihde and Konstantinovic (2007) performed a systematic search of the literature to identify RCTs evaluating patients treated with botulinum toxin as an adjunct to dental implant therapy, maxillofacial conditions including temporo-mandibular disorders (TMD), and cervical dystonia.  Four RCTs met the authors' search criteria in the area of cervical dystonia and chronic facial pain.  No RCTs were identified evaluating dental implant therapy.  Patients with cervical dystonia exhibited significant improvements in baseline functional, pain, and global assessments compared to placebo.  Adverse events were mild and transient with numbers needed to harm (NNH) ranging from 12 to 17.  Patients with chronic facial pain improved significantly from baseline in terms of pain compared to placebo.  Rates of adverse events were less than 1 %.  The authors concluded that botulinum toxin appears relatively safe and effective in treating cervical dystonia and chronic facial pain associated with masticatory hyperactivity.  No literature exists evaluating its use in dental implantology; RCTs are needed to determine its safety and efficacy in dental implantology and other maxillofacial conditions such as bruxism (i.e., teeth clenching or teeth grinding).

Lang et al (2009) reviewed studies involving the treatment of bruxism in individuals with developmental disabilities.  Systematic searches of electronic databases, journals, and reference lists identified 11 studies meeting the inclusion criteria.  These studies were evaluated in terms of: (a) participants, (b) procedures used to assess bruxism, (c) intervention procedures, (d) results of the intervention, and (e) certainty of evidence.  Across the 11 studies, intervention was provided to a total of 19 participants aged 4 to 43 years.  Assessment procedures included dental screening under sedation and interviews with caregivers.  Intervention approaches included prosthodontics, dental surgery, injection of botulinum toxin-a, behavior modification, music therapy, and contingent massage.  Positive outcomes were reported in 82 % of the reviewed studies.  Overall, the evidence base is extremely limited and no definitive statements regarding treatment efficacy can be made.  However, behavior modification and dental or medical treatment options (e.g., prosthodontics) seem to be promising treatment approaches.  At present, a 2-step assessment process, consisting of dental screening followed by behavioral assessment, can be recommended.

In a pilot study, Terre et al (2008) evaluated the efficacy of botulinum toxin injection in the cricopharyngeus muscle in patients with neurological dysphagia caused by alteration in the upper esophageal sphincter (UES) opening and with preserved pharyngeal contraction.  A study was undertaken in 10 patients (7 brain lesions and 3 cervical spinal cord injuries), with a minimum time-lapse of 6 months from neurological lesion to botulinum toxin injection.  Dysfunction of the UES opening and the presence of pharyngeal contraction were diagnosed by videofluoroscopy (VDF) and esophageal manometry (EM).  Botulinum toxin (100 U) injection was guided by endoscopy.  Clinical, VDF, and EM follow-ups were carried out at 3 weeks, 3 and 6 months, and at 1 year post-injection.  Prior to treatment, 6 patients were fed by nasogastric tube.  Videofluoroscopy showed impairment of the UES opening, residue in piriform sinuses, and aspiration in all cases.  During follow-up, there was a decrease in the number of patients that had aspiration: 3 patients at 1 year.  During swallowing, EM showed a mean UES relaxation of 90 % (range of 74.5 to 100 %), residual pressure 3.2 mmHg (range of 0 to 13 mmHg) and pharyngeal amplitude 52 mmHg (range of 25 to 80 mmHg).  At follow-up, a significant improvement in UES relaxation (98 % (89 to 100 %)) and pharyngeal contraction (97 mmHg (35 to 165 mmHg)) was observed.  At 3 months, 6 patients were eating exclusively by mouth.  The authors concluded that 1 single injection of botulinum toxin in the UES has long-lasting effectiveness in patients with neurological dysphagia caused by alteration in the UES opening and with pharyngeal contraction.  Nevertheless, a RCT should be done to confirm these results and rule out the effect of potential spontaneous improvement of neurological injury.

Bashashati et al (2010) stated that diffuse esophageal spasm is a primary esophageal motility disorder.  The prevalence is 3 to 10 % in patients with dysphagia and treatment options are limited.  The author summarized the treatment of diffuse esophageal spasm, including pharmacotherapy, endoscopic treatment, and surgical treatment with a special focus on botulinum toxin injection.  A PubMed search was performed to identify the literature using the search items diffuse esophageal spasm and treatment.  Pharmacotherapy with smooth muscle relaxants, proton pump inhibitors, and antidepressants was suggested from small case series and uncontrolled clinical trials.  Endoscopic injection of botulinum toxin is a well-studied treatment option and results in good symptomatic benefit in patients with diffuse esophageal spasm.  Surgical treatment was reported in patients with very severe symptoms refractory to pharmacologic treatment.  This article summarized the present knowledge on the treatment of diffuse esophageal spasm with a special emphasis on botulinum toxin injection.  Endoscopic injection of botulinum toxin is presently the best studied treatment option but many questions remain unanswered.

Pelvic floor tension myalgia is a diagnosis of exclusion.  It is also known as coccygodynia, diaphragma pelvis spastica, levator ani syndrome, levator spasm syndrome, spastic and pelvic floor syndrome.  There is insufficient evidence to support the use of botulinum toxin for pelvic floor tension myalgia.  A small RCT (n = 12) concluded that botulinum toxin is safe but ineffective (Rao et al, 2009).  A European Consensus Report (Apostolidis et al, 2009) found that evidence for use of botulinum toxin in pelvic floor disorders is inconclusive.

In a Cochrane review, Waseem et al (2011) examined the effects of botulinum toxin injections in adults with LBP.  These investigators searched CENTRAL (The Cochrane Library 2009, issue 3) and MEDLINE, EMBASE, and CINAHL to August 2009; screened references from included studies; consulted with content experts and Allergan.  They included published and unpublished randomized controlled trials without language restrictions.  They included randomized trials that evaluated botulinum neurotoxin (BoNT) serotypes versus other treatments in patients with non-specific LBP of any duration.  Two review authors selected the studies, assessed the risk of bias using the Cochrane Back Review Group criteria, and extracted the data using standardized forms.  They performed a qualitative analysis due to lack of data.  These researchers excluded evidence from 19 studies due to non-randomization, incomplete or unpublished data.  They included 3 randomized trials (n = 123 patients).  Only 1 study included patients with chronic non-specific LBP; the other 2 examined unique subpopulations.  Only 1 of the 3 trials had a low risk of bias and demonstrated that BoNT injections reduced pain at 3 and 8 weeks and improved function at 8 weeks better than saline injections.  The 2nd trial showed that BoNT injections were better than injections of corticosteroid plus lidocaine or placebo in patients with sciatica attributed to piriformis syndrome.  The 3rd trial concluded that BoNT injections were better than traditional acupuncture in patients with third lumbar transverse process syndrome.  Both studies with high risk of bias had several key limitations.  Heterogeneity of the studies prevented meta-analysis.  There is low quality evidence that BoNT injections improved pain, function, or both better than saline injections and very low quality evidence that they were better than acupuncture or steroid injections.  The authors concluded that they identified 3 studies that investigated the merits of BoNT for LBP, but only 1 had a low risk of bias and evaluated patients with non-specific LBP (n = 31).  They stated that further research is very likely to have an important impact on the estimate of effect and the confidence in it.  Future trials should standardize patient populations, treatment protocols and comparison groups, enlist more participants and include long-term outcomes, cost-benefit analysis and clinical relevance of findings.

Nuzzo et al (1997) used botulinum toxin to treat paralytic scoliosis.  A total of 12 children with paralytic scoliosis and severe, complicating additional diseases required surgical delay were included in this study.  Although this use of botulinum toxin is experimental, alternative treatments posed greater risks.  An institutional review board protocol for non-established dosage and indication for treatment was initiated to monitor safety and effect.  Treatment was intended to supplement, not replace, other desirable treatment modalities.  The effect was to be measured by the return of efficacy of conservative treatment in halting curve progression.  Short-term results showed that none of the children had worsened scoliosis; all had some reduction in curve measurement (up to greater than 50 degrees).

Also, an UpToDate review on "Treatment and prognosis of adolescent idiopathic scoliosis" (Scherl, 2011) does not mention the use of botulinum toxin as a therapeutic option.

Cordivari et al (2001) reported the findings of 14 patients with "dystonic clenched fist" (3 with cortico-basal ganglionic degeneration, 7 with Parkinson's disease, and 4 with dystonic-complex regional pain syndrome) who were treated with botulinum toxin A (BTXA, Dysport).  The muscles involved were identified by the hand posture and EMG activity recorded at rest and during active and passive flexion/extension movements of the finger and wrist.  EMG was useful in distinguishing between muscle contraction and underlying contractures and to determine the dosage of BTX.  All patients had some degree of flexion at the proximal metacarpophalangeal joints and required injections into the lumbricals.  The response in patients depended on the severity of the deformity and the degree of contracture.  All patients had significant benefit to pain, with accompanying muscle relaxation, and palmar infection, when present, was eradicated.  Four patients with Parkinson's disease and 1 patient with dystonia-complex regional pain syndrome obtained functional benefit.  Thus, 36 % (5 out of 14) of patients had positive outcomes; not out of the realm of placebo effects.

In a pilot study, Castiglione et al (2011) evaluated the effectiveness of intra-articular injection of botulinum toxin A (BTX-A) in relieving hemiplegic shoulder pain (HSP).  Patients (n = 5) with HSP refractory to standard treatments and pain score at rest greater than 7 on a pain VAS of 0 to 10 cm were included in this study.  Main outcome measure was variation in VAS score at rest and during 90° passive arm abduction 2 and 8 weeks after BTX-A intra-articular injection.  Baseline VAS score was 8.7 +/- 1 at rest and 9.8 +/- 0.4 during passive arm abduction.  It clearly decreased at 2 (1.5 +/- 1.1 at rest, p = 0.001; 3 +/- 1.2 during arm abduction, p < 0.001) and 8 weeks (1.5 +/- 1.2 at rest, p =0.001; 2.3 +/- 1.1 during arm abduction, p < 0.001) after BTX-A intra-articular injection.  The authors found a strong correlation between intra-articular BTX-A injection and pain relief in patients with HSP.  The findings of this result could provide the rationale for RCTs designed to better evaluate the safety and effectiveness of intra-articular BTX-A injection in patients with refractory HSP.

In a double-blind, randomized, parallel group study, Finlayson et al (2011) examined the effect of BTX-A injections to the scalene muscles on pain in subjects with thoracic outlet syndrome (TOS).  Patients were followed-up at 6 weeks, 3 months, and 6 months.  A total of 38 patients referred to physiatrists for management of TOS with BTX-A injection were included.  One subject was lost to follow-up and all other subjects completed the trial.  A 75-unit dose of BTX-A reconstituted with 0.75 cc of normal saline was injected to the anterior scalene (37.5 units) and middle scalene (37.5 units) muscles using EMG guidance.   The primary outcome measure was pain as measured on a horizontal VAS 6 weeks post-injection.  Secondary outcomes were paresthesias measured on a VAS and function measured with the Disabilities of the Arm, Shoulder and Hand (DASH) and Short-form 36 (SF-36) questionnaires.  For the primary outcome measure of VAS scores for pain at 6 weeks, the difference in the means adjusted for baseline VAS scores between placebo and BTX-A was 5.03 mm in favor of BTX-A (95 % CI: -15.7 to 5.7, p = 0.36).  Changes in secondary outcome measures were also not statistically significant.  The authors concluded that BTX-A injections to the scalene muscles did not result in clinically or statistically significant improvements in pain, paresthesias, or function in this population of subjects with TOS.

In a Cochrane review, Rowe and Noonan (2012) evaluated the effectiveness of botulinum toxin in the treatment of strabismus compared with alternative treatment options, and investigated dose effect and complication rates.  These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 11), MEDLINE (January 1950 to December 2011), EMBASE (January 1980 to December 2011), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2011), the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP).  There were no date or language restrictions in the electronic searches for trials.  The electronic databases were last searched on December 5, 2011.  These researchers manually searched the Australian Orthoptic Journal and British and Irish Orthoptic Journal and ESA, ISA and IOA conference proceedings.  They attempted to contact researchers who are active in this field for information about further published or unpublished studies.  They included RCTS of any use of botulinum toxin treatment for strabismus.  Each review author independently assessed study abstracts identified from the electronic and manual searches.  Author analysis was then compared and full papers for appropriate studies were obtained.  These investigators found 4 RCTs that were eligible for inclusion; 2 trials found that there was no difference between the use of botulinum toxin and surgery for patients requiring re-treatment for acquired esotropia or infantile esotropia.  There was no evidence for a prophylactic effect of botulinum toxin in a treatment trial of acute onset 6th nerve palsy.  Botulinum toxin had a poorer response than surgery in a trial of patients requiring treatment for horizontal strabismus in the absence of binocular vision.  Reported complications included ptosis and vertical deviation and ranged from 24 % in a trial using Dysport to 52.17 % and 55.54 % in trials using Botox.  The authors concluded that the majority of published literature on the use of botulinum toxin in the treatment of strabismus consists of retrospective studies, cohort studies or case reviews.  Although these provide useful descriptive information, clarification is needed to ascertain the effective use of botulinum toxin as an independent treatment modality.  Four RCTs on the therapeutic use of botulinum toxin in strabismus have shown varying responses ranging from a lack of evidence for prophylactic effect of botulinum toxin in acute 6th nerve palsy, to poor response in patients with horizontal strabismus without binocular vision, to no difference in response in patients that required re-treatment for acquired esotropia or infantile esotropia.  It was not possible to establish dose effect information.  Complication rates for use of Botox or Dysport  ranged from 24 % to 55.54 %.

Lee et al (2010) evaluated the effect of botulinum toxin type A on nocturnal bruxism.  A total of 12 subjects reporting nocturnal bruxism were recruited for a double-blind, RCT; 6 bruxers were injected with botulinum toxin in both masseters, and 6 with saline.  Nocturnal electromyographic activity was recorded in the subject's natural sleeping environment from masseter and temporalis muscles before injection, and 4, 8, and 12 weeks after injection and then used to calculate bruxism events.  Bruxism symptoms were investigated using questionnaires.  Bruxism events in the masseter muscle decreased significantly in the botulinum toxin injection group (p = 0.027).  In the temporalis muscle, bruxism events did not differ between groups or among times.  Subjective bruxism symptoms decreased in both groups after injection (p < 0.001).  The authors concluded that these findings suggested that botulinum toxin injection reduced the number of bruxism events, most likely mediated its effect through a decrease in muscle activity rather than the central nervous system.  The authors controlled for placebo effects by randomizing the interventions between groups, obtaining subjective and objective outcome measures, using the temporalis muscle as a control, and collecting data at 3 post-injection times.  They stated that the findings of this controlled study supported the use of botulinum toxin injection as an effective treatment for nocturnal bruxism.

Redaelli (2011) assessed the benefits, outcome, and side effects of using botulinum toxin A (BTxA) in the treatment of bruxism.  From January 2009 to January 2010, a total of 120 bruxers were treated; no special examinations were carried out, since the exact diagnoses were made beforehand.  All were treated with BTxA in the masseter muscle with standardized doses and injection sites.  A follow-up examination was made 15 days post-procedure, and all patients responded to a short satisfaction questionnaire; 23 patients were re-injected with additional doses of BTxA for insufficient results.  Subjective results and side effects were assessed.  All patients have declared a good/very good improvement in symptoms.  No significant side effects were seen.  At the study's conclusion, 36 patients (30 %) declared a fair result, 79 (65.8 %) good, and 5 (4.2 %) excellent.  The authors concluded that botulinum toxin A is a simple method of treatment of bruxism, without side effects and appreciated by patients. 

Alonso-Navarro et al (2011) reported their long-term experience in the treatment of bruxism with botulinum toxin type A.  The outcome of 19 patients with severe bruxism who underwent periodical treatment with botulinum toxin A infiltrations in both temporal and masseter muscles, using initial doses of 25 IU per muscle, during a follow-up period ranging from 0.5 to 11 years, was described.  Doses were adjusted in follow-up visits according the response degree.  None of the patients reported side-effects.  Final doses of botulinum toxin ranged from 25 to 40 IU per muscle (mean of 29.7 ± 4.9), and duration of the effect from 13 to 26 weeks (mean of 16.7 ± 5.1).  The authors concluded that botulinum toxin A infiltrations are a safe and useful treatment for patients with severe bruxism.

Arzul et al (2012) stated that hypertrophy of the masticatory muscles most commonly affects the masseter.  Less common cases of isolated or associated temporalis hypertrophy have also been reported.  Para-functional habits, and more precisely bruxism, can favor the onset of the hypertrophy.  This condition is generally idiopathic and can require both medical and/or surgical management.  These investigators presented the case of a 29-year old patient who was referred to their department for an asymmetric swelling of the masticatory muscles.  Physical examination revealed a bilateral hypertrophy of the masticatory muscles, predominantly affecting the right temporalis and the left masseter.  Major bruxism was assessed by premature dental wearing.  The additional examinations confirmed the isolated muscle hypertrophy.  Benign asymmetric hypertrophy of the masticatory muscles promoted by bruxism was diagnosed.  Treatment with injections of type A botulinum toxin was conducted in association with a splint and relaxation.  Its effectiveness has been observed at 6 months.  The authors noted that few cases of unilateral or bilateral temporalis hypertrophy have been reported, added to the more common isolated masseter muscles hypertrophy.  The condition is thought to be favored by para-functional habits such as bruxism.  The conservative treatment consists in reducing the volume of the masticatory muscles using intra-muscular injections of type A botulinum toxin.  Other potential conservative treatments are wearing splints and muscle relaxant drugs.  Surgical procedures aiming to reduce the muscle volume and/or the bone volume (mandibular gonioplasty) can be proposed.

In an evidence-based review, Long et al (2012) evaluated the effectiveness of botulinum toxins on bruxism.  Electronic databases (PubMed, Embase and Science Citation Index), websites (Cochrane Central Register of Controlled Trials and ClinicalTrials.gov) and the literature database of SIGLE (System for Information on Grey Literature in Europe) were searched from January 1990 to April 2011 for RCTs or non-randomized studies assessing the effectiveness of botulinum toxins on bruxism.  There was no language restriction.  Through a pre-defined search strategy, these investigators retrieved 28 studies from PubMed, 94 from Embase, 60 from the Science Citation Index, 2 ongoing clinical trials and 2 from the Cochrane Central Register of Controlled Trials.  Of these, only 4 studies met inclusion criteria and were finally included.  Of the 4 included studies, 2 were RCTs and 2 were controlled before-and-after studies.  These studies showed that botulinum toxin injections can reduce the frequency of bruxism events, decrease bruxism-induced pain levels and satisfy patients' self-assessment with regard to the effectiveness of botulinum toxins on bruxism.  In comparison with oral splint, botulinum toxins are equally effective on bruxism.  Furthermore, botulinum toxin injections at a dosage of less than 100 U are safe for otherwise healthy patients.  The authors concluded that botulinum toxin injections are effective on bruxism and are safe to use.  Therefore, they can be used clinically for otherwise healthy patients with bruxism.

Persaud et al (2013) noted that botulinum toxin (Botox) works by blocking the release of acetylcholine from the cholinergic nerve end plates leading to inactivity of the muscles or glands innervated.  Botox is best known for its beneficial role in facial aesthetics but recent literature has highlighted its usage in multiple non-cosmetic medical and surgical conditions.  These investigators reviewed the current evidence pertaining to Botox use in the head and neck.  A literature review was conducted using the Cochrane Controlled Trials Register, Medline and Embase databases limited to English Language articles published from 1980 to 2012.  The findings suggested that there is level-1 evidence supporting the efficacy of Botox in the treatment of spasmodic dysphonia, essential voice tremor, headache, cervical dystonia, masticatory myalgia, sialorrhea, temporo-mandibular joint disorders, bruxism, blepharospasm, hemi-facial spasm and rhinitis.  For chronic neck pain there is level-1 evidence to show that Botox is ineffective.  Level-2 evidence exists for vocal tics, trigeminal neuralgia, dysphagia and post-laryngectomy esophageal speech.  For stuttering, “first bite syndrome”, facial nerve paresis, Frey's syndrome, oromandibular dystonia and palatal/stapedial myoclonus the evidence is level-4.  Thus, the literature high-lighted a therapeutic role for Botox in a wide range of non-cosmetic conditions pertaining to the head and neck (mainly level-1 evidence).  With ongoing research, the spectrum of clinical applications and number of people receiving Botox will no doubt increase.  Botox appears to justify its title as “the poison that heals”.

Garcia-Ruiz (2013) stated that “At present, botulinum toxin (BT) is one of the most fundamental available drugs in Neurology, only comparable with levodopa.  Botulinum toxin is currently used in those entities characterized by excessive muscle contraction, including dystonia and spasticity.  In addition, BT has been used to control pain associated with increased muscle contraction in dystonia and spasticity, but also is useful to control chronic pain not associated with muscle contraction, such as chronic daily headache.  Finally, BT is useful in sialorrhea and bruxism.  The mechanism of action is complex, mainly acting on terminal neuromuscular junction, but also exhibiting analgesic properties, probably through inhibition of pain neurotransmitters release”.

In a Cochrane review, Fedorowicz et al (2013) evaluated the safety and effectiveness of botulinum toxin type A compared to placebo or no treatment, for the management of benign bilateral masseter hypertrophy.  These investigators searched the following databases from inception to April 2013: the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (via PubMed); EMBASE (via embase.com); Web of Science; CINAHL; Academic Search Premier (via EBSCOhost); ScienceDirect; LILACS (via BIREME); PubMed Central and Google Scholar.  Thee investigators searched 2 bibliographic databases of regional journals (IndMED and Iranmedex), which were expected to contain relevant trials.  They also searched reference lists of relevant articles and contacted investigators to identify additional published and unpublished studies.  Randomized controlled trials and controlled clinical trials (CCTs) comparing intra-masseteric injections of botulinum toxin versus placebo administered for cosmetic facial sculpting in individuals of any age with bilateral benign masseter hypertrophy, which had been self-evaluated and confirmed by clinical and radiological examination were considered for inclusion.  They excluded participants with unilateral or compensatory contralateral masseter hypertrophy resulting from head and neck radiotherapy.  Two review authors independently screened the search results.  For future updates, 2 authors will independently extract data and assess trial quality using the Cochrane risk of bias tool.  Risk ratios (RR) and corresponding 95 % CI will be calculated for all dichotomous outcomes and the mean difference (MD) and 95 % CI will be calculated for continuous outcomes.  These investigators retrieved 683 unique references to studies.  After screening these references, 660 were excluded for being non-applicable.  They assessed 23 full text articles for eligibility and all of these studies were excluded from the review.  The authors were unable to identify any RCTs or CCTs assessing the safety and effectiveness of intra-masseteric injections of botulinum toxin for people with bilateral benign masseter hypertrophy.  They stated that the absence of high level evidence for the effectiveness of this intervention emphasizes the need for well-designed, adequately powered RCTs.

In a pilot study, Climent et al (2013) examined the therapeutic potential of onabotulinumtoxinA in Morton neuroma.  These researchers presented an open-label study with 17 consecutive patients with Morton neuroma and pain of more than 3 months' duration that had not responded to conservative treatment with physical measures or corticosteroid injection.  Patients received 1 onabotulinumtoxinA injection in the area of the neuroma.  The main outcome measure was the variation in the pain on walking evaluated using a VAS before treatment and at 1 and 3 months after treatment.  The secondary outcome was the change in foot function, which was assessed using the Foot Health Status Questionnaire.  In the overall group, the mean initial VAS score on walking was 7.  This mean score had fallen to 4.8 at 1 month after treatment and to 3.7 at 3 months.  Twelve patients (70.6 %) reported an improvement in their pain and 5 patients (29.4 %) reported no change; exacerbation of the pain did not occur in any patient.  Improvements were also observed in 2 of the dimensions of the Foot Health Status Questionnaire: foot pain, which improved from a mean of 38.88 before treatment to 57 at 3 months, and foot function, which improved from a mean of 42.27 before treatment to 59.9 at 3 months.  Clinical variables including age, sex, site and size of the lesion, standing activity, weekly duration of walking, footwear, foot type and footprint had no influence on the outcome.  No adverse effects were reported.  The authors concluded that in this pilot study, injection with onabotulinumtoxinA was shown to be of possible usefulness to relieve the pain and improve function in Morton neuroma.  They stated that this finding opened the door to further clinical research.

Hu and colleagues (2013) systematically reviewed the therapeutic efficacy and safety of BTX-A in trigeminal neuralgia.  PubMed, EMBASE, Cochrane Library Clinical Trials and Web of Science from January 1966 to March 2013 were searched with the terms of "botulinum toxin" and "trigeminal neuralgia", and references of related articles were traced.  Data on the safety and effectiveness of BTX-A in this disorder were extracted and analyzed by at least 2 reviewers.  Data for individual studies were reported, and pooled data were analyzed if appropriate.  A total of 5 prospective studies and 1 double-blind, randomized, placebo-controlled study were identified.  Response was achieved in approximately 70 to 100 % of patients, and the mean pain intensity and frequency were reduced by approximately 60 to 100 % at 4 weeks after treatment in most studies.  Major adverse events were not reported.  The authors concluded that available studies showed BTX-A may be effective in treatment of trigeminal neuralgia.  Moreover, they stated that well-designed randomized, controlled, double-blinded trial is still lacking.  Future BTX-A treatment studies on optimal dose, duration of the therapeutic efficacy, common AEs, and the time and indications for repeat injection would be promising.

A systematic review found that BTX-A may be associated with improvement in the frequency of chronic migraine, but the association of BTX-A with clinical benefit was small (Jackson et al, 2012).  Botulinum toxin A was associated with a reduction in the number of headaches per month from 19.5 to 17.2 for chronic migraine.  The review also found a strong association of placebo with improvement in headaches over time.  The review reported that, in single trials, BTX- A was not associated with fewer migraine headaches per month versus valproate, topiramate, or amitriptyline.

Guidance from the National Institute for Health and Clinical Excellence (NICE, 2012) on BTX-A in chronic migraine concluded that BTX-A is recommended as an option for the prophylaxis of headaches in adults with chronic migraine (defined as headaches on at least 15 days per month of which at least 8 days are with migraine) that has not responded to at least 3 prior pharmacological prophylaxis therapies and whose condition is appropriately managed for medication over-use.  The guidance stated that treatment with BTX- A should be stopped in people whose condition is not adequately responding to treatment (defined as less than a 30 % reduction in headache days per month after 2 treatment cycles) or has changed to episodic migraine (defined as fewer than 15 headache days per month) for 3 consecutive months.

A technology assessment of BTX for chronic migraine (Kim et al, 2014) found it uncertain whether BTX reduces the frequency of headache days, reduces acute headache pain medication, or has any impact on functioning in comparison with saline.  The report concluded that “botulin toxin A injection may result in little or no difference in the number of headache episodes, headache hours and quality of life in comparison to saline injections”.

An assessment of BTX from the Canadian Agency for Drugs and Technologies in Health (CADTH, 2014) concluded: “Two randomized controlled trials (RCTs) (PREEMPT-1 and PREEMPT-2) demonstrated that OA [onabotulinumtoxinA] was statistically superior to placebo for improving health-related quality of life and reducing the number of headache days and migraine/probable migraine days in patients with chronic migraine; however, the absolute difference between the OA and placebo groups was relatively small for this chronic condition (range of -1.4 to -2.3 headache days per 28-day period and -1.6 to -2.3 migraine/probable migraine per 28-day period)”.  The assessment also found that there were significant limitations with the design of the PREEMPT-1 and PREEMPT-2 trials, such as the potential inclusion of patients with medication over-use headache, which precludes an accurate assessment of the clinical benefits of onabotulinumtoxinA in the management of chronic migraine.

An assessment by the California Technology Assessment Forum (Tice et al., 2014) concluded that BTX injections are superior to no therapy for the prevention of chronic migraine, but the evidence is inadequate to determine its comparative effectiveness to lower-cost, commonly-prescribed oral agents for chronic migraine prevention. The CTAF panel concluded that "coverage policies requiring attempts with other treatments before using BOTOX are reasonable and reflect current practice."

An UpToDate review on (Caviness, 2014) states that “Botulinum toxin injections of the levator veli palatini and/or tensor veli palatini have been effective in some cases of essential palatal myoclonus, a form of segmental myoclonus.  In the largest case series, botulinum toxin injections were associated with complete resolution of symptoms (objective, intrusive clicking tinnitus) in four of five treated patients.  One patient had transient side effects that included dysphagia and nasal speech

Fried and Fried (2003) noted that spasticity is commonly seen after spinal cord injury (SCI), and a large percentage of patients with SCI will need treatment to control it.  Although oral medications do a fair job of controlling spasticity in most patients, some patients will need additional forms of treatment.  In many cases, oral medications alone do not adequately control spasticity or the patient cannot tolerate the side effects.  In these instances, botulinum toxin (BTX) may help control the spasticity for approximately 3 months after injection.  The amount of BTX and the injection sites can be tailored to meet individual patient needs.  Botulinum toxins can reduce spasticity, improve function, and reduce the amount of needed assistance.

Marciniak et al (2008) described the use and effects of BTX injections in persons with SCI and focal spasticity.  Chart review of patients with SCI receiving their first injection of BTX for spasticity control at a free-standing urban rehabilitation hospital.  Charts were reviewed for history and level of SCI, 1 of 5 self-identified goals (ambulation, positioning, upper-extremity function, hygiene, and pain control) before and after injection; site and doses of BTX used; and self-reported outcome on clinical follow-up.  Charts of 28 adults receiving BTX were reviewed.  All patients received BTX type A.  Dosages of BTX ranged from 10 to 119 units per muscle.  Improvement was noted for 56 % in ambulation and 71 % in positioning.  Overall, upper-extremity function improved in 78 %, hygiene improved in 66.6 %, and pain decreased in 83.3 %.  Early use of BTX injections (less than 1 year after onset of symptoms) versus late use of BTX injections did not influence effectiveness.  The authors concluded that BTX seems to be an effective treatment for focal spasticity and for reducing disability in persons with SCI.

Ward (2008) noted that spasticity is a physiological consequence of an insult to the brain or spinal cord, which can lead to life-threatening, disabling and costly consequences.  This typically occurs following stroke, brain injury, SCI, multiple sclerosis and other disabling neurological diseases and cerebral palsy.  It is but one feature of the upper motor neuron syndrome and there have been considerable developments in its management through new drugs and technology.  The sole indication for treating spasticity is when it is causing harm and interferes with active or passive functioning.  Successful treatment strategies have now been developed and there is good evidence of treatment effectiveness.  Treatment is essentially aimed at reducing abnormal sensory inputs, which have an impact on excessive and uncontrolled alpha-motor neuron activity.  Attending to the physical characteristics of muscle shortening is the basis of spasticity management.  All pharmacological interventions are adjunctive to a program of physical intervention and there is a good evidence base for this in relation to BTX treatment.  Management therefore aimed at the development of a formal treatment plan is important to document the intended outcomes, which should be written and agreed upon with the patient.  Anti-spastic drugs treat spasticity.  They do not treat contractures and they will not make hemiplegic limbs function, unless the patient's function is impeded by the spasticity.  The management of spasticity is physical and all pharmacological interventions are adjunctive to that.  This article therefore dealt with the principles of management of spasticity and treatment with BTX.  It covered treatment planning, patient assessment, goal-setting and covered the range of available treatments.  It also described how BTX works, the evidence for its use in spasticity management and practical aspects of treatment, such as muscle location, the injection procedure and post-injection care.  Finally, there was a word on the organization of services.  The contribution of BTX to spasticity management is now well-recognized.  The trick in clinical management is to use it intelligently and to know when and when not to use it.  It is a useful short-term means of improving patients' function and the distressing features of spasticity following an insult to the central nervous system.  This is usually against the background of a long-term condition, for which a long-term management strategy is required.  The authors concluded that BTX provided a window of opportunity to improve the outcomes from physical management of the focal and multi-focal problems of spasticity.

Xing et al (2010) explored clinical safety and effectiveness of electro-acupuncture combined with acupoint-injection of BTX A for the treatment of muscle spasticity by SCI.  A total of 38 patients with muscle spasticity by SCI were treated from December 2006 to December 2009 including 26 males and 12 females, with an average age of 45.4 years old ranging from 21 to 68 years.  The patients were randomly divided into 3 groups according to admission time, 13 patients in group A were treated with electro-acupuncture combined with acupoint-injection of BTX A, and 13 patients in group B were treated with acupoint-injection BTX A and 12 patients in group C were treated with electro-acupuncture.  After 6 months, these patients were evaluated by improved muscle Ashworth scoring (MAS) and clinical spasticity index (SCI).  A total of 38 patients were followed-up at 6 months after the treatment.  The result showed that the MAS scores of group A, B, C before treatment were (3.10 +/- 0.14), (3.20 +/- 0.17), (3.10 +/- 0.16), respectively and the CSI scores were (14.10 +/- 0.14), (14.30 +/- 0.11), (14.20 +/- 0.12), respectively; there were no statistical different among the 3 groups (p > 0.05).  After 6 months of treatment, the MAS scores were (1.10 +/- 0.16), (2.10 +/- 0.13), (2.00 +/- 0.14), respectively and the CSI scores were (9.10 +/- 0.11), (12.10 +/- 0.14), (13.10 +/- 0.12), respectively.  The MAS scores and CSI scores of group A were better than the other 2 groups (p < 0.05).  The authors concluded that the combination of Chinese hydropower needles and acupoints with BTX-A injection can achieve a comprehensive treatment and reduce pain and improve life quality quickly.  The electro-acupuncture combined with acupoint-inject BTX A is a novel safe and effective technique for the treatment of muscle spasticity by SCI.

Santamato and colleagues (2010) stated that a few studies have reported the use of botulinum toxin injections after SCI, as this is the gold standard to treat focal spasticity.  These investigators reported such a case here.  A 38-year old woman who had become paraplegic and care-dependent secondary to cervico-thoracic intramedullary ependymoma presented 8 months later with painful lower limb spasticity, which was being treated with oral anti-spastic and benzodiazepine drugs with no therapeutic effect.  These investigators treated the patient with intra-thecal baclofen to reduce her spasticity and in order to avoid the major side-effects of high dosages of oral baclofen.  After motor rehabilitation programs, which included functional electrical stimulation, the patient was able to wear an advanced reciprocating gait orthosis.  However, she experienced painful muscle spasms in her toes of the feet that limited her gait.  Therefore, she was also treated with bilateral injections of BTX type A into the flexor digitorum brevis muscles.  The patient reported relief of spasms and pain, enabling her to wear an advanced reciprocating gait orthosis and facilitating rehabilitation programs.  The authors concluded that the use of BTX type A may be an important adjunctive therapy to increase the therapeutic effect of baclofen on spasticity in small muscles, resulting in a more focal effect, and improving the use of orthoses and the effectiveness of rehabilitation programs in patients after SCI.

Rekand et al (2012) noted that up to 70 % of patients with SCI develop spasticity.  These investigators provided an overview of spasticity management, primarily in patients with SCI.  The study was based on literature searches in PubMed using the key phrases “spasticity” and “spasticity AND spinal cord injury”, and own clinical experience and research.  Spasticity may be general, regional or localized.  Factors such as an over-filled bladder, obstipation, acute infections, syringomyelia or bone fractures may substantially influence the degree of spasticity and must be determined.  An assessment of the clinical and functional consequences for the patient is decisive before management.  Active exercise, physiotherapy and per-oral drugs are the simplest and cheapest options.  Baclofen is the only centrally acting spasmolytic registered in Norway and is the first choice for per-oral treatment.  Benzodiazepines can also be used.  The effect of the tablets is generally limited and there are often pronounced side effects.  Local spasticity can be treated with BTX injections.  The effect is time-limited and the treatment must be repeated.  International guidelines recommend a combination of BTX injections and physiotherapy.  In cases of regional spasticity, particularly in the lower limbs, intra-thecal baclofen administered via a programmable pump may provide a continuous spasm-reducing effect.  Orthopedic surgery or neurosurgery may be an option for selected patients with intractable spasticity.

Also, an UpToDate review on “Chronic complications of spinal cord injury and disease” (Abrams and Wakasa, 2014) states that “Spasticity is common after SCI and has positive as well as negative effects.  Treatment is empiric and is aimed at minimizing pain while maximizing function.  Options include oral medication, intrathecal baclofen, botulinum toxin, and nerve blocks. Refractory spasticity may require surgery”.

Isner-Horobeti and colleagues (2013) noted that botulinum toxin A (BoNT-A) is used in the treatment of muscle hypertrophy but has never been used in chronic exertional compartment syndrome (CECS).  The objective diagnostic criterion in this condition is an abnormally elevated intra-muscular pressure (IMP) in the compartment.  In this study, the IMP was measured 1 minute (P1) and 5 minutes (P5) after the exercise was stopped before and after BoNT-A injection.  In this case-series study, these researchers hypothesized that botulinum toxin A would reduce the IMP (P1 and P5) and eliminate the pain associated with CECS.  Botulinum toxin A was injected into the muscles of moderately trained patients with an anterior or antero-lateral exertional compartment syndrome of the leg.  The BoNT-A dose (mean ± SD) ranged from 76 ± 7 to 108 ± 10 U per muscle, depending on which of the 5 muscles in the 2 compartments were injected.  The primary end-point was IMP (P1, P5).  Secondary end-points were exertional pain, muscle strength, and safety.  Follow-up was conducted up to 9 months.  A total of 25 anterior compartments and 17 lateral compartments were injected in 16 patients.  The time interval (mean ± SD) between the BoNT-A injection and after BoNT-A injection IMP measurement was 4.4 ± 1.6 months (range of 3 to 9 months).  In the anterior compartment, P1 and P5 fell by 63 % ± 17 % (p < 0.00001) and 59 % ± 24 % (p < 0.0001), respectively; in the lateral compartment, P1 and P5 fell by 68 % ± 21 % (p < 0.001) and 63 % ± 21 % (p < 001), respectively.  Exertional pain and muscle strength were monitored, based on the Medical Research Council score.  The exertional pain was completely eliminated in 15 patients (94 %).  In 5 patients (31 %), the strength of the injected muscles remained normal.  In 11 patients (69 %), strength decreased from 4.5 (out of 5) to 3.5 (p < 0.01), although without functional consequences.  In the conditions of this study, BoNT-A showed a good safety profile in patients with CECS.  The authors concluded that in this case-series study, BoNT-A reduced the IMP and eliminated exertional pain in anterior or antero-lateral CECS of the leg for up to 9 months after the intervention.  The mode of action of BoNT-A is still unclear.  They stated that a randomized controlled study should be carried out to determine whether BoNT-A can be used as a medical alternative to surgical treatment.

Furthermore, an UpToDate review on “Chronic exertional compartment syndrome” (Meehan, 2014) does not mention the use of botulinum toxin as a therapeutic option.

Hawlik et al (2014) stated that recent clinical trials suggested that BTX treatment of muscles involved in the development of negative emotions may also have an anti-depressant effect.  These investigators provided a systematic review of the literature regarding BTX in the treatment of major depression.  They screened the databases of Medline and Scopus using the search terms [("botulinum toxin" OR "botox") AND ("antidepressant" OR "depression" OR "depressed")].  The website Clinicaltrials.gov  was screened with the same search terms in order to detect current studies.  As of April 2013, these researchers identified 3 studies that evaluated the anti-depressant effects of BTX in the treatment of major depression.  An improvement in mood after treatment with BTX was seen in a case series of 10 depressed patients.  In a randomized, placebo-controlled study of 30 patients assigned to a verum (BTX, n = 15) or placebo (saline, n = 15) group, treatment with BTX has also shown a positive effect on mood.  Another prospective, open-label study evaluated the anti-depressive effect of BTX in 25 subjects with major depression.  On Clinicaltrials.gov these researchers identified 2 ongoing studies, which are currently investigating the anti-depressant effect of BTX.  The authors concluded that recently published studies have shown a reduction of depressive symptoms after treatment of the glabellar frown lines with BTX injections.  Moreover, they stated that further clinical studies in larger patient samples are needed to prove the safety and effectiveness of BTX injections used for the treatment of depressive disorders.

Isaac et al (2012) described a new technique for the treatment of diplopia secondary to cosmetic botulinum toxin A use.  These researchers reported the cases of 2 consecutive patients who developed diplopia after peri-ocular cosmetic use of botulinum toxin A were treated with intramuscular botulinum toxin A injection into the antagonist extra-ocular muscle.  Diplopia resolved in both patients in less than 1 week with no side effects or complications.  The authors concluded that the injection of intra-muscular botulinum toxin A is an encouraging option for treatment of diplopia secondary to botulinum toxin A use for facial lifting.

The Colorado Division of Workers' Compensation’s guideline on “Traumatic brain injury medical treatment guidelines” (2012) stated that “surgery may be required to eliminate or decrease diplopia and other cranial nerve repair or decompression may be required for functionally disabling conditions such as diplopia”.  The guideline did not mention the use of botulinum toxin for the treatment of diplopia as a consequence of traumatic brain injury.

In fact, Sheen-Ophir and Almog (2013) reported the development of diplopia following subcutaneous injections of botulinum toxin for cosmetic or medical use.  These researchers noted that botulinum toxin A (Botox, Allegan) is a potent neurotoxin that blocks the release of acetylcholine at the neuromuscular junction of cholinergic nerves.  Botulinum toxin was introduced to clinical medicine in 1980.  Since then it has become a major therapeutic drug in many medical sub-specialties and its use for facial rejuvenation has become increasingly popular.  Diplopia after botulinum toxin injection for facial rejuvenation is a rare and transient complication that is related to chemodenervation of adjacent muscle groups.  These investigators reported 3 cases of double vision related to extra-ocular muscle paresis after an injection of botulinum toxin for facial rejuvenation and blepharospasm.  In all 3 cases recovery occurred, without any treatment, over 3 to 4 months (apparently from regeneration of inactivated proteins necessary for degranulation of acetylcholine vesicles).  The clinicians engaged in botulinum toxin injections for facial rejuvenation or blepharospasm, should be aware of the possible complications, and inform the patients about the risk of developing double vision.  The clinicians should take into account and ask about Botox when treating patients complaining of diplopia.

In a retrospective, descriptive and comparative study, Mazlout and colleagues (2013) evaluated the safety and effectiveness of type A botulinum toxin in the treatment of hemi-facial spasm.  A total of 25 patients with hemi-facial spasm followed in the ophthalmology department of Habib Thameur hospital in Tunis over the period from June 2003 to June 2009 were included in this study.  All patients received injections of botulinum toxin type A (Botox).  These investigators carried out 168 botulinum A toxin injections (Botox) with an average of 6.85 ± 4.32 injections per patient.  Doses varied between 12.5 U and 28 U Botox.  A good response to treatment was observed in 92 % of patients with a satisfactory return to daily activities and work.  Based on a subjective scale from 1 to 3, the average total functional benefit was 2.55 ± 0.56.  Average total duration of therapeutic response was 9.35 ± 3.64 weeks.  Local side effects observed were comparable to those described in the literature: ptosis (32.4 %), diplopia (8.2 %), drooping of the labial commissure (11.2 %), lagophthalmos (21.3 %), tearing (7 %), and dry eye (4 %).  No systemic complication was noted.  The authors concluded that botulinum toxin type A provided effective short-term and medium-term results in the treatment of hemi-facial spasm.  It was well-tolerated locally and systemically.  This safety and efficacy made it a valuable therapeutic alternative in the management of hemi-facial spasm.

Furthermore, an UpToDate review on “Overview of diplopia” (Bienfang, 2014) does not mention botulinum toxin as a therapeutic option.

An UpToDate review on “Primary focal hyperhidrosis” (Smith and Pariser, 2014) states that “BTX-A may be an effective treatment for hyperhidrosis in other areas, although data on such use are limited.  Improvement following treatment has been documented in patients treated for facial hyperhidrosis or plantar hyperhidrosis in uncontrolled studies and case reports”.

Furthermore, the Product Insert of Botox lists “Treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients” as one of its FDA-approved indications.  Facial hyperhidrosis is not one of the FDA-approved indications. 

Moericke and colleagues (2014) noted that case studies have shown subcutaneous treatment of BTX-A provides a promising alternative treatment for patients with chronic neuropathic pain.  These researchers determined the clinical effectiveness of subcutaneous injection of BTX-A for treating scar neuroma pain.  They designed a randomized, double-blind, placebo-controlled, cross-over, trial to examine the analgesic effect of BTX-A versus placebo (saline solution).  Screening procedures involved physical examination of the scar as well as subcutaneous injection of local anesthetic.  Patients experiencing greater than or equal to 80 % analgesia with a subcutaneous bupivacaine injection of the scar met diagnostic criteria for scar neuroma.  After completing a baseline pain reporting period of greater than or equal to 30 days, patients were randomized to receive study injection 1 of either BTX-A or placebo.  Study injections were preceded by an injection of local anesthetic to numb the area and ensure accuracy localizing the scar neuroma.  Post-injection, patients were followed until analgesic failure then entered a greater than or equal to30 day wash-out period before receiving the cross-over study injection 2.  Days until analgesic failure were calculated for 27 patients who reached study completion receiving both study injections of BTX-A and placebo.  Results indicated no evidence of a difference between local anesthetic alone and local anesthetic plus BTX-A (log rank p < 0.88).  Interestingly, approximately 25 % of patients did not return to baseline pain for over 200 days post-injection.  The authors concluded that further analysis is needed to examine factors contributing to analgesic response.

Chang et al (2014) noted that upper lip wounds that lie perpendicular to the relaxed skin tension lines are subjected to repetitive dynamic tension caused by the orbicularis oris muscle and are susceptible to unsatisfactory scarring.  In a double-blind, randomized, vehicle-controlled, prospective trial, 60 consecutive patients with unilateral cleft lip undergoing primary cheiloplasties between August of 2011 and June of 2012 were randomized to receive BTX-A or vehicle injections into the subjacent orbicularis oris muscle immediately after wound closure.  Scars were assessed after 6 months using the Vancouver Scar Scale, photographic visual analogue scale, and photographic scar width measurements.  Fifty-nine patients completed the trial.  Measurements of scar widths at 2 defined points revealed significantly better VAS scores and narrower scars in the experimental group.  However, Vancouver Scar Scale assessments were similar between groups.  The authors concluded that BTX-A injections into the subjacent orbicularis oris muscle produced better appearing and narrower cheiloplasty scars, but provided no additional benefits in terms of scar pigmentation, vascularity, pliability, or height.

Brueseke and Lane (2012) noted that botulinum toxin is used to treat pelvic floor tension myalgia; however, its safety profile is poorly understood.  These researchers reported an ischio-rectal fossa abscess after pelvic floor injections of botulinum toxin.  The authors concluded that physicians need to be aware of this possible complication, consider alternate injection techniques and antiseptic preparation before injection.

Also, an UpToDate review on “Approach to the patient with myalgia” (Shmerling, 2014) does not mention the use of botulinum toxin as a therapeutic option.

UpToDate reviews on “Sport-related concussions in children and adolescents: Management” (Meehan and O’Brien, 2014) and “Postconcussion syndrome” (Evans, 2014) do not mention the use of botulinum toxin.

In a retrospective case-series study, Ekbom et al (2010) reviewed their clinical experience and results using botulinum toxin type A (BTX) for the management of adult patients with respiratory compromise due to new onset bilateral vocal fold motion impairment (BVFMI).  The records of 11 patients from 2 institutions with respiratory compromise due to bilateral vocal fold motion impairment were reviewed.  Age, sex, etiology of motion impairment, subjective response to BTX injections, changes in pulmonary function studies pre- and post-injection when available, dosage of BTX required to achieve response, the number of injections per patient, and complications were reported.  All patients were over 18 years old.  There were 3 male and 8 female subjects.  The etiology of BVFMI was due to previous anterior cervical surgery in 9 patients and prolonged intubation in 2.  Ten patients reported symptomatic improvement and returned for an average of 9 injections over the 10-year period of study.  The most common interval between injections was 3 months.  In all patients the dose required to achieve symptomatic improvement was at least 2.5 mouse units injected into each vocal fold.  One patient without relief of symptoms had bilateral cricoarytenoid joint fixation.  Complications were limited to moderate dysphagia in 1 patient and breathy dysphonia in all patients.  The authors concluded that BTX injection into the vocal folds provided temporary relief of symptoms in airway obstruction in adult patients with BVFMI.  Patients require an average of 2.5 units of botulinum injection into each vocal fold and have an average length of response of 3 months.  They stated that BTX injection may be used as a form of temporary relief of airway obstruction in patients wishing to avoid ablative surgery or tracheotomy.  This was a small retrospective study; its findings need to be validated by well-designed studies.

Baxter et al (2014) stated that abnormal vocal cord movement may co-exist with asthma and cause additional upper/middle airway obstruction.  The condition may be a form of muscular dystonia that could contribute to asthma resistant to optimized treatments.  Botulinum toxin causes temporary paralysis of muscle and may be an effective local treatment that improves asthma control.  In an observational study, these researchers evaluated the benefits of unilateral vocal cord injection with BTX in 11 patients (total 24 injections).  Subjects had asthma resistant to optimized treatment and abnormal vocal cord movement.  Responses after BTX treatment were assessed using asthma control test (ACT) scores, vocal cord narrowing quantified by computerized tomography (CT) of the larynx and spirometry.  Side-effects were recorded.  ACT scores improved overall (9.1 ± 2.4 before and 13.5 ± 4.5 after treatment; difference 4.4 ± 4.2; p < 0.001).  There was also an improvement in airway size on CT larynx (time below lower limit of normal at baseline 39.4 ± 37.63 % and improved to 17.6 ± 25.6 % after injection; p = 0.032).  Spirometry was not altered.  One patient experienced an asthma exacerbation but overall side-effects were moderate, chiefly dysphonia and dysphagia.  The authors concluded that although a placebo effect cannot be ruled out, local injection of BTX may be an effective treatment for intractable asthma associated with abnormal vocal cord movement.  They stated that further mechanistic studies and a double-blind randomized controlled trial of BTX treatment are merited.

An UpToDate review on “Hoarseness in adults” (Bruch and Kamani, 2014) mentions the use of BTX for spasmodic dysphonia; but not for bilateral vocal cord paralysis.

Frey syndrome

Frey's syndrome is a frequent sequela of parotidectomy, resulting in facial sweating and flushing because of gustatory stimuli.  Laing et al (2008) noted that the use of botulinum toxin to treat disorders of the salivary glands is increasing in popularity in recent years.  Recent reports of the use of botulinum toxin in glandular hyper-secretion suggest overall favorable results with minimal side-effects.  However, few RCTs mean that data are limited with respect to candidate suitability, treatment dosages, frequency and duration of treatment.  These researchers reported a selection of such cases from their own department managed with botulinum toxin and review the current data on use of the toxin to treat salivary gland disorders such as Frey's syndrome, excessive salivation (sialorrhea), focal and general hyperhidrosis, excessive lacrimation and chronic rhinitis.

Cantarella et al (2010) noted that although botulinum toxin type A has become 1st-line therapy for Frey's syndrome, some patients become resistant.  In a case-series study, these researchers examined if another serotype, botulinum toxin type B, might be an effective alternative.  A total of 7 patients aged 30 to 68 years, with severe Frey's syndrome, underwent the Minor test and had 80 U of botulinum toxin type B per cm(2) (mean total dose, 2,354 U) injected intra-cutaneously in the mapped area of gustatory sweating.  All patients were followed-up for 12 months.  One month after treatment, 6 of the 7 patients reported that gustatory sweating and flushing had resolved, and, in the remaining patient, these symptoms had decreased.  The Minor test confirmed a significant improvement.  The subjective benefits remained stable for 6 months in 4 patients and for 9 months in the remaining 3 patients; 12 months after treatment, all patients still reported some improvement.  The authors concluded that botulinum toxin type B afforded symptomatic relief in a small sample of patients with Frey's syndrome and might be considered a potential alternative to botulinum toxin type A.  Moreover, they stated that no study had yet determined the ideal dose of botulinum toxin type B for Frey's syndrome.  They stated that a larger series of patients is needed to confirm these preliminary results.

A review by Motz and Kim (2016) on Frey syndrome stated that: "Currently, BTA is the most widely used agent for intradermal injection. Previous studies have demonstrated that patients undergoing BTA injection demonstrate improvement in symptoms of gustatory sweating and flushing. In addition, it has been shown to improve patient quality of life. Unfortunately, with BTA injection, symptomatic recurrence has been demonstrated in up to 27% and 92% of patients at 1 and 3 years, respectively. However, despite a high rate of return symptoms after BTA injection, repeat BTA injection has been shown to be effective. For the studies investigating BTA, the injection dose was between 1.9 and 2.5 U/cm2 in the involved area. Unfortunately, no randomized control studies have been documented, and based on a Cochrane Review of the literature, no conclusions can be made on its efficacy."

The National Organization for Rare Disorders (NORD) (Dulguerov, 2017) stated: "In the last decade botulinum A toxin has become established as a therapy for individuals with bothersome Frey syndrome. The therapy consists of local injections of botulinum A toxin in the affected skin. Initial results have demonstrated that this therapy results in the suppression of sweating and causes no significant side effects. Another advantage of botulinum A toxin is that it is minimally invasive compared to other therapies. As in other indications, the effect of botulinum toxin is not permanent, lasting on average about 9-12 months."

The AAN's report on botulinum neurotoxin in the treatment of autonomic disorders and pain (Naumann et al, 2008) stated that botulinum neurotoxin (BoNT) may be considered for gustatory sweating.

Internal Sphincter Achalasia in Hirschsprung's Disease

Guidelines for the diagnosis and management of Hirschsprung-associated enterocolitis (Gosain, et al., 2017) stated: "If there is no anatomic or pathologic cause identified [for recurrent Hirschsprung-associated enterocolitis], non-relaxation of the internal anal sphincter may be the cause of stasis with obstructive symptoms and recurrent HAEC in some patients, and can be confirmed by anorectal manometry. Injection of Clostridium botulinum toxin (Botox, Allergan, Plc) into the intersphincteric groove has been shown to decrease hospital admissions in children with recurrent symptomatology."

Frykman and Short (2012) reviewed the data on botulinum toxin in recurrent HAEC, and found: "In summary, intrasphincteric botox injection for the treatment of recurrent HAEC appears to be safe and can be used for multiple injections if symptoms recur. This treatment reduces the number hospitalizations for enterocolitis and can be effective in improving symptoms in some patients, however it is difficult to predict which patients will respond. Some authors have suggested that improvement of symptoms after botox injection predicts favorable response to myectomy/myotomy, while others have reported data contradicting this relationship."

Trismus

Trismus has been associated with significant morbidity post–radiation therapy, with significant health implications, including reduced nutrition due to impaired mastication, difficulty in speaking, and compromised oral hygiene. Guidelines from the National Cancer Institute (PDQ) on oral complications of chemotherapy and head/neck radiation (NCI, 2016) identify botulinum toxin as a curative approach. "Some therapeutic interventions seem to show some efficacy in decreasing the intensity of cancer treatment–related trismus (e.g., pentoxifylline, Botulinum toxin, exercise using the Therabite device, and the Dynasplint Trismus System). However, this proposed efficacy must be confirmed by randomized controlled studies, which are lacking in this area."

Piriformis Muscle Syndrome

Michela et al (2013) noted that piriformis muscle syndrome (PMS) is caused by sciatic nerve compression in the infra-piriformis canal.  However, the pathology is poorly understood and difficult to diagnose.  These researchers devised a clinical assessment score for PMS diagnosis and developed a treatment strategy.  A total of 250 patients versus 30 control patients with disco-radicular conflict, plus 30 healthy control subjects were enrolled.  A range of tests was used to produce a diagnostic score for PMS and an optimum treatment strategy was proposed.  A 12-point clinical scoring system was devised and a diagnosis of PMS was considered “probable” when greater or equal to 8.  Sensitivity and specificity of the score were 96.4 % and 100 %, respectively, while the positive-predictive value was 100 % and negative-predictive value was 86.9 %.  Combined medication and rehabilitation treatments had a cure rate of 51.2 %; 122 patients (48.8 %) were unresponsive to treatment and received OnabotulinumtoxinA.  Visual analogue scale (VAS) results were “very good/good” in 77 %, “average” in 7.4 % and “poor” in 15.6 %.  Fifteen of 19 patients unresponsive to treatment underwent surgery with “very good/good” results in 12 cases.  The authors concluded that the proposed evaluation score may facilitate PMS diagnosis and treatment standardization.  Rehabilitation has a major role associated in 50 % of the cases with botulinum toxin injections.  Moreover, they stated that “this was an open study, without any comparison group …. It is important to conduct a controlled study in the future to assess the effectiveness of these injections and evaluate their role in the treatment of PMS”.

Aspiration Pneumonia in Neurologically Impaired Children

Faria et al (2015) stated that neurologically impaired children often drool and aspirate saliva leading to recurrent aspiration pneumonia and frequent hospitalizations.  Salivary BTX injection is known to reduce sialorrhea.  These researchers examined if BTX injection affects the frequency and duration of respiratory infections including aspiration pneumonia and hospitalizations in neurologically impaired children.  They performed a retrospective review of patients treated with salivary BTX at a tertiary care pediatric hospital from January 2009 to December 2013.  Each patient was their own control and 180 day pre-injection and post-injection time periods were compared.  Outcomes evaluated included: number of hospital days, intensive care unit days, days of antibiotic treatment, chest X-rays, and infiltrates on chest X-ray.  A total of 13 patients accumulated 539 hospital days.  All children were gastrostomy tube-dependent; 54 % were tracheostomy tube-dependent.  Among all patients, the total hospital days decreased from 385 to 154 (p = 0.02), the mean days treated with antibiotics decreased from 214 to 47 (p = 0.02), and the number of chest X-ray confirmed infiltrates decreased from 20 to 6 (p = 0.02) after injection.  The authors concluded that there was a decrease in hospitalized days, antibiotic usage, and chest X-ray infiltrates after the salivary BTX injection.  Moreover, they stated that a prospective study is needed to evaluate whether this treatment can prevent aspiration pneumonia in neurologically impaired children.

Atrial Fibrillation

In a pilot study, Pokushalov et al (2015) compared the safety and effectiveness of BTX injection into epicardial fat pads for preventing atrial tachyarrhythmias.  Patients with history of paroxysmal atrial fibrillation (PAF) and indication for coronary artery bypass graft (CABG) surgery were randomized to BTX (Xeomin, Merz, Germany; 50 U/1 ml at each fat pad; n = 30) or placebo (0.9 % normal saline, 1 ml at each fat pad; n = 30) injection into epicardial fat pads during surgery.  Patients were followed for 1 year to assess maintenance of sinus rhythm using an implantable loop recorder (ILR).  All patients in both groups had successful epicardial fat pad injections without complications.  The incidence of early post-operative AF within 30 days after CABG was 2 of 30 patients (7 %) in the BTX group and 9 of 30 patients (30 %) in the placebo group (p = 0.024).  Between 30 days and up to the 12-month follow-up examination, 7 of the 30 patients in the placebo group (27 %) and none of the 30 patients in the BTX group (0 %) had recurrent AF (p = 0.002).  There were no complications observed during the 1-year follow-up.  The authors concluded that BTX injection into epicardial fat pads during CABG provided substantial atrial tachyarrhythmia suppression both early as well as during 1-year of follow-up, without any serious adverse events.  The findings of this pilot study need to be validated by well-designed studies with larger sample size and longer follow-up.

Excessive Gingival Display (Gummy Smile)

Nasr et al (2016) stated that to-date, no standardized minimally invasive approach for the treatment of excessive gingival display exists.  These researchers assessed the evidence in the literature regarding the role of BTX injection in the management of gummy smile.  All publications through December 2014 and pertaining to the subject were electronically searched in PubMed, Embase, Scopus, and Web of Science, and the bibliographies of retrieved articles were manually screened.  Out of 33 articles, 29 were discarded based on exclusion criteria.  Although all 4 selected articles were in line with a role for BTX injection in the treatment of gummy smiles and the importance of targeting the levator labii superioris alaeque nasi muscle, studies differed in the type and the dose of toxin administered and the technique adopted.  The authors concluded that injection with BTX is a novel, safe, and cosmetically effective treatment for gummy smile when performed by experienced practitioners.  However, they stated that further RCTs are needed.

Fecal Incontinence

Gourcerol et al (2016) determined the short-term clinical outcomes of BTX-A injections in patients with fecal incontinence of varying etiology.  A total of 26 patients with fecal incontinence were enrolled, 17 with their native rectum and 9 with a neo-reservoir following a proctectomy for rectal cancer.  Botulinum toxin type-A was endoscopically injected into the rectum/reservoir.  Scores for severity (CCS) and quality of life (FIQL) were recorded at baseline and at the 3-month follow-up visit.  The CCS was significantly lower after 3 months (median of 15, range of 4 to 20 versus 8, range of 1 to 19; p = 0.001).  The quality of life improved in 3 of the 4 FIQL domains.  The improvement was maintained in 11 of 12 patients who received more than 1 injection because of recurrent symptoms.  There was no significant predictive factor for the success of BTX-A injections.  The authors concluded that the findings of this study demonstrated that rectal/reservoir injections are an effective short-term treatment for fecal incontinence.  These preliminary findings need to be validated in well-designed studies.

First Bite Syndrome

Lee and colleagues (2009) stated that first bite syndrome (FBS) is the development of pain in the parotid region after the first bite of each meal and can be seen after surgery of the para-pharyngeal space.  These researchers evaluated the effectiveness of intra-glandular injection of BTX type A (BTA) in patients with FBS.  A total of 5 patients with FBS developed after head and neck surgery were treated by injection of BTA into parotid gland.  All patients completed a 4-item quality-of-life survey with a 10-point response scale designed to measure outcome of intra-glandular injection of BTA.  The FBS without or with sialogogue and degree of interference with daily activity with or without eating or drinking improved significantly at 1 and 3 month after injection (p < 0.05).  The authors concluded that BTA injection into affected parotid gland produced a decrease in the severity of FBS and improved the patient's quality of life.

Sims and Suen (2013) presented 3 cases of FBS treated with BTX and reviewed the current literature on available treatment modalities for this difficult to treat syndrome.  A total of 3 patients were injected with 75 Units (U) of BTX into affected parotid glands, focusing on areas of greatest first bite pain.  Two of 3 patients experienced complete relief of symptoms for 4 to 6 months.  The third patient had significant decrease in pain at 4-month follow-up.  The authors concluded that many treatments for FBS have been attempted including: dietary modification, pharmacological treatments, and surgical treatments.  However, few have been successful.  They stated that BTX is a safe and effective treatment for FBS.

Ghosh and Mirza (2016) noted that although FBS usually lasts less than a minute, it is disabling for afflicted individuals and leads to a fear of oral intake.  It is typically seen after para-pharyngeal or deep parotid space surgery.  Intra-parotid injection of BTA has been suggested as a treatment for this condition, but there is little supporting literature to this effect.  In a retrospective case review, these investigators documented their experience using this treatment method for FBS.  A total of 5 patients developed FBS after para-pharyngeal space surgery and were treated by multi-site injection of BTA into the parotid gland.  Between 17.5 and 50 total U of BTA were injected into 4 or more sites in the parotid region; patients were then followed-up every 4 months; 3 of 5 patients reported a significant improvement in symptoms at the 4-month follow-up visit, although complete resolution was not reported.  One patient reported only moderate improvement, and despite 2 series of injections there was no improvement in 1 patient, leading these researchers to question their initial diagnosis.  The authors concluded that unilateral BTA injection into the affected parotid gland produced a decrease in the severity of symptoms.  They stated that BTA is a safe and viable non-invasive treatment for this difficult to treat condition and may lead to permanent resolution of symptoms in some patients.

An UpToDate review on “Salivary gland tumors: Treatment of locoregional disease” (Lydiatt and Quivey, 2015) states that “A rare but very problematic complication of deep lobe parotid and para-pharyngeal space dissections is severe cramping or spasm in the parotid region with the first bite of each meal that diminishes over the next several bites (first bite syndrome).  This is best managed conservatively using analgesics, antidepressants, and gabapentin”.

Knee Pain

Singer et al (2015) noted that anterior knee pain is a highly prevalent condition affecting largely young to middle aged adults.  Symptoms can recur in more than 2/3 of cases, often resulting in activity limitation and reduced participation in employment and recreational pursuits.  Persistent anterior knee pain is difficult to treat and many individuals eventually consider a surgical intervention.  Evidence for long-term benefit of most conservative treatments or surgical approaches is currently lacking.  Injection of BTA to the distal region of vastus lateralis muscle causes a short-term functional "denervation", which moderates the influence of vastus lateralis muscle on the knee extensor mechanism and increases the relative contribution of the vastus medialis muscle.  Initial data suggested that, compared with other interventions for anterior knee pain, BTA injection, in combination with an active exercise program, can lead to sustained relief of symptoms, reduced health care utilization and increased activity participation.  The procedure is less invasive than surgical intervention, relatively easy to perform, and is time- and cost-effective.  The authors concluded that further studies, including larger randomized placebo-controlled trials, are needed to confirm the effectiveness of BTA injection for anterior knee pain and to elaborate the possible mechanisms underpinning pain and symptom relief.

Neuropathic Pain

Pessoa et al (2015) stated that neuropathic pain is a series of well-known conditions caused by diseases or lesions to the somatosensory system.  Due to the better understanding of the pathophysiology of neuropathic pain, previously unexplored therapies have been used with encouraging results.  As such, acetyl-L-carnitine (ALC), alpha-lipoic-acid (ALA), cannabinoids, clonidine, EMA401, botulinum toxin type A, and new voltage-gated sodium channel blockers, can be cited.  Furthermore, new modalities in neuromodulation such as high-frequency spinal cord stimulation, burst stimulation, dorsal root ganglion stimulation, transcranial direct current stimulation, and many others have been showing exciting results.  Besides, changing paradigms may occur with the advent of optogenetics and a better understanding of epigenetic regulation.  The authors concluded that despite the interesting results, RCTs are needed for the majority of the afore-mentioned therapies.

Oh and Chung (2015) noted that BoNT has been used therapeutically for focal dystonia, spasticity, and chronic migraine.  Its spectrum as a potential treatment for neuropathic pain has grown.  Recent opinions on the mechanism behind the anti-nociceptive effects of BoNT suggested that it inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves.  There is some evidence showing the axonal transport of BoNT, but it remains controversial.  These investigators summarized the experimental and clinical evidence of the anti-nociceptive effects, mechanisms, and therapeutic applications of BoNT for neuropathic pain conditions, including post-herpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia.  The PubMed and OvidSP databases were searched from 1966 to May 2015.  These researchers assessed levels of evidence according to the AAN’s guidelines.  Recent studies have suggested that BoNT injection is an effective treatment for post-herpetic neuralgia and is likely efficient for trigeminal neuralgia and post-traumatic neuralgia.  It has not been proven to be an effective treatment for complex regional pain syndrome or occipital neuralgia.

Interstitial Cystitis

Wang et al (2016) stated that the role of intravesical BTX-A injections in bladder pain syndrome/interstitial cystitis (BPS/IC) has not been clearly defined.  These researchers evaluated high-level evidence regarding the safety and effectiveness of BTX-A injections for BPS/IC.  They conducted a comprehensive search of PubMed, Embase, and Web of Science, and conducted a systematic review and meta-analysis of all available RCTs and controlled studies assessing BTX-A injections for BPS/IC.  A total of 7 RCTs and 1 retrospective study were identified based on the selection criteria.  Pooled analyses showed that although BTX-A was associated with a slightly larger volume of post-void residual urine (PVR) (weighted mean difference [WMD] 10.94 ml; 95 % CI: 3.32 to 18.56; p = 0.005), patients in this group might benefit from greater reduction in pelvic pain (WMD -1.73; 95 % CI: -3.16 to -0.29; p = 0.02), Interstitial Cystitis Problem Index (ICPI) scores (WMD -1.25; 95 % CI: -2.20 to -0.30; p = 0.01), and Interstitial Cystitis Symptom Index (ICSI) scores (WMD -1.16; 95 % CI: -2.22 to -0.11; p = 0.03), and significant improvement in daytime frequency of urination (WMD -2.36; 95 % CI: -4.23 to -0.49; p = 0.01) and maximum cystometric capacity (MCC) (WMD 50.49 ml; 95 % CI: 25.27 to 75.71; p < 0.00001).  Nocturia, maximal urinary flow rate, dysuria, and urinary tract infection did not differ significantly between the 2 groups.  The authors concluded that intravesical BTX-A injections might offer significant improvement in bladder pain symptoms, daytime urination frequency, and MCC for patients with refractory BPS/IC, with a slightly larger PVR.  Moreover, they stated that further well-designed, large-scale RCTs are needed to confirm the findings of this analysis.

Myofascial Pain Syndrome

Monnier et al (2006) stated that musculoskeletal pain in patients with rheumatic disorders is among the emerging indications for botulinum toxin therapy.  Preliminary data have been obtained in patients with cervical or thoracolumbar myofascial pain syndrome (MPS), chronic low back pain, piriformis muscle syndrome, tennis elbow, and stiff person syndrome.  At present, the effects of botulinum toxin and its use for pain relief remain controversial.  Carefully designed prospective studies are needed to ascertain the safety and effectiveness of botulinum toxin in pain disorders. 

A randomized study found no effect of botulinum toxin on pain from muscle trigger points.  In a double-blind, randomized, placebo-controlled, parallel clinical trial, Qerama et al (2006) studied the effect of botulinum toxin A on pain from muscle trigger points and on electromyographic (EMG) activity at rest and during voluntary contraction.  A total of 30 patients with trigger points in the infra-spinatus muscles received either 50 units/0.25 ml of botulinum toxin A or 0.25 ml of isotonic saline.  Baseline measures were determined during a run-in period of 1 week.  Outcome measures including local and referred spontaneous pain, pain detection and tolerance thresholds to mechanical pressure, and shoulder movement were assessed at 3 and 28 days after injection.  The interference pattern of the EMG during maximal voluntary effort of infra-spinatus muscle was recorded and a standardized search for spontaneous electrical motor endplate activity at the trigger points was performed before and 28 days after botulinum toxin A or saline injection.  Botulinum injection reduced motor endplate activity and the interference pattern of EMG significantly but had no effect on either pain (spontaneous or referred) or pain thresholds compared with isotonic saline.  The authors concluded that their findings do not support a specific anti-nociceptive and analgesic effect of botulinum toxin A.

The findings from Qerama et al (2006) are in agreement with that of Ojala et al (2006) who, in a double-blind, randomized, controlled cross-over study (n = 31) found that there was no difference between the effect of small doses of botulinum toxin A and those of physiological saline in the treatment of MPS as well as that of Ferrante et al (2005) who, in randomized, double-blind, placebo-controlled study (n = 132) reported that injection of botulinum toxin A directly into trigger points did not improve cervico-thoracic myofascial pain.

There is emerging evidence for the use of botulinum toxin in painful bruxism. In a controlled placebo pilot study with a 6-month follow-up period, Guarda-Nardini and associates (2008) examined the effectiveness botulinum toxin in treating myofascial pain in bruxers.  A total of 20 patients (10 males, 10 females; age range of  25 to 45 years) with a clinical diagnosis of bruxism and myofascial pain of the masticatory muscles were randomly assigned to either a treatment group (10 subjects treated with botulinum toxin injections- botulinum toxin A) or a control group (10 subjects treated with saline placebo injections).  A number of objective and subjective clinical parameters (pain at rest and during chewing; mastication efficiency; maximum nonassisted and assisted mouth opening, protrusive and laterotrusive movements; functional limitation during usual jaw movements; subjective efficacy of the treatment; tolerance of the treatment) were assessed at baseline time and at 1 week, 1 month, and 6 months follow-up appointments.  Descriptive analysis showed that improvements in both objective (range of mandibular movements) and subjective (pain at rest; pain during chewing) clinical outcome variables were higher in the botulinum toxin-treated group than in the placebo-treated subjects.  Patients treated with botulinum toxin A had a higher subjective improvement in their perception of treatment efficacy than the placebo subjects.  Differences were not significant in some cases due to the small sample size.  Results from the present study supported the efficacy of botulinum toxin A to reduce myofascial pain symptoms in bruxers, and provided pilot data which need to be confirmed by further research using larger samples.

Gerwin (2012) reviewed the literature relevant to the treatment of myofascial pain syndrome (MPS) by botulinum injections.  The objective was to critically review the studies to see if they are appropriately designed, conducted, and interpreted to provide guidance in the management of MPS.  The intent was to better understand the mixed results that these studies have provided.  A search was made utilizing PubMed for literature relevant to the use of botulinum toxin in the treatment of MPS.  All identifiable series were reviewed, including open label, single-blinded and double-blinded studies, randomized and controlled, or not.  In general, small case series of only a few patients were not included unless they made a relevant point and there were no available randomized studies or larger studies.  Single case reports were not included.  The studies were evaluated according to their design and the selection of outcome measurements, and the interpretation of results.  The studies were individually critiqued, and an overall assessment and commentary was made of the studies in the field as a whole.  Problems that were common to the studies were robust placebo responders, incomplete treatment of a regional MPS, inappropriate or confounding control populations or treatments, and inappropriate time periods for assessment of outcomes, or mis-interpretation of the time-frame of action of botulinum toxin.  The studies of the effect of botulinum toxin treatment of myofascial trigger points have had mixed results.  However, few studies have been designed to avoid many of the pitfalls associated with a trial of botulinum toxin treatment of trigger points.  Better-designed studies may give results that can be used to guide practice based on reliable evidence.  The author concluded that the available evidence is insufficient to guide clinical practice.

In a Cochrane review, Soares et al (2012) evaluated the effectiveness and safety of botulinum toxin in treating MPS, excluding MPS in neck and head muscles.  The search strategy was composed of terms for myofascial pain and botulinum toxin.  These investigators searched the Cochrane Pain, Palliative and Supportive Care (PaPaS) Review Group's Specialized Register until December 2011, CENTRAL (Cochrane Database of Systematic Reviews 2011, Issue 4), PUBMED (from 1966 to 2011), EMBASE (from 1980 to 2011) and LILACS (from 1982 to 2011).  There was no language restriction.  These researchers included RCTs involving botulinum toxin for treating participants with MPS.  They excluded studies with MPS of the neck and head from this review, as they have already been assessed in existing systematic reviews.  They considered a diagnosis of MPS to be based on the identification of trigger points in the taut band through palpation of sensitive nodules, local twitch response and specific patterns of referred pain associated with each trigger point.  Two review authors independently screened identified studies, extracted data, assessed trial quality and analyzed results using the Cochrane PaPaS Review Group criteria.  A total of 4 studies (n= 233) comparing botulinum toxin A (BTXA) with placebo, met the inclusion criteria.  In one study with 145 participants, a significant improvement rate of pain intensity scores, as shown by the mean difference (MD) of -0.23 (95 % CI: -0.26 to -0.20; p value < 0.00001) and duration of daily pain (MD -1.11; 95 % CI -1.37 to -0.85; p value < 0.00001), was demonstrated when comparing BTXA with placebo.  The 3 other studies showed that there was no statistically significant difference between BTXA and placebo in pain intensity.  The authors concluded that there is inconclusive evidence to support the use of botulinum toxin in the treatment of MPS based on data from four studies with a total of 233 participants, which the authors considered adequate to be included in this review.  Meta-analyses were not possible due to the heterogeneity between studies.  They suggested that in future studies the same methodology to assess pain, a standardized dose of treatment, follow-up of at least 4 months (to observe the maximum/minimum curve of the drug effect) and appropriate data presentation should be used.  They stated that more high-quality RCTs of botulinum toxin for treating MPS need to be conducted before firm conclusions on its effectiveness and safety can be drawn.

Khalifeh et al (2016) conducted a systematic review to study the effectiveness of botulinum toxin type A (BoTN-A) in the treatment of myofascial pain syndrome (MPS).  The authors identified randomized, double-masked, placebo-controlled studies on June 1, 2016, from PubMed, Web of Science, and the Cochrane Library; 3 of the authors assessed the studies for risk of bias . Outcomes included pain reduction on a VAS, the number of responders, and the post-treatment pain threshold to applied pressure using algometry.  The initial search strategy yielded 253 unduplicated references, which the authors reduced to 13 relevant studies.  The authors included 11 studies in the meta-analyses as the investigators of those studies had reported similar outcomes.  Pooled results showed a non-significant improvement in the post-treatment intensity of pain in the BoTN-A group compared with the placebo group at 4 to 6 weeks (standardized difference in means [SDM], -0.110; 95 % CI: -0.344 to 0.124; p = 0.356) and a significant improvement at 2 to 6 months (SDM, -0.360; 95 % CI: -0.623 to -0.096; p = 0 .008).  The number of study participants who responded to treatment was not statistically significantly different between the groups (RR, 1.346; 95 % CI: 0.922 to 1.964; p = 0.123) nor was the increase of pain threshold to pressure (algometry) at 2 months (SDM, 0.131; 95 % CI: -0.178 to 0.440; p = 0.405).  The study investigators reported no major AEs.  The authors concluded that pain was reduced significantly in the group that received BoTN-A compared with the placebo group at 2 to 6 months; but not at 4 to 6 weeks (with moderate quality of the evidence).  They stated that additional studies with larger numbers of participants are needed to confirm these results.

Raynaud's Phenomenon

Zebryk and Puszczewicz (2016) evaluated all existing evidence on the use of BTX-A in the management of Raynaud's phenomenon.  These investigators adopted the PRISMA methodology and searched Cochrane Library, Medline, SCOPUS, EULAR and ACR congresses abstract archives for Raynaud^* and botulinum toxin or onabotulinum.  All studies that contained reports of BTX-A use and its outcome in Raynaud's phenomenon were included in the review.  A total of 11 studies (n = 125) met inclusion criteria; 2 reviewers extracted data from the studies under review and achieved a consensus in their selection.  The main outcomes measured were pain reduction and healing of digital ulcers.  The level of evidence across studies was very low to moderate.  The authors concluded that there is insufficient evidence to evaluate the effectiveness of BTX-A in Raynaud's phenomenon.  They stated that despite many promising reports, further research in the form of RCTs is needed to examine this new treatment method for Raynaud's phenomenon.

Tinnitus

In a systematic review, Slengerik-Hansen and Ovesen (2016) evaluated the effect of BTX treatment on objective tinnitus due to essential palatal tremor (EPT).  In accordance with PRISMA guideline a systematic literature search in 3 databases was performed.  A total of 22 studies fulfilled the inclusion criteria, mainly case reports and case series.  A total of 51 BT treated patients diagnosed with EPT were identified in the literature.  The studies were evaluated with focus on diagnostics, injection technique and BTX dose, follow-up, effect on objective tinnitus, complications, and AEs.  The authors concluded that the included studies suffer from an extremely low evidence level with several sources of bias.  They noted that when optimally injected, BTX appeared to be an effective treatment of objective tinnitus due to EPT, with few AEs and complications.

Trigeminal Neuralgia

Morra et al (2016) examined evidence from published RCTs regarding safety and effectiveness of BTX-A as a possible emerging choice of treatment for trigeminal neuralgia (TN).  They conducted an electronic search in 10 databases/electronic search engines to access relevant publications.  All articles in all languages reporting RCTs on the safety and effectiveness of BTX-A in the treatment of TN were included for systematic review and meta-analysis.  A total of 4 RCTs (n = 178) were identified for final meta-analysis.  The overall effect favored BTX-A versus placebo in terms of proportion of responders (RR = 2.87, 95 % CI: 1.76 to  4.69, p < 0.0001) with no significant detected heterogeneity (p = 0.31; I(2) = 4 %).  Paroxysms frequency per day was significantly lower for BTX-A group (MD = -29.79, 95 % CI: -38.50 to -21.08, p < 0.00001) with no significant heterogeneity (p = 0.21; I(2) = 36 %).  The authors concluded that despite limited data, these results suggested that BTX-A may be an effective and safe therapeutic option for patients with TN.  Moreover, they stated that further larger and well-designed RCTs are needed to translate these findings into better clinical outcome and better quality of life for TN patients.

Animus

In a systematic review, Emile et al (2016) evaluated the safety and effectiveness of BTX-A in the management of patients with anismus.  An organized search of published literature was conducted using electronic databases including: PubMed/Medline, and Cochrane Central Register of Controlled Trials, also an internet-based search using "Google Scholar" service was conducted.  Both comparative and observational studies were included.  They excluded irrelevant articles, editorials, case reports, reviews, and meta-analyses.  The studies that followed the patients less than 6 mo were excluded.  Variables collected were demographic data of the patients, technique of BTX-A injection and number of sessions, short-term and long-term clinical improvement, post-injection changes in EMG, defecography, manometry, and balloon expulsion test, and complications recorded after BTX-A injection.  A total of 7 studies comprising 189 patients were included in the review.  The median age of the patients was 41.2 years and female-to-male ratio was 1.3:1.  The median dose of BTX-A injected per procedure was 100 IU (range of 20 to 100 IU).  Lateral injection was done in 5 trials and combined lateral and posterior injections in 2 trials; 3 studies used endorectal ultrasonography-guided technique, 1 study used EMG-guided technique, whereas the remaining 3 studies used manual palpation with the index finger.  The median percentage of patients who reported initial improvement of symptoms was 77.4 % (range of 37.5 % to 86.7 %), this percentage declined to a median of 46 % (range of 25 % to 100 %) at 4 months after injection of BTX-A.  Rates of improvement evaluated by balloon expulsion test, EMG, and defecography ranged between (37.5 % to 80 %), (54 % to 86.7 %), and (25 % to 86.6 %), respectively; 14 (7.4 %) patients developed complications after injection of BTX-A.  Complication rates across the studies ranged from 0 % to 22.6 %.  The authors concluded that initial satisfactory improvement of symptoms after BTX-A injection remarkably deteriorated after 3 months of the procedure.  However, repeated injection may provide better sustained results with no additional morbidities.  They stated that further analysis of more patients is needed to conclude the safety of BTX-A for the treatment of anismus.

Bladder Exstrophy

UpToDate reviews on “Clinical manifestations and initial management of infants with bladder exstrophy” (Borer, 2016a) and “Surgical management and postoperative outcome of children with bladder exstrophy” (Borer, 2016b) do not mention botulinum toxin as a management tool.

Episodic Migraines

Simpson et al (2016) updated the 2008 AAN guidelines regarding botulinum neurotoxin for blepharospasm, cervical dystonia (CD), headache, and adult spasticity.  They searched the literature for relevant articles and classified them using 2004 AAN criteria.

Blepharospasm:

• OnabotulinumtoxinA (onaBoNT-A) and incobotulinumtoxinA (incoBoNT-A) are probably effective and should be considered (Level B)
• AbobotulinumtoxinA (aboBoNT-A) is possibly effective and may be considered (Level C)

Cervical Dystonia:

• AboBoNT-A and rimabotulinumtoxinB (rimaBoNT-B) are established as effective and should be offered (Level A)
• OnaBoNT-A and incoBoNT-A are probably effective and should be considered (Level B)

Adult Spasticity:

• AboBoNT-A, incoBoNT-A, and onaBoNT-A are established as effective and should be offered (Level A)
• RimaBoNT-B is probably effective and should be considered (Level B), for upper limb spasticity
• AboBoNT-A and onaBoNT-A are established as effective and should be offered (Level A) for lower-limb spasticity

Headache:

• OnaBoNT-A is established as effective and should be offered to increase headache-free days (Level A) and is probably effective and should be considered to improve health-related quality of life (Level B) in chronic migraine
• OnaBoNT-A is established as ineffective and should not be offered for episodic migraine (Level A) and is probably ineffective for chronic tension-type headaches (Level B)

Forced Eyelid Closure Syndrome

Kaffenberger et al (2017) noted that objective tinnitus associated with eyelid closure is a rare clinical entity with only a few reported cases.  This association previously was identified as forced eyelid closure syndrome (FECS) and involves an aberrant neural reflex between cranial nerve VII (activating the orbicularis oculi muscle) and cranial nerve V (activating the tensor tympani muscle).  These investigators presented a 52-year old Caucasian female with a 2-month history of FECS who was successfully treated with intra-palatal botulinum toxin, with full resolution of her objective tinnitus symptoms.  The authors stated that this was the first reported use of BTX in FECS.  The effectiveness of this approach needs to be validated by further investigation.

Hypertrophic Scars

In a meta-analysis, Zhang et al (2016) evaluated the effectiveness of BTX-A in the prevention of maxillofacial and neck scars.  Information came from the following electronic databases: Medline, PubMed, Cochrane Library, and Embase (time was ended by August 31, 2015) to retrieve RCTs evaluating the effect of the BTX-A for hypertrophic scar on the maxillofacial or neck.  All languages were included as long as they met the inclusion criteria.  The effects of BTX-A were evaluated by comparing the width of the scar, patient satisfaction, and the VAS, respectively.  Pooled weighted mean differences (WMDs), pooled ORs, and 95 % CI were calculated.  A total of 9 RCTs (n =  539) were included.  A statistically significant difference in scar width was identified between the BTX-A group and control group (non-BTX-A used) (WMD = -0.41, 95 % CI: -0.68 to -0.14, p = 0.003).  A statistically significant difference in patient satisfaction was observed between the BTX-A group and control group (OR = 25.76, 95 % CI: 2.58 to 256.67, p = 0.006).  In patients regarding VAS, a statistically significant difference was also observed between the BTX-A group and control group (WMD = 1.30, 95 % CI: 1.00 to 1.60, p < 0.00001).  The authors concluded that the findings of this meta-analysis confirmed that BTX-A is a suitable potential therapy for the prevention of hypertrophic scars in patients in the maxillofacial and neck areas.

Pain Control in Breast Reconstruction with Tissue Expanders

Tissue expander placement is a common means of reconstruction after mastectomy.  Many patients report significant pain and discomfort with the tissue expansion process.  Because placement is sub-pectoral, it was hypothesized that injection of the pectoralis muscle with BTX could decrease pain associated with tissue expanders.  Winocour and colleagues (2014) examined the effectiveness of BTX-A injections for pain relief following placement of subpectoral tissue expanders and breast implants.  Medline and Embase were searched from their inception to December 2012 to identify studies reporting the effectiveness of peri-operative BTX-A injections following breast surgery with subpectoral prostheses.  Study designs included controlled and uncontrolled studies.  A total of 7 studies met the inclusion criteria (2 prospective controlled cohort, 3 retrospective cohort and 2 case series); 5 studies assessed the effectiveness of BTX-A and 3 measured pain improvement as a primary outcome.  The studies enrolled 427 women: 91.8 % received intra-operative BTX-A injection at the time of tissue expander breast reconstruction and 4.7 % following augmentation mammaplasty.  Only 3.5 % of women received BTX-A injections in the post-operative setting.  Overall, all the studies demonstrated improvement in pain and favorable side effect profile without any major AEs.  However, the quality of this evidence was low.  The authors concluded that these findings suggested that BTX-A may alleviate post-operative pain associated with the placement of subpectoral tissue expanders and implants, and the available data on outcome assessment of this practice were inconsistent and lack methodological rigor.  They stated that with paucity of high-level evidence to support this practice in implant-based breast surgery, further studies are needed.

In a pilot study, Gabriel et al (2015) evaluated the role of a neurotoxin (BTX-A) in expander-based breast reconstruction.  A total of 30 patients underwent mastectomies with immediate expander or acellular dermal matrix reconstruction.  The neurotoxin group (n = 15) received 40 U of neurotoxin into each pectoralis major muscle through 4 serial injections and the placebo group (n = 15) received 4 serial injections of 0.9 % saline.  All patients were followed over 1 year, and patient demographics, VAS, laterality, office visits, amount of expansion and number of times to full expansion, and amount of narcotics required were recorded. S tatistical significance was considered as p < 0.05.  There were no significant differences between the 2 groups in terms of age, laterality, expander size, or complications (p = 0.46 to 0.66).  There was a significant difference between the 2 groups in the VAS score, demonstrating decreased pain in the neurotoxin group (p < 0.05).  In addition, there was a significant increase in the volume of expansion per visit in the neurotoxin group as compared to the placebo group (p < 0.05).  There was no significant difference in narcotic use in the first 3 days after surgery; however, there was a significant decrease in use of narcotics from 7 to 45 days in the neurotoxin group (p < 0.05).  There were no complications associated with the use of the neurotoxin.  The authors concluded that the infiltration of the pectoralis major muscle with neurotoxin in immediate, expander-based reconstruction may be beneficial in reducing pain and expediting expansions.  These preliminary findings of a pilot study need to be validated by well-designed studies.

In a prospective, randomized, double-blinded controlled trial, Lo and Aycock (2015) evaluated the effects of intra-operative injection of 100 U of BTX into the pectoralis muscle on one side versus placebo on the contralateral side during immediate tissue expander reconstruction after bilateral mastectomy.  Patients were enrolled in the study between October 2009 and February 2012.  Pre-operative and post-operative pain scores, number and volume of tissue expansion, and complications were recorded.  The paired-t test was used to compare pre-operative to post-operative changes in pain between the BTX and placebo injections.  A total of 23 patients were enrolled in the trial.  There was no statistically significant difference between pre-operative to post-operative changes in the pain scores on the BTX side compared to the control side at any time-point post-operatively.  All pain scores trended to zero over time.  The authors concluded that intra-operative injection of the pectoralis muscle with BTX was not an effective method to improve pain control in tissue expander reconstruction.

Spina Bifida

Hascoet et al (2017) conducted a systematic review of current evidence regarding the effectiveness of intra-detrusor injections of BTX-A in spina bifida patients with neurogenic detrusor overactivity (NDO) refractory to anti-muscarinics.  A research has been conducted on Medline and Embase using the keywords: ("spina bifida" or "myelomeningocele" or "dysraphism") and "toxin".  The search strategy and studies selection were performed using the PICOS method according to the PRISMA statement.  A total of 12 published series were included (n = 293 patients).  All patients were less than 18 years old.  There was no randomized study comparing BTX-A versus placebo and most studies had no control group.  Most studies reported a clinical and urodynamic improvement with resolution of incontinence in 32 to 100 % of patients, a decrease in maximum detrusor pressure from 32 to 54 %, an increase of maximum cystometric capacity from 27 to 162 %, and an improvement in bladder compliance of 28 to 176 %; 2 studies suggested lower effectiveness in patients with low compliance bladder compared to those with isolated detrusor over-activity.  The authors concluded that intra-detrusor injections of BTX-A could be effective in children with spina bifida; but this assumption is not supported by high level of evidence studies; and there are no data available in adult patients.

Bladder Pain Syndrome

Ochoa Vargas and Garcia Perdomo (2018) determine the safety and effectiveness of BTX-A, compared with other interventions for the treatment of bladder pain syndrome (BPS) to improve quality of life (QOL).  This systematic review fulfilled all the requirements of the Cochrane manual and PRISMA reporting guidelines; BPS patients over 18 years of age who were treated with BTX-A were included.  Studies were searched in published databases and no published literature from inception to the present day.  Risk of bias analysis was done using the Cochrane risk of bias tool.  A total of 88 articles were found with the designed search strategies.  After exclusions, 4 studies were included in the qualitative analyses --  Kasyan et al (2012) compared BTX-A with hydrodistention; Manning et al (2014) compared the injection of BTX-A with the injection of normal saline in previously hydrodistended bladders.  In both cases, primary end-point was measured by the O'Leary-Sant questionnaire score; El-Bahnasy et al (2009) compared BTX-A with BCG administration, through Global Response Assessment; and Kuo et al (2015) compared hydrodistention plus suburothelial injections of BTX-A with hydrodistention plus normal saline injections.  Reduction in pain was estimated by VAS bladder pain score.  A similar efficacy to their controls had been found in Kasyan and Manning studies.  El-Bahnasy had found improvement in BTX-A in all parameters.  Kuo el al (2015) found a significantly reduction in pain in the BTX-A group.  Regarding the risk of bias, 3 studies did not have adequate descriptions of selection, performance and detection bias.  The study of Manning et al (2014) had low risk of selection, attrition and reporting bias.  The authors concluded that there is inadequate evidence to conclude the effectiveness of BTX-A for the treatment of interstitial cystitis to improve QOL.Knee Osteoarthritis:

Nguyen and Rannou (2017) noted that international guidelines recommend that the management of knee osteoarthritis (OA) combine both non-pharmacological and pharmacological interventions.  Intra-articular (IA) therapies are considered part of this multi-modal approach and are well-established FDA and European Medicines Agency (EMA)-approved treatments.  In this study, safety data for knee OA, including IA corticosteroids, hyaluronic acid, platelet-rich plasma and BTX were critically reviewed, and evidence- and practice-based measures to improve safety of IA therapies were discussed.  The incidence of AEs attributable to IA therapies across clinical trials in knee OA was very low, and barely reached significance when compared to the incidence of AEs in the comparator group.  These events were exceptionally serious.  Mild differences between products have been inconsistently reported mainly for IA HA.  One can distinguish self-limited AEs such as post-injection pain and swelling that were the most frequently reported AEs, from AEs that were not self-limited but rare such as septic arthritis.  The authors concluded that the safety of IA therapies can be improved by applying simple measures designed to prevent AEs.  However, even though no specific safety concerns had been raised to-date about IA therapies, the quality of evidence was low, and there is a need to improve the monitoring and reporting of safety data from clinical trials and post-marketing surveillance.

Obesity

Bustamante and colleagues (2017) stated that the effectiveness of gastric injections of BTA for the treatment of obesity is not well known since results in literature are discrepant.  These researchers systematically reviewed and meta-analyzed the available data to evaluate the real effect of BTA therapy.  They searched Medline, Embase, Cochrane, Scopus, Ebsco, LILACS, and BVS.  They considered eligible only RCTs enrolling obese patients comparing BTA versus saline injections.  The initial search identified 8,811 records; 6  studies fulfilled eligibility criteria.  After critical appraisal, 2 articles were excluded and these investigators meta-analyzed the remainder.  The MD for absolute weight loss and BMI reduction were 0.12 [95 % CI: - 1.14 to 1.38] and - 0.06 [95 % CI: - 0.92 to 0.81], respectively.  The authors concluded that treatment of obesity with BTA is not effective.

Osteo-articular Joint Pain

Courseau and colleagues (2018) evaluated the effectiveness of intra-articular injections of BTA into the painful joint diseases through a systematic review of the literature and a meta-analysis of RCTs.  These investigators searched via PubMed, ACR and EULAR congresses and grey literature for the studies reported until June 2016 and addressing the issue of BT intra-articular injections in patients with refractory joint pain.  Randomized trials were included.  For the meta-analysis, these researchers compared for each study numeric rating scale (NRS) from 0 to 10 before treatment and 1 or 2 months and 6 months after, in BTA and control group.  They also compared separately low-dose and high-dose of BT at 1 or 2 months evaluation.  Out of 269 selected articles, 8 were analyzed and 6 studies were included in the meta-analysis involving a total of 382 patients.  On the 5 trials comparing NRS at 1 or 2 months regardless the dose of BT, 4 trials showed a positive effect of BT compared to control on the NRS, 1 found no effect, the overall WMD (95 % CI) was -1.10 (-1.62 to -0.58) (p < 0.0001, I = 63 %).  On the 4 trials with a low-dose of BT (100 units) comparing NRS at 1 or 2 months, 3 trials showed significant results with a positive effect of BTA injection compared to control on the NRS, the 4th study failed to find any effect.  The overall WMD (95 % CI) was -0.95 (-0.02 to -1.88) (p = 0.05, I = 67 %).  On the 2 trials using a high-dose of BT (200 units) comparing NRS at 1 or 2 months, an almost zero effect of BT, with an overall WMD (95 % CI) of 0.13 (-0.55 to 0.81), (p = 0.71, I = 0 %).  On the 3 trials comparing NRS at 6 months there was an overall WMD (95 % CI) of -0.57 (-1.98 to 0.83) (p = 0.42, I = 73 %).  The authors concluded that BTA intra-articular injections had short-term benefits with a statistically significant decrease in NRS pain score of around 1 point in patients with refractory joint pain.  Furthermore, a decrease in the pain score was also observed at 6 months; but with a non-significant result.

Popliteal Artery Entrapment Syndrome

Hislop and colleagues (2014) noted that there is no published data on the effectiveness of botulinum injection in the management of functional popliteal artery entrapment syndrome (PAES).  These investigators had commenced a pilot study using intramuscular peri-arterial injection of BTX-A to treat functional PAES with promising initial results.  They hoped to publish the outcomes as their cohort size increased, but at present this remained an unproven intervention.

Joy and Raudales (2015) stated that botulinum toxin has been proposed as a therapeutic option for PAES.  If there is functional popliteal artery compression by a hypertrophied or thick region of muscle, theoretically, treatment aimed at reducing the volume and/or tone of the muscle could reduce the stress on the artery.  It is proposed that such treatment may reduce the volume of the muscle without the same degree of potential functional consequences resulting from surgical myotomy.  The authors noted that more investigation is clearly needed.

Hislop and co-workers (2017) examined if ultrasound (US)-guided injection of BTX-A is a viable alternative to surgical intervention for the treatment of functional PAES.  A total of 27 patients met diagnostic criteria confirming the presence of functional PAES and agreed to go ahead with US-guided BTX-A injection at the level of artery occlusion.  Patients were assessed and treated at baseline and given the option for “top-up” injections at 6 and 12 months.  Patients provided subjective symptom reports at 6 and 12 months post-intervention.  No patients reported being worse off after the intervention; 59 % of patients were categorized as having a good response (i.e., initial improvement that was maintained at 12 months), 22 % a mixed response (i.e., an initial improvement that subsequently reduced over 12 months) and 19 % a poor response (i.e., no difference) to treatment.  The authors concluded that US-guided BTX-A injection represents a viable alternative to surgery in the treatment of functional PAES.  Moreover, they stated that further study will help determine the optimum dose and frequency of injection to prevent recurrence of symptoms.

Sialorrhea (Chronic)

Sialorrhea is a common symptom among individuals who suffer from neurological disorders including Parkinson's disease, amyotrophic lateral sclerosis (ALS), cerebral palsy (CP) or who have experienced a stroke. The condition can occur from difficulty retaining saliva inside the mouth, issues with swallowing and from problems controlling facial muscles (Mertz, 2018).

On July 3, 2018, Merz North America, Inc. announced the U.S. FDA approval for Xeomin (incobotulinumtoxinA) for the treatment of chronic sialorrhea, or excessive drooling, in adult patients 18 years of age and older.

FDA approval was based on a double-blind, placebo-controlled, randomized phase 3 trial that evaluated the safety and efficacy of incobotulinumtoxinA (Xeomin 100 Units and 75 Units) to placebo in adult patients (age 18 years and older) with chronic sialorrhea. A total of 184 patients presenting with at least 3 months of chronic sialorrhea resulting from Parkinson’s disease, atypical parkinsonism, stroke, or traumatic brain injury were enrolled in the study. Patients with a history of aspiration pneumonia, amyotrophic lateral sclerosis, salivary gland or duct malformation, and gastroesophageal reflux disease were excluded. The study consisted of a 16-week main phase, followed by an extension period of dose-blinded treatment with Xeomin.

In the main phase, a fixed total dose of Xeomin (100 Units or 75 Units) or placebo was administered into the parotid and submandibular salivary glands in a 3:2 dose ratio. The co-primary efficacy variables were the change in unstimulated Salivary Flow Rate (uSFR) and the change in Global Impression of Change Scale (GICS) at Week 4 post-injection. A total of 173 treated patients completed the main phase of the study. For both the uSFR and GICS, Xeomin 100 Units was significantly better than placebo; however, Xeomin 75 Units did not show that it was significantly better than placebo.

In the extension period, patients received up to 3 additional treatments with Xeomin 100 Units or 75 Units every 16±2 weeks, for a total exposure duration of up to 64 weeks. Patients had periodic dental examinations to monitor for changes in dentition and oral mucosa. A total of 151 patients completed the extension period (Merz, 2018).

Patients with neuromuscular disorders with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g.,myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of Xeomin (Mertz, 2018).

Xeomin has not been studied in the pediatric age group and is therefore not recommended in pediatric patients.

The most common adverse reactions (greater than or equal to 4%) were tooth extraction, dry mluth, diarrhea, and hypertension.

Ventral Hernia

Weissler and colleagues (2017) noted that ventral hernia represents a surgical challenge plagued by high morbidity and recurrence rates.  Primary closure of challenging hernias is often prohibited by severe lateral retraction and tension of the abdominal wall musculature.  Botulinum toxin injections have recently been identified as a potential pre-operative means to counteract abdominal wall tension, reduce hernia size, and facilitate fascial closure during hernia repair.  This systematic review and meta-analysis examined outcomes associated with BTX injections in the setting of ventral hernia, and demonstrated an opportunity to leverage this product for use in abdominal wall reconstruction.  A literature review was conducted according to PRISMA guidelines using MeSH terms “ventral hernia”, “herniorrhaphy”, “hernia repair”, and “botulinum toxins”.  Relevant studies reporting pre- and post-injection data were included.  Outcomes of interest included changes in hernia defect width and lateral abdominal muscle length, recurrence, complications, and patient follow-up.  Qualitative findings were also considered to help demonstrate valuable themes across the literature.  Of 133 results, 12 were included for qualitative review and 3 for quantitative analysis.  Meta-analysis revealed significant hernia width reduction (mean = 5.79 cm; n = 29; p < 0.001) and lateral abdominal wall muscular lengthening (mean = 3.33 cm; n = 44; p < 0.001) following BTX injections.  Mean length of follow-up was 24.7 months (range of 9 to 49).  The authors concluded that BTX injections offered potential in ventral hernia management by reducing hernia width and lengthening abdominal wall muscles prior to repair.  They stated that although further studies are needed, there is a significant opportunity to bridge the knowledge gap in pre-operative practice measures for ventral hernia risk reduction.

Elstner et al (2016) noted that the operative management of complex ventral hernia poses a formidable challenge, despite recent advances in surgical techniques.  Recurrence rates after complex ventral hernia repair remain high, and increase with each failed attempt.  These researchers examined the effect of pre-operative abdominal wall chemical component relaxation using botulinum toxin A (BTA) to induce temporary flaccid paralysis in order to facilitate laparoscopic repair of large complex ventral hernia.  This was a prospective evaluation of 27 patients from January 2013 to August 2015 who underwent ultrasound (US)-guided BTA injections to the lateral abdominal wall muscles prior to elective complex ventral hernia repair.  Non-contrast serial CT imaging was obtained pre- and post-BTA injection to measure change in fascial defect size and abdominal wall muscle thickness and length.  Fascial defects were closed and hernias repaired using laparoscopic or laparoscopic-assisted intra-peritoneal onlay mesh (IPOM) techniques.  A total of 27 patients received pre-operative BTA injections which were well-tolerated with no complications.  Comparison of pre-BTA and post-BTA CT imaging demonstrated a significant increase in mean length of the lateral abdominal wall from 15.7 cm pre-BTA to 19.9 cm post-BTA (p < 0.0001), with mean un-stretched length gain of 4.2 cm/side (range of  0 to 11.7 cm/side).  All hernias were surgically reduced and repaired with mesh, with no early recurrences.  The authors concluded that pre-operative administration of BTA was a safe and effective technique in the pre-operative preparation of patients undergoing elective complex ventral hernia repair.  This technique lengthened and relaxed the laterally retracted abdominal muscles and enabled laparoscopic closure of large complex ventral hernia.  This was a small (n = 27), non-randomized  study that lacked a control/comparison group.

In a systematic review, Alam et al (2016) evaluated the available literature regarding methods for abdominal wall expansion and compared the outcome of primary fascial closure rates.  These investigators performed a systematic search of PubMed and Embase databases using the search terms "abdominal wall hernia", "ventral hernia", "midline hernia", "botulinum toxin", "botox", "dysport", "progressive preoperative pneumoperitoneum", and "tissue expanders".  Study quality was assessed using the methodological index for non-randomized studies.  A total of 21 of the 105 studies identified met the inclusion criteria.  Progressive pre-operative pneumoperitoneum (PPP) was performed in 269 patients across 15 studies with primary fascial closure being achieved in 226 (84 %); 16 patients had a recurrence (7.2 %) and the complication rate was 12 % with 2 reported mortalities.  There were 4 studies with 14 patients in total undergoing abdominal wall expansion using tissue expanders with a fascial closure rate of 92.9 % (n = 13).  A recurrence rate of 10.0 % (n = 1) was reported with 1 complication and no mortalities.  Follow-up ranged from 3 to 36 months across the studies.  There were 2 studies reporting the use of botulinum toxin (BTX) with 29 patients in total.  A primary fascial closure rate of 100 % (n = 29) was demonstrated although a combination of techniques including component separation and Rives-Stoppa repair were used.  There were no reported complications related to the use of BTX.  However, the short-term follow-up in many cases and the lack of routine radiological assessment for recurrence suggested that the recurrence rate has been under-estimated.  The authors concluded that PPP, tissue expanders and BTX were safe and feasible methods for abdominal wall expansion prior to incisional hernia repair.  In combination with existing techniques for repair, these methods may help provide the crucial extra tissue mobility required to achieve primary closure.

In a prospective, pilot study, Farooque et al (2016) reported their preliminary results with BTX injection causing flaccid paralysis (relaxation) of the lateral abdominal wall muscles prior to surgery.  These investigators measured the effect of pre-operative BTX prior to elective repair of recurrent abdominal hernias.  Under US control, 2 weeks prior to surgery, 50 units of BTX was injected into the external oblique, internal oblique and transversus abdominis muscles at 3 sites on each side of the lateral abdominal wall (total dose 300 units).  Pre- and post-BTX abdominal CT measured changes in abdominal wall muscle thickness and length.  All hernias were repaired with laparoscopic or laparoscopic-assisted mesh techniques in a 1- or 2-staged procedure.  A total of 8 patients received BTA injections that were tolerated with no complications.  Post-BTX pre-operative CT showed a significant increase in mean length of lateral abdominal wall from 18.5 cm pre-BTX to 21.3 cm post-BTX (p = 0.017) with a mean un-stretched length gain of 2.8 cm per side (range of 0.8 to 6.0 cm).  All hernias were surgically reduced with mesh with no early recurrence.  The authors concluded that pre-operative BTA injection prior to complex abdominal hernia repair was a safe procedure that causes flaccid relaxation, elongation and thinning of the lateral abdominal muscles and decrease in hernia defect.  Moreover, they stated that further evaluation is needed, BTX injections may be a useful adjunct to surgical repair of complex incisional hernias.

Elstner et al (2018) stated that component separation (CS) is a technique which mobilizes flaps of innervated, vascularized tissue, enabling closure of large ventral hernia defects using autologous tissue.  Disadvantages include extensive tissue dissection when creating these myofascial advancement flaps, with potential consequences of significant post-operative skin and wound complications.  These researchers examined the benefit of a novel, ultra-minimally invasive single port anterior CS technique.  This was a prospective study of 16 external oblique (EO) releases performed in 9 patients and 4 releases performed in 3 fresh frozen cadavers.  All patients presented with recurrent complex ventral hernias, and were administered pre-operative BTX to their lateral oblique muscles to facilitate defect closure.  At the time of elective laparoscopic repair, patients underwent single-port endoscopic EO release using a single 20-mm incision on each side of the abdomen.  Measurements were taken using real-time US.  Post-operatively, patients underwent serial examination and abdominal CT assessment.  Single-port endoscopic EO release achieved a maximum of 50-mm myofascial advancement per side (measured at the umbilicus).  No complications involving wound infection, hematoma, or laxity/bulge have been noted.  All patients proceeded to laparoscopic or laparoscopic-open-laparoscopic intra-peritoneal mesh repair of their hernia, with no hernia recurrences to-date.  The authors concluded that single-port endoscopic EO release holds potential as an adjunct in the repair of large ventral hernia defects.  It is easy to perform, is safe and efficient, and entails minimal disruption of tissue planes and preserves abdominal wall perforating vessels.  It requires only 1 port-sized incision on each side of the abdomen, thus minimizing potential for complications.  Moreover, they stated that further detailed quantification of advancement gains and morbidity from this technique is needed, both with and without prior administration of BTX to facilitate closure.

Furthermore, UpToDate reviews on “Management of ventral hernias” (Brooks and Cone, 2018), “Laparoscopic ventral hernia repair” (Shah and Liang, 2018), “Abdominal access techniques used in laparoscopic surgery” (Pryor and Gracia, 2018), and “Overview of abdominal wall hernias in adults” (Brooks, 2018) do not mention botulinum toxin as a management tool.

Cricopharyngeal Dysfunction

Schneider et al (1994) noted that botulinum toxin (BTX) is known as a relatively safe and efficacious agent for the treatment of various neurologic and ophthalmologic disorders.  Since dysphagia and deglutition problems combined with aspiration are often caused by spasticity, hypertonus, or delayed relaxation of the upper esophageal sphincter (UES), conventional treatment including lateral cricopharyngotomy was replaced by localized injections of botulinum toxin into the cricopharyngeal muscle (CM) in a series of 7 patients.  The study comprised patients with slight dysphagia caused by isolated hypertonus of the UES, as well as patients with severe deglutition disorders, complete inability to swallow, and aspiration problems.  Pre-operative diagnostic evaluation included careful history-taking, physical examination, cineradiography, and esophageal manometry to exclude other causes of dysphagia.  For precise localization, injections were performed under general anesthesia after location of the CM by direct esophagoscopy and electromyographic (EMG) guidance.  Injections were administered into the dorsomedial part and on both sides into the ventrolateral parts of the muscle.  Depending on the severity of symptoms and the intraluminal pressure of the UES, the dose varied between 80 and 120 units (BTX-A [Botox] from Dysport).  The treatment outcome was evaluated by a disability rating score: patients' complaints were scored by subjective and objective parameters before and after injection.  All but 2 patients experienced complete relief or marked improvement of their complaints.  There were no severe side effects or post-operative complications.  The authors concluded that local botulinum toxin injection proved to be an effective alternative treatment to invasive procedures for patients with isolated dysfunction of the UES, and also for patients with more complex deglutition problems combined with aspiration.

Haapaniemi et al (2001) stated that dysphagia is a common symptom in various neurological disorders affecting pharyngeal functions.  Cricopharyngeal dysfunction is one of the major findings in these patients.  The most effective treatment for restoring normal swallowing function in persistent cricopharyngeal dysfunction is cricopharyngeal myotomy, especially when mechanical obstruction or a well-localized neuromuscular dysfunction, such as a CM spasm, is present.  However, when there is a more diffuse neurological disorder present the results of surgery are more disappointing.  In unclear cases, or in patients with temporary problems, no good method other than swallowing training, bougienage, and tube feeding are available.  During the past decade, BTX has been found to be of therapeutic value in the treatment of a variety of neurological disorders associated with inappropriate muscular contractions such as torticollis and spasmodic dysphonia.  Recently, injections of BTX in patients with CM dysfunction have been reported to result in marked relief of dysphagia.  These investigators described their experiences with BTX injections to treat 4 patients suffering from deglutition problems and cricopharyngeal dysphagia of different origins; BTX was injected into the CM that was identified by endoscopy under general anesthesia; no major side effects were observed and 3 patients obtained a significant improvement of esophageal symptoms after the 1st injection; treatment had limited effect in 1 patient who had reflux disease and only slight cricopharyngeus dysfunction.

Kelly et al (2013) reviewed the dysphagia-related outcomes and quality of life (QOL) in a series of patients with UES dysfunction treated with cricopharyngeal (CP) BTX injection, and identified patient characteristics or CP muscle histologic features that predict efficacy of BTX injection.  These researchers carried out a retrospective chart review on patients with UES dysfunction who underwent CP BTX injection.  Dysphagia-related QOL questionnaires based on the Eating Assessment Tool (EAT-10) were mailed to patients.  A total of 49 patients (30 women, 19 men; average age of 59 +/- 16 years) with UES dysfunction have been treated at the authors’ institution with CP BTX injection since 2000; 17 of these patients also underwent CP myotomy.  Injections of BTX were occasionally repeated after the treatment effect subsided, and the BTX dose varied widely (average of 39 +/- 19 units).  Improvement in symptoms was noted by 65 % of patients.  The overall complication rate was minimal, although many patients complained of transient worsening of dysphagia after CP BTX injection.  Biopsy specimens of the CP muscle were evaluated in the subset of patients with CP BTX injection who proceeded to myotomy, with results of neuropathic, myopathic, and mixed histologic subtypes.  The EAT-10 scores demonstrated a general trend toward improved swallowing outcomes after CP BTX injection.  The authors concluded this study reviewed findings from the largest published series of BTX treatment of UES dysfunction and evaluated the efficacy, patient satisfaction, and complications of this procedure; dysphagia-related QOL outcomes appeared to be improved after CP BTX injection.

In a prospective, open study, Woisard-Bassols et al (2013) evaluated changes in the swallowing and dietary status after BTX-A injection into the UES in a series of patients with CM dysfunction associated with pharyngo-laryngeal weakness during at least 1 year follow-up after treatment.  Patients who had a CM dysfunction associated with pharyngo-laryngeal weakness and who were at risk for aspiration were included in the study.  The upper border of the cricoid cartilage was identified and the CM localized using a standard EMG.  The dose of BTX-A was determined depending on the results of EMG performed just before the injection.  Outcomes were assessed by the penetration-aspiration scale (PAS), the level of residue in the pyriform sinus and the National Institute of Health-Swallow Safety Scale (NIH-SSS) on a video fluoroscopic swallowing (VFSS) assessment, the patient's subjective impressions of their ability to swallow by the Deglutition Handicap Index (DHI), and changes in dietary status by the Functional Oral Intake Scale.  A total of 11 patients underwent the complete assessment of swallowing function at 1, 3, 6, and 12 months.  After the first set of treatment, 7 patients had a good response and 4 did not respond.  A significant decrease in the PAS score (p = 0.03), the amount of residue (p = 0.04) and the NIH-SSS score (p = 0.03) was observed 3 months after the injection in comparison with the first VFSS before the treatment.  A relapse of dysphagia occurred in 3 out of the 11 treated patients; at 3 and 4 months for 2 patients with a Wallenberg syndrome, and at 11 months for a patient with cranial nerve paralysis after a surgery for a glomus tumor; 2 of them underwent a 2nd injection.  One patient had a good response and remained stable for at least 1 year.  The second did not respond either to the 2nd injection or to a myotomy of the CM.  The third one is waiting for further surgery (myotomy).  Therefore, at the end of the study and after a follow-up of at least 12 months, 5 patients out of the 11 enrolled had a good result. The authors concluded that percutaneous injection of BTX-A into the UES could be a useful solution to improve cricopharyngeal dysfunction, despite the underlying pharyngo-laryngeal weakness.

Sharma et al (2015) examined the efficacy of endoscopic-guided BTX injection into the CM and determined the duration of its effects.  A 3-year prospective study of 12 patients undergoing injection of BTX was conducted, with a telephone survey to assess dysphagia pre-operatively, and at 1, 3 and 6 months post-treatment, using the MD Anderson Dysphagia Inventory.  Median age was 66.2 years.  Causes of cricopharyngeal dysphagia included idiopathic cricopharyngeal hypertrophy (67 %), previous cerebrovascular accident (17 %), cranial nerve palsy (8 %) and previous chemo-radiotherapy to the neck (8 %).  There were no complications; 2 patients had repeat injections after 6 months.  There was significant improvement in MD Anderson Dysphagia Inventory scores at 1 and 3 months versus pre-operative scores (73.1 ± 14.9 versus 46.9 ± 7.6, p = 0.0001, and 65.1 ± 11.5 versus 46.9 ± 7.6, p = 0.0001), but not at 6 months (51.0 ± 11.0 versus 46.9 ± 7.6, p = 0.14).  The authors concluded that endoscopic-guided injection of BTX into the cricopharyngeus muscle was a safe and effective method for treating CM dysfunction, lasting up to 6 months.

Kocdor et al (2016) stated that cricopharyngeal dysfunction may lead to severe dysphagia and aspiration.  In a systematic review, these investigators evaluated the existing studies on the effectiveness of myotomy, dilatation, and BTX injection in the management of cricopharyngeal dysphagia.  PubMed and Web of Science databases were searched to identify eligible studies by using the terms "cricopharyngeal dysfunction", "cricopharyngeal myotomy", "cricopharyngeal botox", "cricopharyngeal dilation" and their combinations from 1990 to 2013.  This was supplemented by hand-searching relevant articles.  Eligible articles were independently assessed for quality by 2 authors; statistical analysis was performed.  The database search revealed 567 articles; 32 articles met eligibility criteria and were further evaluated.  The reported success rates of BTX injections was between 43 % and 100 % (mean = 76 %), dilation 58 % and 100 % (mean = 81 %), and myotomy 25 % and 100 % (mean = 75 %).  In logistic regression analysis of the patient-weighted averages, the 78 % success rate with myotomy was significantly higher than the 69 % success rate with BTX injections (p = 0.042), whereas the intermediate success rate of 73 % with dilation was not significantly different from that of either myotomy (p = 0.37) or BTX (p = 0.42).  There was a statistically significant difference between endoscopic and open myotomy success rates (p = 0.0025).  Endoscopic myotomy had a higher success rate, with a 2.2 odds ratio.  The authors concluded that the success rate of myotomy was significantly higher than the success rate of BTX injections in cricopharyngeal dysfunction.  Moreover, endoscopic myotomy was found to have a higher success rate compared to open myotomy.

In a retrospective study, Kim et al (2017) examined the safety and effectiveness of office-based EMG-guided injection of BTX in the CM of patients who did not show upper esophageal sphincter passage in a swallowing study in spite of maximal swallowing rehabilitation.  A total of 36 patients who showed no or limited ability to oral feed after maximum swallowing rehabilitation were enrolled.  Video fluoroscopic swallowing study, flexible endoscopic evaluation of swallowing, disability rating scale, penetration aspiration score, and National Institutes of Health swallowing safety scale were used in the evaluation of dysphagia.  Success was defined as independence on gastrostomy for patients who previously were dependent on gastrostomy and improvement in disability rating scale score after BTX injections.  The success rate was 63.9 %.  The complication rate was very low, with only 1 patient showing temporary unilateral vocal fold paralysis; BTX injection was more effective in patients with cranial nerve IX or X palsy than in those without it (p = 0.006).  The authors concluded that this procedure can be a simple, safe, and effective tool in patients with cricopharyngeal dysfunction after swallowing rehabilitation, especially for cranial nerve IX or X palsy.

Furthermore, an UpToDate review on “Oropharyngeal dysphagia: Clinical features, diagnosis, and management” (Lembo, 2018) states that “Botulinum toxin injection should be reserved for patients with cricopharyngeal dysfunction who are not candidates for surgery or endoscopic balloon dilation and should only be performed in centers of expertise.  Botulinum toxin is injected under endoscopic guidance with either a rigid or flexible endoscope”.

Post-Parotidectomy Sialocele

In a prospective, non-randomized, non-blinded, pilot study, Vargase and co-workers (2000) reported their experience in treating 4 cases (2 men and 2 women) of recurrent siacloceles with BTX-A after parotid surgery.  Subjects with persistent post-parotidectomy sialoceles who had undergone various treatment failures were included.  The diagnosis was made by fine-needle aspiration of the mass based on well-recognized cytologic features of the entity, as well as an elevated amylase level and no evidence of tumor or infection.  Sialoceles were aspirated before local injection of BTX-A (30 to 50 U) subcutaneously.  Patients were followed-up 1 week after receiving BTX-A injection and then at monthly intervals.  They were extensively questioned and examined for any evidence of side effects or recurrence.  All patients had total resolution of sialocele or external salivary fistula within 1 month of treatment.  None of the patients to-date had demonstrated recurrences at 7 through 13 months, and there were no complications, particularly facial nerve weakness.  The authors concluded that these findings suggested that BTX-A offered a highly safe, effective, and non-invasive method of treatment in post-parotidectomy sialocele.

Chow and Kwok (2003) noted that sialocele is an uncommon complication of parotidectomy.  Most cases resolve after conservative therapy consisting of repeated aspiration and pressure dressing.  The condition is, however, occasionally resistant to such therapy.  These investigators report on a 52-year old man who had a 10-year history of right parotid swelling.  Following fine-needle aspiration cytology, Warthin's tumor was diagnosed, but after elective parotidectomy, a swelling developed and parotid sialocele was diagnosed; BTX-A was given after the sialocele had persisted for almost 3 weeks after surgery, and after conservative management had been tried; the sialocele disappeared after 2 doses of treatment.  The authors concluded that BTX therapy was an effective treatment for persistent sialocele.

Arnaud and colleagues (2008) noted that salivary fistulas and sialoceles are rare complications of post-traumatic or post-operative parotid gland and duct injuries.  Local injections of BTX-A represent a new and effective treatment for complications of these injuries, which is less invasive, stressful and lengthy than conventional methods.  The authors reported 5 cases in which 3 salivary fistulas and 2 sialoceles were successfully treated by BTX injections.  The therapeutic protocol was described; it allowed simple management of these complications and use of smaller doses than those described in the literature for treatment of sialoceles.  The authors recommended use of BTX injections in first intention for management of salivary fistulas and sialoceles.

Pantel and associates (2013) reported on the case of a 41-year old man who developed a sialocele after partial parotidectomy for a parotid pleomorphic adenoma.  The sialocele was effectively treated by a single injection with BTX-B combined with multiple needle aspirations.  Ultrasound-guided infiltration of 2,500 mouse-units of BTX-B in the residual parotid gland tissue under local anesthesia.  Repeated needle aspirations were performed before and after the infiltration; 10 days after the injection, the patient was free of any discomfort.  The authors concluded that BTX-B was effective in the management of post-operative sialocele after parotid gland surgery.

Jeffe and Sulman (2015) noted that parotid sialoceles are bothersome complications of parotidectomy and penetrating injury to the parotid gland.  Though typically self-limited and responsive to conservative management, they could be particularly difficult to manage in the pediatric population where even conservative interventions are less well-tolerated.  These researchers presented the case of a 4-year old child with a post-traumatic parotid sialocele that was successfully managed with a single injection of BTX- B.  The authors concluded that to their knowledge, this was the 1st reported case of the use of BTX for this purpose in the pediatric population.

Melville and colleagues (2018) stated that buccal squamous cell carcinoma (SCC) is an aggressive form of oral carcinoma with a high recurrence rate.  Injury to the parotid duct is often unavoidable when surgically treating buccal SCC because of the intimate anatomic relation among the buccal mucosa, Stensen duct, and parotid gland.  It is often difficult to achieve negative margins and preserve the integrity of the parotid duct.  Sialocele formation is a frequent and untoward complication owing to extravasation of saliva into the surgical defect, which delays healing, creates fistulas, and produces painful facial swelling.  Currently, no consensus exists regarding the management of a parotid sialocele.  Multiple investigators have described different modalities of treatment, such as repeated percutaneous needle aspiration, pressure dressings, anti-sialagog therapy, radiotherapy, BTX, and surgical techniques, including duct repair, diversion, ligation, drain placement, and parotidectomy.  With approval from the institutional review board (IRB) of the University of Texas Health Sciences Center at Houston, 3 cases of parotid sialocele and non-healing fistulas successfully treated with Botox (onabotulinumtoxinA) after tumor extirpation, neck dissection, and reconstruction with a microvascular free flap were presented.  At the University of Texas Health Sciences Center at Houston, the radiation oncologist preferred not to start adjunctive radiation treatment with a non-healing wound or a drain in the field of radiation.  Ideally, a standard timing of adjuvant radiotherapy is 6 to 8 weeks after surgery and 60 cGy should be completed before 7 months.  The authors concluded that with the use of Botox, the non-healing wound resolved and the drain was removed at least 2 weeks before the initiation of adjunctive radiotherapy, thus minimizing the delay in adjuvant treatment.

Hwang and colleagues (2018) stated that sialocele is a subcutaneous cavity containing saliva, most often caused by facial trauma or iatrogenic complications.  In subcondylar fractures, most surgeons are conscious of facial nerve injury; however, they usually pay little attention to the parotid duct injury.  These investigators reported the case of a 41-year old man with a sialocele, approximately 5×3 cm in size, which developed 1 week after subcondylar fracture reduction.  The sialocele became progressively enlarged despite conservative management; CT showed a thin-walled cyst between the body and tail of the parotid gland.  Fluid leakage outside the cyst was noted where the skin was thin.  Sialography showed a cutting edge of the inferior interlobular major duct before forming the common major duct that seemed to be injured during the subcondylar fracture reduction process.  These investigators decided on prompt surgical treatment, and the sialocele was completely excised.  A duct from the parotid tail, secreting salivary secretion into the cyst, was ligated; BTX was administrated to block the salivary secretion and preventing recurrence.  Treatment was successful.  In addition, the authors found that parotid major ducts were enveloped by the deep lobe and extensive dissection during the subcondylar fracture reduction may cause parotid major duct injury.

Endometriosis

An AHRQ Comparative Effectiveness Review on “Noncyclic chronic pelvic pain therapies for women: Comparative effectiveness” (Andrews et al, 2012) stated that the Vanderbilt Evidence-based Practice Center systematically reviewed evidence on therapies for women age 18 and over with non-cyclic chronic pelvic pain (CPP).  These investigators focused on the prevalence of conditions thought to occur commonly with CPP; changes in pain, functional status, quality of life, and patient satisfaction resulting from surgical and nonsurgical treatment approaches; harms of nonsurgical approaches; evidence for differences in surgical outcomes if an etiology for CPP is identified post-surgery; and evidence for selecting one intervention over another after an approach fails.  They searched Medline via PubMed, PsycInfo®, Embase Drugs and Pharmacology, and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases as well as the reference lists of included studies.  These researchers included studies published in English from January 1990 to May 2011.  They excluded intervention studies with fewer than 50 adult women with CPP; cross-sectional studies or case series with fewer than 100 women with CPP addressing the prevalence of co-morbidities; and studies lacking relevance to CPP treatment.  Of 36 included studies, 18 were randomized controlled trials (RCTs) (2 good, 3 fair, and 13 poor quality); 3 were cohort studies (3 poor quality); and 15 were cross-sectional studies addressing the prevalence of co-morbidities (quality varied by comorbidity).  The most frequently reported co-morbidities were dysmenorrhea, dyspareunia, and irritable bowel syndrome (IBS).  Among studies addressing surgical interventions, there was no evidence that laparoscopic uterosacral nerve ablation (LUNA) is more effective than simple diagnostic laparoscopy and no evidence of benefit of lysis of adhesions.  Evidence was insufficient to comment on relief of pain after hysterectomy.  Nine studies of non-surgical approaches assessed hormonal therapies for endometriosis-associated CPP and reported similar effectiveness among active agents.  One exception was an RCT comparing raloxifene with placebo, which reported more rapid return of pain in the raloxifene group.  Few studies assessed non-hormonal medical or non-pharmacologic management; benefits were reported in single studies of a pelvic physiotherapy approach, botulinum toxin, pelvic ultrasonography, and an integrated management approach.  No studies provided evidence relating to a trajectory of care.  Reporting of harms data was very limited.  The authors concluded that improved characterization of the targeted condition, intervention, and population in CPP research was necessary to inform treatment choices for this commonly reported entity.  A uniform definition of CPP and standardized evaluation of participants are lacking across the literature.  Study populations likely vary widely, and studies may be reporting effects from treating symptoms rather than a diagnosed condition.  Thus, the understanding of potential treatment effects was diluted.  Similarly, understanding co-morbidity prevalence with CPP was difficult, as conditions may be considered part of the differential diagnosis or a concomitant condition.  Among studies addressing treatment effects, little evidence demonstrated the effectiveness of surgical approaches.  Studies of non-surgical approaches typically addressed hormonal management of endometriosis-related CPP and were not placebo-controlled, thus limiting the ability to understand whether hormonal therapies would be beneficial for women with CPP without endometriosis and whether pain relief is due simply to the placebo effect.  Some studies reported benefits of other non-surgical approaches, but non-hormonal and non-pharmacologic management remain under-studied.

Furthermore, an UpToDate review on “Endometriosis: Treatment of pelvic pain” (Schenken, 2018) does not mention botulinum toxin as a therapeutic option.

Hyperactive and Hypertrophic Frontalis Muscles from Chronic Compensatory Brow Elevation

In an interventional case-series study, Ben Simon and associates (2005) reported 7 patients with paradoxical use of the frontalis muscle despite post-surgical correction of ptosis with good post-operative eyelid position.  Successful treatment with Botox facilitated motor relearning and cessation of muscle contraction.  This trial included 7 patients, in 2 eye-plastic clinics, who underwent successful surgical correction of upper eyelid ptosis.  Clinical history, clinical photographs, treatment, and follow-up were reviewed and the main outcome measures were frontalis muscle contraction and upper eyelid position.  Patients underwent successful surgical correction of ptosis but continued using the frontalis muscle despite good eyelid position post-operatively.  Frontalis contraction ceased spontaneously in 2 patients, but needed Botox injection in 5.  The effects of a single treatment of Botox lasted from 3 months to 2 years, longer than the expected effect of the toxin.  The authors concluded that patients with long-standing eyelid ptosis may paradoxically continue utilizing the frontalis after successful surgical correction and despite good post-operative eyelid position.  Cessation of frontalis contraction could be achieved with a single injection of Botox.  The authors hypothesized that chemo-denervation, achieved with Botox, may influence the central nervous system (CNS) to relearn the set point for muscle contraction and may be associated with permanent motor relearning.  Spontaneous resolution of muscle contraction could occur in the first months following surgery.

In a prospective, interventional case-series study, Naik and colleagues (2008) evaluated the effectiveness of anterior chemo-denervation of levator palpebrae superioris with Botox to induce temporary ptosis for corneal protection, and evaluated the incidence of superior rectus under-action.  Patients with ocular surface pathology requiring temporary tarsorrhaphy underwent transcutaneous anterior chemo-denervation of levator palpebrae superioris with Botox.  The onset and duration of ptosis, corneal healing, and superior rectus under-action was evaluated.  A total of 10 eyes of 10 patients underwent transcutaneous anterior chemo-denervation of levator muscle; 5 patients had Bell’s palsy with exposure keratopathy, 4 patients had persistent epithelial defect, and 1 had neurotrophic ulcer.  The median age at presentation was 30 years.  Median dose of Botox injection was 12.5 U (range of 10 to 15 U).  The mean palpebral fissure height of 9 mm (SD +/- 2.1 mm) before injection, reduced to 2.8 mm (SD +/- 1.9 mm) at 1-week post-injection.  More than 50 % reduction in palpebral fissure height was seen in 9 out of 10 eyes (90 %, 95 % CI: 71.4 to 100 %) at 1 week, 7 of 9 eyes (77.8 %, 95 % CI: 50.6 to 100 %) at 2 weeks, and 2 of 9 eyes (22.2 %, 95 % CI: 0 to 49.4 %) at 4 weeks, and returned to pre-treatment level after mean duration of 9.2 weeks (range of 5 to 16 weeks).  Superior rectus under-action was not noted in any of the patient (95 % CI: 0 to 30 %).  Corneal pathology improved in all cases.  The authors concluded that anterior chemo-denervation of levator palpebrae superioris with Botox induced significant temporary ptosis and aided in corneal healing; anterior placement of Botox injection may avoid superior rectus under-action.

The authors noted that this study had several drawbacks.  It had a small sample size (n = 10), and was non-comparative.  Moreover, the difference in bio-equivalence between Botox and Dysport made comparison with previous studies difficult.  However, this prospective series suggested that anterior chemo-denervation of the levator was likely to reduce the chances of simultaneous superior rectus underaction.  They stated that a comparative study randomizing both techniques of injection using standard toxin dose is needed to validate these preliminary findings.

Lumbar Dystonia / Lumbar Spasticity

An UpToDate on “Treatment of dystonia” (Comella, 2018) does not mention “lumbar” or “spine” or “spinal” dystonia.

Post-Traumatic Headaches

Lippert-Gruner (2012) noted that pharmacotherapy of acute post-traumatic tension headaches consists of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs).  Treatment of chronic tension-type head-aches consists mainly of tricyclic anti-depressants; local injection of BTX is one of the comparatively newer therapeutic options.  No data on the treatment of post-traumatic headaches with BTX exist.  In this case report, a 62-year old woman with a history of major traumatic brain injury (TBI) 5 years previously developed chronic tension-type headaches of an oppressive nature.  The results of treatment with oral medication were not satisfactory.  The patient was treated with local injections of 22 IU Botox into the frontalis muscle and corrugator supercilii muscle.  After only 5 days, the headaches had improved and after 10 days the patient was symptoms-free even when under stress.  The authors concluded that sufficiently large-scale clinical trials are needed to examine the effects of BTX on post-traumatic headaches.

Conidi (2016) stated that post-traumatic headache (migraine) is the most common symptom of concussion and TBI.  These investigators carried out an expert opinion-based review along with a literature review (PubMed) examining known interventional procedures for post-traumatic headache using the keywords post-traumatic headache, post-traumatic migraine headache, concussion, mild traumatic brain injury, and traumatic brain injury and the following categories: mechanism, pathophysiology, treatment, physical therapy, neuro-stimulation, Botox A/onabotulinum toxin, and surgical intervention.  The results returned a total of 181 articles of which 52 were selected.  None of the articles included randomized placebo-controlled studies, and most were either prospective or retrospective case analysis and/or review articles or consensus opinion papers, with most studies yielding positive results.  The authors concluded that despite a lack of hard evidence, interventional procedures, alone or in combination, appeared to be an effective treatment for post-traumatic headaches.

Furthermore, UpToDate reviews on “Postconcussion syndrome” (Evans, 2018a) and “Sequelae of mild traumatic brain injury” (Evans, 2018b) do not mention botulinum toxin as a therapeutic option.

Treatment of Complications Associated with Breast Implants for Mammoplasty

Li and co-workers (2018) stated that breast implants have been safely and efficiently used in the plastic surgery department.  With the increasing demand for aesthetics, these silicone implants were not only used in breast augmentation surgery but also in breast reconstruction after mastectomy.  Nevertheless, breast prosthesis implantation brings a lot of complications (e.g., post-operative chronic pain, capsule contracture, prosthesis displacement and prosthesis rupture and infection in severe cases).  From the year 1998, BTX-A has been reported to be effective for pain control, capsule contracture lessening, expander enlargement and so on.  However, these studies included all kinds of study types: randomized, double-blinded RCT, non-randomized trial, retrospective analysis and case series, besides the outcomes were varied.  In a systematic review and meta-analysis, these researchers reviewed how BTX-A acts in the field of mammaplasty and discussed the relative mechanisms of BTX-A and the related research progress.  They searched PubMed, Embase, Cochrane, Web of science, Clinical trials, Wanfang Database and VIP from inception until March 2018 for papers reporting the use of BTX-A in the breast surgery using implants deep within the pectoralis major muscle; system review, viewpoints and case reports were excluded.  A total of 10 articles met the criteria for inclusion including 6 prospective controlled (2 RCT; 4 other trails), 3 retrospective cohorts, and 1 case series.  These studies were all about patients using BTX-A during or after breast surgery with expanders or prostheses.  A total of 682 patients were enrolled, 543 (79.61 %) accepted BTX-A injection, 185 underwent mastectomies with immediate reconstruction, 13 with delayed reconstruction, 295 mastectomies with either immediate or delayed reconstruction, and 189 with breast augmentation using silicone prostheses.  The study time ranging from 4 months to 13 years, 15 patients (2.76 %) received BTX-A injection more than 2 times, 9.2 % received less than 75 U BTX-A, 34.3 % 75-100 U, 0.18 % 250 U, and in 56.4 % the dosage was not stated.  No complications associated with BTX-A were mentioned, almost all the studies reported efficacy for pain control.  Other assessments included increased speed of expander enlargement and volume were mentioned in 4 papers, 2 articles analyzed the VAS, 3 suggested relief of capsular contracture, 2 reported lower narcotic use, 3 mentioned shorter hospital stays, and 1 proved lowering the rate of unplanned expander.  It appeared all the studies demonstrated the valid usage of BTX-A, but the quality of this evidence was still under the line.  The authors concluded that they could try to use BTX-A as a new method in the field of mammaplasty.  There are so many advantages such as post-operative pain relief, reducing the hospital stay, and increasing operation success rate, but rigorous methodological evidence is still lacking.  They stated that a lot of studies were retrospective, only 2 studies used the RCT method.  These researchers stated that to obtain strong evidence to clarify the usage of BTX-A, more randomized, double-blinded, controlled trials are needed.  Level of Evidence = III.

Treatment of Muscle Spasm due to Churg Strauss Disease

An UpToDate review on “Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)” (King, 2018) does not mention botulinum toxin as a therapeutic option.

Treatment of Facial Scars or Mastectomy Scars

Chen and colleagues (2018) evaluated 38 patients (study group, n = 21; control, n = 17) with obvious scar on their faces to explore the effect of W-plasty combined Botox-A injection in improving appearance of scar.  W-plasty combined Botox injection surgery was performed for patients in the study group.  The authors concluded that W-plasty combined Botox-A injection could significantly improve the appearance of sunk scar in the face.  This approach might provide a new insight in the treatment of scar repair.  However, these researchers stated that to draw a valid conclusion, a further investigation with a larger sample size is needed.  The drawbacks of this study included: the sample sizes of these 2 groups were comparatively small, thus, the relate subgroup analysis was not carried out.  Meanwhile, due to the small sample size, a potential criterion for the dose of Botox-A was not documented.  Moreover, to further examine the effect of Botox-A injection in improving appearance of scar, healing ability of scars underlying different muscles should be concerned in the future.  In addition, to draw a valid conclusion, a single W-plasty or Botox-A injection control group should be considered.

Furthermore, there are not robust clinical trials that demonstrated the safety and efficacy of botulinum toxin injection for the treatment of mastectomy scars.

EMG Guidance for Botulinum Toxin Injections

Grigoriu et al (2015) conducted a systematic review of the impact of different injection-guiding techniques on the effectiveness of botulinum toxin type A (BoNT-A) for the treatment of focal spasticity and dystonia.  Data sources included Medline via PubMed, Academic Search Premier, PASCAL, the Cochrane Library, Scopus, SpringerLink, Web of Science, EM Premium, and PsycINFO.  Two reviewers independently selected studies based on pre-determined inclusion criteria.  Data relating to the aim were extracted.  Methodological quality was graded independently by 2 reviewers using the Physiotherapy Evidence Database assessment scale for randomized controlled trials (RCTs) and the Downs and Black evaluation tool for non-RCTs.  Level of evidence was determined using the modified Sackett scale.  A total of 10 studies were included; 7 were randomized.  There was strong evidence (level 1) that instrumented guiding (ultrasonography [US], electrical stimulation [ES], electromyogram [EMG]) was more effective than manual needle placement for the treatment of spasmodic torticollis, upper limb spasticity, and spastic equinus in patients with stroke, and spastic equinus in children with cerebral palsy (CP); 3 studies provided strong evidence (level 1) of similar effectiveness of US and ES for upper and lower limb spasticity in patients with stroke, and spastic equinus in children with CP, but there was poor evidence or no available evidence for EMG or other instrumented techniques.  The authors concluded that these results strongly recommend instrumented guidance of BoNT-A injection for the treatment of spasticity in adults and children (ES or US), and of focal dystonia such as spasmodic torticollis (EMG).  No specific recommendations can be made regarding the choice of instrumented guiding technique, except that US appears to be more effective than ES for spastic equinus in adults with stroke.

In a RCT, Wu et al (2016) examined the safety and efficacy of EMG- and palpation-guided botulinum toxin type A injection in cervical dystonia (CD) patients.  A total of 68 CD patients were randomly allocated to 2 groups, receiving botulinum toxin type A injections guided by either palpation (Group A) or EMG (Group B).  The primary end-point was defined as the difference in the Tsui score between groups at 16 weeks.  The secondary end-points were the visual analog scale (VAS) and Hospital Anxiety and Depression Scale (HADS) scores and Clinical and Patient Global Impression of Change (CGIC and PGIC).  A total of 65 patients completed the study.  No significant difference was observed in the Tsui score between groups A and B at 4, 8, and 12 weeks after treatment (p > 0.05).  However, 16 weeks after treatment, the Tsui score of group A was significantly higher than that of group B.  For both groups, the degree of pain at each time-point during follow-up significantly reduced after treatment.  However, no significant difference was observed in VAS scores between the 2  groups.  Interestingly, the patient HADS score decreased without statistical significance 8 weeks following treatment.  No significant difference in HADS scores was observed between the 2 groups.  Additionally, there was no significant difference in PGIC and CGIC between the 2 groups.  However, CGIC was significantly higher than PGIC.  No significant difference in adverse reactions was observed between groups; CD patients treated with EMG guidance experienced a significantly more pain at the injection site but a significantly lower adverse event occurrence rate of dysphagia when compared to CD patients treated with palpation guidance only.  The authors concluded that CD patients treated with EMG guidance experienced a prolonged benefit as measured by the Tsui scale when compared to CD patients treated with palpation guidance alone; EMG-guided injection resulted in a lower incidence of dysphagia and higher incidence of discomfort at the injection site than palpation-guided injection.

In a Cochrane review, Marques et al (2016) compared the safety, efficacy, and tolerability of botulinum toxin type B (BtB) versus placebo in patients with CD.  These researchers included 4 RCTs of moderate overall methodological quality, including 441 participants with CD; 3 studies excluded participants known to have poorer response to Bt treatment, therefore including an enriched population with a higher probability of benefiting from Bt treatment.  None of the trials was independently funded.  All RCTs evaluated the effect of a single Bt treatment session using doses between 2,500 U and 10,000 U; BtB was associated with an improvement of 14.7 % (95 % confidence interval [CI]: 9.8 % to 19.5 %) in the patients' baseline clinical status as assessed by investigators, with reduction of 6.8 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-total score) at week 4 after injection (95 % CI: 4.54 to 9.01).  Mean difference (MD) in TWSTRS-pain score at week 4 was 2.20 (95 % CI: 1.25 to 3.15).  Overall, both participants and clinicians reported an improvement of subjective clinical status.  There were no differences between groups in the withdrawals rate due to adverse events (AEs) or in the proportion of participants with AEs.  However, BtB-treated patients had a 7.65 (95 % CI: 2.75 to 21.32) and a 6.78 (95 % CI: 2.42 to 19.05) increased risk of treatment-related dry mouth and dysphagia, respectively.  Statistical heterogeneity between studies was low-to-moderate for most outcomes.  All tested dosages were effective against placebo without clear-cut evidence of a dose-response gradient.  However, duration of effect (time until return to baseline TWSTRS-total score) and risk of dry mouth and dysphagia were greater in the subgroup of participants treated with higher BtB doses.  Subgroup analysis showed a higher improvement with BtB among BtA-non-responsive participants, although there were no differences in the effect size between the BtA-responsive and non-responsive subgroups.  The authors concluded that a single BtB-treatment session was associated with a significant and clinically relevant reduction of CD impairment including severity, disability and pain, and was well-tolerated, when compared with placebo.  However, BtB-treated patients were at an increased risk of dry mouth and dysphagia.  There were no data from RCTs evaluating the safety and effectiveness of repeated BtB injection cycles.  There were no RCT data to allow the authors to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, and impact on quality of life (QOL).

In a Cochrane review, Castelao et al (2017) compared the safety, efficacy, and tolerability of botulinum toxin type A (BtA) versus placebo in people with CD.  These investigators included 8 RCTs of moderate overall risk of bias, including 1,010 participants with cervical dystonia; 6 studies excluded participants with poorer responses to BtA treatment, therefore including an enriched population with a higher probability of benefiting from this therapy.  Only 1 trial was independently funded.  All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 236 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport).  BtA was associated with a moderate-to-large improvement in the participant's baseline clinical status as assessed by investigators, with reduction of 8.06 points in the TWSTRS total score at week 4 after injection (95 % CI: 6.08 to 10.05; I2 = 0 %) compared to placebo, corresponding on average to a 18.7 % improvement from baseline. The MD in TWSTRS pain subs-core at week 4 was 2.11 (95 % CI: 1.38 to 2.83; I2 = 0 %).  Overall, both participants and clinicians reported an improvement of subjective clinical status.  There were no differences between groups regarding withdrawals due to AEs.  However, BtA treatment was associated with an increased risk of experiencing an AE (risk ratio (RR) 1.19; 95 % CI: 1.03 to 1.36; I2 = 16 %).  Dysphagia (9 %) and diffuse weakness/tiredness (10 %) were the most common treatment-related AEs (dysphagia: RR 3.04; 95 % CI: 1.68 to 5.50; I2 = 0 %; diffuse weakness/tiredness: RR 1.78; 95 % CI: 1.08 to 2.94; I2 = 0 %).  Treatment with BtA was associated with a decreased risk of participants withdrawing from trials.  These researchers had moderate certainty in the evidence across all of the afore-mentioned outcomes.  They found no evidence supporting the existence of a clear dose-response relationship with BtA, nor a difference between BtA formulations, nor a difference with use of EMG-guided injection.  Due to clinical heterogeneity, these investigators did not pool data regarding health-related QOL, duration of clinical effect, or the development of secondary non-responsiveness.  The authors concluded that they had moderate certainty in the evidence that a single BtA treatment session was associated with a significant and clinically relevant reduction of cervical dystonia-specific impairment, including severity, disability, and pain, and that it was well-tolerated, when compared with placebo.  There was also moderate certainty in the evidence that people treated with BtA were at an increased risk of developing AEs, most notably dysphagia and diffuse weakness.  There were no data from RCTs evaluating the safety and effectiveness of repeated BtA injection cycles.  There was no evidence from RCTs to allow the authors to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, the impact on QOL, or the duration of treatment effect.

Samotus et al (2018) noted that botulinum toxin type A (BoNT-A) injections is the accepted 1st-line therapy for CD, however, numerous patients discontinue treatment early due to perceived sub-optimal relief.  To improve BoNT-A therapy for CD, proper assessment of neck motion and selection of relevant muscles and dosing must be met.  Kinematic technology may improve treatment outcomes by guiding physicians to better tailor muscle selection and BoNT-A dosing for CD therapy.  A total of 28 CD participants were placed into either group: expert injector determined injection patterns by visual assessment ("vb") versus injection patterns based on kinematics interpreted by an expert injector ("kb").  Injections occurred at weeks 0, 16 and 32 with follow-ups at weeks 6, 22 and 38.  Kinematics utilized 4 sensors to capture the severity of multi-axial, static neck posturing (e.g., torticollis) and dynamic, spasmodic/tremor movements while participants were seated; TWSTRS score changes were evaluated over 38 weeks.  For the "kb" participants, there was a significant 28.8 % (- 11.25 points) reduction in TWSTRS total score at week 6, as well as significant reduction in severity and disability TWSTRS sub-scores (parts I and II) with maintained improvement at subsequent visits.  As for the "vb" participants had a significant reduction in total TWSTRS score by 28.5 % (- 9.84 points) after week 22.  Disability score for the "vb" group trended towards improvement over 38 weeks.  The authors concluded that clinical judgement guided by kinematic analysis of CD biomechanics could result in faster optimal muscle selections and minimize use of higher BoNT-A doses as compared to visual determination, thereby achieving comparable and potentially better treatment outcomes.  These researchers did not use EMG-guidance for their injections.

Appendix

International Headache Society Criteria for Migraine Diagnosis

According to the International Headache Society, the diagnosis of migraine can be made according to the following criteria:

• 5 or more attacks for migraine without aura (For migraine with aura, only 2 attacks are sufficient for diagnosis); and
• 4 hours to 3 days in duration; and
• 2 or more of the following:
   
  • "Aggravation by or causing avoidance of routine physical activity" ; and/or
  • "Moderate or severe pain intensity"; and/or
  • Pulsating; and/or
  • Unilateral (affecting half the head); and

• 1 or more of the following:

  • "Nausea and/or vomiting"; and/or
  • Sensitivity to both light (photophobia) and sound (phonophobia).

Source: IHS, 2004.

Table: Botulinum Toxin Dosing

Sources: Prescribing Information for Botox, Dysport, Myobloc, and Xeomin; Micromedex DrugDex.

The above policy is based on the following references: