MOVEMENT DISORDERS

Botulinum Neurotoxins in the Management of Movement Disorders

Advisory Editor
Alberto Albanese, MD
Professor
Instituto Nazionale Neurologico Carlo Besta
Universita Cattolica del Sacro Cuore
Milano, Italy

Introduction

The therapeutic use of botulinum neurotoxins (BoNTs) has evolved most dramatically in the field of movement disorders and has been applied to a wide spectrum of dyskinesias. In addition to the clinical benefits derived from BoNT therapy in a variety of movement disorders, studies of the neurophysiologic effects of BoNT have provided considerable insights into the functional organization and control of neuromuscular activity.

The wide clinical spectrum of movement disorders encompasses pyramidal, parkinsonian, and cerebellar features and dyskinesias, as shown in Figure 1.

Figure 1. Movement disorders and their symptoms.

Movement disorders are neurological conditions that affect the speed, fluency, quality, and ease of movement. These disorders are characterized by abnormal movements (dyskinesias), by poverty of movement (bradykinesia/akinesia), or by disturbance in the execution of movements (ataxia) and encompass pyramidal disorders, cerebellar disorders, parkinsonian syndromes, Huntington’s disease, dystonias, and other motor disturbances. The dysfunctions that cause movement disorders affect the motor parts of the central nervous system. Movement disorders can be caused by degenerative conditions of environmental or genetic origin or by non-degenerative conditions such as trauma.

 Dr. Albanese describes the characteristics of movement disorders. (MPEG)

Current treatment approaches

Movement disorders encompass a broad spectrum of diverse neuromotor abnormalities that require a variety of different therapeutic targets and modalities. The treatment approach to movement disorders is usually symptomatic. In general, pharmacological treatments for movement disorders include drugs that act on the central nervous system and interfere with specific neurotransmitters, especially dopamine, acetylcholine, and gamma-aminobutyric acid. Surgical approaches that have central nervous system effects include ablations and neurostimulation. Treatments that focus on the peripheral nervous system include chemical denervation with BoNT and selective surgical denervation.

Focal dystonias can be symptomatically treated with BoNT, central nervous system acting drugs (eg, anticholinergics, benzodiazepines), or with deep brain stimulation, if patients are refractory to drug treatment (Singer, 2001; WE MOVE Web site, Dystonia; Marks, 2005). Certain types of myoclonus can be treated with clonazepam, sodium valproate, barbiturates, or primidone (Mysoline®) (NINDS Web site, Myoclonus fact sheet). Currently available treatments for tic disorders include behavioral therapy and drugs such as haloperidol, pimozide, clonidine, and clonazepam (Singer, 2001). Deep brain stimulation is under investigation for this indication (Singer 2001). The dopamine-receptor-blocking drugs (neuroleptics) are considered to be the most effective anti-tic agents (Jankovic, 2001). However, these agents produce substantial side effects, including tardive dyskinesia, sedation, depression, weight gain, and hepatotoxicity (Jankovic, 2001). The most common treatment for essential tremor is propranolol, which acts on the sympathetic nervous system and is not well tolerated by all patients (Zesiewicz et al, 2005; Chen and Swope, 2003; PDRhealth Web site, Your arteries, high cholesterol, and angina). Side effects include low blood pressure, bradycardia, and fatigue (Zesiewicz et al, 2005; Chen and Swope, 2003; Sampaio and Ferreira, 2002). Most other systemic medications used in treating movement disorders have substantial side effects that often result in discontinuation of treatment. Moreover, the symptomatic relief produced by these medications is limited. Accordingly, the use of BoNT provides a very useful therapeutic tool for a wide variety of these disorders.

Botulinum neurotoxins in the treatment of movement disorders

BoNT has been shown to be effective and well tolerated in a number of different movement disorders. Table 1 lists all the proposed indications in the field of movement disorders and allied syndromes. Many, but not all, of the proposed indications have gained consensus in current practice.

Table 1. Proposed indications for botulinum neurotoxin treatments of movement disorders and allied syndromes.

Therapeutic application of BoNT has focused on spasticity, dystonia, and tremor, although it has also been used in several other classes of movement disorders. BoNT blocks the release of the neurotransmitter acetylcholine at the neuromuscular junction, thus inhibiting muscular contraction (Jankovic and Brin, 1991; Bell et al, 2000). The therapeutic benefits of BoNT in movement disorders stem primarily from its relaxation of skeletal muscles (Jankovic, 2004). However, recent evidence has suggested that peripherally injected BoNT can affect central pathways as well (Jankovic and Brin, 1991; Bell et al, 2000).  BoNT denervates gamma as well as alpha motor neurons; this denervation of the intrafusal muscle fibers reduces muscle spindle afferent input to the central nervous system and may also alter sensorimotor and proprioceptive pathways (Aoki, 2001; Modugno et al, 1998). These mechanisms may also contribute to the therapeutic effects of BoNT in focal dystonias.

Dystonias

BoNT treatment for cervical dystonia was analyzed in four recent Cochrane reviews. The first review evaluated BoNT type A therapy and included results from 13 randomized, placebo-controlled trials. They were short-term studies (6 to 16 weeks) of BoNT type A enrolling 680 patients overall. All trials reported a benefit of a single injection cycle of BoNT type A for cervical dystonia but did not provide controlled evidence of the long-term effects of repeated BoNT type A injections. Enriched trials using patients previously treated with BoNT type A suggested that further injection cycles maintained efficacy in most patients. The most frequently reported treatment-related adverse events were neck weakness, dysphagia, dry mouth/sore throat, voice changes/hoarseness, and local pain at injection site. Most of the adverse events in patients receiving BoNT type A were transient and either mild or moderate; no serious adverse events were associated with the use of BoNT type A (Costa et al, 2005a).

The second review evaluated BoNT type B and included 3 short-term (16 weeks) studies enrolling 308 participants. All were multicenter studies conducted in the United States; all patients included had previously received BoNT type A. A single injection of BoNT type B improved cervical dystonia (Costa et al, 2005b). A similar conclusion was reached in another review that included the same 3 trials (Figgitt and Noble, 2002).

The third review compared BoNT type A versus BoNT type B, but no preliminary results were yet available from two ongoing trials (Costa et al, 2005c).

The fourth review analyzed BoNT type A versus anticholinergics and found only one randomized trial comparing BoNT type A versus trihexyphenidyl in 66 patients with cervical dystonia. The results favored BoNT type A (Costa et al, 2005d).

An open randomized study compared the cost and effectiveness of a trained outreach nurse practitioner giving injections of BoNT with the standard procedure carried out by medical practitioners within the clinic. The patients had spasmodic torticollis, blepharospasm, hemifacial spasm, or other segmental dystonia, hemidystonia, or generalized dystonia. The study found that the outreach nurse service was as effective and safe as the standard clinic-based service and that the patients preferred it. Although the costs of the National Health System were slightly higher in the nurse practitioner group, the overall costs for society were lower than in the clinic-based service (Whitaker et al, 2001).

 Dr. Albanese describes the features of dystonias. (MPEG)

 Effects of botulinum neurotoxin therapy in dystonias. (MPEG)

The clinical effects of BoNT therapy for blepharospasm, cerebral palsy, upper motor neuron syndrome including spasticity, and cervical dystonia are reviewed in separate modules. The efficacy of BoNT therapy has been reported in patients with spasmodic dysphonia (laryngeal dystonia), a focal dystonia affecting the larynx (Blitzer and Sulica, 2001; Tisch et al, 2003; Maronian et al, 2004). Spasmodic dysphonias are classified as adductor or abductor depending on whether spasms cause glottal opening or closing (Blitzer and Sulica, 2001). BoNT is considered the first line of treatment for adductor spasmodic dysphonia (Blitzer and Sulica, 2001; Blitzer et al, 1998; Tisch et al, 2003; Maronian et al, 2004).

A number of open-label studies and retrospective chart analyses confirm the efficacy of BoNT in the treatment of spasmodic dysphonia, with successful outcomes of treatment in approximately 80% to 100% of patients (Tisch et al, 2003; Blitzer et al, 1998; Maronian et al, 2004). The duration of efficacy has been reported to range from 10 to 16 weeks (Tisch et al, 2003; Blitzer et al, 1998). Blitzer et al reviewed the long-term clinical outcomes of 900 patients who were followed for up to 12 years (Blitzer et al, 1998). Patients with adductor spasmodic dysphonia regained approximately 90% of normal function lasting an average of 15.1 weeks; those with abductor spasmodic dysphonia had an average benefit of 67% of normal function lasting 10.5 weeks. Treatment was well tolerated and no reduction in clinical efficacy was observed with repeated treatments. A prospective review of 144 patients with spasmodic dysphonia treated with BoNT found that treatment was highly effective, with nearly 82% of patients achieving a median treatment rating of “excellent” or “very good” for a mean duration of 4 months (Tisch et al, 2003). Treatment was unsatisfactory in only 3.5% of patients. This study found, as did the studies reviewed by Blitzer et al, that abductor spasmodic dysphonia responded less favorably to BoNT than did adductor spasmodic dysphonia (Blitzer et al, 1998; Blitzer and Sulica, 2001; Tisch et al, 2003).

Bielamowicz et al evaluated the efficacy of unilateral versus bilateral injections of BoNT type A in patients with adductor spasmodic dysphonia (Bielamowicz et al, 2002). The study found that unilateral injections produced clinical improvement for >3 months with fewer side effects in a larger proportion of patients compared with bilateral injections (Bielamowicz et al, 2002).

One Cochrane review analyzed BoNT type A for spasmodic dysphonia and considered the available evidence insufficient to draw firm recommendations. Only one randomized study was included in this review and no conclusions were drawn about the effectiveness of BoNT for all types of spasmodic dysphonia (Watts et al, 2004).

Botulinum neurotoxin treatment for spasmodic dysphonia (laryngeal dystonia). (MPEG)

Disorders of the larynx

The observed clinical benefit of BoNT in the treatment of dystonias has led to its use in other disorders of the larynx involving excessive muscular contractions (Blitzer and Sulica, 2001). BoNT has been shown to result in increased fluency in stuttering patients, but its use for this disorder has not been widely accepted. BoNT injections have been shown to benefit patients with essential voice tremor and vocal tics of Tourette’s syndrome and permit nonsurgical treatment in patients with dysphagia resulting from cricopharyngeal spasm (Blitzer and Sulica, 2001).

Botulinum toxin in parkinsonian syndromes

Patients with parkinsonian syndromes can benefit from BoNT treatment for many symptoms associated with these conditions. Some indications are better established than others, but, in principle, a BoNT consultation should be available at every clinic devoted to parkinsonian syndromes (Table 2). Motor symptoms amenable to treatment with BoNT include dystonia (Pacchetti et al, 1995; Jankovic and Brin, 1991), contractures, and, possibly, freezing of gait (Giladi et al, 2001); non-motor symptoms include sialorrhea (Dogu et al, 2004; Friedman and Potulska, 2001), bladder hyperreflexia, constipation (Albanese et al, 2003; Albanese et al, 1997), and benign prostatic hyperplasia (Maria et al, 2003). Table 2 summarizes indications for BoNT treatment of parkinsonian patients.

Table 2. Indications for botulinum neurotoxin treatment of parkinsonian patients.

Botulinum toxin in essential hand tremor

Two randomized placebo-controlled trials in patients with essential hand tremor found that BoNT type A improved clinical ratings significantly more than placebo (Brin et al, 2001; Jankovic et al, 1996). However, improvements in functional disability and performance on motor tasks were not consistently better in the BoNT-treated group compared with the placebo group. Jankovic et al compared 50 U of BoNT type A (BOTOX®; Allergan, Inc., Irvine, CA) and placebo injections in 25 patients with essential hand tremor in a randomized double-blind trial (Jankovic et al, 1996). Significantly greater improvement (P < .05) was observed on the tremor severity rating scale in patients treated with BoNT compared with placebo, but there were no significant differences in functional rating scale scores.

Brin et al compared 50-U and 100-U doses of BoNT type A (BOTOX®) with placebo in 133 patients with essential hand tremor. Postural tremor, but not kinetic tremor, assessed with clinical rating scales, improved significantly more with both BoNT doses compared with placebo. However, minimal improvements were observed in motor tasks and functional ability in the BoNT type A treated group (Brin et al, 2001).

In a very interesting study that provides further insight into the mechanism of action of BoNT, Modugno et al observed that in patients with essential hand tremor, BoNT treatment restored the presynaptic inhibition between forearm antagonist muscles. These results confirm the concurrent action of BoNT on the extrafusal and intrafusal motor endplates, with the latter resulting in reduced spindle afferent input to the spinal cord (Modugno et al, 1998).

Botulinum Toxin in Tic Disorders

Tics are sudden, brief, intermittent, involuntary, or semivoluntary movements or sounds, typically involving simple or coordinated, repetitive or sequential movements, gestures, and utterances. Simple motor tics involve only a single muscle or muscle group and cause a brief, jerking movement (clonic tics), a briefly sustained abnormal posture (dystonic tics), or an isometric contraction (tonic tics). Motor and phonic tics are frequently preceded by premonitory sensations, which consist of localizable paresthesia or discomfort; these sensations are temporarily relieved after the execution of the tic (Jankovic, 2001).

Figure 2. Schematic representation of the clinical elements of Tourette’s syndrome.

Used with permission from Jankovic J. Tourette’s syndrome. N Engl J Med. 2001;345:1184-1192.
Although the neuropathology underlying motor and vocal tics is unclear, they are thought to have an organic basis. A number of studies suggest that Tourette’s syndrome is an inherited developmental disorder of synaptic neurotransmission resulting in the disinhibition of the cortico-striatal-thalamic-cortical circuitry (Jankovic, 2001; Robertson, 2000).

Several studies evaluated the effectiveness of BoNT injections in treating tic disorders. The premise for the use of BoNT is that it might inhibit the abnormal muscle contractions that characterize the motor component of tic disorders.
A recent open-label study assessed the effect of BoNT type A on phonic tics in 30 patients with Tourette’s syndrome (Porta et al, 2004). Patients received BoNT injections in both vocal cords and were evaluated after 15 days and then 4 times over a 12-month period. Following treatment, 93% of patients showed an improvement in phonic tics, with 50% experiencing no phonic tics at all. The number of patients having hourly intervals between tics increased from 17% to 23%, whereas the number having tics every few seconds decreased from 30% to 3%. Furthermore, treatment had a positive effect on patients’ assessment of social life and work and school activities: before treatment, 50% reported that their condition severely impacted their social life and 47% said it had a severe effect on work or school activities. Following treatment, these values decreased to 13% and 10%, respectively.

Marras et al conducted a randomized, double blind, placebo-controlled crossover study of the effect of BoNT in 18 patients with simple motor tics (Marras et al, 2001). The primary outcome measure was the proportional change in number of treated tics per minute as observed on a 12-minute videotape segment. Secondary outcome measures were the number of untreated tics per minute, the Shapiro Tourette Syndrome Severity Scale score, numerical assessments of the urge to perform the treated tic (0 to 4) and the premonitory sensation associated with the treated tic (0 to 4), and the patient’s global impression of change. BoNT produced a significantly greater reduction (39%) in the number of treated tics per minute compared with placebo (5.8% increase). BoNT also significantly reduced the average change in urge scores. However, despite these changes, patients did not report a greater overall benefit from BoNT treatment compared with placebo (Marras et al, 2001). The investigators note that their finding of no significant change in subjective rating of overall patient well-being might be attributable to insufficient statistical power to show an effect or the relative mildness of the tic disorders in this patient population (median Shapiro Tourette Syndrome Severity Score of 3, maximum possible score of 6; median Tourette Syndrome Global Score of 9.3, maximum possible score of 100), which would limit the ability to demonstrate significant improvement in overall severity and disability scores (Marras et al, 2001).

Kwak et al evaluated the response to BoNT type A in 35 Tourette’s syndrome patients using a clinical rating scale (0 = no improvement to 4 = marked improvement) (Kwak et al, 2000). The mean peak effect response was 2.8 (range, 0 to 4), with a mean duration of benefit of 14.4 weeks. In addition to improving the motor component of tics, BoNT type A relieved the premonitory sensations in 84% of the patients (Kwak et al, 2000). This study confirmed the findings of an earlier pilot study by Jankovic that BoNT treatment ameliorates both the involuntary movements and the premonitory sensory component associated with some tics (Jankovic, 1994).

These studies point to the need for additional large, well-controlled studies to evaluate the utility of BoNT in tic disorders. As the understanding of the complex pathophysiology underlying Tourette’s syndrome and other tic disorders advances, the optimal role for therapeutic BoNT as well as its putative mechanisms of action in these disorders will become clearer.

Summary

Numerous studies examining a wide range of different movement disorders have demonstrated that BoNT therapy provides effective symptomatic improvement in disorders that are characterized by abnormal or excessive muscular contraction. The efficacy and safety of BoNT in movement disorders are suggested by long-term follow-up assessments. Further study of BoNT in the treatment of movement disorders could refine the optimal doses and injection procedures and also establish predictive models to identify patients most likely to benefit from treatment.

References and further reading

Albanese A, Brisinda G, Bentivoglio AR, Maria G. Treatment of outlet obstruction constipation in Parkinson’s disease with botulinum neurotoxin A. Am J Gastroenterol. 2003;98:1439-1440.

Albanese A, Maria G, Bentivoglio AR, Brisinda G, Cassetta E, Tonali P. Severe constipation in Parkinson’s disease relieved by botulinum toxin. Mov Disord. 1997;12:764-766.

Aoki KR. Pharmacology and immunology of botulinum toxin serotypes. J Neurol.

2001;248(suppl 1):3-10.

Bell MS, Vermeulen LC, Sperling KB. Pharmacotherapy with botulinum toxin: harnessing nature’s most potent neurotoxin. Pharmacotherapy. 2000;20:1079-1091.

Bielamowicz S, Stager SV, Badillo A, Godlewski A. Unilateral versus bilateral injections of botulinum toxin in patients with adductor spasmodic dysphonia. J Voice. 2002;16:117-123.

Blitzer A, Brin MF, Fahn S, Lovelace RE. Localized injections of botulinum toxin for the treatment of focal laryngeal dystonia (spastic dysphonia). Laryngoscope. 1988;98:193-197.

Blitzer A, Brin MF, Stewart CF. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope. 1998;108:1435-1441.

Blitzer A, Sulica L. Botulinum toxin: basic science and clinical uses in otolaryngology. Laryngoscope. 2001;111:218-226.Brin MF, Lyons KE, Doucette J, et al. A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology. 2001;56:1523-1528.

Chen JJ, Swope DM. Essential tremor: diagnosis and treatment. Pharmacotherapy. 2003;23:1105-1122.

Clarke CE. Parkinson’s disease and movement disorders. Diagnosis and treatment guidelines for the practicing physician. J Neurol Neurosurg Psychiatry. 2001;70:822-823.

Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database Syst Rev. 2005a; CD003633.

Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev. 2005b; CD004315.

Costa J, Borges A, Espirito-Santo C, et al. Botulinum toxin type A versus botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev. 2005c; CD004314.

Costa J, Espirito-Santo C, Borges A, Ferreira JJ, Coelho M, Sampaio C. Botulinum toxin type A versus anticholinergics for cervical dystonia. Cochrane Database Syst Rev. 2005d; CD004312.

Dogu O, Apaydin D, Sevim S, Talas DU, Aral M. Ultrasound-guided versus ‘blind’ intraparotid injections of botulinum toxin-A for the treatment of sialorrhoea in patients with Parkinson’s disease. Clin Neurol Neurosurg. 2004;106:93-96.

Figgitt DP, Noble S. Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia. Drugs. 2002;62:705-722.

Friedman A, Potulska A. Botulinum toxin for treatment of parkinsonian sialorrhea. Neurol Neurochir Pol. 2001;35(suppl 3):23-27.

Giladi N, Gurevich T, Shabtai H, Paleacu D, Simon ES. The effect of botulinum toxin injections to the calf muscles on freezing of gait in parkinsonism: a pilot study. J Neurol. 2001;248:572-576.

Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry. 2004;75:951-957.

Jankovic J. Botulinum toxin in the treatment of dystonic tics. Mov Disord. 1994;9:347-349.

Jankovic J. Tourette’s syndrome. N Engl J Med. 2001;345:1184-1192.

Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med. 1991;324:1186-1194.

Jankovic J, Schwartz K, Clemence W, Aswad A, Mordaunt J. A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor. Mov Disord. 1996;11:250-256.

Kwak CH, Hanna PA, Jankovic J. Botulinum toxin in the treatment of tics. Arch Neurol. 2000;57:1190-1193.

Maria G, Brisinda G, Civello IM, Bentivoglio AR, Sganga G, Albanese A. Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology. 2003;62:259-264.

Marks WJ. Deep brain stimulation for dystonia. Curr Treat Options Neurol. 2005;7:237-243.

Maronian NC, Waugh PF, Robinson L, Hillel AD. Tremor laryngeal dystonia: treatment of the lateral cricoarytenoid muscle. Ann Otol Rhinol Laryngol. 2004;113:349-355.

Marras C, Andrews D, Sime E, Lang AE. Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial. Neurology. 2001;56:605-610.

Modugno N, Priori A, Berardelli A, Vacca L, Mercuri B, Manfredi M. Botulinum toxin restores presynaptic inhibition of group Ia afferents in patients with essential tremor. Muscle Nerve. 1998;21:1701-1705.

NINDS Web site. Myoclonus fact sheet. Available at: http://www.ninds.nih.gov/disorders/myoclonus/detail_myoclonus.htm. Accessed September 21, 2005.

Pacchetti C, Albani G, Martignoni E, Godi L, Alfonsi E, Nappi G. “Off” painful dystonia in Parkinson’s disease treated with botulinum toxin. Mov Disord. 1995;10:333-336.

PDRhealth Web site. Your arteries, high cholesterol, and angina. Available at: http://www.pdrhealth.com/content/lifelong_health/chapters/fgac12.shtml. Accessed October 14, 2005.

Porta M, Maggioni G, Ottaviani F, Schindler A. Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci. 2004;24:420-423.

Robertson MM. Tourette syndrome, associated conditions and the complexities of treatment. Brain. 2000;123(pt 3):425-462.

Sampaio C, Ferreira J. Essential tremor. Clin Evid. 2002;7:1169-1178.

Singer HS. The treatment of tics. Curr Neurol Neurosci Rep. 2001;1:195-202.

Tisch SH, Brake HM, Law M, Cole IE, Darveniza P. Spasmodic dysphonia: clinical features and effects of botulinum toxin therapy in 169 patients—an Australian experience. J Clin Neurosci. 2003;10:434-438.

Watts CC, Whurr R, Nye C. Botulinum toxin injections for the treatment of spasmodic dysphonia. Cochrane Database Syst Rev. 2004; CD004327.

WE MOVE Web site. Dystonia:other medications used to treat dystonia. Available at: http://www.mdvu.org/library/disease/dystonia/dys_motm.html. Accessed September 21, 2005.

Whitaker J, Butler A, Semlyen JK, Barnes MP. Botulinum toxin for people with dystonia treated by an outreach nurse practitioner: a comparative study between a home and a clinic treatment service. Arch Phys Med Rehabil.2001;82:480-484.

Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2005;64:2008-2020.