CERVICAL DYSTONIA

Botulinum Neurotoxins in the Management of Cervical Dystonia

Advisory Editor
Joseph Jankovic, MD, Co-Chairman
Professor of Neurology
Director, Parkinson’s Disease Center and Movement Disorders Clinic
Department of Neurology
Baylor College of Medicine
Houston, Texas

Click to view PTN 2 FOOTAGE

Cervical dystonia: clinical features

Cervical dystonia (CD), the most common adult-onset focal dystonia (Dauer et al, 1998; Velickovic et al, 2001), produces patterned, repetitive clonic (spasmodic) or tonic (sustained) muscle contractions that result in abnormal movements and postures of the shoulders, head, and neck (Table 1). CD may produce neck turning (torticollis), neck extension (retrocollis), neck flexion (anterocollis), and head tilt (laterocollis) as well as lateral or sagittal shift. Oscillatory movements of the head have been described in 60% of CD patients in one study (Jankovic et al, 1991). Postural changes may extend to affect the trunk, and the condition may be exacerbated by a particular activity or by stress.

Table 1: Cervical dystonia: summary of clinical features

Transitory improvements in CD are reported to occur in the morning after a period of rest, after alcohol ingestion, and in the majority of the patients through certain sensory tricks (gestes antagonistiques) or specific positions that improve their abnormal posture (Schramm et al, 2004). Usually the dystonia progresses during the first 5 years before stabilizing (Jankovic et al, 1991), although it may progress over 2 decades (Velickovic et al, 2001). Pain, which may or may not correlate with the severity of the dystonia, is an important component of CD, occurring in approximately 75% of patients (Chan et al, 1991; Velickovic et al, 2001) (Figure 1).

Figure 1: Pain distribution in cervical dystonia. Adapted from Galvez-Jimenez N, Lampuri C, Patino-Picirrillo R, Hargreave MJ, Hanson MR. Dystonia and headaches: clinical features and response to botulinum toxin therapy. In: Fahn S, Hallett M, DeLong M, eds. Dystonia 4: Advances in Neurology . Vol. 94. Philadelphia: Lippincott Williams & Wilkins; 2004: 321-328. Used with permission.

In some cases CD may spontaneously improve, and it can remit in up to 25% of cases, particularly in younger individuals. Unfortunately, in almost all these cases the remission is short-lived and almost all eventually relapse (Jankovic et al, 1991). CD occurs more frequently (1.5 to 1.9 times) in women than in men (Chan et al, 1991; Jankovic et al, 1991), and once present spreads segmentally in approximately 20% of patients (Jankovic, 2004a). The exact etiology of CD is unclear, but the pathophysiology of focal dystonias is thought to involve a dysfunction of the basal ganglia (Berardelli et al, 1998). There is increasing evidence that genetic factors may contribute to the development of CD, such as DYT1 dystonia, a generalized dystonia starting in childhood, in which CD may be an important component (Velickovic et al, 2001). However, phenotypic expression of CD appears to depend on both environmental and genetic factors (Stacy, 2000). Other causes of dystonia include certain drugs, particularly those that block dopamine receptors, and trauma (Jankovic, 2004c).

Diagnosis of cervical dystonia

In addition to the signs described above, diagnostic considerations for CD include differentiation from pseudodystonia, where there is abnormal head and neck posture resulting from syringomyelia, atlanto-axial dislocation (eg, neck injury that can occur in whiplash), or lymphadenopathy. Another example of dystonic movement involving the neck that could be misdiagnosed as CD is dystonic tic (Velickovic et al, 2001; Brin and Benabou, 1999; Dauer et al, 1998). Dystonia involving the neck can also be seen in patients with Parkinson’s disease and other parkinsonian disorders, which sometimes evolve into severe truncal flexion (camptocormia, termed “the bent spine syndrome”) (Azher and Jankovic, 2005; Dauer et al, 1998). When a secondary cause of abnormal head position or dystonia is suspected, neuroimaging studies including head and cervical magnetic resonance imaging (MRI) may be useful in diagnosis (Dauer et al, 1998).

Treatment of cervical dystonia

Cervical dystonia may be treated by physical therapy such as stretching and range-of-motion exercises, as well as with muscle relaxation and cervical braces. Oral medications include anticholinergic agents, dopamine receptor antagonists, and GABA-mimetic agents. The efficacy of these medications is limited, although roughly 40% of patients derive some symptomatic relief from anticholinergic agents (Adler and Kumar, 2000; Brin and Benabou, 1999). Botulinum neurotoxins (BoNTs) have a high rate of efficacy combined with a low incidence of side effects and are considered the first choice in therapy for cervical dystonia (Brin and Benabou, 1999; Comella et al, 2000; Dauer et al, 1998). Both BoNT type A and BoNT type B are approved in the United States and Europe for treatment of CD. Pharmacologic management of CD with oral agents or BoNT is symptomatic rather than curative. In patients who fail to respond to pharmacotherapy, a surgical approach may be appropriate. Surgical options include selective dorsal ramisectomy, bilateral pallidotomy, or globus pallidus deep brain stimulation (Adler and Kumar, 2000).

Combinations of these therapies may be appropriate.  For example, physical therapies are recommended for most patients receiving BoNT in order to extend the benefits (Brin and Benabou, 1999 ).Because BoNT may change movement patterns, physical therapies may help patients relearn normal postures and functional control. For patients in whom BoNT is not sufficiently successful, other pharmacotherapeutic modalities can be tried. Pharmacotherapy also may alleviate symptoms that remain after BoNT therapy. Surgical options should be reserved for patients refractory to all conservative treatment approaches.

Chemodenervation: botulinum neurotoxins in the treatment of cervical dystonia

Currently, three preparations of BoNT are commercially available for clinical use: two preparations of BoNT type A—Botox® (Allergan, Irvine, Calif), which is generally available, and Dysport® (Ipsen Biopharm, Wrexham, UK), which is chiefly used in Europe; and one preparation of BoNT type B—Myobloc® (Elan Pharmaceuticals, Dublin), available in the United States and Europe. The 2 types are antigenically distinct and possess different mechanisms of action.

To achieve the best possible response, BoNT treatment must be tailored to the individual needs of the patient. The administration of BoNT requires specialized skills and a detailed understanding of both the pharmacology of BoNT and the structural and functional anatomy of the affected area—dosing and injection sites vary with clinical presentation, movement patterns may be complex and vary over time, and the injection site and dosage have to be adjusted accordingly .Occasionally, electromyographic (EMG) guidance is helpful when the target muscles are difficult to palpate.

Overall, the outcome of treatment is substantially dependent upon the presence of contractures and skill of the clinician. A patient who has had untreated CD for an extended period and as a result has developed contractures is not an optimal candidate for BoNT treatment (Jankovic, 2004b; 2004c ). Abnormal postures typically seen in patients with torticollis, retrocollis, laterocollis, and anterocollis and the muscles frequently injected to correct these abnormal postures are shown in Table 2, and illustrations of the injection sites of most of these muscles are shown in Figures 2 through 7.

Table 2: Muscles to be treated in CD determined by presentation

Studies of the effects of BoNTs on dystonias and other movement disorders (writer's cramp, essential tremor) have provided insights into the pathophysiology of these disorders and into the mechanism of action of BoNT, indicating that its therapeutic action extends beyond the muscle relaxation achieved by chemical denervation (Gilio et al, 2000). Although the mechanism of chemical denervation by BoNT at the neuromuscular junction is well understood, its role in changes in muscle spindles and pain mechanisms, as well as possible secondary changes at the level of the basal ganglia, thalamus, and cortex, are intriguing and warrant further investigation.

Figure 2: Sternocleidomastoid muscle; approximate dose 40 U to 70 U unilateral or bilateral* (Botox ® units†) (Walker, 2003).

*Dosage varies with head movement.

†Units are Botox units.

Figure 3: Trapezius; approximate dose 10 U to 20 U unilateral or bilateral* (Botox ® units†) (Walker, 2003).

*Dosage varies with head movement.

†Units are Botox units.

Figure 4: Splenius capitis; approximate dose 20 U bilateral or 40 U to 50 U unilateral* (Botox ® units†) (Walker, 2003). *Dosage varies with head movement.

†Units are Botox units.

Figure 5: Semispinalis capitis; approximate dose 10 U to 30 U unilateral or bilateral* (Botox ® units)† (Walker, 2003).

*Dosage varies with head movement.

†Units are Botox units.

Figure 6: Levator scapulae; approximate dose 15 U to 35 U unilateral or bilateral* (Botox ® units)† (Walker, 2003).

*Dosage varies with head movement.

†Units are Botox units.

Figure 7: Platysma; approximate dose 10 U bilateral* (Botox ® units) (Walker, 2003).

*Dosage varies with head movement.

†Units are Botox units.

Evidence-based medicine reviews

BoNT has been shown to be effective and well tolerated in many studies of CD. One published evidence-based systematic review of BoNT in the management of cervical dystonia concluded that the efficacy of BoNT therapy is strongly supported by a number of double-blind, randomized, placebo-controlled trials as well as numerous open-label studies (Ceballos-Baumann, 2001). Meta-analysis of the effect size of BoNT therapy has not been performed because individual investigations have utilized a vast array of disparate outcome measures and criteria for treatment success, which have not been amenable to pooled analyses. Using evidence-based criteria, Jankovic et al (2004d) systematically examined the effects of BoNT type A on patient-reported outcomes. These studies provide evidence that BoNT type A has meaningful benefits for quality of life in treated patients. Another meta-analysis of 36 studies involving 2309 subjects treated with BoNT found no reports of severe adverse events (Naumann and Jankovic, 2004), and roughly 25% in the BoNT type A-treated group (353/1425 patients) reported mild to moderate adverse events compared with 15% in the control group (133/884 patients, P<.001). Focal weakness was the only adverse event that occurred significantly more often in BoNT type A-treated patients than in controls.

Clinical studies in cervical dystonia

Randomized controlled trials of BoNT therapy for CD include double-blind, placebo-controlled studies, comparative studies with other active interventions, dose-response evaluations, use of EMG guidance, and double-blind comparisons of different preparations and serotypes (Brans et al, 1996; Brashear et al, 1999; Brin et al, 1999; Jankovic and Orman, 1987; Lew et al, 1997; Lorentz et al, 1991; Lu et al, 1995; Ostergaard et al, 1994; Poewe et al, 1998; Wissel et al, 2001; Blackie and Lees, 1990). Several double-blind, placebo-controlled studies confirmed the efficacy of BoNT type A using a range of outcome variables, including clinical and video assessment of the severity of dystonic movements and posture, patient-rated changes in pain and ability to perform activities of daily living, improvements in the Tsui Scale, EMG changes, global assessment of improvement, and a global rating taking into account efficacy and adverse events (Blackie and Lees, 1990; Gelb et al, 1989; Greene et al, 1990; Jankovic and Orman, 1987; Lorentz et al, 1991; Lu et al, 1995; Ostergaard et al, 1994; Poewe et al, 1998). Brashear reported data from a multicenter trial involving 170 subjects with cervical dystonia (Brashear, 2001). BoNT type A was administered in an open-label study for 12 weeks. Patients who responded to the open-label BoNT type A treatment and demonstrated a CD Severity Scale (CDSS) rating severity score of at least 4 or greater were randomized to BoNT type A or placebo for the second phase of the study. Results indicated that the BoNT type A group showed a significant treatment-related response at weeks 2, 4, 6, 8, and 10 compared with the placebo group (Figure 8) (Brashear, 2001).

Time Posttreatment in Period II (Weeks)

* P <.05; ** P <.01.

Figure 8: Change from baseline in head position as measured by the CDSS. The mean baseline head position score was 9.2 ± 4.8 in the Botox ® group and 9.3 ± 4.2 in the placebo group. The change from baseline in CDSS score was significantly greater in the Botox® group than in the placebo group at all follow-up visits ( P ≤.046), and the between-group difference ranged from -1.03 to -2.13. Brashear A. The botulinum toxins in the treatment of cervical dystonia. Semin Neurol . 2001;21:85-90, with permission.

A number of interesting observations have emerged from these controlled trials.

• Injection of a higher dose of BoNT in a greater number of neck muscles is required for patients with complex CD (Lu et al, 1995). Positive dose-response relationships have been noted for degree and duration of subjective improvement, improvement on clinical global rating, and the need for reinjection at 8 weeks (Poewe et al, 1998).
• One multicenter, randomized controlled trial evaluated the dose response to BoNT type A therapy (Poewe et al, 1998). Reductions in the modified Tsui Score were significant at week 4 for groups treated with 500- and 1000-unit (U), but not 250-U, doses (Dysport®), versus placebo ( P<.05) (Poewe et al, 1998). In addition, the occurrence of adverse events overall and the incidence of neck muscle weakness and voice changes were dose related (Poewe et al, 1998). Accordingly, these investigators recommend initiating BoNT type A therapy at a lower dose (500 U Dysport®), with upward titration at subsequent injection cycles if necessary.

Finally, one randomized, double-blind, active-controlled trial compared BoNT type A with trihexyphenidyl in cervical dystonia patients using a double-dummy, parallel-group design (Brans et al, 1996). The changes in the disability section of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS–Disability; primary outcome), Tsui Scale, and the General Health Perception Subscale were significantly greater in the BoNT-treated group compared with the trihexyphenidyl group. Moreover, adverse effects were reported significantly less frequently in the BoNT group (Brans et al, 1996).

Potential effects of neutralizing antibodies on BoNT therapy for CD

Questions remain about the long-term efficacy of BoNT in CD and the potential for development of resistance, with repeated treatments often leading to a progressive decline in therapeutic response. It has been suggested that this decline may be caused by development of neutralizing antibodies to BoNT. Assessment of the frequency of occurrence of blocking antibodies (measured by the mouse protection assay) indicates that about an equal number of patients treated with either of the currently available BoNT type A products have developed immunoresistance. The clinical impact of antibody formation is highlighted by a study of BoNT use in patients with children having cerebral palsy who were treated with BoNT type A for their spasticity (Herrmann et al, 2004). As shown in Figure 9, 31.8% of these patients developed antibodies as measured by the mouse phrenic nerve hemidiaphragm test. Fifty percent of these antibodies develop after 8 treatments, and 82% of these patients were secondary nonresponders. There was a significant correlation between a lack of response and the presence of these antibodies ( P<.001) .

Solid line=pooled data for Botox ® and Dysport®.

Dashed line=95% confidence limits.

Figure 9: The proportion of patients with antibodies increases with the number of treatments in a study using the original (pre-1998) formulation of Botox (r). Herrmann J, Geth K, Mall V, et al. Clinical impact of antibody formation to botulinum toxin A in children. Ann Neurol. 2004;55:732-735. Copyright (c) 2004, Wiley-Liss, Inc., A Wiley Company. Reproduced with permission of John Wiley & Sons, Inc.

It is important to emphasize that this study, and essentially all the studies published on the presence of antibodies, have been based on use of the original Botox® formulation. The lower incidence of antibodies to the new, current formulation with a much lower protein loading has been demonstrated in a recent study (Jankovic et al, 2003). The frequency of the occurrence of antibodies in patients treated with the original Botox® was compared with the frequency in patients treated only with the current Botox® formulation (used since 1998). Of patients treated only with the original Botox®, 9.5% had antibodies, whereas none of the patients treated with the current formulation showed evidence of antibodies (Figure 10). This is relevant because most of the literature on immunogenicity is based on use of the original Botox®.

Figure 10: Immunogenicity of original and current BoNT type A (Botox®) formulations in cervical dystonia.

An open-label study now in progress was undertaken primarily to assess the development of neutralizing antibodies and to track clinical responsiveness and adverse events in patients chronically treated with the new formulation of BoNT type A (Botox®) (Comella et al, 2004). At the time of the available report, 326 patients had been enrolled. The mean dose of BoNT type A was 176 U, and 88% to 100% of patients reported a favorable clinical response. Of the 1031 blood samples tested, 99.5% were negative for neutralizing antibodies. Only 1 patient tested positive; this patient tested negative on the first visit, then became positive, and later became negative again. Analysis suggests that the result represents a false positive.

Adverse events were collected for 1078 treatment sessions; the most frequently reported adverse events were dysphagia in 8.5% of patients, neck or shoulder weakness in 8.4%, and neck pain in 6.5%. This interim analysis clearly shows that BoNT type A is effective and safe in patients with CD. The clinical benefits may vary over a series of injections and absence of response does not necessarily reflect development of antibodies. However, it is important to note that if a patient does not respond to a particular injection, this does not necessarily mean that the patient has developed blocking antibodies. In fact, the same patient may respond at a subsequent visit to exactly the same dose injected in the same muscles.

Long-term use of BoNT type A for CD

The results of recent long-term studies suggest that although resistance to BoNT type A is a clinical possibility, it is not a significant concern when considering the use of the currently available formulations. A retrospective analysis of patients at a referral center in Canada provided data over a 10-year period during which BoNT type A was used for treatment of various movement disorders, including CD (Hsiung et al, 2002). Patients included in the analysis received BoNT injections at least 12 weeks apart with no boosters. Treatment response was classified as:

• Sustained benefit: continued improvement of ≥50% relative to baseline
• Primary resistance: <25% improvement after 2 to 3 consecutive trials with increasing doses of BoNT type A

• Secondary resistance: ≥50% improvement for at least 2 treatment cycles followed by <25% improvement after 2 or more subsequent treatment cycles

Table 3: Summary of findings of a retrospective study of patients treated over an extended period with BoNT type A

Adapted from Hsiung G-YR, Das SK, Ranawaya BM, Lafontaine AL, Suchowersky O. Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord. 2002;17:1288-1293.

The investigators concluded that BoNT was safe for long-term use in CD and other movement disorders, with minor adverse effects and good tolerability. These results are similar to those described in a recent report (Haussermann et al, 2004) of a follow-up of 100 patients who had initiated treatment with BoNT type A 10 to 12 years earlier. It found that BoNT remains effective and safe for approximately 60% of CD patients for more than 10 years. In a longitudinal study of 45 patients who have received BoNT treatments continuously for at least 12 years (mean duration, 15.8 ± 1.5 years), the mean response rating following the last injection was 3.7 ± 0.6 (0 = no effect, 4 = marked improvement) and the mean total duration of response was 15.4 ± 3.4 weeks (Mejia et al, 2005). The peak duration of response ( P<.005) and dose per visit ( P<.0001) increased since the initial visit and the global rating P<.02) and peak effect ( P<.05) improved. Twenty adverse events occurred in 16/45 (35.6%) patients after their initial visit and 11 adverse events in 10/45 (22.2%) patients at the most recent injection visit. Blocking antibodies were confirmed in 4/22 (18%) patients who underwent antibody testing because of nonresponsiveness; all of the secondary nonresponders were exposed to the original Botox®. This longest reported follow-up of BoNT type A (Botox®) injections confirms the long-term efficacy and safety of this treatment.

Each of these investigations builds on and extends the findings of a retrospective chart review of a shorter study involving 102 CD patients (Brashear et al, 2000). In those who had received 4 injections of BoNT type A, the mean per-patient duration of effect across 4 visits was 15.5 weeks (range, 12.2 to 24.3 weeks). Brans et al evaluated the long-term effect of BoNT type A therapy on impairment and functional health with respect to disability, handicap, and quality of life in 64 CD patients who participated in a double-blind trial and were followed for another 12 months (Brans et al, 1998). Fifty-four patients continued treatment after 12 months of follow-up and sustained improvement on all rating scales used to evaluate treatment efficacy. Effectiveness of treatment appeared to increase during the follow-up period, suggesting a cumulative clinical effect (Brans et al, 1998) or disease-modifying potential. Finally, Kessler et al evaluated the long-term effects of BoNT type A therapy in 303 CD patients who received at least 6 injection cycles and noted sustained significant benefit as measured by disease severity scores (Kessler et al, 1999). Secondary treatment failure was seen in roughly 5% of patients, but antibody tests revealed neutralizing serum antibodies in only 2%. The investigators concluded that BoNT type A therapy for CD produces clinical efficacy and roughly comparable responses to BoNT injection even after 5 years of treatment (Kessler et al, 1999).

BoNT type B in CD

BoNT type B is antigenically distinct from BoNT type A and possesses a different mechanism of action. Three randomized, double-blind, placebo-controlled clinical trials evaluated the safety and efficacy of BoNT type B in the treatment of CD (Brashear et al, 1999; Brin et al, 1999; Lew et al, 1997).  Patients were treated with a single dose of BoNT type B ranging from 2500 U to 10,000 U. The primary efficacy outcome in each study was the TWSTRS total score. Additional efficacy measures included the TWSTRS severity, disability, and pain subscale scores; the Patient Analog Pain Assessment; and Patient’s and Physician’s Global Assessments of Change. In all 3 studies, BoNT type B treatment produced significantly greater improvements in TWSTRS total score and other efficacy variables compared with placebo treatment. The clinical benefits of BoNT type B treatment lasted 12 to 16 weeks and were noted in both BoNT type A-responsive and BoNT type A-resistant patients (Lew et al, 2000). BoNT type B therapy was well tolerated and most reported adverse events were transient and mild to moderate in severity. Adverse events with BoNT type B are similar to those with BoNT type A in that their incidence is usually dose related; dysphagia is the most frequent side effect in CD patients, although dry mouth appears to be much more frequent with BoNT type B (Myobloc®) than with other types of BoNT. In a review of 24 patients with CD treated with BoNT type B, Berman et al found that 50% continued to benefit for up to 64 months and 8 developed secondary resistance. Prior resistance to BoNT type A was considered an important risk factor for the development of antibodies to BoNT type B (Berman et al, 2004), a finding confirmed by the ongoing Botulinum Toxin Type B Observational Study (BOS) (Jankovic et al, 2005).

Challenges and issues in the treatment of cervical dystonia

Although it is clear that BoNT is clinically effective in treating CD, a number of unresolved issues remain. There is no consensus regarding selection of injection sites, dosing, or the relative efficacy of the different serotypes. Administration of BoNT therapy for CD is sometimes practiced intuitively, from experience, rather than according to evidence-based science (Ceballos-Baumann, 2001). A guiding therapeutic principle for administering BoNT injections is to strive for optimal results with the lowest possible dosage and frequency of administration to minimize the risk of immunoresistance. However, there are no accepted dosing guidelines. The clinical presentation of CD varies among patients and within individual patients over time. Rapid jerky movements and slow postural abnormalities combine to move or tilt the head in different directions. In most patients, the initial schema of BoNT injections needs to be progressively adapted to follow the changing pattern of muscle activity. Such changes are responsible for a percentage of cases of secondary failure that needs to be quantified.

The involvement of previously inactive neck muscles has been considered an aftermath of BoNT-induced muscle weakness. However, increased activity of noninjected muscles, and a switch from 1 most active muscle to another, has been shown to occur not only in patients treated with BoNT but also in those treated orally with anticholinergic drugs. This suggests that the variable pattern of muscle activation is a feature of CD unrelated to BoNT treatment (Bentivoglio and Albanese, 1999; Brans et al 1998).

There also is little agreement regarding the efficacy measures that best quantify response to treatment. The lack of disease-specific assessments and outcome measures is thought to be a source of variation among studies of CD. The CDSS was developed to provide an objective, reliable, standardized measure of treatment response (O’Brien et al, 2001). However, there have been few critical analyses comparing a variety of available outcome measures and including the CDSS. One such analysis explored how well various changes in measures before and after BoNT treatment were able to discriminate between subjects who dropped out versus those who continued treatment (Lindeboom et al, 1998). The effect sizes of change in impairment (Tsui Scale) and in pain (TWSTRS–Pain) were similar in those who continued treatment and in those who dropped out, reflecting poor sensitivity of these outcome measures. In contrast, the scales measuring functional health (TWSTRS–Disability) and the disability, handicap, and global disease burden scale did distinguish between dropouts and patients remaining in treatment (Lindeboom et al, 1998). Further study is needed to resolve uncertainty about which outcome measures best reflect treatment efficacy.

Summary

Numerous studies have demonstrated that BoNT therapy provides effective symptomatic improvement in CD. The efficacy and safety of BoNT in CD has also been confirmed in long-term follow-up assessments. Currently, there are no universally acknowledged clinical practice guidelines or treatment algorithms. Further study of the use of BoNT in the treatment of CD could enhance current clinical guidelines and treatment recommendations.

For further information on the use of botulinum toxins in the treatment of cervical dystonia, please visit http://www.neurotoxininstitute.org/docs/BTX-CD_Toxin2005_Jankovic-MBclean.pdf for Dr. Jankovic’s presentation “An Update on Cervical Dystonia,” from the Toxins 2005 meeting in Denver, Colorado, June 2005.

References and Further Reading

Adler CH, Kumar R. Pharmacological and surgical options for the treatment of cervical dystonia. Neurology. 2000;55(suppl 5):S9-S14.

Azher SN, Jankovic J. Camptocormia: Pathogenesis, classification and response to therapy. Neurology. 2005;65:355-359.

Bentivoglio AR, Albanese A. Botulinum toxin in motor disorders. Curr Opin Neurol. 1999;12:447-456.

Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain. 1998;121:1195-1212.

Berman B, Seeberger L, Kumar R. Long-term safety, efficacy, dosing, and development of resistance with botulinum toxin type B in cervical dystonia. Mov Disord. 2005;20:233-237.

Blackie JD, Lees AJ. Botulinum toxin treatment in spasmodic torticollis. J Neurol Neurosurg Psychiatry. 1990;53:640-643.

Brans JW, Lindeboom R, Aramideh M, Speelman JD. Long-term effect of botulinum toxin on impairment and functional health in cervical dystonia. Neurology. 1998;50:1461-1463.

Brans JW, Lindeboom R, Snoek JW, et al. Botulinum toxin versus trihexyphenidyl in cervical dystonia: a prospective, randomized, double-blind controlled trial. Neurology. 1996;46:1066-1072.

Brans JW, Aramideh M, Koelman JH, et al. Electromyography in cervical dystonia: changes after botulinum and trihexyphenidyl. Neurology. 1998;51:815-819.

Brashear A. The botulinum toxins in the treatment of cervical dystonia. Semin Neurol. 2001;21:85-90.

Brashear A, Lew MF, Dykstra DD, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia. Neurology. 1999;53:1439-1446.

Brashear A, Watts MW, Marchetti A, Magar R, Lau H, Wang L. Duration of effect of botulinum toxin type A in adult patients with cervical dystonia: a retrospective chart review. Clin Ther. 2000;22:1516-1524.

Brin MF, Benabou R. Cervical dystonia (torticollis). Curr Treat Options Neurol. 1999;1:33-43.

Brin MF, Lew MF, Adler CH, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology. 1999;53:1431-1438.

Ceballos-Baumann AO. Evidence-based medicine in botulinum toxin therapy for cervical dystonia. J Neurol. 2001;248(suppl 1):I/14-I/20.

Chan J, Brin MF, Fahn S. Idiopathic cervical dystonia: clinical characteristics. Mov Disord. 1991:6:119-126.

Comella CL, Jankovic J, Brin MF. Use of botulinum toxin type A in the treatment of cervical dystonia. Neurology. 2000;55(suppl 5):S15-S21.

Comella CL, Jankovic J, Daggett S, Mordaunt J, Brin MF. Interim results of an observational study of neutralizing antibody formation with the current preparation of botulinum toxin type A treatment for cervical dystonia. Neurology. 2004;62(suppl 5): A511.

Dauer WT, Burke RE, Greene P, Fahn S. Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain. 1998;121:547-560.

Dressler D, Benecke R. Autonomic side effects of botulinum toxin type B treatment of cervical dystonia and hyperhidrosis. Eur Neurol . 2003;49:34-38.

Galvez-Jimenez N, Lampuri C, Patino-Picirrillo R, Hargreave MJ, Hanson MR. Dystonia and headaches: clinical features and response to botulinum toxin therapy. In: Fahn S, Hallett M, DeLong M, eds. Dystonia 4: Advances in Neurology. Vol. 94. Philadelphia: Lippincott, Williams & Wilkins; 2004:321-328(chap 43).

Gelb DJ, Lowenstein DH, Aminoff MJ. Controlled trial of botulinum toxin injections in the treatment of spasmodic torticollis. Neurology. 1989;39:80-84.

Gilio F, Curra A, Lorenzano C, Modugno N, Manfredi M, Berardelli A. Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol. 2000;48:20-26.

Greene P, Kang U, Fahn S, Brin M, Moskowitz C, Flaster E. Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology. 1990;40:1213-1218.

Haussermann P, Marczoch S, Klinger C, Landgrebe M, Conrad B, Ceballos-Baumann A. Long-term follow-up of cervical dystonia patients treated with botulinum toxin A. Mov Disord. 2004:19:303-308.

Herrmann J, Geth K, Mall V, et al. Clinical impact of antibody formation to botulinum toxin A in children. Ann Neurol. 2004:55:732-735.

Hsiung G-YR, Das SK, Ranawaya R, LaFontaine A-L, Suchowersky O. Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord. 2002:17:1288-1293.

Jankovic J. Treatment of cervical dystonia. In: Brin MF Comella C, Jankovic J, eds. Dystonia: Etiology, Clinical Features and Treatment. Philadelphia: Lippincott Williams & Wilkins; 2004a:159-166 .

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

Jankovic J. Treatment of cervical dystonia with botulinum toxin. Mov Disord. 2004c;19(suppl 8):S109-S115.

Jankovic J, Esquenazi A, Fehlings D, Freitag F, Lang AM, Naumann M. Evidence-based review of patient reported outcomes with botulinum toxin type A. Clin Neuropharmacol. 2004d;27:234-244.

Jankovic J, Hunter C, Atassi MZ. Botulinum toxin type B observational study (BOS). Mov Disord. 2005;20(suppl 10):S31.

Jankovic J, Leder S, Warner D, Schwartz K. Cervical dystonia: clinical findings and associated movement disorders. Neurology. 1991;41:1088-1091.

Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology. 1987;37:616-623.

Jankovic J, Vuong KD, Ahsan J. Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology. 2003;60:1186-1188.

Kessler KR, Skutta M, Benecke R; German Dystonia Study Group. Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. J Neurol. 1999;246:265-274.

Lew MF, Adornato BT, Duane DD, et al. Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia . Neurology. 1997;49:701-707.

Lew MF, Brashear A, Factor S. The safety and efficacy of botulinum toxin type B in the treatment of patients with cervical dystonia: summary of three controlled clinical trials. Neurology. 2000;55(suppl 5):S29-S35.

Lindeboom R, Brans JW, Aramideh M, Speelman HD, De Haan RJ. Treatment of cervical dystonia: a comparison of measures for outcome assessment. Mov Disord. 1998;13:706-712.

Lorentz IT, Subramaniam SS, Yiannikas C. Treatment of idiopathic spasmodic torticollis with botulinum toxin A: a double-blind study on twenty-three patients. Mov Disord. 1991;6:145-150.

Lu CS, Chen RS, Tsai CH. Double-blind, placebo-controlled study of botulinum toxin injections in the treatment of cervical dystonia. J Formos Med Assoc. 1995;94:189-192.

Mejia NI, Vuong KD, Jankovic J. Long-term botulinum toxin efficacy, safety, and immunogenicity. Mov Disord. 2005;20:592-597.

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.

Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 2004;20:981-990.

O'Brien C, Brashear A, Cullis P, et al. Cervical dystonia severity scale reliability study. Mov Disord . 2001;16:1086-1090.

Odergren T, Hjaltason H, Kaakkola S, et al. A double blind, randomised, parallel group study to investigate the dose equivalence of Dysport Ò and Botox Ò in the treatment of cervical dystonia. J Neurol Neurosurg Psychiatry. 1998;64:6-12.

Ostergaard L, Fuglsang-Frederiksen A, Werdelin L, Sjo O, Winkel H. Quantitative EMG in botulinum toxin treatment of cervical dystonia. A double-blind, placebo-controlled study. Electroencephalogr Clin Neurophysiol. 1994;93:434-439.

Poewe W, Deuschl G, Nebe A, et al; German Dystonia Study Group. What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo controlled, dose ranging study using Dysport. J Neurol Neurosurg Psychiatry . 1998;64:13-17.

Ranoux D, Gury C, Fondarai J, Mas JL, Zuber M. Respective potencies of Botox and Dysport: a double blind, randomised, crossover study in cervical dystonia. J Neurol Neurosurg Psychiatry . 2002;72:459-462.

Schramm A, Reiners K, Naumann M. Complex mechanisms of sensory tricks in cervical dystonia. Mov Disord. 2004;19:452-458.

Siggelkow S, Kossev A, Moll C, Dauper J, Dengler R, Rollnik JD. Impaired sensorimotor integration in cervical dystonia: a study using transcranial magnetic stimulation and muscle vibration. J Clin Neurophysiol. 2002;19:232-239.

Stacy M. Idiopathic cervical dystonia: an overview. Neurology. 2000;55(suppl 5):S2-S8.

Tsui JK, Eisen A, Stoessl AJ, Calne S, Calne DB. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet. 1986;2:245-247.

Velickovic M, Benabou R, Brin MF. Cervical dystonia pathophysiology and treatment options. Drugs. 2001;61:1921-1943.

Walker FO. Botulinum toxin therapy for cervical dystonia. Phys Med Rehabil Clin N Am. 2003;14:749-766.

Wissel J, Kanovsky P, Ruzicka E, et al. Efficacy and safety of a standardised 500 unit dose of Dysport Ò (Clostridium botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: results of a prospective, multicentre, randomised, double-blind, placebo-controlled, parallel group study. J Neurol. 2001;248:1073-1078.