Botulinum toxin treatment of tremors Joseph Jankovic, MD, and K e n n e t h Schwartz, PA
Article abstract-We report the results of an open trial of botulinum toxin (Botox) in the treatment of 51 patients with disabling tremors, classified as dystonic (14), essential (12), combination of dystonic and essential ( 2 2 ) , parkinsonian (l), peripherally induced (l),and midbrain (1). The average age of the patients was 55.8 years, and duration of symptoms was 13.9 years. During a total of 160 treatment visits, an average of 242 2 75 units of Botox was injectedper visit in cervical muscles of 42 patients with head tremor and 95 k 38 in forearm muscles of 10patients with hand tremor; one patient was injected in both. The average peak effect for all patients was rated as 3.0 (0 to 4 scale). Thirty-five (67%)patients improved (peak effect 2 1 ) . The average latency from injection to response was 6.8 days, and the average duration of maximum improvement was 10.5 weeks. Local complications, lasting an average of 20.6 days, were noted in 17 (40%)patients injected for head tremor, consisting chiefly of dysphagia in 12 (29%),transient neck weakness in four (lo%),and local pain in two (5%).Six (60%)patients with hand tremor had transient focal weakness. EMG recordings showed decreased amplitude of EMG bursts after Botox treatment. The results of this pilot study indicate that Botox injections can be used to control tremor in patients in whom other forms of therapy have failed. NEUROLOGY 1991;41:1185-1188
Injections of botulinum toxin (Botox) have been used effectively in the t r e a t m e n t of focal dystonias, hemifacial spasm, a n d other local Dystonic syndromes are often accompanied by S o m e of these tremors are produced by r h y t h m i c dystonic contractions, some are phenomenologically similar to essential tremor, and some have features of both types of tremor. During the course of treating hundreds of patients with Botox over the past 6 years, we observed that an improvement of dystonia was frequently associated with a reduction in the amplitude of t h e coexisting tremor in t h e injected body part. The reduction i n tremor often contributed to a meaningful improvement in motor function. W e therefore designed this pilot study to independently examine the effects of Botox on tremor. T h e effects of this t r e a t m e n t in 51patients with disabling tremor are presented. Methods. Patients referred to the Movement Disorders Clinic for management of disabling tremor were selected for this pilot study. Although some patients had associated dystonia, parkinsonism, or other neurologic disorders, all considered tremor as the primary source of their disability. T o be included in the study, all patients must have had tremor severe enough to cause occupational disability, notable impairment in activities of daily living, or an unacceptable level of social embarrassment. Furthermore, all patients must have had a trial of optimal pharmacologic therapy (three patients had thalamotomy). Patients with hand tremor had an action tremor, most evident when the arm was held against gravity (postural tremor), during goal-directed movements such as the finger-to-nose test (kinetic tremor), or while performing some activity such as writing (task-specific t r e m ~ r ) .Head ~.~ tremor can be considered a postural tremor because the cer-
vical muscles must contract to maintain the head in an erect posture. When there is a coexistent dystonia, the tremor in the affected body part is influenced by its position. For example, dystonic head tremor in a patient with torticollis to the right tends to increase when the head is maintained in a primary position or when it turns to the left, in a direction opposing the dystonic pulling. In contrast to dystonic tremor, essential tremor is less dependent on a particular position. Presence of dystonia in the affected body part, marked effects of position on the amplitude of the tremor, and asymmetry in the oscillation can be used to differentiate dystonic from essential tremor in most cases. The distinction between essential and dystonic tremor, however, is not always easy to make, and both types of tremor frequently coexist. All patients signed a written consent form approved by the Institutional Review Boards for Human Research of Baylor College of Medicine and The Methodist Hospital. In addition to a complete neurologic examination, they were videotaped, and their tremor was recorded by surface EMG prior to injection. The severity of tremor was rated by one of the investigators (J.J.) on a 0 to 4 scale (0 = no tremor; 1 = mild, barely noticeable tremor; 2 = moderate tremor without functional impairment; 3 = moderate tremor, moderate functional impairment; 4 = severe, incapacitating tremor). The patients also rated their tremor in a daily diary; those who had impairment of their handwriting were asked to draw a spiral and write “Today is a nice day.” The diaries were reviewed to determine the “latency,” ie, the interval (in days) between the injection and the first sign of improvement. “Peak effect” score, defined as the maximum benefit after the injection, was determined by one of the investigators (J.J.) and was partly based on a review of the patient’s history, diary, and an interview of the patient’s spouse or friends. The peak effect was rated on a 0 to 4 scale (0 = no effect; 1 = mild improvement; 2 = moderate improvement, but no change in function; 3 = moderate improvement in severity and function; 4 =
From the Parkinson’s Disease Center and Movement Disorders Clinic, and Department of Neurology, Baylor College of Medicine, Houston, TX. Received November 15,1990. Accepted for publication in final form February 4,1991. Address correspondence and reprint requeststo Dr. Joseph Jankovic, Department of Neurology, Baylor College of Medicine, 6550 Fannin # 1801,Houston, TX 77030.
August 1991 NEUROLOGY 41 1186
Table 1. Results (N = 51) Variable
Mean f SD
P E A K EFFECT TREMOR
(Min-Max) NUMBER
Peak effect tremor Head tremor Hand tremor Essential tremor Dystonic tremor Combination tremor Latency of effect (days) Duration of total response (wks) Duration of maximum response (wks)
3.0 3.0 2.0 3.4 3.5 3.0 6.8
f 1.2 f 1.1 f 1.7 k 1.4 f 7.2
(0-4) (0-4) (0-4) (1-4) (2-4) (0-4) (0-35)
12.5 f 7.5
(0-36)
10.5 f 6.4
(0-26)
t 0.9 k 0.6
60
46
50 40
30 20 10
0 0
Results. There were 51 patients evaluated in a total of 160 visits. The average age was 55.8 k 11.8(range, 19 to 80) years, the age of onset was 42.1 k 13.7 (range, 5 to 66), and the duration of symptoms was 13.9 k 12.6 (range, 1 to 52) years. Sites of involvement included neck (42 patients; 13 dystonic, 8 essential, 20 combination, 1 midbrain) and hand (10 patients; 4 essential, 1 dystonic, 3 combination, 1parkinsonian, 1peripherally 1186 NEUROLOGY 4 1 August 1991
3
2
1
4
RATING PATIENTS
marked improvement in severity and function). The “maximum” duration of improvement was the number of weeks during which the patient experienced peak effect; “total” duration was the entire period (in weeks) after the injection during which the patients noted any improvement. The patients were asked to return for their repeat injections in 3 months. If patients returned before the previous injection completely wore off, then the total duration of benefit was considered indeterminable. Tremor was recorded simultaneously with both a digital storage oscilloscope and a computer-based analog/digital converter connected to high-gain amplifiers. Placement of the surface electrodes was photographed so that the electrodes could be accurately repositioned during follow-up recordings. Two-second traces were recorded on an integral plotter with the oscilloscope. Files created over a continuous 5-minute interval were sampled a t 2 kHz with 12-bitresolution and were used to determine burst frequency, peak burst amplitude, and duration of EMG burst patterns. The clinical score and the EMG data were entered and constantly updated in a relational database. Botox injections. Botox (Oculinum) was prepared according to established procedures4The diluted solution (20 units per 0.1-ml sterile 0.9% saline without preservatives) was drawn into a l-ml tuberculin syringe, and the toxin was injected with a 0.5-inch, 30-gauge needle into superficial muscles and with a 1.5-inch, 26-gauge needle into deep muscles. Patients with lateral (negation) oscillation of the head were injected in both splenius capitis muscles and in one or both sternocleidomastoid muscles if there was an anterior-posterior (affirmation) component. Asymmetric dosages or additional neck muscle injections were often required in patients with dystonic tremor. The total dosage was distributed into four to six different sites anatomically related to those muscles involved in the production of the tremor: wrist extensors (predominantly extensor carpi radialis and ulnaris) and wrist flexors (predominantly flexor carpi radialis and ulnaris). The dosages in the opposing muscle groups varied, depending in part on whether there was evidence of coexistent dystonia.
A5
VISITS
I
Figure I. Distribution of response determined by peak effect.
induced). Average severity of tremor was 3.1 k 0.8 (range, 1to 4) at the time of first injection, indicating at least moderate functional impairment. An average of 242 k 75 units of Botox was injected per visit, 107 k 38 units per cervical musqle, in 42 patients with head tremor. In 10 patients with hand tremor, we injected an average of 95 k 38 units in the forearm muscles. One patient was injected in both neck and forearm muscles. The peak effect tremor response was 3.0, indicating moderate improvement in severity and function (table 1,figure 1).Of the eight patients who failed to improve after one visit (peak effect of 0 or l), seven showed improvement (peak effect of 2 or better) at other visits. There was no significant difference in response (peak effect) between the various types of tremor (dystonic [14 patients], essential 1121,anda combination of dystonic and essential tremor [23]), and there was no difference in response between head or hand tremors (paired t test). While patients with dystonic tremor seemed to respond better than those with other tremors (table l),this difference was not statistically significant. Onset of effect had an average latency of 6.8 days, average duration of total response, 12.5 weeks, and duration of maximum response, 10.5 weeks. Response rating between first and last visit showed no change, indicating no average change in effectiveness over the duration of the study. Initial severity of tremor, in most instances either 3 or 4, did not predict treatment efficacy. Fourteen patients returned for a second EMG recording an average of 37.5 f 47.0 days after the injection. Although we asked all patients to return for followup recordings, only those from the local geographic area could comply. There is no evidence, however, that these patients responded differently from those who did not have a repeat EMG; the peak effect response was the same in both groups (paired t test). Thirteen patients showed definite improvement; seven had complete absence of tremor (no tremor bursts) in the injected muscles, and six demonstrated decreased EMG burst amplitude ranging from one-half to one-fortieth of the
B
A
Figure 2. Reduction i n tremor amplitude after Botor injections into (A) forearm muscles i n a patient with postural hand tremor and ( B ) into splenius capitis muscles i n a patient with lateral head oscillation.
Table 2. Complications
Any complication Localized weakness Hand Neck Dysphagia Disabling complications
Patients
Visits
23/51 (45.1%) 9/51 (17.6%) 6/10 (60.0%) 4/42 (9.5%) 12/42 (28.6%) 0
31/160 (19.4%) 12/160 (7.5%) 8/20 (40.0%) 24/141 (17.0%) 14/141 (9.9%) 0
recorded signal prior to injection (figure 2, A and B). Reductions in EMG burst amplitude were significantly different before and after treatment Gr, < 0.01 by paired t test). There was no change in frequency (5.0 f 0.7 Hz before versus 4.5 +- 1.9 Hz after), burst duration (107.7 f 33.1 msec before versus 76.9 ? 36.6 msec after), interburst intervals (83.8 k 29.8 msec before versus 77.5 f 32.3 msec after), or synchronicity of EMG activity in the involved musculature. Only local complications occurred, consisting of transient weakness of the injected muscles, noted in nine (18%)patients and 12 (7.5%) visits, and dysphagia (only after cervical muscle injections), noted in 12 (29%)patients and 14 (9.9%)visits (table 2). The complications lasted an average of 20.6 days: hand weakness, 23.9 days; neck weakness, 21.8 days; and dysphagia, 8.4 days. None of the patients considered
these complications disabling, and all stated that, given a choice, they preferred the transient weakness to the disabling tremor.
Discussion. Botox injections are now considered the most effective treatment in a variety of focal dystonias, including blepharospasm, torticollis, and spasmodic dysphonia, and in hemifacial spasm.g This is the first report of the use of Botox in the treatment of medically (and surgically) intractable tremors. All 51 patients included in this pilot study had disabling tremor despite optimal medical and, in three cases, surgical therapy. In this study, we concentrated chiefly on head and limb tremors; we did not include patients with voice tremor, most of whom also benefitted when Botox was injected into their left vocal fold. Improvement of voice tremor has been previously suggested but not yet fully described.1° Nearly two-thirds of our patients improved, as determined by clinical rating scales. While there was a trend for patients with hand tremor and with combination of dystonic and essential tremor to respond less favorably than those with the other types of tremor, this difference was not statistically significant. In 13 of 14 patients tested, the reduction in the clinical rating score was accompanied by a reduction in amplitude as demonstrated by marked lowering or complete disappearance of EMG burst activity in the affected body August 1991 NEUROLOGY 41 1187
duction with Botox is via a weakening of the contracting muscles, which affects “the final common pathway,” we believe that the efficacy of this treatment in tremor should be the same or similar irrespective of its etiology.” Future studies should examine which clinical variables, anatomic locations, and etiologies determine the effects of Botox on tremor. Acknowledgments We thank the Cullen Foundation for partly supporting this study. We also thank Zenith Computers for the use of a 33-MHz 386 computer and R.C. Electronics, who provided the 1-MHz A/D boardand acquisition/analysis software.
Figure 3. Improvement i n handwriting after Botox injection into wrist flexors and extensors of a patient with essential tremor.
part (figure 2). Functional improvement in tremor, however, is sometimes difficult t o express quantitatively. Many patients reported marked improvement in their handwriting (figure 3). Others were delighted because they no longer spilled liquids, were not embarrassed to eat in public, could hold newspapers while reading, were able to place contact lenses, and could perform other coordinated movements that were impossible before the Botox injections. Therefore, in addition to the clinical scales and EMG, functional rating scales will be used in future studies of tremor to capture this functional improvement. A complication, usually consisting of local weakness and dysphagia, occurred in 45% of patients and 19%of visits. Nearly all patients, however, considered these symptoms minor when compared with the disability caused by their tremor. With further experience in this procedure, we expect a reduction in the complication rate and further improvement in effectiveness. A double-blind,placebo-controlled study is needed to confirm our initial findings. However, the results of this pilot trial are so remarkable that they should encourage further investigation into this new application of Botox therapy. Since the presumed mechanism of tremor re-
1188 NEUROLOGY 41 August 1991
References 1. Brin MF, Fahn S, Moskowitz CB, et al. Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237-254. 2. Cohen LG, Hallett M, Geller B, Hochberg F. Treatment of focal dystonias of the hand with botulinum toxin injections. J Neurol Neurosurg Psychiatry 1989;52:355-363. 3. Jankovic J , Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology 1990;40:277-280. 4. Jankovic J , Schwartz K, Donovan DT. Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990;53:633-639. 5. Jankovic J, Fahn S. Dystonic syndromes. In: Jankovic J , Tolosa E, eds. Parkinson’s disease and movement disorders. Baltimore: Urban & Schwarzenberg, 1988:283-314. 6. Rosenbaum F, Jankovic J. Focal task-specific tremor and dystonia: categorization of occupational movement disorders. Neurology 1988;38:522-527. 7. Lou J-S, Jankovic J . Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234-238. 8. Jankovic J , Leder S, Warner D, Schwartz K. Cervical dystonia: clinical findings and associated movement disorders. Neurology 1991;41:1088-1091. 9. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology 1990;40:1332-1336. 10. Ludlow CL, Sedory SE, Fujita M, Naunton RF. Treatment of voice tremor with botulinum toxin injection [Abstract].Neurology 1989;39(suppl 1):353. 11. Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186-1194.
Botulinum toxin treatment of tremors Joseph Jankovic and Kenneth Schwartz Neurology 1991;41;1185 DOI 10.1212/WNL.41.8.1185 This information is current as of August 1, 1991 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1991 by Edgell Communications, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Article abstract-We report the results of an open trial of botulinum toxin (Botox) in the treatment of 51 patients with disabling tremors, classified as dystonic (14), essential (12), combination of dystonic and essential ( 2 2 ) , parkinsonian (l), peripherally induced (l),and midbrain (1). The average age of the patients was 55.8 years, and duration of symptoms was 13.9 years. During a total of 160 treatment visits, an average of 242 2 75 units of Botox was injectedper visit in cervical muscles of 42 patients with head tremor and 95 k 38 in forearm muscles of 10patients with hand tremor; one patient was injected in both. The average peak effect for all patients was rated as 3.0 (0 to 4 scale). Thirty-five (67%)patients improved (peak effect 2 1 ) . The average latency from injection to response was 6.8 days, and the average duration of maximum improvement was 10.5 weeks. Local complications, lasting an average of 20.6 days, were noted in 17 (40%)patients injected for head tremor, consisting chiefly of dysphagia in 12 (29%),transient neck weakness in four (lo%),and local pain in two (5%).Six (60%)patients with hand tremor had transient focal weakness. EMG recordings showed decreased amplitude of EMG bursts after Botox treatment. The results of this pilot study indicate that Botox injections can be used to control tremor in patients in whom other forms of therapy have failed. NEUROLOGY 1991;41:1185-1188
Injections of botulinum toxin (Botox) have been used effectively in the t r e a t m e n t of focal dystonias, hemifacial spasm, a n d other local Dystonic syndromes are often accompanied by S o m e of these tremors are produced by r h y t h m i c dystonic contractions, some are phenomenologically similar to essential tremor, and some have features of both types of tremor. During the course of treating hundreds of patients with Botox over the past 6 years, we observed that an improvement of dystonia was frequently associated with a reduction in the amplitude of t h e coexisting tremor in t h e injected body part. The reduction i n tremor often contributed to a meaningful improvement in motor function. W e therefore designed this pilot study to independently examine the effects of Botox on tremor. T h e effects of this t r e a t m e n t in 51patients with disabling tremor are presented. Methods. Patients referred to the Movement Disorders Clinic for management of disabling tremor were selected for this pilot study. Although some patients had associated dystonia, parkinsonism, or other neurologic disorders, all considered tremor as the primary source of their disability. T o be included in the study, all patients must have had tremor severe enough to cause occupational disability, notable impairment in activities of daily living, or an unacceptable level of social embarrassment. Furthermore, all patients must have had a trial of optimal pharmacologic therapy (three patients had thalamotomy). Patients with hand tremor had an action tremor, most evident when the arm was held against gravity (postural tremor), during goal-directed movements such as the finger-to-nose test (kinetic tremor), or while performing some activity such as writing (task-specific t r e m ~ r ) .Head ~.~ tremor can be considered a postural tremor because the cer-
vical muscles must contract to maintain the head in an erect posture. When there is a coexistent dystonia, the tremor in the affected body part is influenced by its position. For example, dystonic head tremor in a patient with torticollis to the right tends to increase when the head is maintained in a primary position or when it turns to the left, in a direction opposing the dystonic pulling. In contrast to dystonic tremor, essential tremor is less dependent on a particular position. Presence of dystonia in the affected body part, marked effects of position on the amplitude of the tremor, and asymmetry in the oscillation can be used to differentiate dystonic from essential tremor in most cases. The distinction between essential and dystonic tremor, however, is not always easy to make, and both types of tremor frequently coexist. All patients signed a written consent form approved by the Institutional Review Boards for Human Research of Baylor College of Medicine and The Methodist Hospital. In addition to a complete neurologic examination, they were videotaped, and their tremor was recorded by surface EMG prior to injection. The severity of tremor was rated by one of the investigators (J.J.) on a 0 to 4 scale (0 = no tremor; 1 = mild, barely noticeable tremor; 2 = moderate tremor without functional impairment; 3 = moderate tremor, moderate functional impairment; 4 = severe, incapacitating tremor). The patients also rated their tremor in a daily diary; those who had impairment of their handwriting were asked to draw a spiral and write “Today is a nice day.” The diaries were reviewed to determine the “latency,” ie, the interval (in days) between the injection and the first sign of improvement. “Peak effect” score, defined as the maximum benefit after the injection, was determined by one of the investigators (J.J.) and was partly based on a review of the patient’s history, diary, and an interview of the patient’s spouse or friends. The peak effect was rated on a 0 to 4 scale (0 = no effect; 1 = mild improvement; 2 = moderate improvement, but no change in function; 3 = moderate improvement in severity and function; 4 =
From the Parkinson’s Disease Center and Movement Disorders Clinic, and Department of Neurology, Baylor College of Medicine, Houston, TX. Received November 15,1990. Accepted for publication in final form February 4,1991. Address correspondence and reprint requeststo Dr. Joseph Jankovic, Department of Neurology, Baylor College of Medicine, 6550 Fannin # 1801,Houston, TX 77030.
August 1991 NEUROLOGY 41 1186
Table 1. Results (N = 51) Variable
Mean f SD
P E A K EFFECT TREMOR
(Min-Max) NUMBER
Peak effect tremor Head tremor Hand tremor Essential tremor Dystonic tremor Combination tremor Latency of effect (days) Duration of total response (wks) Duration of maximum response (wks)
3.0 3.0 2.0 3.4 3.5 3.0 6.8
f 1.2 f 1.1 f 1.7 k 1.4 f 7.2
(0-4) (0-4) (0-4) (1-4) (2-4) (0-4) (0-35)
12.5 f 7.5
(0-36)
10.5 f 6.4
(0-26)
t 0.9 k 0.6
60
46
50 40
30 20 10
0 0
Results. There were 51 patients evaluated in a total of 160 visits. The average age was 55.8 k 11.8(range, 19 to 80) years, the age of onset was 42.1 k 13.7 (range, 5 to 66), and the duration of symptoms was 13.9 k 12.6 (range, 1 to 52) years. Sites of involvement included neck (42 patients; 13 dystonic, 8 essential, 20 combination, 1 midbrain) and hand (10 patients; 4 essential, 1 dystonic, 3 combination, 1parkinsonian, 1peripherally 1186 NEUROLOGY 4 1 August 1991
3
2
1
4
RATING PATIENTS
marked improvement in severity and function). The “maximum” duration of improvement was the number of weeks during which the patient experienced peak effect; “total” duration was the entire period (in weeks) after the injection during which the patients noted any improvement. The patients were asked to return for their repeat injections in 3 months. If patients returned before the previous injection completely wore off, then the total duration of benefit was considered indeterminable. Tremor was recorded simultaneously with both a digital storage oscilloscope and a computer-based analog/digital converter connected to high-gain amplifiers. Placement of the surface electrodes was photographed so that the electrodes could be accurately repositioned during follow-up recordings. Two-second traces were recorded on an integral plotter with the oscilloscope. Files created over a continuous 5-minute interval were sampled a t 2 kHz with 12-bitresolution and were used to determine burst frequency, peak burst amplitude, and duration of EMG burst patterns. The clinical score and the EMG data were entered and constantly updated in a relational database. Botox injections. Botox (Oculinum) was prepared according to established procedures4The diluted solution (20 units per 0.1-ml sterile 0.9% saline without preservatives) was drawn into a l-ml tuberculin syringe, and the toxin was injected with a 0.5-inch, 30-gauge needle into superficial muscles and with a 1.5-inch, 26-gauge needle into deep muscles. Patients with lateral (negation) oscillation of the head were injected in both splenius capitis muscles and in one or both sternocleidomastoid muscles if there was an anterior-posterior (affirmation) component. Asymmetric dosages or additional neck muscle injections were often required in patients with dystonic tremor. The total dosage was distributed into four to six different sites anatomically related to those muscles involved in the production of the tremor: wrist extensors (predominantly extensor carpi radialis and ulnaris) and wrist flexors (predominantly flexor carpi radialis and ulnaris). The dosages in the opposing muscle groups varied, depending in part on whether there was evidence of coexistent dystonia.
A5
VISITS
I
Figure I. Distribution of response determined by peak effect.
induced). Average severity of tremor was 3.1 k 0.8 (range, 1to 4) at the time of first injection, indicating at least moderate functional impairment. An average of 242 k 75 units of Botox was injected per visit, 107 k 38 units per cervical musqle, in 42 patients with head tremor. In 10 patients with hand tremor, we injected an average of 95 k 38 units in the forearm muscles. One patient was injected in both neck and forearm muscles. The peak effect tremor response was 3.0, indicating moderate improvement in severity and function (table 1,figure 1).Of the eight patients who failed to improve after one visit (peak effect of 0 or l), seven showed improvement (peak effect of 2 or better) at other visits. There was no significant difference in response (peak effect) between the various types of tremor (dystonic [14 patients], essential 1121,anda combination of dystonic and essential tremor [23]), and there was no difference in response between head or hand tremors (paired t test). While patients with dystonic tremor seemed to respond better than those with other tremors (table l),this difference was not statistically significant. Onset of effect had an average latency of 6.8 days, average duration of total response, 12.5 weeks, and duration of maximum response, 10.5 weeks. Response rating between first and last visit showed no change, indicating no average change in effectiveness over the duration of the study. Initial severity of tremor, in most instances either 3 or 4, did not predict treatment efficacy. Fourteen patients returned for a second EMG recording an average of 37.5 f 47.0 days after the injection. Although we asked all patients to return for followup recordings, only those from the local geographic area could comply. There is no evidence, however, that these patients responded differently from those who did not have a repeat EMG; the peak effect response was the same in both groups (paired t test). Thirteen patients showed definite improvement; seven had complete absence of tremor (no tremor bursts) in the injected muscles, and six demonstrated decreased EMG burst amplitude ranging from one-half to one-fortieth of the
B
A
Figure 2. Reduction i n tremor amplitude after Botor injections into (A) forearm muscles i n a patient with postural hand tremor and ( B ) into splenius capitis muscles i n a patient with lateral head oscillation.
Table 2. Complications
Any complication Localized weakness Hand Neck Dysphagia Disabling complications
Patients
Visits
23/51 (45.1%) 9/51 (17.6%) 6/10 (60.0%) 4/42 (9.5%) 12/42 (28.6%) 0
31/160 (19.4%) 12/160 (7.5%) 8/20 (40.0%) 24/141 (17.0%) 14/141 (9.9%) 0
recorded signal prior to injection (figure 2, A and B). Reductions in EMG burst amplitude were significantly different before and after treatment Gr, < 0.01 by paired t test). There was no change in frequency (5.0 f 0.7 Hz before versus 4.5 +- 1.9 Hz after), burst duration (107.7 f 33.1 msec before versus 76.9 ? 36.6 msec after), interburst intervals (83.8 k 29.8 msec before versus 77.5 f 32.3 msec after), or synchronicity of EMG activity in the involved musculature. Only local complications occurred, consisting of transient weakness of the injected muscles, noted in nine (18%)patients and 12 (7.5%) visits, and dysphagia (only after cervical muscle injections), noted in 12 (29%)patients and 14 (9.9%)visits (table 2). The complications lasted an average of 20.6 days: hand weakness, 23.9 days; neck weakness, 21.8 days; and dysphagia, 8.4 days. None of the patients considered
these complications disabling, and all stated that, given a choice, they preferred the transient weakness to the disabling tremor.
Discussion. Botox injections are now considered the most effective treatment in a variety of focal dystonias, including blepharospasm, torticollis, and spasmodic dysphonia, and in hemifacial spasm.g This is the first report of the use of Botox in the treatment of medically (and surgically) intractable tremors. All 51 patients included in this pilot study had disabling tremor despite optimal medical and, in three cases, surgical therapy. In this study, we concentrated chiefly on head and limb tremors; we did not include patients with voice tremor, most of whom also benefitted when Botox was injected into their left vocal fold. Improvement of voice tremor has been previously suggested but not yet fully described.1° Nearly two-thirds of our patients improved, as determined by clinical rating scales. While there was a trend for patients with hand tremor and with combination of dystonic and essential tremor to respond less favorably than those with the other types of tremor, this difference was not statistically significant. In 13 of 14 patients tested, the reduction in the clinical rating score was accompanied by a reduction in amplitude as demonstrated by marked lowering or complete disappearance of EMG burst activity in the affected body August 1991 NEUROLOGY 41 1187
duction with Botox is via a weakening of the contracting muscles, which affects “the final common pathway,” we believe that the efficacy of this treatment in tremor should be the same or similar irrespective of its etiology.” Future studies should examine which clinical variables, anatomic locations, and etiologies determine the effects of Botox on tremor. Acknowledgments We thank the Cullen Foundation for partly supporting this study. We also thank Zenith Computers for the use of a 33-MHz 386 computer and R.C. Electronics, who provided the 1-MHz A/D boardand acquisition/analysis software.
Figure 3. Improvement i n handwriting after Botox injection into wrist flexors and extensors of a patient with essential tremor.
part (figure 2). Functional improvement in tremor, however, is sometimes difficult t o express quantitatively. Many patients reported marked improvement in their handwriting (figure 3). Others were delighted because they no longer spilled liquids, were not embarrassed to eat in public, could hold newspapers while reading, were able to place contact lenses, and could perform other coordinated movements that were impossible before the Botox injections. Therefore, in addition to the clinical scales and EMG, functional rating scales will be used in future studies of tremor to capture this functional improvement. A complication, usually consisting of local weakness and dysphagia, occurred in 45% of patients and 19%of visits. Nearly all patients, however, considered these symptoms minor when compared with the disability caused by their tremor. With further experience in this procedure, we expect a reduction in the complication rate and further improvement in effectiveness. A double-blind,placebo-controlled study is needed to confirm our initial findings. However, the results of this pilot trial are so remarkable that they should encourage further investigation into this new application of Botox therapy. Since the presumed mechanism of tremor re-
1188 NEUROLOGY 41 August 1991
References 1. Brin MF, Fahn S, Moskowitz CB, et al. Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237-254. 2. Cohen LG, Hallett M, Geller B, Hochberg F. Treatment of focal dystonias of the hand with botulinum toxin injections. J Neurol Neurosurg Psychiatry 1989;52:355-363. 3. Jankovic J , Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology 1990;40:277-280. 4. Jankovic J , Schwartz K, Donovan DT. Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990;53:633-639. 5. Jankovic J, Fahn S. Dystonic syndromes. In: Jankovic J , Tolosa E, eds. Parkinson’s disease and movement disorders. Baltimore: Urban & Schwarzenberg, 1988:283-314. 6. Rosenbaum F, Jankovic J. Focal task-specific tremor and dystonia: categorization of occupational movement disorders. Neurology 1988;38:522-527. 7. Lou J-S, Jankovic J . Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234-238. 8. Jankovic J , Leder S, Warner D, Schwartz K. Cervical dystonia: clinical findings and associated movement disorders. Neurology 1991;41:1088-1091. 9. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology 1990;40:1332-1336. 10. Ludlow CL, Sedory SE, Fujita M, Naunton RF. Treatment of voice tremor with botulinum toxin injection [Abstract].Neurology 1989;39(suppl 1):353. 11. Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186-1194.
Botulinum toxin treatment of tremors Joseph Jankovic and Kenneth Schwartz Neurology 1991;41;1185 DOI 10.1212/WNL.41.8.1185 This information is current as of August 1, 1991 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1991 by Edgell Communications, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
