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Botulinum Toxin Injections
INJECTION TECHNIQUES: PRINCIPLES AND PRACTICE 1047-9651/95 $0.00
+ .20
BOTULINUM TOXIN INJECTIONS Lawrence R. Robinson, MD, and Leilei Wang, MD, PhD
A number of excellent articles have reviewed the basic science and some of the clinical principles behind the use of botulinum toxin type A (Botox) for the use of motor control disorder^.'^-'^, 14. l9 Hence, this article reviews some of the common clinical applications and then predominantly addresses the techniques of Botox injection. CLINICAL APPLICATIONS OF BOTOX INJECTION
Therapeutic Botox injection is primarily useful for treatment of various types of focal dystonia, including spasmodic torticollis, spasmodic dysphonia, blepharospasm, orofacial dystonia (Meige syndrome), and hemifacial spasm (which is caused by a different pathophysiology than the other dystonias). As of this writing, the Food and Drug Administration (FDA) has not yet approved Botox for all of these uses, although it is approved for blepharospasm, hemifacial spasm, strabismus, and other facial nerve disorders. Some patients with focal manifestations of upper motor neuron syndromes, such as stroke or multiple sclerosis, in whom one or a few muscles are affected, may also benefit from Botox injection. Botox is probably not useful, however, for disorders in which there is diffuse (rather than focal) hyperactivity in large muscles, for example, generalized limb spasticity or Parkinson's disease. With injection of increasing numbers of large muscles, the total dose required increases the risk of adverse effects, increases the costs, and consequently makes the treatment impractical. One of the more common dystonias physiatrists are likely to encounter is spasmodic torticollis, more accurately described as cervical dystonia. The pathophysiology of this disorder is not well known, in part because few people die of the disorder and there is not a good animal model of the disease. There is a variety of evidence that supports involvement of the brain stem or basal
From the Department of Rehabilitation Medicine, University of Washington School of Medicine, and Harborview Medical Center, Seattle (LRR); and Rehabilitation and Spine Center, P.S., Everett (LW),Washington PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA VOLUME 6 NUMBER 4 NOVEMBER 1995
897
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ROBINSON & WANG
ganglia or both." Some patients will report that trauma, surgery, cervical radiculopathy, hypertension, emotional stress, or thyroid disease3h, 21 were associated with the start of symptoms. Although neck rotation is common, many patients also have flexion or extension and lateral tilting. Multiple muscles, not just sternocleidomastoid, are usually involved. For this reason the term cervical dystonia is often preferred.13 In our experience, commonly involved muscles include sternocleidomastoid, levator scapulae, splenius capitus, and cervical paraspinal muscles, and trapezius. Polymyographic recordings have been used to identify specific muscle groups in individual patients: although this is not usually especially helpful for diagnosis or treatment. In addition to abnormal posturing, pain is a common complaint in this patient population group, and is reported in up to 6896 of such patients.13Infrequently, about 10% of the time, the cervical dystonias are associated with other dystonias such as blepharospasm, spasmodic dysphonia, or orofacial dystonia (Meige syndrome), perhaps suggesting a common etiology l3 for these di~eases.~, A number of studies, including several well-done double-blind randomized trials, have shown the value of Botox in the treatment of spasmodic torticollis.', 2, 4, 7, 9, 12, 13, 20 The rate of success in relieving pain and reducing abnormal posturing approaches 90%; more than 80% of patients report a 50% or better impro~ement.~ Although there is some controversy regarding the use of electromyography (EMG) during injection, many, including ourselves, have found this to be very valuable in helping to identify which muscles to inject and to locate actively contracting m ~ s c l eA . ~study from Comella et a14 randomized 52 patients with spasmodic torticollis to one of two groups: (1) EMG-guided injection in which muscles were selected for Botox injection using both clinical and EMG examination and then injected with EMG assistance, and (2) clinically guided injection in which muscles were selected for Botox injection based solely on clinical examination and injected without EMG assistance. Although the percentage of patients showing any improvement after Botox was similar in both groups, a significantly greater magnitude of improvement was present in the group who had injections under EMG guidance. Dosages and the selection of muscles to be injected need to be decided individually for each patient and reassessed with each injection. Not only are the patterns of muscle overactivity very variable between patients but also these may change from month to month in the same patient. A trial using fixed doses applied to the sternocleidomastoid and trapezius muscles failed to show much in the way of objective changes,15 suggesting that EMG guidance and use of individualized protocols is preferable to a standard protocol for every patient. GENERAL PRINCIPLES OF BOTOX USE Evaluating the Patient
A thorough patient evaluation is required before injection. Obviously, inadequate patient evaluation or inappropriate patient selection will produce poor results and may ultimately do harm to the patient. Most importantly, the diagnosis needs to be convincingly established and other (malignant or reversible) causes of dystonia ruled out (for example, brain stem tumor or Wilson's disease). In our center, this usually involves comprehensive assessment by a
BOTULINUM TOXIN INJECTIONS
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neurologist, though it is not always necessary to perform any other laboratory studies (for example, magnetic resonance imaging [MRI]) on every patient. Review of other forms of therapy, such as medications or physical therapy, should also be done before injection. For patients taking narcotics or benzodiazapenes, it is often helpful to plan ahead of time how these medications will be managed once Botox will have taken effect. Physical therapy for muscular relaxation is often of moderate symptomatic help as an adjunct to Botox injections but is rarely sufficient alone in the treatment of dystonias. Further, some patients may be performing exercises that could potentially strengthen the same muscles that are being targeted (to weaken) with Botox; these should be discontinued.
Informing the Patient The success of a program of Botox injections will depend, in large part, on the discussions that occur with the patient before the first injection and the expectations that result from these discussions. Several points should be reviewed with the patient as the possibility of Botox injection is initially addressed. First, realistic expectations of beneficial effects should be brought up. For instance, those with cervical dystonias might expect to achieve neutral head position but not necessarily normal full neck range of motion. Similarly, patients with focal upper-limb dystonias may have improved upper-limb function but may not be able to write or play a musical instrument as they had before the onset of symptoms. Second, potential adverse effects should be reviewed. Typically patients are told that most adverse effects are related to either too much weakness in the muscles injected or weakness in nearby muscles resulting from spread of toxin. The delay in onset of adverse effects is similar to that of the beneficial effects, starting a few days after injection and maximal at 1 to 2 weeks. Examples of adverse effects include dysphagia (resulting from spread to muscles of swallowing) or difficulty holding the head up in the case of cervical dystonias; weakness in other hand muscles after injection for writer's cramp; or breathiness after injection for adductor spasmodic dysphonia. Of course, there are also risks of adverse effects similar to most other injections, such as infection, bleeding, and allergic reaction. Antibody formation, seen especially with higher doses, could reduce the effectiveness of the toxin. Because the cost of the toxin is so high (roughly $350 per 100-unit vial), the total price of the injection is usually brought up in the adverse effect category as well. Third, patients are usually told that there is no exact scientific way to determine how many units should be used in each muscle, or even which combination of muscles should be injected, and that a best guess injection is given at first. Initial results may be only partially effective, and follow-up injections will need to be tailored accordingly. In this regard patients are often encouraged to keep a diary of the results of injection so that they feel a part of the evaluation and decision-making process for modifying and optimizing the injection at the time of the next visit. Fourth, the patients are told they will usually first notice effects of the toxin at 2 to 3 days after injection, and the maximal effect will occur at 1 to 2 weeks. Expected duration of effects (both good and bad) is about 3 to 4 months (occasionally as short as 2 months or as long as 6 months), and repeat injections will be required at regular intervals. Patients should also be reminded that Botox
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injection does not provide a permanent cure, and injections will likely be required for an indefinite period of time. Finally, patients should be told who to contact if problems occur and when to return for follow-up; usually patients are told to call if there are any problems but otherwise to return to the clinic when symptoms recur.
INJECTION TECHNIQUE
Bioactivity The most sensitive way to quantify the bioactivity of Botox is through in vivo assay, although in vitro phrenic nerve-hemidiaphragm preparations have also been used. In the United States, dosages of Botox used for therapeutic purposes are typically measured in international units (abbreviated IU or U). One international unit is the amount that kills 50% of 18 to 20 Swiss-Webster female mice (that is, the LD,,). Dosages can also be measured by weight of the toxin in nanograms (that is, ng or 10-9g),but efficacy will vary using weight as a measure, depending on methods of preparation and storage. For example, 1 ng of the toxin used in Britain typically contains 40 IU, whereas the same weight of the American toxin usually contains only 2.5 IU.lflBased on studies in the monkey, the LD,, for human beings has been estimated to be a single dose of around 3000 to 5000 IU; typical therapeutic dosages for torticollis are in the range of 10% or less of this amount.
Drug Storage and Preparation
Even though Botox is one of the most potent biologic toxins known, it is very heat labile (it was once contemplated for chemical warfare programs but, because of its heat lability, was considered a poor choice). Botox needs to be kept frozen at colder than -5°C in lyophilized form until just before its use. The lyophilized toxin is supplied in 100-IU vials. Once thawed and dissolved, it must be kept refrigerated at Z°C to 8°C and used within 4 hours. Any unused drug should be discarded. After the patient is evaluated and the decision is made to perform the injection, the toxin is removed from the freezer and reconstituted into an appropriate volume. As stated in the drug information pamphlet included with the toxin, one should use normal saline without bacteriostatic agents as a diluent because the benzyl alcohol in preserved normal saline inactivates the toxin. The concentration of the solution is based on practical concerns such as the total injection volume and units needed per muscle. A variety of dilutions can be used, but the authors have found a dilution of 4 mL per 100-unit vial to be useful; this provides 25 IU per mL. When injecting normal saline into the bottle, one must be careful to instill the saline slowly and gently, avoiding bubbling or violent agitation, because foaming denatures the toxin and results in a loss of biologic activity. This requires strong distraction on the syringe to ensure a slow drip of saline into the vacuum-prepared bottle. If the reconstituted solution is not clear, colorless, and free of particulate matter or if no vacuum is present during reconstitution, the vial should not be used and should be returned to the manufacturer.
BOTULINUM TOXIN INJECTIONS
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Deciding Which Muscles to Inject The decision of which muscles to inject is often difficult, but remains critical to performing a successful injection. Usually four findings are used to decide on initial injections. First, the patient's neck position (for cervical dystonias) or limb position (limb dystonias) is evaluated. Many times it is helpful to ask the patient to perform the activity that causes symptoms, such as writing (for writer's cramp) or playing a musical instrument. Second, muscles are palpated to determine which muscles are most active. Third, areas of pain or pulling are reviewed because these are often areas of strong muscle activity. Fourth, based on the first three findings, needle EMG activity is used to determine the relative contribution of each muscle sampled to the abnormal movement or posture. The EMG is usually the most reliable because deeper muscles are often not palpable or visible. With patients coming for repeat injections, time is also spent finding out which areas were not helped by the last dose and might need further attention. EMG Recordings Although some investigators do not use EMG recordings during injection, there are studies in the literature documenting a superior effect with simultaneous recording, as opposed to blind injection^.^ There are a number of 27-gauge injection needles commercially available for injection that are Teflon coated except for the tip and allow for EMG recording. Usually a wire is already attached to the disposable needle, but a clip may be used if needed. A conventional electromyograph is used for recording, but recording parameters differ from those of conventional diagnostic EMG. The low-frequency filter is raised to at least 100 Hz (usually 300 Hz) to reduce volume conduction from distant muscles as well as baseline wander from needle and wire movement. The sweep speed is slowed to 50 or 100 msecldiv to allow inspection of patterns of muscle activity, such as bursts that coincide with rotational tremor of the neck; individual motor unit inspection (usually done at faster sweep speeds) is usually of little importance. The level of muscle activity is judged subjectively by the examiner. The patient is instructed to let his or her head or limb assume its natural position (that is, not to fight any abnormal posture). When areas of muscles with high levels of electrical activity are encountered and motor unit potentials appear and sound sharp, injection is performed.
Injection The actual injection of the toxin is not substantially different from other intramuscular injections. Once well-defined, crisp, EMG activity is recorded from the needle tip, aspiration is attempted to avoid injection into a vascular structure and up to 0.5 mL is slowly injected. Usually EMG activity is decreased as soon as the injection is started, but this may be caused by the mechanical effects of the solution expanding the muscle away from the needle tip, rather than an immediate effect of the toxin.
Follow-up and Interpreting Results Usually no specific early follow-up is needed after a Botox injection unless adverse reactions occur. Most patients are told to make an appointment when
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symptoms start to recur, which often occurs at about 3 months. Only occasionally are patients asked to call or visit earlier, when it is thought clinically helpful to see patients during maximal effect of the toxin. Obviously, if one only relies on seeing patients when they need another injection, one will not observe the beneficial effects of the toxin and will need to rely on the patient's report only. Suboptimal results are usually related to too little or too much injected toxin, injection into the wrong muscle(s), or spread of toxin into other muscles. When too little effect has been produced and it is thought that too little toxin was injected, it is often best to wait at least 1 month before additional injections in order to reduce the risk of antibody formation. Rapid successive (that is, less than 1 month apart) injections may increase this risk. When the use of too much toxin produces excessive weakness, patients can be counseled that this will wear off and a lower dose can be used next time; for dysphagia, referral to a speech pathologist may be necessary. Injection into the wrong muscles should be suspected if the injected muscles are weak but symptoms persist. A common example is that of cervical dystonia when the sternocleidomastoid is adequately injected, but symptoms persist because of levator scapulae activity. Spread of toxin into other nearby muscles cannot always be avoided; hence, dysphagia may be a consequence of injection for cervical dystonia. Despite using the best localizing technique, a finite risk of spread of toxin exists. There are also, of course, the usual risks associated with any injection such as infection, bleeding, and pneumothorax.
CONCLUSION Botox is a successful treatment for a number of dystonic conditions including cervical dystonias, spasmodic dysphonia, hemifacial spasm, blepharospasm, and limb dystonia. Other uses, such as for focal spasticity, may also be developed. Although there is a good deal of scientific evidence to support the use of Botox for these conditions, appropriate patient selection and strict attention to the details of injection technique will optimize the beneficial effects.
References
1. Blackie JD, Lees AJ: Botulinum toxin treatment in spasmodic torticollis. J Neurol Neurosurg Psychiatry 53:640-643, 1990 2. Brin MF, Fahn S, Moskowitz C, et al: Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 2237-254, 1987 3. Clark JB: Cervical dystonia following exposure to high G forces. Aviat Space Environ Med 61:935-937, 1990 4. Comella CL, Buchman AS, Tanner CM, et al: Botulinum toxin injection for spasmodic of benefit with electromyographic assistance. Neuroltorticollis: Increased mamitude ogy 42:87&882, 1992 5. Deuschl G, Heinen F, Kleedorfer B, et al: Clinical and polymyographic investigation of svasmodic torticollis. T Neurol239:9-15, 1992 6. ~ u i n DD: e Spasmodic torticollis. In Jankovic J, Tolosa E (ed):Facial Dyskinesias. New York, Raven Press, 1988, pp 135-150 7. Dubinsky RM, Gray CS, Vetere OB, et al: Electromyographic guidance of botulinum toxin treatment in cervical dystonia. Clin Neuropharmacol 14:262-267, 1991 8. Erbguth F, Kilian KD, Claus D, et al: Treatment of spasmodic torticollis with local injections of botulinum toxin A. Dtsch Med Wochenschr 116:567-572, 1991
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9. Greene P, Kang U, Fahn S, et al: Double blind, placebo controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 40:1215-1218,1990 10. Jankovic J, Brin MF: Therapeutic uses of botulinum toxin. N Engl J Med 324:11861194, 1991 11. Jankovic J, Fahn S: Dystonic syndromes. In Jankovic J, Tolosa E (eds): Parkinson's Disease and Movement Disorders. Baltimore, Urban & Schwarzenberg, 1988, pp 283314 12. Jankovic J, Schwartz K, Donovan DT: Botuliium toxin treatment of cranial cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 53:633439, 1990 13. Jankovic J, Leder S, Warner D, et al: Cervical dystonia: Clinical findings and associated movement disorders. Neurology 41:1088-1091, 1991 14. Jankovic J, Orman J: Botulinum A toxin for cranial cervical dystonia: A double blind, placebo controlled study. Neurology 37:616423, 1987 15. Koller W, Vetere OB, Gray C, et al: Failure of fixed dose, fixed muscle injection of botulinum toxin in torticollis. Clin Neuropharmacol 13:355-358, 1990 16. 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 6:145-150, 1991 17. Moore AP, Blurnhardt LD: A double blind trial of botulinum toxin "A" in torticollis, with one year follow up. J Neurol Neurosurg Psychiatry 54813-816, 1991 18. Poewe W, Schelosky L, Kleedorfer B, et al: Treatment of spasmodic torticollis with local injections of botulinum toxin. One year follow up in 37 patients. J Neurol 239:21-25, 1992 19. Robinson LR, Hillel AD: Botulinum toxin treatment for motor control disorders. Phys Med Rehabil Clin North Am 4:731-744, 1993 20. Stell R, Thompson PD, Marsden CD: Botulinum toxin in spasmodic torticollis. J Neurol Neurosurg Psychiatry 51:920-923, 1988 21. Truong DD, Dubinsky R, Hermanowicz N: Posttraumatic torticollis. Arch Neurol 48:221-223. 1991 Address reprint requests to Lawrence R. Robinson, MD Rehabilitation Medicine, Room 4C-29, Box 359740 Harborview Medical Center 325 Ninth Avenue Seattle, WA 98104
+ .20
BOTULINUM TOXIN INJECTIONS Lawrence R. Robinson, MD, and Leilei Wang, MD, PhD
A number of excellent articles have reviewed the basic science and some of the clinical principles behind the use of botulinum toxin type A (Botox) for the use of motor control disorder^.'^-'^, 14. l9 Hence, this article reviews some of the common clinical applications and then predominantly addresses the techniques of Botox injection. CLINICAL APPLICATIONS OF BOTOX INJECTION
Therapeutic Botox injection is primarily useful for treatment of various types of focal dystonia, including spasmodic torticollis, spasmodic dysphonia, blepharospasm, orofacial dystonia (Meige syndrome), and hemifacial spasm (which is caused by a different pathophysiology than the other dystonias). As of this writing, the Food and Drug Administration (FDA) has not yet approved Botox for all of these uses, although it is approved for blepharospasm, hemifacial spasm, strabismus, and other facial nerve disorders. Some patients with focal manifestations of upper motor neuron syndromes, such as stroke or multiple sclerosis, in whom one or a few muscles are affected, may also benefit from Botox injection. Botox is probably not useful, however, for disorders in which there is diffuse (rather than focal) hyperactivity in large muscles, for example, generalized limb spasticity or Parkinson's disease. With injection of increasing numbers of large muscles, the total dose required increases the risk of adverse effects, increases the costs, and consequently makes the treatment impractical. One of the more common dystonias physiatrists are likely to encounter is spasmodic torticollis, more accurately described as cervical dystonia. The pathophysiology of this disorder is not well known, in part because few people die of the disorder and there is not a good animal model of the disease. There is a variety of evidence that supports involvement of the brain stem or basal
From the Department of Rehabilitation Medicine, University of Washington School of Medicine, and Harborview Medical Center, Seattle (LRR); and Rehabilitation and Spine Center, P.S., Everett (LW),Washington PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA VOLUME 6 NUMBER 4 NOVEMBER 1995
897
898
ROBINSON & WANG
ganglia or both." Some patients will report that trauma, surgery, cervical radiculopathy, hypertension, emotional stress, or thyroid disease3h, 21 were associated with the start of symptoms. Although neck rotation is common, many patients also have flexion or extension and lateral tilting. Multiple muscles, not just sternocleidomastoid, are usually involved. For this reason the term cervical dystonia is often preferred.13 In our experience, commonly involved muscles include sternocleidomastoid, levator scapulae, splenius capitus, and cervical paraspinal muscles, and trapezius. Polymyographic recordings have been used to identify specific muscle groups in individual patients: although this is not usually especially helpful for diagnosis or treatment. In addition to abnormal posturing, pain is a common complaint in this patient population group, and is reported in up to 6896 of such patients.13Infrequently, about 10% of the time, the cervical dystonias are associated with other dystonias such as blepharospasm, spasmodic dysphonia, or orofacial dystonia (Meige syndrome), perhaps suggesting a common etiology l3 for these di~eases.~, A number of studies, including several well-done double-blind randomized trials, have shown the value of Botox in the treatment of spasmodic torticollis.', 2, 4, 7, 9, 12, 13, 20 The rate of success in relieving pain and reducing abnormal posturing approaches 90%; more than 80% of patients report a 50% or better impro~ement.~ Although there is some controversy regarding the use of electromyography (EMG) during injection, many, including ourselves, have found this to be very valuable in helping to identify which muscles to inject and to locate actively contracting m ~ s c l eA . ~study from Comella et a14 randomized 52 patients with spasmodic torticollis to one of two groups: (1) EMG-guided injection in which muscles were selected for Botox injection using both clinical and EMG examination and then injected with EMG assistance, and (2) clinically guided injection in which muscles were selected for Botox injection based solely on clinical examination and injected without EMG assistance. Although the percentage of patients showing any improvement after Botox was similar in both groups, a significantly greater magnitude of improvement was present in the group who had injections under EMG guidance. Dosages and the selection of muscles to be injected need to be decided individually for each patient and reassessed with each injection. Not only are the patterns of muscle overactivity very variable between patients but also these may change from month to month in the same patient. A trial using fixed doses applied to the sternocleidomastoid and trapezius muscles failed to show much in the way of objective changes,15 suggesting that EMG guidance and use of individualized protocols is preferable to a standard protocol for every patient. GENERAL PRINCIPLES OF BOTOX USE Evaluating the Patient
A thorough patient evaluation is required before injection. Obviously, inadequate patient evaluation or inappropriate patient selection will produce poor results and may ultimately do harm to the patient. Most importantly, the diagnosis needs to be convincingly established and other (malignant or reversible) causes of dystonia ruled out (for example, brain stem tumor or Wilson's disease). In our center, this usually involves comprehensive assessment by a
BOTULINUM TOXIN INJECTIONS
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neurologist, though it is not always necessary to perform any other laboratory studies (for example, magnetic resonance imaging [MRI]) on every patient. Review of other forms of therapy, such as medications or physical therapy, should also be done before injection. For patients taking narcotics or benzodiazapenes, it is often helpful to plan ahead of time how these medications will be managed once Botox will have taken effect. Physical therapy for muscular relaxation is often of moderate symptomatic help as an adjunct to Botox injections but is rarely sufficient alone in the treatment of dystonias. Further, some patients may be performing exercises that could potentially strengthen the same muscles that are being targeted (to weaken) with Botox; these should be discontinued.
Informing the Patient The success of a program of Botox injections will depend, in large part, on the discussions that occur with the patient before the first injection and the expectations that result from these discussions. Several points should be reviewed with the patient as the possibility of Botox injection is initially addressed. First, realistic expectations of beneficial effects should be brought up. For instance, those with cervical dystonias might expect to achieve neutral head position but not necessarily normal full neck range of motion. Similarly, patients with focal upper-limb dystonias may have improved upper-limb function but may not be able to write or play a musical instrument as they had before the onset of symptoms. Second, potential adverse effects should be reviewed. Typically patients are told that most adverse effects are related to either too much weakness in the muscles injected or weakness in nearby muscles resulting from spread of toxin. The delay in onset of adverse effects is similar to that of the beneficial effects, starting a few days after injection and maximal at 1 to 2 weeks. Examples of adverse effects include dysphagia (resulting from spread to muscles of swallowing) or difficulty holding the head up in the case of cervical dystonias; weakness in other hand muscles after injection for writer's cramp; or breathiness after injection for adductor spasmodic dysphonia. Of course, there are also risks of adverse effects similar to most other injections, such as infection, bleeding, and allergic reaction. Antibody formation, seen especially with higher doses, could reduce the effectiveness of the toxin. Because the cost of the toxin is so high (roughly $350 per 100-unit vial), the total price of the injection is usually brought up in the adverse effect category as well. Third, patients are usually told that there is no exact scientific way to determine how many units should be used in each muscle, or even which combination of muscles should be injected, and that a best guess injection is given at first. Initial results may be only partially effective, and follow-up injections will need to be tailored accordingly. In this regard patients are often encouraged to keep a diary of the results of injection so that they feel a part of the evaluation and decision-making process for modifying and optimizing the injection at the time of the next visit. Fourth, the patients are told they will usually first notice effects of the toxin at 2 to 3 days after injection, and the maximal effect will occur at 1 to 2 weeks. Expected duration of effects (both good and bad) is about 3 to 4 months (occasionally as short as 2 months or as long as 6 months), and repeat injections will be required at regular intervals. Patients should also be reminded that Botox
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ROBINSON & WANG
injection does not provide a permanent cure, and injections will likely be required for an indefinite period of time. Finally, patients should be told who to contact if problems occur and when to return for follow-up; usually patients are told to call if there are any problems but otherwise to return to the clinic when symptoms recur.
INJECTION TECHNIQUE
Bioactivity The most sensitive way to quantify the bioactivity of Botox is through in vivo assay, although in vitro phrenic nerve-hemidiaphragm preparations have also been used. In the United States, dosages of Botox used for therapeutic purposes are typically measured in international units (abbreviated IU or U). One international unit is the amount that kills 50% of 18 to 20 Swiss-Webster female mice (that is, the LD,,). Dosages can also be measured by weight of the toxin in nanograms (that is, ng or 10-9g),but efficacy will vary using weight as a measure, depending on methods of preparation and storage. For example, 1 ng of the toxin used in Britain typically contains 40 IU, whereas the same weight of the American toxin usually contains only 2.5 IU.lflBased on studies in the monkey, the LD,, for human beings has been estimated to be a single dose of around 3000 to 5000 IU; typical therapeutic dosages for torticollis are in the range of 10% or less of this amount.
Drug Storage and Preparation
Even though Botox is one of the most potent biologic toxins known, it is very heat labile (it was once contemplated for chemical warfare programs but, because of its heat lability, was considered a poor choice). Botox needs to be kept frozen at colder than -5°C in lyophilized form until just before its use. The lyophilized toxin is supplied in 100-IU vials. Once thawed and dissolved, it must be kept refrigerated at Z°C to 8°C and used within 4 hours. Any unused drug should be discarded. After the patient is evaluated and the decision is made to perform the injection, the toxin is removed from the freezer and reconstituted into an appropriate volume. As stated in the drug information pamphlet included with the toxin, one should use normal saline without bacteriostatic agents as a diluent because the benzyl alcohol in preserved normal saline inactivates the toxin. The concentration of the solution is based on practical concerns such as the total injection volume and units needed per muscle. A variety of dilutions can be used, but the authors have found a dilution of 4 mL per 100-unit vial to be useful; this provides 25 IU per mL. When injecting normal saline into the bottle, one must be careful to instill the saline slowly and gently, avoiding bubbling or violent agitation, because foaming denatures the toxin and results in a loss of biologic activity. This requires strong distraction on the syringe to ensure a slow drip of saline into the vacuum-prepared bottle. If the reconstituted solution is not clear, colorless, and free of particulate matter or if no vacuum is present during reconstitution, the vial should not be used and should be returned to the manufacturer.
BOTULINUM TOXIN INJECTIONS
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Deciding Which Muscles to Inject The decision of which muscles to inject is often difficult, but remains critical to performing a successful injection. Usually four findings are used to decide on initial injections. First, the patient's neck position (for cervical dystonias) or limb position (limb dystonias) is evaluated. Many times it is helpful to ask the patient to perform the activity that causes symptoms, such as writing (for writer's cramp) or playing a musical instrument. Second, muscles are palpated to determine which muscles are most active. Third, areas of pain or pulling are reviewed because these are often areas of strong muscle activity. Fourth, based on the first three findings, needle EMG activity is used to determine the relative contribution of each muscle sampled to the abnormal movement or posture. The EMG is usually the most reliable because deeper muscles are often not palpable or visible. With patients coming for repeat injections, time is also spent finding out which areas were not helped by the last dose and might need further attention. EMG Recordings Although some investigators do not use EMG recordings during injection, there are studies in the literature documenting a superior effect with simultaneous recording, as opposed to blind injection^.^ There are a number of 27-gauge injection needles commercially available for injection that are Teflon coated except for the tip and allow for EMG recording. Usually a wire is already attached to the disposable needle, but a clip may be used if needed. A conventional electromyograph is used for recording, but recording parameters differ from those of conventional diagnostic EMG. The low-frequency filter is raised to at least 100 Hz (usually 300 Hz) to reduce volume conduction from distant muscles as well as baseline wander from needle and wire movement. The sweep speed is slowed to 50 or 100 msecldiv to allow inspection of patterns of muscle activity, such as bursts that coincide with rotational tremor of the neck; individual motor unit inspection (usually done at faster sweep speeds) is usually of little importance. The level of muscle activity is judged subjectively by the examiner. The patient is instructed to let his or her head or limb assume its natural position (that is, not to fight any abnormal posture). When areas of muscles with high levels of electrical activity are encountered and motor unit potentials appear and sound sharp, injection is performed.
Injection The actual injection of the toxin is not substantially different from other intramuscular injections. Once well-defined, crisp, EMG activity is recorded from the needle tip, aspiration is attempted to avoid injection into a vascular structure and up to 0.5 mL is slowly injected. Usually EMG activity is decreased as soon as the injection is started, but this may be caused by the mechanical effects of the solution expanding the muscle away from the needle tip, rather than an immediate effect of the toxin.
Follow-up and Interpreting Results Usually no specific early follow-up is needed after a Botox injection unless adverse reactions occur. Most patients are told to make an appointment when
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symptoms start to recur, which often occurs at about 3 months. Only occasionally are patients asked to call or visit earlier, when it is thought clinically helpful to see patients during maximal effect of the toxin. Obviously, if one only relies on seeing patients when they need another injection, one will not observe the beneficial effects of the toxin and will need to rely on the patient's report only. Suboptimal results are usually related to too little or too much injected toxin, injection into the wrong muscle(s), or spread of toxin into other muscles. When too little effect has been produced and it is thought that too little toxin was injected, it is often best to wait at least 1 month before additional injections in order to reduce the risk of antibody formation. Rapid successive (that is, less than 1 month apart) injections may increase this risk. When the use of too much toxin produces excessive weakness, patients can be counseled that this will wear off and a lower dose can be used next time; for dysphagia, referral to a speech pathologist may be necessary. Injection into the wrong muscles should be suspected if the injected muscles are weak but symptoms persist. A common example is that of cervical dystonia when the sternocleidomastoid is adequately injected, but symptoms persist because of levator scapulae activity. Spread of toxin into other nearby muscles cannot always be avoided; hence, dysphagia may be a consequence of injection for cervical dystonia. Despite using the best localizing technique, a finite risk of spread of toxin exists. There are also, of course, the usual risks associated with any injection such as infection, bleeding, and pneumothorax.
CONCLUSION Botox is a successful treatment for a number of dystonic conditions including cervical dystonias, spasmodic dysphonia, hemifacial spasm, blepharospasm, and limb dystonia. Other uses, such as for focal spasticity, may also be developed. Although there is a good deal of scientific evidence to support the use of Botox for these conditions, appropriate patient selection and strict attention to the details of injection technique will optimize the beneficial effects.
References
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9. Greene P, Kang U, Fahn S, et al: Double blind, placebo controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 40:1215-1218,1990 10. Jankovic J, Brin MF: Therapeutic uses of botulinum toxin. N Engl J Med 324:11861194, 1991 11. Jankovic J, Fahn S: Dystonic syndromes. In Jankovic J, Tolosa E (eds): Parkinson's Disease and Movement Disorders. Baltimore, Urban & Schwarzenberg, 1988, pp 283314 12. Jankovic J, Schwartz K, Donovan DT: Botuliium toxin treatment of cranial cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 53:633439, 1990 13. Jankovic J, Leder S, Warner D, et al: Cervical dystonia: Clinical findings and associated movement disorders. Neurology 41:1088-1091, 1991 14. Jankovic J, Orman J: Botulinum A toxin for cranial cervical dystonia: A double blind, placebo controlled study. Neurology 37:616423, 1987 15. Koller W, Vetere OB, Gray C, et al: Failure of fixed dose, fixed muscle injection of botulinum toxin in torticollis. Clin Neuropharmacol 13:355-358, 1990 16. 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 6:145-150, 1991 17. Moore AP, Blurnhardt LD: A double blind trial of botulinum toxin "A" in torticollis, with one year follow up. J Neurol Neurosurg Psychiatry 54813-816, 1991 18. Poewe W, Schelosky L, Kleedorfer B, et al: Treatment of spasmodic torticollis with local injections of botulinum toxin. One year follow up in 37 patients. J Neurol 239:21-25, 1992 19. Robinson LR, Hillel AD: Botulinum toxin treatment for motor control disorders. Phys Med Rehabil Clin North Am 4:731-744, 1993 20. Stell R, Thompson PD, Marsden CD: Botulinum toxin in spasmodic torticollis. J Neurol Neurosurg Psychiatry 51:920-923, 1988 21. Truong DD, Dubinsky R, Hermanowicz N: Posttraumatic torticollis. Arch Neurol 48:221-223. 1991 Address reprint requests to Lawrence R. Robinson, MD Rehabilitation Medicine, Room 4C-29, Box 359740 Harborview Medical Center 325 Ninth Avenue Seattle, WA 98104