Effectiveness of repeated treatment with botulinum toxin type A across different conditions.Abstract: This review assessed the overall effectiveness of repeated treatments with botulinum toxin type A botulinum toxin type A
Botox, Botox Cosmetic, Dysport (UK), Vistabel (UK)
Pharmacologic class: Neurotoxin
Therapeutic class: Neuromuscular blocker
Pregnancy risk category C
Action(BoNTA) across different conditions, as documented in the published literature. Forty-four original research articles reporting on 16 different conditions were identified that included data on the duration or efficacy of multiple treatments with BoNTA. All of the 44 studies found sustained or enhanced improvement in efficacy and/or duration over the follow-up period, which ranged from a few treatments to more than 10 years. Dosages did not change over time in 22 of the studies, increased in 4 studies, were not reported over time in 17 studies, and tended to increase then decrease in one study. Seven studies reported a statistically significant increase in the efficacy or duration of BoNTA over time. Results suggest that continued benefit with repeated BoNTA treatment is widely reported in the literature.
Key Words: muscle tone, dystonia dystonia /dys·to·nia/ (-to´ne-ah) dyskinetic movements due to disordered tonicity of muscle.dyston´ic
dystonia musculo´rum defor´mans , spasticity spasticity /spas·tic·i·ty/ (spas-tis´i-te) the state of being spastic; see spastic (2).
1. A spastic state or condition.
2. Spastic paralysis. , cerebral palsy cerebral palsy (sərē`brəl pôl`zē), disability caused by brain damage before or during birth or in the first years, resulting in a loss of voluntary muscular control and coordination.
Botulinum toxin type A (BoNTA) is a focal, injectable in·ject·a·ble
Capable of being injected. Used of a drug.
A drug or medicine that can be injected. therapeutic that is important in the treatment of certain conditions of increased or aberrant aberrant /ab·er·rant/ (ah-ber´ant) (ab´ur-ant) wandering or deviating from the usual or normal course.
1. muscular activity, such as focal dystonias, focal spasticity, glabellar lines, and some urologic and gastrointestinal disorders. (1,2) Botulinum toxin type A has also been used for the treatment of disorders that are not strictly neuromuscular neuromuscular /neu·ro·mus·cu·lar/ (-mus´ku-ler) pertaining to nerves and muscles, or to the relationship between them.
1. , such as headache and musculoskeletal musculoskeletal /mus·cu·lo·skel·e·tal/ (-skel´e-t'l) pertaining to or comprising the skeleton and muscles.
Relating to or involving the muscles and the skeleton. pain, (3,4) and is an established treatment for focal hyperhidrosis. (5)
Botulinum toxin type A acts by inhibiting the release of acetylcholine acetylcholine (əsēt'əlkō`lēn), a small organic molecule liberated at nerve endings as a neurotransmitter. It is particularly important in the stimulation of muscle tissue. from neuromuscular and autonomic autonomic /au·to·nom·ic/ (aw?to-nom´ik) not subject to voluntary control. See under system.
1. Functionally independent; not under voluntary control. cholinergic fibers cholinergic fiber
Any of the nerve fibers that transmit impulses to other nerve cells or to muscle fibers or gland cells by acetylcholine. in the local region of injection. (6-8) These actions form the basis for its effects in neuromuscular conditions and hypersecretory disorders. However, recent evidence also suggests that botulinum toxin type A inhibits the release of selected neuropeptides neuropeptides (ner·ō·pepˑ·tīdz),
n.pl endogenous protein molecules that influence neural activity by carrying information directly to the cells and tissues. , (9,10) which has been suggested as a possible mechanism for its effects on headache/migraine and musculoskeletal pain. (10,11)
Treatment with botulinum toxin type A typically produces temporary and reversible clinical effects. This temporary action allows treatment to be individualized in·di·vid·u·al·ize
tr.v. in·di·vid·u·al·ized, in·di·vid·u·al·iz·ing, in·di·vid·u·al·iz·es
1. To give individuality to.
2. To consider or treat individually; particularize.
3. for each patient based on clinical need (eg, adjustments in doses and/or injection sites). Studies have shown that repeated treatments are usually necessary to maintain benefit in chronic conditions.
Over the years, botulinum toxin type A has proven to be an extremely useful long-term treatment for focal dystonias, providing consistent benefit to the majority of patients following repeated injections. (12-14) Long-term studies of botulinum toxin type A treatment for adult spasticity, cerebral palsy, and glabellar lines are just beginning to appear in the literature. (2,15,16) As botulinum toxin type A gains importance as a treatment for these and other chronic conditions, it is critical to determine its long-term effectiveness to provide a basis for the long-term expectations and plans of patients, practitioners, and payer organizations. This review examines the literature on repeated botulinum toxin type A injections across different disorders and conditions.
The following search terms were used to identify clinical studies from the MEDLINE The online medical database of the U.S. National Library of Medicine (NLM) whose parent is the National Institutes of Health, Bethesda, MD. MEDLINE contains millions of articles from thousands of medical journals and publications. The consumer section of the site (http://medlineplus. , EMBase, Biosis, SciSearch, JICST JICST Japan Information Center of Science and Technology , and Pascal databases: botulinum toxin type A or BOTOX. Abstracts and non-English language studies were excluded. From this list, original research articles were identified in which patients received multiple botulinum toxin type A injections and the authors either summarized or presented data on the duration or efficacy of repeated injections. A number of long-term or repeated treatment studies were excluded because data were not presented, or were not separated, by treatment. (17-33) Several other studies were excluded because they used outcome measures that were not classifiable as clinical efficacy or duration measures. (34-37) Articles that examined the disposition of patients treated with botulinum toxin type A over time but did not include efficacy or duration data were grouped and considered separately.
Although several different formulations of botulinum bot·u·li·num or bot·u·li·nus
An anaerobic, rod-shaped bacterium (Clostridium botulinum) that secretes botulin and inhabits soils. neurotoxins are available in various countries, each has a unique clinical profile and dosing requirements and is non-interchangeable with the others. (38) For this reason, we have confined our review to a single botulinum toxin type A preparation (BOTOX[TM]; Allergan), which has been examined in a large number of published studies; doses refer specifically to this product.
Studies with Data on Repeated Treatments
A total of 44 original research studies were identified in the literature that included data on the duration or efficacy of repeated injections of botulinum toxin type A. In all of these studies, the benefits of repeated botulinum toxin type A treatments were sustained or increased over the follow-up period (Table 1). In approximately half of these studies (21 of 44), statistics were used to determine whether efficacy or duration changed over time (Table 1). The definition of efficacy varied by study and condition but remained consistent over time within any given report. Most studies defined duration as the interval between treatments (Table 2). Doses were constant or did not change significantly over time in 22 of the 44 studies (Table 1). Seventeen additional studies did not report doses over time. Doses increased over time in 4 of the studies. (44,58,64,67) One additional study (53) listed doses that appeared to initially increase then slightly decrease over time. One of the studies that reported consistent doses over time for two subgroups of patients reported a decrease followed by an increase over time for one other subgroup of patients. (56)
Seven of the studies reviewed here reported a statistically significant increase in the efficacy or duration of botulinum toxin type A over time. (2,3,15,16,44,63,68) Doses remained constant in all of these studies, except one in which the lower dose was associated with an increase in duration (44) and another that did not report doses over time. (3) In several other studies, the authors noted a trend toward decreased (43) or increased (50) duration that was not statistically significant. In several additional studies, our examination of the data suggested a trend toward enhanced improvement, but the authors did not offer this interpretation. (66,76)
The studies followed patients for varying time periods ranging from a few treatments to more than 10 years of treatment, and spanned 16 different conditions (Table 1). Seventeen studies followed patients (or a subgroup of patients) for more than an average of 4 treatments, and most of these (12 of 17; 71%) included patients with dystonias or hemifacial spasm Hemifacial spasm or HFS is a neurological disorder in which blood vessels constrict the seventh cranial nerve and cause varying degrees of facial spasming, typically originating around the eye of the afflicted side of the face. (Table 1). However, several studies that followed patients for 6 treatments or more included individuals with adult spasticity, spastic spastic /spas·tic/ (spas´tik)
1. of the nature of or characterized by spasms.
2. hypertonic, so that the muscles are stiff and movements awkward.
1. cerebral palsy, and chronic tension-type headache Tension-type headache
A dull pain that seems to exert pressure on the head; the most common form of headache.
Mentioned in: Cluster Headache . (3,15,16) Although most of the studies included 50 patients or fewer, 15 followed more than 100 patients and 6 followed more than 200 patients over the course of repeated treatments (Table 1).
The studies could be generally grouped into 2 categories. In the first type, patients in the study had received varying numbers of treatments and thus different numbers of patients were included at each time point in the analysis of long-term effects. The reasons for this variability in N values at each time point included inter-individual variations in duration, patients discontinuing the study, patient accrual, patients lost to follow up, no further need for treatments, or other factors (Table 1). For instance, many of the studies were reviews of all patients at a single clinic or prospective studies of consecutive patients who had received BoNTA treatment for a given condition (see patient sample column in Table 1). At the time of analysis, patients had been treated for different lengths of time and this is reflected in the different numbers of patients at the different time points. The second type of study involved the assessment of the same subgroup of patients after multiple treatments (Table 1). Some studies in the first category analyzed the data for a subgroup of patients who had all received the same number of treatments (Table 1). (12,39,51,52,59,60,63) Still other studies recruited patients to specific inclusion/exclusion criteria inclusion/exclusion criteria Clinical research The medical or social reasons why a person may/may not qualify for participation in a clinical trial (Table 1). Many studies did not report how they selected patients for inclusion in the study (Table 1).
Studies of Patient Disposition
Five studies were identified that followed the disposition of patients treated with botulinum toxin type A to determine whether or not they continued treatment over time (Table 3). (77-81) Results of these studies indicate that the majority of patients with blepharospasm bleph·a·ro·spasm
Spasmodic winking caused by the involuntary contraction of an eyelid muscle.
spasm of the orbicularis oculi muscle of the eyelid. , cervical dystonia cervical dystonia Spasmodic torticollis, see there , Meige syndrome Meige syndrome Neurology A movement disorder characterized by blepharospasm, oromandibular dystonia, sometimes spasmodic dysphonia, See Blepharospasm. , and hemifacial spasm continued botulinum toxin type A treatment--some up to 11 years or until death of unrelated causes (Table 3). In contrast, the single study of patients with focal hand dystonia found that most patients discontinued treatment over the course of 2 years. (81)
Discussion and Implications
All of the 44 studies reviewed here that examined the effects of repeated botulinum toxin type A treatments found sustained or enhanced improvement over the follow-up period, which ranged from a few treatments to more than 10 years of treatment. The consistent benefits were not due to increasing doses over time, as the majority of studies found no significant change in doses, although 17 of the studies did not report whether doses were consistent over time. The results of these studies spanned 16 different conditions, suggesting that the continued benefit with repeated injections is widely applicable. The consistent benefits of botulinum toxin type A are particularly well documented for hemifacial spasm and the craniocervical dystonias, and are buttressed but·tress
1. A structure, usually brick or stone, built against a wall for support or reinforcement.
2. Something resembling a buttress, as:
a. The flared base of certain tree trunks.
b. by studies of patient disposition over time. Spastic cerebral palsy and adult spasticity were also well represented in this review, with studies documenting consistent or enhanced benefits from approximately 4 to 6 treatments with botulinum toxin type A.
An exception to the consistent improvement observed across most of the conditions may be in the treatment of focal hand dystonias. We found only one study that followed writer's cramp writ·er's cramp
A cramp or spasm of the muscles of the fingers, hand, and forearm during writing.
writer's cramp patients over multiple treatments. (81) In this study, 24 of the 37 patients discontinued botulinum toxin type A treatment over time, with reasons for discontinuation dis·con·tin·u·a·tion
A cessation; a discontinuance.
Noun 1. discontinuation - the act of discontinuing or breaking off; an interruption (temporary or permanent)
discontinuance cited as no benefit (n = 5), inadequate improvement in hand performance (n = 7), loss of response (n = 4), dystonia no longer a problem (n = 3), and other reasons (n = 5).
Although several studies of patients with achalasia Achalasia Definition
Achalasia is a disorder of the esophagus that prevents normal swallowing.
Achalasia affects the esophagus, the tube that carries swallowed food from the back of the throat down into the stomach. met the inclusion criteria
Inclusion criteria are a set of conditions that must be met in order to participate in a clinical trial. for this review, achalasia is clearly different from the other conditions studied here in that many patients require only a single treatment over the course of 2 years. (70,72) Thus, data are reported in the achalasia studies as the numbers of patients who underwent multiple treatments to control their symptoms instead of mean scores for efficacy or duration, as is the case for the other conditions.
Enhanced Benefit with Repeated Treatments
Seven of the studies reviewed here found a significant enhancement in patient response over the course of repeated treatments. There are several possible explanations for these findings. Carryover effects from the previous injection are possible, as many patients return for reinjection before their symptoms return to baseline. The remaining subclinical subclinical /sub·clin·i·cal/ (sub-klin´i-k'l) without clinical manifestations.
Not manifesting characteristic clinical symptoms. Used of a disease or condition. amount of muscle relaxation may add to the relaxation produced by the next injection, enhancing its apparent effect. This explanation may be tenable ten·a·ble
1. Capable of being maintained in argument; rationally defensible: a tenable theory.
2. for subtle enhancements in efficacy but seems unlikely to account for a progressive increase in benefit with each treatment (16,63) or the large increases in duration reported in an adult spasticity study. (15)
Another possible explanation that applies particularly to functional outcome measures is that the patient may adapt to reduced muscle tone over the course of injections and, as a result, may perform better on functional tests. This may be the case in cerebral palsy patients, for whom cumulative functional improvements have been reported in two studies. (16,63) In studies of children, improvements over time are confounded with biologic development and thus cannot be unequivocally attributed to the treatment, particularly in the absence of a parallel control cohort. However, another study found that patients with cerebral palsy who were treated with modalities Modalities
The factors and circumstances that cause a patient's symptoms to improve or worsen, including weather, time of day, effects of food, and similar factors. other than surgery or botulinum toxin Botulinum toxin (botulin)
A neurotoxin made by Clostridium botulinum; causes paralysis in high doses, but is used medically in small, localized doses to treat disorders associated with involuntary muscle contraction and spasms, in addition to strabismus. did not show spontaneous improvement in equinus deformity Deformity
See also Lameness.
Calmady, Sir Richard
born without lower legs. [Br. Lit.: Sir Richard Calmady, Walsh Modern, 84]
embittered young man with club foot seeks fulfillment. [Br. Lit. over seven years. (82) In Garcia Ruiz et al, (16) physical therapy remained constant over the time studied, but Balkrishnan et al (63) did not include physical therapy in their analysis.
Yet another possible explanation for the enhanced benefits over time is that botulinum toxin type A may indirectly alter sensory feedback to the central nervous system. (83-86) In preclinical studies preclinical studies,
n.pl a term used to describe research done before a clinical study. May be laboratory or epidemiologic research. , local injection of botulinum toxin type A has been found to reduce afferent afferent /af·fer·ent/ (af´er-ent)
1. conveying toward a center.
2. something that so conducts, such as a fiber or nerve.
adj. discharge of muscle spindles muscle spindle
A stretch receptor found in vertebrate muscle. , indicating a modulatory effect on sensory feedback. (87) Indirect support for the sensory feedback hypothesis comes from a study of cervical dystonia patients who showed electromyographic changes in the contralateral contralateral /con·tra·lat·er·al/ (-lat´er-al) pertaining to, situated on, or affecting the opposite side.
adj. , uninjected sternocleidomastoid sternocleidomastoid /ster·no·clei·do·mas·toid/ (-kli?do-mas´toid) pertaining to the sternum, clavicle, and mastoid process.
adj. following repeated treatments, but not after a single treatment. (36) However, none of the studies reviewed here reported enhanced benefits in cervical dystonia patients, although we cannot rule out such benefits for a subgroup of patients or subtle effects that were not detected on the broad rating scales (eg, 5-point Likert-type scales) used in most of the studies.
In addition to the potential explanations for enhanced benefit that have already been offered, a psychological/learned component to the enhanced benefits cannot be ruled out in the absence of placebo controls, which none of the studies included.
Implications for Clinically Relevant Neutralizing Antibody neu·tral·iz·ing antibody
An antibody that reacts with an infectious agent, usually a virus, and destroys or inhibits its infectiveness and virulence. Formation
The results of this review further suggest that neutralizing antibody formation is not a clinical issue for most patients undergoing long-term treatment with the preparation of botulinum toxin type A studied here. We base this suggestion on the continued response reported in all of the studies, in addition to the high percentage of patients who remain on treatment in observational studies observational studies,
n.pl an investigational method involving description of the associations be-tween interventions and outcomes. Outcomes research and practice audits are examples of this investigational method. . Neutralizing antibody formation is often associated with decreasing efficacy, and higher doses are needed to maintain benefit. (88) That we did not find decreasing efficacy or higher doses in most studies suggests a relative lack of clinically significant neutralizing antibody formation. In one of the few studies that actually tested for neutralizing antibodies, only 1 of 207 patients was found to be positive for neutralizing antibodies. (66) The patient had received 4 injections of botulinum toxin type A. The low rate of neutralizing antibody formation is supported by those of an ongoing multicenter study of patients with cervical dystonia who have received up to 9 treatments with BoNTA. (89) In this study, 99.5% of 1,036 serum samples from 326 patients have tested negative for neutralizing antibodies, 0.1% have tested positive, and 0.4% have given inconclusive results.
Each type of study used to examine the consistency of botulinum toxin type A effects has particular advantages and disadvantages. Many of the studies included the analysis of different patient numbers at each treatment session. Some of these studies included all patients who presented at a single clinic with a given disorder and thus the results are not limited to a selected subgroup that elected to stay with treatment over the long term (ie, self-selection bias). Other studies recruited a group of patients to participate, some of whom discontinued for a variety of reasons, potentially biasing the analysis toward those who elected to stay with the treatment. In neither case is it possible to conclude that the patients with the fewest treatments would respond the same way as those who received the most treatments. For instance, in some cases, the decreasing patient numbers at each treatment were due to differential need for retreatment (5,66) or continuing accrual into the study (Table 1). Thus, we cannot predict whether patients who have received only a few treatments would respond similarly to those for whom longer-term treatment data are available.
In contrast, following a subgroup of patients over successive treatment sessions permits conclusions about the consistency of benefits in that particular subgroup. However, these conclusions may not be generalized to others with this disorder due to self-selection bias, need for more frequent treatments in the subgroup with a high number of treatments, or other reasons.
Analysis of the treatment history or disposition of all patients may assume that patients would only consistently return for retreatment if they were deriving continued benefit. Such studies do not allow conclusions about whether duration or efficacy remains constant over time, but permit assessment of whether patients remain on long-term treatment in actual clinical practice, which provides information about the broad group of patients who qualify for and receive botulinum toxin type A treatment for a given condition.
It is difficult to overstate the importance of long-term patient responsiveness to botulinum neurotoxin neurotoxin /neu·ro·tox·in/ (noor´o-tok?sin) a substance that is poisonous or destructive to nerve tissue.
See neurolysin. therapy. Treatment failure has both health and financial costs. Additional physician visits and trials of other treatments can be frustrating frus·trate
tr.v. frus·trat·ed, frus·trat·ing, frus·trates
a. To prevent from accomplishing a purpose or fulfilling a desire; thwart: and expensive. Surgery is invasive and, for some indications, irreversible. Moreover, patients may not experience as great a benefit from the alternate therapy or may experience more adverse effects. (90) For instance, the incidence of treatment-related adverse events in a recent controlled trial controlled trial Clinical research A clinical study in which one group of participants receives an experimental drug while the other receives either a placebo or an approved–'gold standard' therapy. See Blinding, Double-blinded. of botulinum toxin type A for the treatment of focal spasticity in adults was 18.8% (n = 64) compared with 17.7% (n = 62) in the placebo group. (91) In a recent open label trial of tizanidine, a drug approved by the FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. for spasticity, 89% of patients experienced at least one adverse event that was deemed possibly related to treatment, including 62% with somnolence somnolence /som·no·lence/ (som´no-lens) drowsiness or sleepiness, particularly in excess.
1. A state of drowsiness; sleepiness.
2. and 32% with dizziness. (92) Although studies with lower and higher adverse event rates can be cited for both drugs, the low rate and localized nature of adverse events with botulinum toxin type A are evident throughout the literature. (93)
Well-designed follow-up studies are important to evaluate the potentially enhanced benefits from successive botulinum injections and their effect on patient quality of life and treatment satisfaction (including factors of convenience, cost, and adverse effects). In some conditions, it may be possible to identify a subgroup of patients who are likely to receive enhanced benefit from repeated treatments, which may then affect treatment decisions.
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The sensory root of a spinal nerve. Also called posterior root.
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Nerve cells in the brain, brain stem, and spinal cord that connect the nervous system and the muscles.
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The institution of measures to protect a person from a disease to which he or she has been, or may be, exposed. Also called preventive treatment. in primary headache Primary headache
A headache that is not caused by another disease or medical condition. Tension headaches are a subtype of primary headache.
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Of, relating to, affecting, or near the larynx. dystonia): a 12-year experience in more than 900 patients. Laryngoscope la·ryn·go·scope
A tubular endoscope that is inserted through the mouth and into the larynx and that is used for examining the interior of the larynx.
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Ptosis is the term used for a drooping upper eyelid. Ptosis, also called blepharoptosis, can affect one or both eyes.
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plural of velum. MF, Richter JE, Wachsberger D, et al. Complexities of managing achalasia at a tertiary referral center: use of pneumatic dilatation dilatation /dil·a·ta·tion/ (dil?ah-ta´shun)
1. the condition, as of an orifice or tubular structure, of being dilated or stretched beyond normal dimensions.
2. the act of dilating or stretching. , Heller myotomy Heller myotomy is a surgical procedure in which the muscles of the cardia (lower esophageal sphincter or LES) are cut, allowing food and liquids to pass to the stomach. It is used to treat achalasia, a disorder in which the lower esophageal sphincter fails to relax properly, making , and botulinum toxin injection. Am J Gastroenterol 2004;99:1029-1036.
29. Neubrand M, Schcurlen C, Schepke M, et al. Long-term results and prognostic factors in the treatment of achalasia with botulinum toxin. Endoscopy endoscopy
Examination of the body's interior through an instrument inserted into a natural opening or an incision, usually as an outpatient procedure. Endoscopes include the upper gastrointestinal endoscope (for the esophagus, stomach, and duodenum), the colonoscope (for the 2002;34:519-523.
30. Niamtu J III. Botulinum toxin A botulinum toxin A Oculinum Neurology One of several toxins produced by C botulinum, of which the 150 kD type A toxin has been purified and used to treat various neuromuscular junction disorders including strabismus, blepharospasm, spasmodic torticollis, : a review of 1,085 oral and maxillofacial maxillofacial /max·il·lo·fa·cial/ (-fa´sh'l) pertaining to the maxilla and the face.
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31. Tsui JK, Fross RD, Calne S, et al. Local treatment of spasmodic torticollis spasmodic torticollis Wry neck, see there, aka cervical dystonia with botulinum toxin. Can J Neurol Sci 1987;14(3 Suppl):533-535.
32. Pullman Pullman.
1 Former town, since 1889 part of Chicago, Ill. It was founded in 1880 by George M. Pullman as a model community for workers of his sleeping-car company; all property was company owned, and administration policies were paternalistic. SL, Greene P, Fahn S, et al. Approach to the treatment of limb disorders with botulinum toxin A: experience with 187 patients. Arch Neurol 1996;53:617-624.
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34. Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis Torticollis Definition
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35. Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology 1995;45:1743-1746.
36. Erdal J, Ostergaard L, Fuglsang-Frederiksen A, et al. Long-term botulinum toxin treatment of cervical dystonia: EMG EMG
A diagnostic test that records the electrical activity of muscles. changes in injected and noninjected muscles. Clin Neurophysiol 1999;110:1650-1654.
37. Borodic GE, Ferrante R. Effects of repeated botulinum toxin injections on orbicularis oculi muscle orbicularis oculi muscle
see Table 13.1F. . J Clin Neuroophthalmol 1992;12:121-127.
38. Physician's Desk Reference Physician's Desk Reference (PDR),
n an informational, scientifically validated resource that provides information relating to indications, chemical formulations, actions and potential hazards associated with most medicinal remedies currently being used. . BOTOX[R] (Botulinum Toxin Type A). Montvale, NJ, Thomson PDR PDR
A trademark for Physicians' Desk Reference, a group of reference books containing drug listings, especially one for prescription drugs.
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40. Shorr N, Seiff SR, Kopelman J. The use of botulinum toxin in blepharospasm. Am J Ophthalmol 1985;99:542-546.
41. Dutton JJ, Buckley EG. Botulinum toxin in the management of blepharospasm. Arch Neurol 1986;43:380-382.
42. Elston JS. Long-term results of treatment of idiopathic idiopathic /id·io·path·ic/ (id?e-o-path´ik) self-originated; occurring without known cause.
1. Of or relating to a disease having no known cause; agnogenic. blepharospasm with botulinum toxin injections. Br J Ophthalmol 1987;71:664-668.
43. Ainsworth JR, Kraft SP. Long-term changes in duration of relief with botulinum toxin treatment of essential blepharospasm and hemifacial spasm. Ophthalmology 1995;102:2036-2040.
44. Snir M, Weinberger D, Bourla D, et al. Quantitative changes in botulinum toxin a treatment over time in patients with essential blepharospasm and idiopathic hemifacial spasm. Am J Ophthalmol 2003;136:99-105.
45. Nussgens Z, Roggenkamper P. Long-term treatment of blepharospasm with botulinum toxin type A. Ger J Ophthalmol 1995;4:363-367.
46. Engstrom PF, Arnoult JB, Mazow ML, et al. Effectiveness of botulinum toxin therapy for essential blepharospasm. Ophthalmology 1987;94:971-975.
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48. Ruusuvaara P, Setala K. Long-term treatment of involuntary facial spasms using botulinum toxin. Acta Ophthalmol (Copenh) 1990;68:331-338.
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50. Gonnering RS. Treatment of hemifacial spasm with botulinum A toxin: results and rationale. Ophthal Plast Reconstr Surg 1986;2:143-146.
51. Flanders M, Chin D, Boghen D. Botulinum toxin: preferred treatment for hemifacial spasm. Eur Neurol 1993;33:316-319.
52. Chen RS, Lu CS, Tsai CH. Botulinum toxin A injection in the treatment of hemifacial spasm. Acta Neurol Scand 1996;94:207-211.
53. Jankovic J, Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology 1990;40:277-280.
54. Dubinsky RM, Gray CS, Vetere-Overfield B, et al. Electromyographic guidance of botulinum toxin treatment in cervical dystonia. Clin Neuropharmacol 1991;14:262-267.
55. Brashear A, Watts MW, Marchetti A, et al. Duration of effect of botulinum toxin type A in adult patients with cervical dystonia: a retrospective chart review. Clin Ther 2000;22:1516-1524.
56. Hsiung GY, Das SK, Ranawaya R, et al. Long-term efficacy of botulinum toxin A in treatment of various movement disorders Movement Disorders Definition
Movement disorders are a group of diseases and syndromes affecting the ability to produce and control movement.
Description over a 10-year period. Mov Disord 2002;17:1288-1293.
57. Damrose JF, Goldman SN, Groessl EJ, et al. The impact of long-term botulinum toxin injections on symptom severity in patients with spasmodic dysphonia. J Voice 2004;18:415-422.
58. Ludlow CL, Bagley J, Yin SG, et al. A comparison of injection techniques using botulinum toxin injection for treatment of the spasmodic dysphonias. J Voice 1992;6:380-386.
59. Rubin AD, Wodchis WP, Spak C, et al. Longitudinal effects of Botox injections on voice-related quality of life (V-RQOL) for patients with adductory spasmodic dysphonia: part II. Arch Otolaryngol Head Neck Surg 2004;130:415-420.
60. Hogikyan ND, Wodchis WP, Spak C, et al. Longitudinal effects of botulinum toxin injections on voice-related quality of life (V-RQOL) for patients with adductory spasmodic dysphonia. J Voice 2001;15:576-586.
61. Aronson AE, McCaffrey TV, Litchy WJ, et al. Botulinum toxin injection for adductor adductor /ad·duc·tor/ (ah-duk´tor) [L.] that which adducts, as the adductor muscle.
n. spastic dysphonia dysphonia /dys·pho·nia/ (-fo´ne-ah) a voice impairment or speech disorder.dysphon´ic
Difficulty in speaking, usually evidenced by hoarseness. : patient self-ratings of voice and phonatory effort after three successive injections. Laryngoscope 1993;103: 683-692.
62. Mehta RP, Goldman SN, Orloff LA. Long-term therapy for spasmodic dysphonia: acoustic and aerodynamic outcomes. Arch Otolaryngol Head Neck Surg 2001;127:393-399.
63. Balkrishnan R, Manuel JC, Smith BP, et al. Longitudinal examination of health outcomes associated with botulinum toxin use in children with cerebral palsy. J Surg Orthop Adv 2004;13:76-80.
64. Koman LA, Brashear A, Rosenfeld S, et al. Botulinum toxin type a neuromuscular blockade neuromuscular blockade Neurology The partial or complete inhibition of motor activity at a neuromuscular junction Etiology 1. Reduction of post-synaptic receptors–eg, myasthenia gravis; 2. in the treatment of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial. Pediatrics 2001;108:1062-1071.
65. Rodriguez AA, McGinn M, Chappell R. Botulinum toxin injection of spastic finger flexors in hemiplegic hem·i·ple·gia
Paralysis affecting only one side of the body.
[Late Greek hmipl patients. Am J Phys Med Rehabil 2000;79:44-47.
66. Gordon MF, Brashear A, Elovic E, et al. Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology 2004;63:1971-1973.
67. Acquadro MA, Borodic GE. Treatment of myofascial pain myofascial pain (mīˈ·ō·fāˑ·shē· with botulinum A toxin. Anesthesiology anesthesiology (ăn'ĭsthē'zēŏl`əjē), branch of medicine concerned primarily with procedures for rendering patients insensitive to pain, and for supporting life systems under the strains of anesthesia and surgery. 1994;80:705-706.
68. Wehrmann T, Kokabpick H, Jacobi V, et al. Long-term results of endoscopie injection of botulinum toxin in elderly achalasic patients with tortuous tor·tu·ous
Having many turns; winding or twisting.
tortuous adjective Referring to complexly twisted thing. Cf Tortious. megaesophagus or epiphrenic diverticulum diverticulum
Small pouch or sac formed in the wall of a major organ, usually the esophagus, small intestine, or large intestine (the most frequent site of problems). . Endoscopy 1999;31:352-358.
69. D'Onofrio V, Annese V, Miletto P, et al. Long-term follow-up of achalasic patients treated with botulinum toxin. Dis Esophagus esophagus (ĭsŏf`əgəs), portion of the digestive tube that conducts food from the mouth to the stomach. When food is swallowed it passes from the pharynx into the esophagus, initiating rhythmic contractions (peristalsis) of the 2000;13:96-101.
70. Annese V, Basciani M, Borrelli O, et al. Intrasphincteric injection of botulinum toxin is effective in long-term treatment of esophageal achalasia esophageal achalasia
An esophageal obstruction that develops due to failure of the esophagogastric sphincter to relax, causing the upper esophagus to fill with retained food. Also called cardiospasm. . Muscle Nerve 1998;21:1540-1542.
71. Allescher HD, Storr M, Seige M, et al. Treatment of achalasia: botulinum toxin injection vs pneumatic balloon dilation dilation /di·la·tion/ (di-la´shun)
1. the act of dilating or stretching.
1. : a prospective study with long-term follow-up. Endoscopy 2001;33:1007-1017.
72. Kolbasnik J, Waterfall WE, Fachnie B, et al. Long-term efficacy of Botulinum toxin in classical achalasia: a prospective study. Am J Gastroenterol 1999;94:3434-3439.
73. Storr M, Allescher HD, Rosch T, et al. Treatment of symptomatic diffuse esophageal spasm Diffuse Esophageal Spasm Definition
Diffuse esophageal spasm is a term used to define an uncoordinated or spastic esophagus.
Description by endoscopic en·do·scope
An instrument for examining visually the interior of a bodily canal or a hollow organ such as the colon, bladder, or stomach.
en injections of botulinum toxin: a prospective study with long-term follow-up. Gastrointest Endosc 2001;54:754-759.
74. Lewin JS, Bishop-Leone JK, Forman AD, et al. Further experience with Botox injection for tracheoesophageal tracheoesophageal /tra·cheo·esoph·a·ge·al/ (tra?ke-o-e-sof?ah-je´al) pertaining to the trachea and esophagus.
Of or relating to the trachea and the esophagus. speech failure. Head Neck 2001;23:456-460.
75. Lowe PL, Cerdan-Sanz S, Lowe NJ. Botulinum toxin type A in the treatment of bilateral primary axillary hyperhidrosis: efficacy and duration with repeated treatments. Dermatol Surg 2003;29:545-548.
76. Giannantoni A, Mearini E, Di Stasi SM, et al. New therapeutic options for refractory neurogenic neurogenic /neu·ro·gen·ic/ (-jen´ik)
1. forming nervous tissue.
2. originating in the nervous system or from a lesion in the nervous system. detrusor detrusor /de·tru·sor/ (de-troo´ser) [L.]
1. a body part that pushes down.
2. detrusor urinae (detrusor muscle of the bladder).
n. overactivity o·ver·ac·tive
Active to an excessive or abnormal degree: an overactive child.
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77. Mauriello Jr, JA Dhillon S, Leone T, et al. Treatment selections of 239 patients with blepharospasm and Meige syndrome over 11 years. Br J Ophthalmol 1996;80:1073-1076.
78. Mauriello JA Jr., Leone T, Dhillon S, et al. Treatment choices of 119 patients with hemifacial spasm over 11 years. Clin Neurol Neurosurg 1996;98:213-216.
79. Mauriello JA, Aljian J. Natural history of treatment of facial dyskinesias with botulinum toxin: a study of 50 consecutive patients over seven years. Br J Ophthalmol 1991;75:737-739.
80. Brashear A, Bergan K, Wojcieszek J, et al. Patients' perception of stopping or continuing treatment of cervical dystonia with botulinum toxin type A. Mov Disord 2000;15:150-153.
81. Karp BI, Cole RA, Cohen cohen
(Hebrew: “priest”) Jewish priest descended from Zadok (a descendant of Aaron), priest at the First Temple of Jerusalem. The biblical priesthood was hereditary and male. LG, et al. Long-term botulinum toxin treatment of focal hand dystonia. Neurology 1994;44:70-76.
82. Damron TA, Greenwald TA, Breed AL. Chronologic outcome of surgical tendoachilles lengthening lengthening (lengkˑ·the·ning),
n the use of various massage or muscle energy techniques to relax and stretch muscle and connective tissue. and natural history of gastroc-soleus contracture contracture /con·trac·ture/ (-cher) abnormal shortening of muscle tissue, rendering the muscle highly resistant to passive stretching. in cerebral palsy: a two-part study. Clin Orthop Relat Res 1994;301:249-255.
83. Ludlow CL, Hallett M, Sedory SE, et al. The pathophysiology pathophysiology /patho·phys·i·ol·o·gy/ (-fiz?e-ol´ah-je) the physiology of disordered function.
1. of spasmodic dysphonia and its modification by botulinum toxin. In: Berardelli A, Benecke R, Manfredi M, Marsden CM (eds).Motor Disturbances II. New York New York, state, United States
New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of , Academic Press, 1990, pp 273-288.
84. Brin MF, Blitzer A, Stewart C, et al. Treatment of spasmodic dysphonia (laryngeal dystonia) with local injections of botulinum toxin: review and technical aspects. In: Blitzer A, Brin MF, Sasaki CT, Fahn S, Harris KS (eds). Neurological Disorders This is a list of major and frequently observed neurological disorders (e.g. Alzheimer's disease), symptoms (e.g.back pain), signs (e.g. aphasia) and syndromes (e.g. Aicardi syndrome). of the Larynx larynx (lâr`ĭngks), organ of voice in mammals. Commonly known as the voice box, the larynx is a tubular chamber about 2 in. (5 cm) high, consisting of walls of cartilage bound by ligaments and membranes, and moved by muscles. . New York, Thieme, 1992, pp 214-228.
85. Zwirner P, Murry T, Swenson M, et al. Effects of botulinum toxin therapy in patients with adductor spasmodic dysphonia: acoustic, aerodynamic, and videoendoscopic findings. Laryngoscope 1992;102:400-406.
86. Giladi N, Meer J, Kidan H, et al. Long-term remission of idiopathic cervical dystonia after treatment with botulinum toxin. Eur Neurol 2000;44:144-146.
87. Filippi GM, Errico P, Santarelli R, et al. Botulinum-A toxin effects on rat jaw muscle spindles. Acta Oto-Laryngol 1993;113:400-404.
88. Dressler D, Munchau A, Bhatia KP, et al. Antibody-induced botulinum toxin therapy failure: can it be overcome by increased botulinum toxin doses? Eur Neurol 2002;47:118-121.
89. Comella CL, Jankovic J, Daggett S, et al. Interim results of an observational study In statistics, the goal of an observational study is to draw inferences about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator. of neutralizing antibody formation with the current preparation of botulinum toxin type A treatment for cervical dystonia. Neurology 2004;62(7 Suppl 5):A511.
90. Brans JW, Lindeboom R, Snoek snoek
n. pl. snoek or snoeks
A large, small-scaled marine food fish (Thyristes atun) of the family Gempylidae, widely distributed in the Southern Hemisphere. JW, et al. Botulinum toxin versus trihexyphenidyl in cervical dystonia: a prospective, randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. , double-blind controlled trial. Neurology 1996;46:1066-1072.
91. Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection Noun 1. intramuscular injection - an injection into a muscle
injection, shot - the act of putting a liquid into the body by means of a syringe; "the nurse gave him a flu shot" of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002;347:395-400.
92. Gelber DA, Good DC, Dromerick A, et al. Open-label dose-titration safety and efficacy study of tizanidine hydrochloride tizanidine hydrochloride
Pharmacologic class: Alpha-adrenergic agonist (centrally acting)
Therapeutic class: Skeletal muscle relaxant
Pregnancy risk category C
Actionin the treatment of spasticity associated with chronic stroke. Stroke 2001;32:1841-1846.
93. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin 2004;20:981-990.
Artists who seek perfection in everything are those who cannot attain it in anything. --Gustave Flaubert
Mark Forrest Gordon, MD, and Rich Barron, MS
From North Shore-Long Island Jewish Health Systems, New Hyde Park New Hyde Park, village (1990 pop. 9,728), Nassau co., SE N.Y., on Long Island; inc. 1927. It is a residential community with some manufacturing and truck farms. Nearby is the uninc. town of North New Hyde Park (1990 pop. 14,359). , NY, and Allergan, Inc., Irvine, CA.
Reprint requests to Rich Barron, MS, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612. Email: Barron_Rich@Allergan.com
Mr. Rich Barron is an employee of Allergan Inc. (the makers of BOTOX[R]) and receives corporate stock as part of his employee compensation. Dr. MF Gordon has served as an investigator in Allergan-sponsored trials. He has received research grants, consultant fees (advisory boards), and speaker fees from Allergan, Inc.
Accepted February 3, 2006.
RELATED ARTICLE: Key Points
* Forty-four original research articles reporting on 16 different conditions were identified that included data on the duration or efficacy of multiple treatments with botulinum toxin type A.
* All of the 44 studies found sustained or enhanced improvement in efficacy and/or duration over the follow-up period, which ranged from a few treatments to more than 10 years.
* Seven studies reported a statistically significant increase in the efficacy or duration of botulinum toxin type A over time.
* Results suggest that continued benefit with repeated botulinum toxin type A treatment is widely reported in the literature.
Table 1. Summary of studies that examined efficacy and/or duration of repeated BoNTA treatments Patient Condition Reference sample (a) Patients (N) (b) BL 39 1,2 168; 25 discontin (subgroup of 12 > 14 txs) BL, HFS, MeS 40 1 22 BL 41 4 77 BL, OMD 42 4 101; 12 discontin BL, HFS, MeS 12 2,4 232 (subgroup of 50: [greater than or equal to]8 txs) BL, HFS 43 2 32 (same) BL, HFS 44 2 27 (same) BL 45 2 115 BL, MeS 46 1,2 76 (subgroup of 11: 5 txs) BL, HFS 47 1 28 (same) BL, HFS 48 4 31 (BL) 20 (HFS) HFS 49 2 (but 4 65 (same) clinics) HFS 50 4 17; 2 discontin HFS 51 1,2 65; 14 discontin (subgroup of 12: 9 txs) HFS 52 1,2 137 (subgroups of 20: 3txs; 11: 4txs) CD 53 1 232; 27 discontin CD, BL 14 2 157 (same) CD 54 3 84 CD 55 2 60 (same) HFS, facial and 56 2 235; 109 discontin (f) limb dystonias SD 57 1,2 102 (subgroup of 12: 6 txs) SD 58 1,2 178 (subgroup of 21: 4-5 txs) SD 59,60 1,2 42; 6 discontin (subgroup of 11: 5 txs) SD 61 4 10 (same) SD 62 1 91 CP 63 3 180; 17 discontin CP 64 3 207; 86 discontin (g) CP 16 3 8 (same 12 mos) 5 (same 24 mos) SPAST 65 3 14 SPAST 15 3 34 (6 discontin) SPAST 66 3 111 (23 discontin) MFP 67 Case 2 (same) reports ACH 68 3 20 ACH 69 3 37 ACH 70 1 57 (7 discontin) ACH 71 1 23 ACH 72 1 30 DES 73 3 9 TESF 74 3 23; 2 discontin CTTH 3 3 30 (same) HH (ax) 5 3 207 (33 discontin) HH (ax) 75 3 12 Glab lines 2 3 405 (subgroup of 258: 3 txs) Detruss 76 3 40 (same) overactiv Condition No. of treatments Outcome assessed BL 1 to 41 (mean 7.5) Efficacy Duration BL, HFS, MeS 1 to 9 Duration BL Mean 2.5 Efficacy Duration BL, OMD [greater than or equal to] 3 Duration BL, HFS, MeS 1 to 18 (mean 4.5) Efficacy Duration BL, HFS 12 Duration BL, HFS 4 to 6 years Duration Dose BL 3 to 8 years Duration BL, MeS 1 to 6 (mean 2.9) Duration BL, HFS [greater than or equal to]6 Duration Dose BL, HFS 1 to 5 Duration HFS 10 years Efficacy Duration HFS 1 to 5 Duration HFS 9 Efficacy Duration HFS Mean 1.7 Duration CD Mean 2.5 (3 months to 4 years) Dose Duration CD, BL [greater than or equal to]5 Efficacy Duration CD 1 to 6 (Mean 2.7) Dose Efficacy Duration CD 4 Dose Duration HFS, facial and [greater than or equal to]2 years Efficacy limb dystonias Dose SD Up to 2 years Efficacy SD 2 to 10 Efficacy Duration Dose SD 1 to 7 Quality of life SD 3 Efficacy Duration SD 1 to 3 Efficacy CP Mean 4; exact value NS Function Efficacy CP Mean 1.5 years Duration Efficacy Dose CP 6 Efficacy SPAST 1 to 3 Efficacy SPAST [greater than or equal to] 6 Efficacy Duration Dose SPAST Up to 4 Efficacy MFP 2 Efficacy Daily activity ACH 1 to 5 (Mean 2.5) Duration ACH 1 or 2 Efficacy ACH 1 to 3 Efficacy ACH 1 or 2 Efficacy ACH 1 to 3 Efficacy DES 1 or 2 Efficacy TESF 1 to 3 Efficacy CTTH 6 Efficacy HH (ax) 1 to 3 Efficacy HH (ax) 2 to 4 Duration Glab lines Up to 3 Efficacy Detruss Mean 3.4 Efficacy overactiv Response with repeated Condition treatments Statistics (c) Doses over time BL Sustained N Not reported Sustained BL, HFS, MeS Sustained N Same BL Sustained N Not reported BL, OMD Sustained N Not reported (but authors stated decrease) BL, HFS, MeS Sustained N Not change Sustained BL, HFS Sustained Y Dose stable after (nonsignificant first few txs decrease) BL, HFS BL low dose Y Dose increased if increased response deemed HFS sustained HFS, inadequate BL increased BL Sustained Y No change in dose/ duration relationship (d) BL, MeS Sustained Y Same BL, HFS Sustained Y Nonsignificant increase BL, HFS Sustained N Not reported, implied similar HFS Sustained Y No change HFS Nonsignificant Y Not reported increase HFS Sustained Y Not reported HFS Sustained Y Not reported CD Sustained N Appeared to slightly increase then decrease CD, BL Sustained N No change CD Sustained (e) N No change CD Sustained Y Not reported HFS, facial and Sustained Y CD, HFS no change limb dystonias (NS increase); BL dec then inc SD Sustained N Not reported SD Sustained Y Inc if less than optimal response SD Sustained Y Not reported SD Sustained (g) Y Not reported SD Sustained N Not reported CP Increased Y (WeeFIM) Not reported CP Sustained (h) N Increased Sustained Increased (h) CP Increased Y Same SPAST Sustained N Same SPAST Sustained Y No change Increased Sustained SPAST Sustained or N No change increased MFP Increased N Doses increased 50 to 150 U ACH Increased Y Same ACH 35 responded to 1 N Same or 2 txs ACH Sustained N Same ACH 19 responded to 1 N Not reported or 2 txs ACH 23 responded to 1 N Same to 3 txs DES Sustained N Same TESF 20 responded to 1 N Not reported or 2 txs CTTH Sustained to Y Not reported increased HH (ax) Sustained N Same HH (ax) Sustained (i) N Same Glab lines Increased Y Same Detruss Sustained Y Same overactiv (a) 1=all patients who received BoNTA for a given disorder at a single clinic; 2=subgroup of patients at a single clinic who received a specified number of treatments with BoNTA for a given disorder; 3=recruited sample that met specific inclusion/exclusion criteria; 4=not specified (many of these appeared to include all or consecutive patients at a single clinic but this was not specifically stated). (b) Number of patients enrolled in the study and discontinuation rate, if reported. (c) Comparing treatments over time. (d) Doses over time examined as duration-dosage quotient weeks/unit. (e) Efficacy, dose, and duration were generally sustained from treatments 3 to 6; treatments 1 and 2 tended to show slightly higher efficacy scores and/or durations, but trends were not statistically analyzed and patient numbers at each injection ranged from 6 to 84. (f) Reasons for discontinuation: primary resistance (n = 22), surgery (n = 21), secondary resistance (n = 18), lost to follow up (n = 17), practicality (eg, patient moved; n = 17), remission (n = 8), death due to causes not related to treatment (n = 3), adverse events (n = 3). (g) Patient-rated efficacy varied over the postinjection course and the timing of improvement was not the same for all of the treatments, although the overall duration was not statistically different between treatments. (h) Reasons for discontinuation: reasons unrelated to treatment (n = 47), lack of efficacy (n = 39), not evaluable (n = 4); duration appeared to be sustained through treatment 8, although the number of patients decreased from 207 at treatment 1 to 31 at treatment 8; too few patients had >8 treatments to draw any conclusions and no statistics were calculated on these data. (i) Durations between treatments 2-3 and 3-4 appeared to be comparable (means 158.7 and 141.3 days). The duration was longer for the first injection (mean 205.7 days); however, this value represents all patients in the study, even those who did not need further injections. Statistics were not calculated on these data. ACH, achalasia; ax, axillary; BL, blepharospasm; CD, cervical dystonia; CP, cerebral palsy; CTTH, chronic tension-type headache; Detruss overactiv, detrussor overactivity (neurogenic); dec, decrease; inc, increase; DES, diffuse esophageal spasm; discontin, discontinued; Glab, glabellar; HA, headache; HFS, hemifacial spasm; HH, hyperhidrosis; LD, laryngeal dystonia; MeS, Meige syndrome; MYO, myokymia; NS, not specified; OMD, oromandibular dystonia; SD, spasmodic dysphonia; STRAB, strabismus; SPAST, spasticity; TESF, tracheoesophageal speech failure; tx, treatment; Same, same exact dose used at each treatment; No change, no significant change in doses over treatments; MFP, myofascial face pain. Table 2. Assessment methods used in the various studies (a) Assessment Method Studies Duration: time 15,41,43-47,49,52,55,61,64,75 between treatments Duration: not 12,40,42,48,50,68 specified Efficacy: Likert-type 2,3,12,14,39,44,46,49,51,58,61,69,70,71-73 symptom rating scales Efficacy: Disease- 14,54,65,66 specific clinical scales Function or quality 5,16,59,60,63,64,66 of life scales Other Time to disabling symptoms (39) Patient--rated (diary) duration of benefit (56) Vocal recordings (57) Vocal fold movement (58) Translaryngeal airflow, other mechanical variables (62) Patient report--no scale (67) Speech fluency (74) 50% decrease in sweating (5) Urodynamics, incontinence (76) Spasm--free period (51) Duration of any improvement (14,53) Time to patient-reported worsening (54) Days with positive voice ratings (58) (a) Some studies used more than one method. Table 3. Studies that examined BoNTA patient disposition over time Condition Reference N No. of treatments Outcome assessed BL, MeS 77 228 Up to 11 years Continuation (a) BL, HFS, 78 50 Mean 10.4 Natural history MeS HFS 79 108 1 to 24 Natural history CD 80 133 [greater than or equal to] Continuation 6 years Focal hand 81 37 Up to 6 years Continuation dystonia Condition Results with repeated treatments BL, MeS 202 were still treated with BoNTA, 18 did not seek futher txs, 5 remission, 3 surgery BL, HFS, 26 returned for txs, 3 no response, 3 went into remission, MeS 6 treated until death (unrelated to tx), 6 received repeated txs at other centers, 5 lost to follow up, I had only 1 tx HFS At a median of 30 months follow up, 55 patients still receiving injections, 10 failed to respond, 4 stopped treatment for other reasons, 5 in remission after 1 to 6 injections, 4 treated until they died of causes unrelated to injections, 8 received repeated injections at other centers, 22 lost to follow up CD 104 continued treatment and 29 stopped; 1/3 reported the first injection was most helpful, 1/3 felt all were similarly effective Focal hand 24 patients followed for 2 years discontinued treatment dystonia (a) The number of patients who continued BoNTA therapy. BL, blepharospasm; CD, cervical dystonia; HFS, hemifacial spasm; MeS, Meige syndrome; tx,treatment