The effect of patient factors on response outcomes toBotox treatment of spasmodic dysphonia

Injection of botulinum toxin (Botox) into the laryngeal muscleshas become the treatment of choice for controlling the symptoms of spasmodic dysphonia (SD). Currently, no specific battery of objective tests to assess the outcome is universally accepted. The purpose of this study was to investigate demographic, clinical, and treatment factors with voice outcome following Botox injection. Sixty-eight patients with adductor SD who underwent at least one Botox injection during a 5-year period were studied. Voice outcome measures were made from patient self-reporting scales and included overall vocal quality, length of response, and duration of breathiness. Vocal quality was significantly correlated with the underlying severity of vocal symptoms prior to treatment, incidence of breathiness and unilateral versus bilateral injection. The length of response was greater in males and following bilateral injections. An increased period of breathiness significantly correlated with bilateral injections.     

Botulinum Toxin Type B for Treatment of Spasmodic Dysphonia: A Case Report

Although treatment with botulinum toxin type A (BTXA) has become the standard of care for most patients with laryngeal dystonia, its use is limited by the development of resistance to the toxin in some patients. Botulinum toxin type B (BTXB) has been found to be safe and effective in the treatment of cervical dystonia, but it has not been used previously to treat spasmodic dysphonia. Our experience with BTXB in a patient who developed resistance to BTXA suggests that BTXB may be safe and effective for the treatment of laryngeal dystonia, as well.     

Botulinum toxin treatment of spasmodic dysphonia: Techniques, indications, efficacy

A group of 58 patients with spasmodic dysphonia (SD) was treated perorally or transcutaneously with botulinum toxin (BT), and followed for at least 6 months. Most were treated by peroral injection using indirect laryngoscopy to facilitate precise placement. An effort was made to disperse the toxin over the entire thyroarytenoid muscle in order to affect the greatest number of motor end-plates using the smallest possible effective dose. Severely symptomatic patients with primarily adductor SD had the best results. A potentiation effect is suggested by analysis of a subpopulation of patients, mostly injected unilaterally, for whom the outcome was more favorable for those who had had prior injections. One-month postinjection studies reflect significant improvement in measured readings of a standard passage, and this is consistent with the subjective and perceptual improvements noted. There were no severe complications. Peroral injection seems inadvisable for patients with mixed or abductor SD as well as for those with an uncontrollable gag reflex.     

Immunologic Characterization of Spasmodic Dysphonia Patients Who Develop Resistance to Botulinum Toxin

The immune status of six spasmodic dysphonia patients who became resistant to botulinum toxin was compared to that of a series of patients who remained responsive. The two groups were similar in terms of age, sex, and cumulative dose of toxin. Five of the resistant patients had a significant titer of anti-botulinum toxin IgG antibodies, as determined by enzyme-linked immunosorbent assay (ELISA). These same five resistant patients had a circulating titer of anti-heavy chain antibodies, but only three of these patients had a circulating titer of anti-light chain antibodies, as determined by Western blotting. By contrast, none of the responsive patients had antibodies against the holotoxin or its two chains. Interestingly, two of the resistant patients also had a low circulating titer of anti-botulinum toxin IgA antibodies. None of the responsive patients was IgA-positive. The cumulative dose of botulinum toxin administered to resistant patients was lower than that customarily associated with emergence of immunity in dystonia patients.     

Botulinum Toxin Therapy for Abductor Spasmodic Dysphonia

Botulinum toxin has been widely accepted as an effective therapy for controlling the symptoms of adductor spasmodic dysphonia (ADSD). Reported experience with botulinum treatment for abductor spasmodic dysphonia (ABSD) has been less impressive. Factors that may impair outcomes for ABSD include differences in the pathophysiology of ADSD and ABSD and limitation of maximal dose from airway restriction with posterior cricoarytenoid muscle (PCA) weakness. We report our experience with botulinum injection of the PCA with an asymmetric dose escalation protocol, based on clinical observations that in ABSD, abductor spasms are often stronger on one side, usually the left. The nondominant side was injected with 1.25 units. Dominant side dose began at 5 units, with step-wise increments of 5 units per week until one of three endpoints was reached: Elimination of breathy voice breaks, complete abductor paralysis of the dominant side, or airway compromise. Fourteen of 17 patients achieved good or fair voice, with dominant-side doses ranging from 10 to 25 units. Exercise intolerance limited PCA dose in two patients. One patient had persisting breathiness that improved with medialization thyroplasty. Asymmetric botulinum toxin injection into PCA muscles can suppress abductor spasm in patients with ABSD, but breathiness may persist, because of inadequate glottal closure.     

Differential phonatory characteristics of four women with amyotrophic lateral sclerosis

Patients with specific neural subsystem involvement are often reported to present with particular perceptual characteristics of voice. This has been true for diseases such as amyotrophic lateral sclerosis (ALS), a progressive disease in which mixed neurologic signs are present. This article reports acoustic data on the phonatory performance of four women diagnosed with ALS who had initial bulbar signs and progressive phonatory deterioration. The data presented here demonstrate that the phonatory characteristics of women with ALS are not uniform, but in fact may vary greatly from patient to patient.     

The impact of long-term botulinum toxin injections on symptom severity in patients with spasmodic dysphonia

Injection of botulinum toxin (BT) into the muscles of the larynx is an effective treatment for the symptoms of spasmodic dysphonia (SD). To date, however, there have been no studies that have used blinded raters to assess the efficacy of BT injections on overall symptom severity in a cohort of SD patients followed over a prolonged period. In this study, 102 subjects with SD were treated with serial BT injections for up to 2 years. Voice recordings were obtained at several time points during treatment and were played to a panel of expert and novice listeners who rated them based on overall symptom severity in a single-blind fashion. Subjects demonstrated significant improvement over baseline at all time points. In addition, patients showed a sustained responsiveness to therapy over time. These results provide support for the efficacy of serial BT injections for SD and suggest that successful treatment may depend, in part, on patients' early recognition of returning symptoms.     

Botulinum toxin

The National Institutes of Health Consensus Development Conference on Clinical Use of Botulinum Toxin brought together neurologists, ophthalmologists, otolaryngologists, speech pathologists, and other health care professionals as well as the public to address the mechanisms of action of botulinum toxin, the indications and contraindications for botulinum toxin treatment, the general principles of technique of injection and handling for its safe and effective use, and the short-term and long-term side effects and complications of therapy. Following 2 days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared their consensus statement. Among their findings, the panel recommended that (a) botulinum toxin therapy is safe and effective for treating strabismus, blepharospasm, hemifacial spasm, adductor spasmodic dysphonia, jaw-closing oromandibular dystonia, and cervical dystonia; (b) botulinum toxin is not curative in chronic neurological disorders; (c) the safety of botulinum toxin therapy during pregnancy, breast feeding, and chronic use during childhood is unknown; (d) the long-term effects of chronic treatment with botulinum toxin remain unknown; and (e) botulinum toxin should be administered by committed interdisciplinary teams of physicians and related health care professionals with appropriate instrumentation. The full text of the consensus panel's statement follows.     

Botulinum toxin in the treatment of recalcitrant mutational dysphonia

Mutational falsetto is the failure of the normal drop in vocal pitch at puberty. Voice therapy almost always achieves an appropriate pitch; however, in cases of failure, surgical treatment has also been recommended. We report a case of a 47-year-old man with an above-average fundamental frequency and a thin voice quality in the absence of any signs of androgen insufficiency. Laryngeal examination revealed atrophy of the vocalis muscle. Voice therapy was unsuccessful in achieving a stable voice. Injection of 15 units of botulinum toxin into each cricothyroid muscle initially resulted in aphonia, but the voice returned by 1 week. Average fundamental frequency was 84 Hz at 1 week, 104 Hz at 1 month, and 100 Hz at 1 year. We hypothesize that mutational dysphonia is an habitual dysfunction of the voice with inappropriate activation of the cricothyroid muscle and disuse of laryngeal adductor muscles. Temporary deactivation of the cricothyroid muscle enforces adoption of a more appropriate vocal mechanism. Botulinum toxin as an adjunct to voice therapy should be considered before surgical alteration of the glottis in patients with recalcitrant mutational falsetto.     

Acoustic analysis of voice in individuals with amyotrophic lateral sclerosis and perceptually normal vocal quality

Currently, early phonatory changes in amyotrophic lateral sclerosis(ALS) are not well understood. The aim of this study was to compare acoustic parameters of voice in ALS subjects who demonstrated perceptually normal vocal quality on sustained phonation with a control group. We hypothesized that objective analysis of voice would reveal significant differences on specific acoustic parameters of voice compared to the control group. Results revealed statistically significant differences between the two groups on measures related to frequency range and phonatory stability. The findings suggest that early bulbar signs affecting the laryngeal system may be present in patients with ALS before the occurrence of perceptually aberrant vocal characteristics.     

Pharmacological agents that improve botulinum toxin efficacy in the treatment of spasmodic dysphonia

Botulinum toxin (botox) injection into the thyroarytenoid (TA) muscle is currently the most favored treatment for spasmodic dysphonia. However, results are often inconsistent. The purpose of this study was to identify a fast-acting neuromuscular blocking agent that could mimic botox effects to screen patients for therapy while still in the clinic. If the agent was noninteractive, it could also be injected coincidentally with botox and the resulting changes in voice used to predict the delayed effects due to botox. Evoked electromyography responses were recorded from the TA muscle in animal experiments to determine the time course for neuromuscular depression by botox and three fast-acting blocking agents: lidocaine, tubocurarine, and succinylcholine. Tubocurarine and succinylcholine proved to be suitable screening or predictor agents of botox efficacy, since they were reversible and mimicked botox action. In contrast, lidocaine produced irreversible effects.     

The Effect of Botulinum Toxin A on the Vocal Symptoms of Spastic Dysarthria: A Case Study

The vocal symptoms of spastic dysarthria and spasmodic dysphonia have many similar features. Botulinum toxin has been used effectively to treat spasmodic dysphonia. This study was designed to determine what vocal changes occur in an individual with spastic dysarthria following Botulinum toxin A injection into the thyroarytenoid muscles. Measures were obtained preinjection and three times postinjection. Acoustic and aerodynamic results were comparable to those reported for individuals with spasmodic dysphonia. The most marked change was increased DC airflow. Despite persistent breathiness, the participant reported great satisfaction with the result, particularly because of her more appropriate loudness. In addition, everyday listeners perceived significantly less listener burden and more relaxed and pleasant vocal quality postinjection.     

Unilateral Versus Bilateral Injections of Botulinum Toxin in Patients with Adductor Spasmodic Dysphonia

Both unilateral and bilateral thyroarytenoid muscle injections of Botox provide effective management of voice symptoms in patients with adductor spasmodic dysphonia; however, the preferred injection technique has not been established. In this study, 16 patients were treated with unilateral injections (72 injections total) and 33 patients were managed with bilateral injections (133 injections total). Individual assignments to injection type were based on treatment previously received and dose was adjusted according to the patient's previous treatment response. An optimal treatment included a benefit lasting 3 months or more with side effects lasting 2 weeks or less. Compared to patients receiving bilateral injections, those receiving unilateral injections more frequently noted a benefit of 3 months or more (p = 0.03), side effects of 2 weeks or less duration (p = 0.03), as well as both a 3-month benefit and a 2-week or less side effect (p = 0.0004). Injection type had no effect on optimal Botox dosing with repeat injections. Successive unilateral injections at the same dose were more likely (p = 0.012) than successive bilateral injections to produce the same or longer duration of benefit. We conclude that a unilateral injection routine has a more optimal and consistent treatment effect/side effect profile.     

Technique of percutaneous EMG-guided botulinum toxin injection of the larynx for spasmodic dystonia

Percutaneous electromyography (EMG)-guided technique of botulinum toxin (BT) injection of the larynx evolved from similar techniques for extraocular muscle injection in strabismus, as well as from experience with diagnostic laryngeal EMG. This technique permits rapid accurate injection of BT into the laryngeal muscles. Although usually injected into the thyroarytenoid muscle, BT can also be directed to the posterior cricoarytenoid and cricothyroid muscles. Complications are minimal and of short duration.     

A comparison of injection techniques using botulinum toxin injection for treatment of the spasmodic dysphonias

The benefit duration and side effects following effective treatment of spasmodic dysphonia or voice tremor using botulinum toxin injection were studied following 477 open trial unilateral or bilateral injections provided to 178 patients. A comparison of unilateral and bilateral injections in male and female patients with adductor spasmodic dysphonia demonstrated an increased benefit duration following unilateral injections in women, longer periods of breathiness in men than in women following bilateral or unilateral injections, and a trend for reduced benefit durations following repeated treatments using bilateral injections. Outcomes were similar in the adductor spasmodic dysphonia and vocal tremor groups following thyroarytenoid injection while benefit durations were reduced and side effects lasted longer in patients with abductor spasmodic dysphonia following cricothyroid injections. Long-term benefit > 1 year occurred in 12.3% of patients following injection.     

Combined-modality treatment of adductor spasmodic dysphonia with botulinum toxin and voice therapy

A combined-modality treatment program consisting of botulinum toxin injection (Botox) and voice therapy was used to treat 17 subjects diagnosed with adductor spasmodic dysphonia (ADD SD). Ten subjects with ADD SD served as the control and were given Botox only. Voice therapy after Botox injection was directed toward reducing the hyperfunctional vocal behaviors, primarily glottal overpressure at voice onset and anterior-posterior squeezing. The results indicated that subjects who underwent combined-modality treatment maintained significantly higher mean airflow rates for significantly longer periods. Moreover, there was a carryover effect in these patients when they received Botox only. Adductor spasmodic dysphonia is treated most effectively when intrinsic laryngeal muscle spasms are reduced or eliminated by Botox injection and extrinsic hyperfunctional vocal behaviors are treated with voice therapy     

Clinically relevant aspects of the mechanism of action of botulinum neurotoxin

Botulinum neurotoxin is a highly potent substance obtained from organisms such as Clostridium botulinum, Clostridium barati and Clostridium butyricum. The toxin is synthesized as a single chain polypeptide that is cleaved to yield a heavy chain (100,000 Da) and a light chain (50,000 Da) linked by a disulfide bond. The neurotoxin is tissue-targeted to peripheral cholinergic nerve endings, where it acts to poison transmission. The toxin binds to the cell surface, undergoes receptor-mediated endocytosis, then acts intracellularly to block exocytosis. Because the toxin blocks neuromuscular transmission, it is useful for treating neurologic disorders revealed as spastic dystonias.