Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders. METHODS: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I-IV). RESULTS: The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies). RECOMMENDATIONS: Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.

Functional neuroanatomy of human vocalization: an H215O PET study.

Vocalization in lower animals is associated with a well-described visceromotor call system centered on the mesencephalic periacqueductal grey matter (PAG), which is itself regulated by paramedian cortical structures. To determine the role this phylogenetically older system plays in human phonation, we contrasted voiced and unvoiced speech using positron emission tomography and then evaluated functional connectivity of regions that significantly differentiated these conditions. Vocalization was associated with increased and highly correlated activity within the midline structures--PAG and paramedian cortices--described in lower mammalian species. Concurrent activation and connectivity of neocortical and subcortical motor regions--medial and lateral premotor structures and elements of basal ganglia thalamocortical circuitry--suggest a mechanism by which this system may have come under an increasing degree of voluntary control in humans. Additionally, areas in the temporal lobe and cerebellum were selectively activated during voiced but not unvoiced speech. These regions are functionally coupled to both visceromotor and neocortical motor areas during production of voiced speech, suggesting they may play a central role in self-monitoring and feedback regulation of human phonation.

Acoustic measures of symptoms in abductor spasmodic dysphonia.

Speech of patients with abductor spasmodic dysphonia (ABSD) was analyzed using acoustic analyses to determine: (1) which acoustic measures differed from controls and were independent factors representing patients' voice control difficulties, and (2) whether acoustic measures related to blinded perceptual counts of the symptom frequency in the same patients. Patients' voice onset time for voiceless consonants in speech were significantly longer than the controls (p = 0.015). A principle components analysis identified three factors that accounted for 95% of the variance: the first factor included sentence and word duration, frequency shifts, and aperiodic instances; the second was phonatory breaks; and the third was voice onset time. Significant relationships with perceptual counts of symptoms were found for the measures of acoustic disruptions in sentences and sentence duration. Finally, a multiple regression demonstrated that the acoustic measures related well with the perceptual counts (r2 = 0.84) with word duration most highly related and none of the other measures contributing once the effect of word duration was partialed out. The results indicate that some of the voice motor control deficits, namely aperiodicity, phonatory breaks, and frequency shifts, which occur in patients with ABSD, are similar to those previously found in adductor spasmodic dysphonia. Results also indicate that acoustic measures of intermittent disruptions in speech, voice onset time, and speech duration are closely related to the perception of symptom frequency in the disorder.

Assessment of posterior cricoarytenoid botulinum toxin injections in patients with abductor spasmodic dysphonia.

In this study, we compared 2 techniques for injection of botulinum toxin type A (Botox) into the posterior cricoarytenoid (PCA) muscle for the treatment of abductor spasmodic dysphonia (ABSD). Fifteen patients with ABSD were enrolled in a prospective randomized crossover treatment trial comparing the 2 injection techniques. The PCA muscle was injected with 5 units on each side, with the injections staged 2 weeks apart, via either a percutaneous posterior-lateral approach or a transnasal fiberoptic approach. Eleven patients reported some benefit with the injections; however, the patient-perceived benefits were not related to changes in symptoms on blinded counts by speech pathologists. No significant reductions in the numbers of breathy breaks occurred with either technique, and no differences were found between techniques. Although patients perceived a benefit, blinded symptom counts did not substantiate these benefits. Thus, PCA muscle injections of Botox provided limited benefits to patients with ABSD, demonstrating the need for a more effective therapy for these patients.

Identification of symptoms for spasmodic dysphonia and vocal tremor: a comparison of expert and nonexpert judges.

UNLABELLED: Spasmodic dysphonia is a rare voice disorder that is most successfully treated by injection of botulinum toxin (i.e., BOTOX) into the affected laryngeal muscles. BOTOX is currently available for use by professionals outside of metropolitan voice centers who may be unfamiliar with this rare disorder. Patients may seek assessment and treatment locally from clinicians who are unfamiliar with the speech symptoms for adductor-type (ADSD) or abductor-type (ABSD) spasmodic dysphonia. Although these disorders have been described in the literature, the symptoms have not been well defined and may appear similar to those of vocal tremor or muscle tension dysphonia (MTD). Thus, patients with spasmodic dysphonia might not be easily identified by local clinicians for treatment. The purpose of the current study was to determine whether voice clinicians with infrequent exposure to patients with spasmodic dysphonia could learn to identify speech symptoms for ADSD and ABSD comparable to voice clinicians with extensive experience with these disorders. The ratings of five nonexpert judges were compared to the ratings obtained from three expert judges. The results of this study demonstrated that nonexpert judges could be trained to identify the speech symptoms associated with ADSD, ABSD, and vocal tremor. While the nonexpert judges tended towards false positive judgements for the speech symptoms of interest, the overall speech symptom profiles for each type of voice disorder appeared comparable to those obtained from the expert judges. The symptom identificationscales used, therefore, have potential for use by clinicians unfamiliar with these disorders for correctly identifying persons with symptoms of ADSD and ABSD. EDUCATIONAL OBJECTIVES: Readers will be able to (1) define the predominant speech symptoms reflective of the voice disorder categories of ABSD, ADSD, and vocal tremor; and (2) describe the methods utilized in a new perceptual training protocol for teaching clinicians how to identify predominant speech symptoms associated with the voice disorder categories of ABSD, ADSD, and vocal tremor.

Adductor muscle activity abnormalities in abductor spasmodic dysphonia.

OBJECTIVE: To determine laryngeal muscle activation abnormalities associated with speech symptoms in abductor spasmodic dysphonia (ABSD). STUDY DESIGN: Bilateral laryngeal muscle recordings from the posterior cricoarytenoid, thyroarytenoid, and cricothyroid muscles were conducted in 12 ABSD patients. Patients' measures were compared during speech breaks and during speech without breaks and with 10 normal controls. RESULTS: Significant group differences were found in the thyroarytenoid muscle; the patients had significantly greater activity on the right side both during speech breaks and nonbreaks in comparison with the controls. Cricothyroid muscle levels were also increased on the right in the patients. CONCLUSION: An asymmetry in adductor muscle tone between the 2 sides in ABSD may account for difficulties with maintaining phonation and voice onset after voiceless consonants. SIGNIFICANCE: These abnormalities may indicate why PCA BOTOX injections have not been as effective in ABSD as thyroarytenoid injections have been in adductor spasmodic dysphonia.

Emerging clinical applications of electrical stimulation: opportunities for restoration of function.

Emerging clinical application of electrical stimulation in three systems is reviewed. In the bladder, stimulation of sacral posterior roots reduces reflex incontinence and significantly improves bladder capacity. With the combination of anterior and posterior root stimulation, bladder control can be achieved without the need for rhizotomy. Preliminary research demonstrates that bladder contractions may also be generated by stimulation of the urethral sensory branch of the pudendal nerve, even after acute spinal cord transection, while inhibition of the bladder and control of urge incontinence can be achieved by stimulation of the whole pudendal nerve. Spinal cord stimulation can modulate the activity of the intrinsic cardiac nervous system involved in the regulation of regional cardiac function and significantly reduce the pain associated with angina pectoris. Finally in the area of upper airway disorders, functional electrical stimulation has great potential for increasing life support as well as for quality of life in chronic ailments, particularly obstructive sleep apnea and dysphagia.

Effects of levodopa on laryngeal muscle activity for voice onset and offset in Parkinson disease.

The laryngeal pathophysiology underlying the speech disorder in idiopathic Parkinson disease (IPD) was addressed in this electromyographic study of laryngeal muscle activity. This muscle activity was examined during voice onset and offset gestures in 6 persons in the early stages of IPD who were not receiving medication. The purpose was to determine (a) if impaired voice onset and offset control for speech and vocal fold bowing were related to abnormalities in laryngeal muscle activity in the nonmedicated state and (b) if these attributes change with levodopa. Blinded listeners rated the IPD participants' voice onset and offset control before and after levodopa was administered. In the nonmedicated state, the IPD participants' vocal fold bowing was examined on nasoendoscopy, and laryngeal muscle activity levels were compared with normal research volunteers. The IPD participants were then administered a therapeutic dose of levodopa, and changes in laryngeal muscle activity for voice onset and offset gestures were measured during the same session. Significant differences were found between IPD participants in the nonmedicated state: those with higher levels of muscle activation had vocal fold bowing and greater impairment in voice onset and offset control for speech. Similarly, following levodopa administration, those with thyroarytenoid muscle activity reductions had greater improvements in voice onset and offset control for speech. In this study, voice onset and offset control difficulties and vocal fold bowing were associated with increased levels of laryngeal muscle activity in the absence of medication.

Effects of adductor muscle stimulation on speech in abductor spasmodic dysphonia.

OBJECTIVE: To determine whether adductor laryngeal muscle stimulation might be a beneficial treatment alternative for abductor spasmodic dysphonia (ABSD). STUDY DESIGN: Baseline comparisons were made on measures of voiceless consonant and syllable duration between patients with ABSD and normal control subjects, and speech and voice production with and without muscle stimulation were compared within 10 patients with ABSD. METHODS: Baseline group comparisons were conducted on measures of syllable and voiceless consonant duration between the patients and the control subjects. Neuromuscular stimulation was applied to the thyroarytenoid or lateral cricoarytenoid muscles in the patients during extended phonation, and measures were made of fundamental frequency and sound pressure level in the stimulated and nonstimulated conditions. Voiceless consonant duration was compared with and without adductor laryngeal muscle stimulation during syllable repetitions and sentences in the patients. RESULTS: Before stimulation, the patients had increased syllable durations in comparison with control subjects (P = .003). Repeated within-patient comparisons with and without stimulation demonstrated significant (P < .008) reductions in voiceless consonant durations during syllable repetition. The more severely affected patients had the greatest reductions in voiceless consonant duration during sentence production. CONCLUSIONS: Adductor muscle stimulation improved speech production in patients with ABSD, and the improvement was greatest in the most severely affected patients. Therefore adductor muscle stimulation has potential for benefiting patients with ABSD.

Aging effects on motor units in the human thyroarytenoid muscle.

OBJECTIVES: To determine whether age differences are present in the human laryngeal thyroarytenoid muscle that would indicate that different normative values would be needed for identifying motor unit abnormalities. STUDY DESIGN: Twenty-six consecutively recruited healthy subjects between the ages of 21 and 72 years participated in a laryngeal electromyography study. METHODS: Bipolar needle electrodes were used to record motor unit action potentials from several locations in the right and left thyroarytenoid muscles of each subject. The duration of a motor unit was measured when at least 10 firings of the same motor unit could be identified. On the average, four units were measured per muscle. RESULTS: In the subjects less than 60 years of age, motor unit duration did not increase significantly with age. However, motor units from subjects greater than 60 years of age had longer durations than those from subjects less than 60 years of age (P < .00005), and 25% of the units measured in subjects greater than 60 years of age had longer durations than any of the units measured in subjects less than 60 years of age. Further, the older subjects differed from each other in their mean unit durations (P < .0001). In subjects less than 60 years of age, significantly longer durations were found for units innervated by the longer, left-side recurrent laryngeal nerve in comparison with the right-side nerve (P = .005). CONCLUSIONS: Different mean and SD values should be used for patients less than and greater than 60 years of age and for the right and left sides, when evaluating motor units in the thyroarytenoid muscles.

Modulation of laryngeal responses to superior laryngeal nerve stimulation by volitional swallowing in awake humans.

Laryngeal sensori-motor closure reflexes are important for the protection of the airway and prevent the entry of foreign substances into the trachea and lungs. The purpose of this study was to determine how such reflexes might be modulated during volitional swallowing in awake humans, when persons are at risk of entry of food or liquids into the airway. The frequency and the amplitude of laryngeal adductor responses evoked by electrical stimulation of the internal branch of the superior laryngeal nerve (ISLN) were studied during different phases of volitional swallowing. Subjects swallowed water on command while electrical stimuli were presented to the ISLN at various intervals from 500 ms to 5 s following the command. Laryngeal adductor responses to unilateral ISLN stimulation were recorded bilaterally in the thyroarytenoid muscles using hooked wire electrodes. Early ipsilateral R1 responses occurred at 17 ms, and later bilateral R2 began around 65 ms. The muscle responses to stimuli occurring during expiration without swallowing were quantified as control trials. Responses to stimulation presented before swallowing, during the swallow, within 3 s after swallowing, and between 3 and 5 s after a swallow were measured. The frequency and amplitude of three responses (ipsilateral R1 and bilateral R2) relative to the control responses were compared across the different phases relative to the occurrence of swallowing. Results demonstrated that a reduction occurred in both the frequency and amplitude of the later bilateral R2 laryngeal responses to electrical stimulation for up to 3 s after swallowing (P = 0.005). The amplitude and frequency of ipsilateral R1 laryngeal responses, however, did not show a significant main effect following the swallow (P = 0.28), although there was a significant time by measure interaction (P = 0.006) related to reduced R1 response amplitude up to 3 s after swallowing (P = 0.021). Therefore, the more rapid and shorter unilateral R1 responses continued to provide some, albeit reduced, laryngeal protective functions after swallowing, whereas the later bilateral R2 responses were suppressed both in occurrence and amplitude for up to 3 s after swallowing. The results suggest that R2 laryngeal adductor responses are suppressed following swallowing when residues may remain in the laryngeal vestibule putting persons at increased risk for the entry of foreign substances into the airway.

Effects of botulinum toxin on pathophysiology in spasmodic dysphonia.

To determine the mechanism of symptom relief with treatment by botulinum toxin injection in persons with adductor spasmodic dysphonia (ADSD), we evaluated the effects of unilateral thyroarytenoid muscle injections on both injected and noninjected muscles in 10 subjects with ADSD, using electromyography on both sides of the larynx before and after treatment. The subjects' speech symptoms were reduced (p = .005) 2 weeks following injection, when the electromyographic study occurred. Muscle activation levels and the numbers of spasmodic muscle bursts decreased significantly (p < or = .03) postinjection in both the injected and noninjected muscles. The reductions in laryngeal muscle bursts correlated with symptom reduction (r > or = .7) in all muscles. Reductions in laryngeal muscle bursts did not relate to either absolute or normalized levels of muscle activity before or after botulinum toxin injection. The results suggest that changes in the central pathophysiology are responsible for changes in speech symptoms following treatment.

Chronic intermittent stimulation of the thyroarytenoid muscle maintains dynamic control of glottal adduction.

Patients with laryngeal motor control disorders need improved dynamic glottal closure for speech and swallowing. To evaluate the functional outcome of intermittent chronic thyroarytenoid muscle stimulation in an animal model, 6 canines were implanted with bilateral Medtronic Xtrel systems containing Peterson-type electrodes in the inferior and superior portions of the thyroarytenoid muscle. Stimulation was on one side only at 60 Hz, for 5 s on and 5 s off, over 8 h, 5 days per week, up to 8 months. Monthly videorecordings were done under anesthesia to measure the voltage threshold for detectable movement on each side, and vocal fold displacement and velocity during maximal stimulation of each side. Movement thresholds were lower in the inferior portion of the thyroarytenoid muscle (P

Speech and oral motor learning in individuals with cerebellar atrophy.

The purpose of this study was to determine whether cerebellar pathology interferes with motor learning for either speech or novel tasks. Practice effects were contrasted between persons with cerebellar cortical atrophy (CCA) and control participants on previously learned real speech, nonsense speech, and novel nonspeech oral-movement tasks. Studies of limb motor learning suggested that control participants would evidence reduced variability, increased speed of movement, and reduced movement amplitude with practice as compared with the CCA group. No significant differences were found between the real- and nonsense-speech tasks. For both speech tasks, although neither group reduced their movement variability with practice, both groups significantly reduced jaw closing displacement and velocity with practice. For the novel nonspeech oral-movement task, no change with practice was observed in either group in terms of variability, amplitude, or peak velocity. No effects of cerebellar pathology were seen in either the speech- or oral-movement tasks. These results demonstrated that with practice of speech tasks, a previously learned motor skill, movement speed and displacement decreased in both groups. Therefore, the effects of practice differed between previously learned speech tasks and the novel oral-movement task regardless of cerebellar pathology.

Three-dimensional changes in the upper airway during neuromuscular stimulation of laryngeal muscles.

During swallowing, airway protection depends upon adequate glottal closure and laryngeal elevation to prevent the entry of substances into the airway. Three-dimensional changes in the upper airway during laryngeal muscle stimulation in a canine model were quantified in animals implanted with Peterson type stimulating electrodes in the inferior and superior portions of the thyroarytenoid muscle, together with a reference electrode. Computer tomography scanning was performed on an IMATRON scanner with a 3 mm slice thickness advanced at overlapping 1 mm increments. Stimulation of the thyroarytenoid muscle produced adductions of the vocal fold towards the midline and changes in the supraglottic region as well as the glottis; the glottic wall was compressed medially above and below the glottis. These results suggest that chronic neuromuscular stimulation can effect glottic protection by reducing the glottal opening and may be beneficial for patients with central control disorders affecting airway protection during swallowing.

Laryngeal afferent stimulation enhances Fos immunoreactivity in periaqueductal gray in the cat.

The main functions of the larynx are protection of the airways, respiration, and vocalization. Previous studies have suggested a link between the mechanisms controlling vocalization and afferent feedback from the larynx. We inquired whether stimulation of the laryngeal afferents that run in the internal branch of the superior laryngeal nerve (ISLN) activates neurons of the periaqueductal gray (PAG), a midbrain region implicated in vocalization. We counted the number of neurons expressing Fos, the protein product of the immediate early gene c-fos, in the PAG. The counts were done both in experimental cats after electrical stimulation of the ISLN and nonstimulated controls. We also investigated the possible presence of nitric oxide synthase, an enzyme that synthesizes nitric oxide, in PAG neurons that respond to laryngeal afferent stimulation by double labeling for reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase and Fos. Fos expression was significantly greater (P < or = 0.00714) in the lateral and dorsolateral regions of the PAG in the experimental group than in the controls. The Fos-immunoreactive neurons did not contain NADPH-diaphorase, a marker for nitric oxide synthase. Our study suggests that laryngeal afferent stimulation activates neurons in discrete longitudinal columns of the PAG including the regions that have previously been shown to be involved in vocalization, and that these neurons do not contain nitric oxide synthase.

Laryngeal long latency response conditioning in abductor spasmodic dysphonia.

Previously, we demonstrated that patients with adductor spasmodic dysphonia (ADSD) have a disinhibition of laryngeal responses to sensory input. In this study, sensorimotor responses to stimulation of the superior laryngeal nerve were compared between 10 subjects with abductor spasmodic dysphonia (ABSD) and 15 normal volunteers. The groups had similar latency and frequency characteristics of their unconditioned adductor responses (p>.05). The conditioned R1 (early) responses of the subjects with ABSD were greater and more variable in amplitude than those of the normal volunteers (p< or =.008). Similar R2 (late) conditioning effects were found in both groups, with a nonsignificant trend toward reduced inhibition of contralateral R2 responses at lower interstimulus intervals (p = .01) in the patient group. Thus, inhibitory mechanisms that modulate the R1 laryngeal sensorimotor pathway in the brain stem may be abnormal in subjects with ABSD. Abnormal modulation of laryngeal sensorimotor responses seems present in both types of spasmodic dysphonia.

Glutamate receptor subunits in the nucleus of the tractus solitarius and other regions of the medulla oblongata in the cat.

The nucleus of the tractus solitarius (NTS) is a primary termination zone for laryngeal, gustatory, cardiovascular, respiratory, gastrointestinal, and other visceral afferents. Although considerable information is available on the neurochemical aspects of the NTS in general, very little is known about glutamate receptors that may underlie many of the different functions mediated by the NTS. In addition, most previous glutamate receptor distribution studies were performed in the rat, whereas the cat, the subject of many physiological experiments involving the NTS, has received little attention. In the present study, the immunohistochemical distribution of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-selective glutamate receptor subunits (GluR1, GluR2/3, GluR4) and the N-methyl-D-aspartate (NMDA) receptor subunit NR1 in the cat caudal brainstem was investigated by using subunit-specific antibodies. In the NTS, statistically significant differences were seen in the distribution of each antibody. Highest labeling was seen for GluR2/3 in most subnuclei, whereas GluR1-immunoreactive neurons were found more frequently than were NR1- or GluR4-immunoreactive neurons. GluR1 immunolabeling was particularly high in the interstitial subnucleus, whereas GluR2/3 immunolabeling was particularly high in the intermediate subnucleus. Qualitatively, labeling for GluR4 was most common in glia. The present results indicate that glutamate receptors show different subunit distributions in the subnuclei of the NTS and in other adjacent structures. This finding suggests that neurons in these structures are designed to respond differently to excitatory input.