Clinical manifestations

Presentation and course

The onset of laryngeal dystonia is insidious in most patients (84%), initially presenting as nonspecific hoarseness with gradual worsening of vocal quality over months to years (93; 07; 200). In a small proportion of patients, the onset is sudden (93). The most common inciting events identified by patients are stress, upper respiratory infection, pregnancy, and parturition (39; 05).

Laryngeal dystonia may be divided into three types (abductor laryngeal dystonia, adductor laryngeal dystonia, and mixed type laryngeal dystonia), depending on the specific intrinsic laryngeal muscles that are most affected. Adductor laryngeal dystonia is the most common form and accounts for up to 82% of cases (24). Abductor laryngeal dystonia occurs in 17% of cases, and the mixed type (both abductor and adductor laryngeal dystonia) is rare (25).

If the adductor muscles (thyroarytenoid, lateral cricoarytenoid, or interarytenoid muscles) are affected, then the laryngeal dystonia is termed “adductor laryngeal dystonia.” Quick glottic closure, because the adductor muscles spasm closed, interrupts airflow during phonation leading to breaks during vowels. The result is a classic strained, strangled speaking pattern (123). If the abductor musculature (posterior cricoarytenoid muscles) is affected, the laryngeal dystonia is termed “abductor laryngeal dystonia.” Patients have spasms when transitioning to a voice after a voiceless consonant. Prolonged vocal fold abduction during the voiceless consonant and spasms of the vocal cords in the open position prevent the rapid closure of the vocal cords during transition to vowels. The result is a breathy, effortful speaking pattern with poor generation of volume.

There is less consensus on the features of adductor laryngeal dystonia than the features of abductor laryngeal dystonia (124). Only 53% of 46 laryngeal dystonia specialists agreed that intermittent glottal stops were a feature of adductor laryngeal dystonia, and 47% agreed that patient report of speaking effort was a feature of adductor laryngeal dystonia. Of 46 laryngeal dystonia specialists, 97% agreed that intermittent breathy breaks are a feature of abductor laryngeal dystonia.

Tremor may coexist with dystonia in as many as one third of patients (108), although this is more common in females (152). Fine wire electromyography has revealed that both the thyroarytenoid and the lateral cricoarytenoid muscles might be affected in adductor laryngeal dystonia, even if the thyroarytenoid is more predominant (106). The thyroarytenoid and lateral cricoarytenoid muscles are equally involved in laryngeal dystonia with tremor (106).

Patients may have a mixed laryngeal dystonia with both adductor and abductor musculature affected, which may result in speech with both phonatory breaks from adductor spasms and breathy breaks from adductor spasms.

Laryngeal dystonia most commonly affects normal speech, typically in the normal talking range of pitch, volume, and speed. Laughing, whispering, screaming, and yawning may normalize the voice. Voice improvements also occur when the patient is taken by surprise or in sudden danger. These characteristics are likely related to the task-specific nature of dystonia. Vocal spams occur during speaking, but not during emotional vocalization (laughing, crying, shouting) because of the difference in the human vocalization system and human speech system. The neural systems involved in speech, which is learned, are likely not involved in emotional vocalization, which is an innate trait. The vocalization system includes the anterior cingulate, the periaqueductal gray, and the reticular system in the medulla and the laryngeal motor neurons in the nucleus ambiguous (97). On the other hand, the human speech system includes the laryngeal motor cortex to the laryngeal motor neurons in the nucleus ambiguous, the corticobulbar tract, the frontal opercular speech system, the primary motor cortex, the supplementary motor area, the posterior temporal gyrus, and the supramarginal gyrus (113; 191).

Some patients report that sensory tricks, such as touching the larynx, supporting the head, or lying down may improve speech. The fluency may also be improved by speaking in a higher pitch. Vacation often brings an improvement whereas stress can worsen vocal quality. Some patients report sedatives or consumption of alcohol reduce symptoms, although this is more characteristic of vocal tremor (103). Most patients report voice worsening with speaking in public or on the telephone (89).

Table 1. Factors Influencing Subjective Severity of Laryngeal Dystonia

Reports of task-specific laryngeal dystonia occurring only with singing (singer’s laryngeal dystonia) have also been described (24). Respiratory laryngeal dystonia results in laryngeal adductor spasms during respiration. Patients with this form of dystonia usually complain of dysphonia, but also dyspnea and inspiratory stridor, although not usually hypoxia (203).

Prognosis and complications

Laryngeal dystonia tends to emerge gradually in midlife and then reaches a plateau in terms of severity. Spontaneous remission has not been reported in laryngeal dystonia, which can be seen with cervical dystonia (128).

Untreated laryngeal dystonia may be associated with increased psychological comorbidity. A study of 44 patients with adductor laryngeal dystonia revealed substantial degrees of perceived handicap and low perceived control of the condition (98). Rates of anxiety and depression appear to be higher in patients with laryngeal dystonia and other voice disorders compared to the general population (216). In an analysis of 142 patients receiving botulinum toxin injections for laryngeal dystonia, anxiety was present in 13.4%, and depression was present in 2.8% (84).

Laryngeal dystonia can functionally affect work productivity (89). Patients with laryngeal dystonia report a 20% to 30% mean decrease in voice-related work productivity, which is ameliorated after treatment with botulinum toxin injections (141). The work productivity decreases are mainly in the form of presenteeism (140). Additionally, individuals with laryngeal dystonia reported seeking jobs without high voice demands and avoiding communication (16). However, a study using the Communication Participation Item Bank questionnaire showed that changes in communicative participation were not statistically significant, pre- and post-botulinum toxin treatment (58). The authors attributed this finding to demographic variables and different levels of access to care within their studied population.

Other studies show that treatment alters functional disability and quality of life. Hoogikyan and colleagues reported improvements in voice-related quality of life scores before and after treatment with botulinum toxin (80), although these results were not replicated in a study of individuals over the age of 65 (217).

However, botulinum toxin, the treatment for laryngeal dystonia, wears off after a variable period of time (2 to 6 months). Therefore, repeated treatment is needed, possibly lifelong. According to a national survey, most practitioners who provide botulinum toxin injections for laryngeal dystonia work at an academic care center (135). This may limit access to repetitive treatment and cause burden and loss of work productivity for those who live in more rural or remote areas.

Clinical vignette

Case 1. The patient in his late 40s was working in law enforcement and doing a sting operation at a warehouse location. On-site, there was a lot of construction dust. He began to have vocal difficulties that he felt were due to laryngitis from irritant exposure, but his voice did not return even when he moved to a different project location. His voice continued to deteriorate and became more strained and effortful. About 10 years later, he saw a speech-language pathologist with some improvement in his voice. He then noticed that while on amusement-park rides with his grandchildren, his voice was reproducibly normal. His speech-language pathologist accompanied him to the amusement park to witness this change in his voice and, thus, diagnosed him with laryngeal dystonia. He did not seek treatment until 2013 and was initially treated with 1 unit of botulinum toxin A to the bilateral thyroarytenoid muscles. He had significant breathiness and some difficulty with swallowing, and his dose was reduced. Currently, he receives an asymmetrical dose of 0.15 units of botulinum toxin A to one thyroarytenoid muscle and 0.25 units of botulinum toxin A to the contralateral thyroarytenoid muscle with vocal improvement from 40% to 50% normal function at baseline (when the effects of botulinum toxin have dissipated) to 80% to 90% of normal vocal function at the peak effect of the botulinum toxin injection with minimal breathiness or dysphagia.

Case 2. A 43-year-old female reported acute onset of voice changes in July 2016. She endorsed a strained effortful and “garbled” voice quality. She noted improvement in vocal quality with singing and with alcohol consumption. She was seen by her local ENT and referred to a speech-language pathologist and then further referred to the university for evaluation and management. As the vice president of her community college who frequently spoke to large groups, she had an extraordinary demand for voice use and quality in her vocational capacity. She was a nonsmoker and was otherwise healthy, with no other medical problems and no family history of neurologic disorders.

The patient was diagnosed with adductor laryngeal dystonia and initially treated with LEMG-guided botulinum toxin injections with a good effect. But after 2 years of treatment, she struggled with her injections causing too much initial breathiness and a shorter-than-desired duration of peak voicing. She was changed to an endoscopic approach to her injections and currently receives botulinum toxin injections to the bilateral thyroarytenoid and to the interarytenoid musculature. Her total dose is 2.5 units every 10 weeks of which she typically experiences 1 week of initial breathiness and mild dysphagia to liquids and 9 weeks of effect. She reports 4 weeks of peak voicing (90% to 100% of normal function), with a gradual decline to her baseline of 15% to 20% of normal function.

Biological basis

Etiology and pathogenesis

Classifying laryngeal dystonia as a medical disorder rather than psychiatric is attributed to Dedo after a recurrent laryngeal nerve resection (45). Nevertheless, the etiological and pathophysiological mechanisms underlying laryngeal dystonia are not known. Histologic analysis of the recurrent laryngeal nerves in two patients who underwent recurrent laryngeal nerve resection revealed no apparent signs of either destruction or degeneration; however, the percentage of thin nerve fibers (diameter ranging from 5 to 10 microns) was higher than in normal controls (110). In another study, slight morphometric differences were found between the recurrent laryngeal nerve removed from patients with laryngeal dystonia and control recurrent laryngeal nerves in two groups, but these cannot explain causation of laryngeal dystonia (36).

Focal dystonias, such as laryngeal dystonia, are generally thought to be due to dysfunction in the basal ganglia. However, there is evidence to suggest that laryngeal dystonia is caused by abnormalities of large-scale brain networks, rather than due to pathology limited to the basal ganglia (67).

Postmortem brainstem examination in two patients with laryngeal dystonia revealed several neuropathological changes compared to controls (191). This included small clusters of inflammation in the reticular formation surrounding the solitary tract, spinal trigeminal nuclei, and in the pyramids in addition to neuronal degeneration and depigmentation in the substantia nigra and locus coeruleus.

Neurophysiological studies reveal that patients with adductor laryngeal dystonia have a shortened cortical silent period compared with healthy controls (171; 172; 199). Cortical silent period is the temporary interruption of electromyographic signal from a muscle with resulting interruption of voluntary muscle contraction after transcranial stimulation of the contralateral motor cortex, which is a way of measuring intracortical inhibition within the primary motor cortex. The laryngeal dystonia patient has abnormal blink reflex recovery, further pointing to a loss of inhibitory control (40). Loss of inhibitory control is also seen in many other focal dystonic conditions (151), and the underlying defect may be impaired inhibition at the cortical level leading to a decrease in the requirement for activation with voluntary motor commands (37). Measurements of excitability over the dominant primary motor cortex during “linguistic” and “non-linguistic” tasks following transcranial magnetic stimulation have been shown to differ in patients with laryngeal dystonia compared with healthy controls (199). Following treatment with botulinum toxin, there is restoration of these changes (199). A study utilizing EEG found excessively large synchronization between somatosensory and premotor cortical areas in patients with laryngeal dystonia (101).

Sharbrough and colleagues described abnormal auditory brainstem responses in 7 of 18 patients with laryngeal dystonia, indicating slower brainstem conduction along the auditory pathway (184). In another study of six patients with adductor laryngeal dystonia using the auditory brainstem response, five of six patients had a compromised capacity of the auditory brainstem to conduct impulses (64). In a study of 12 patients with laryngeal dystonia using three different auditory brainstem response parameters, 75% were abnormal. Three of the 12 had prolonged wave I–V interpeak latency, and seven had pathologic wave V latency shifts at a high stimulus rate (177). These findings were not confirmed by Middleton in a study of 14 patients with laryngeal dystonia with normal hearing (142).

Devous and colleagues suspected that in laryngeal dystonia, there was a dysfunction of cortical perfusion, cortical electrophysiology, or both, based on quantitative topographic electrophysiologic mapping and SPECT (50). Hirano and colleagues suggested that the functional deficit of the supplementary motor area might be related to laryngeal dystonia (78). Studying a 59-year-old male patient with adductor type laryngeal dystonia during phonation with PET, Hirano and colleagues noted remarkable activities during phonation in the left motor cortex, Broca area, cerebellum, and the auditory cortices, whereas the supplementary motor area was not activated. In normal subjects, significant activities were observed during vocalization in the supplementary motor area, whereas the auditory association area was not activated, even though the subjects heard their own voice (76). Similar to patients with laryngeal dystonia, normal subjects showed activation in the motor area, Broca area, and the cerebellum. The auditory association area was not activated during normal vocalization but came to be activated when the speaker’s own voice was distorted (76; 77), as is the case with the laryngeal dystonia strained voice. As the supplementary motor area is known to function for motor planning, programming (164) is usually activated in normal phonation, and damage of the supplementary motor area causes a severe disturbance of voluntary vocalization.

When functional MRI (fMRI) measurements were performed during vocal motor tasks in patients with laryngeal dystonia and compared with healthy volunteers, reduced activation of primary sensorimotor as well as premotor and sensory association cortices during vocalization in patients with laryngeal dystonia were noted (72). Another study utilizing fMRI found reduced functional connectivity between the left inferior parietal cortex, putamen, and bilateral premotor cortex (15).

Gray matter volume, cortical thickness, and brain activation on fMRI were increased in the laryngeal sensorimotor cortex, inferior frontal gyrus, superior or middle temporal and supramarginal gyri, and cerebellum in a study of 40 patients with laryngeal dystonia compared with controls (192). Phenotype-specific abnormalities have been reported in adductor and abductor forms of laryngeal dystonia on high-resolution MRI and diffusion-weighted imaging. Differences in cortical thickness and white matter fractional anisotropy were observed in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiate (20). In addition, genotype-specific abnormalities were seen between sporadic and familial cases in the left superior temporal gyrus, the supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus.

Lenticular nucleus hyperechogenicity has been observed on transcranial sonography in patients with laryngeal dystonia (213). A study examining a combination of independent component analysis and linear discriminant analysis of resting-state functional magnetic resonance imaging data found abnormal functional connectivity within sensorimotor and frontoparietal networks in patients with laryngeal dystonia compared with control subjects (14). In addition, differences in abnormal functional connectivity appeared to distinguish between the different clinical phenotypes of laryngeal dystonia, as well as between the genetic and sporadic forms. Differences in cortical surface area have also been described in subjects with laryngeal dystonia compared with control subjects in regions associated with sensorimotor integration, motor preparation, and motor execution, as well as in areas of processing of auditory and visual information (111).

In a PET study using [11C] raclopride (RAC) to assess striatal dopaminergic neurotransmission, patients with laryngeal dystonia demonstrated decreased RAC displacement during symptomatic speech production compared with controls, indicating decreased dopaminergic transmission (189). RAC displacement was increased during the unaffected task of asymptomatic tapping, possibly representing a compensatory adaptation of the nigrostriatal dopaminergic system.

Epidemiology

The prevalence of primary laryngeal dystonia is estimated to be 5.9 per 100,000 (10). Laryngeal dystonia occurs more often in women than in men (25; 194; 02). The overall ratio ranges between 1.4 to 3.8 females to 1 male (25; 194). In one series, women made up to 79.3% of the population with laryngeal dystonia (02). In another series, laryngeal dystonia has a female preponderance (77.6%), with an average age of onset at 51 years (152). Males make up a larger percentage of the abductor laryngeal dystonia population than the adductor laryngeal dystonia population. Broken down into subgroups, the female-to-male ratio was 4.1:1 for adductor laryngeal dystonia and 2.2:1 for abductor laryngeal dystonia (182). Izdebski and colleagues reported that in a series of 200 patients with laryngeal dystonia, the age of onset was 41 years (+13.25 SD), with a range of 6 to 65 years for males, and 45.4 years (+13.3 SD), with a range of 7 to 78 years for females (93).

Factors associated with an increased risk of laryngeal dystonia, in small or isolated case-controlled studies, include a past history of mumps, blepharospasm, tremor, and intense occupational voice use (201); a personal history of cervical dystonia, sinus and throat illnesses, rubella, and dust exposure (202); a family history of voice disorders and tremor (25); an immediate family history of vocal tremor and meningitis; and an extended family history of head and neck tremor, ocular disease, and meningitis (202).

Prevention

There are no known methods to prevent laryngeal dystonia.

Differential diagnosis

Confusing conditions

The differential diagnosis of laryngeal dystonia is broad and includes both organic disorders and functional disorders. Table 2 lists some differential diagnoses of laryngeal dystonia. Essential voice tremor and muscle tension dysphonia can cause voice breaks; thus, they can form the most important differential diagnoses.

Vocal tremor, a condition acoustically characterized by low-frequency oscillations in voice, can occur in isolation or as a component of essential tremor. Essential tremor is a progressive action tremor and consists of involuntary and rhythmic movements at 4 to 12 Hz of one or more antagonistic muscles or muscle groups. It affects approximately 1% of all people and nearly 5% of those older than 65 years (122). Eighteen to 30% of patients with essential tremor have a vocal tremor (197). The movement disorder in vocal tremor is rhythmic rather than spasmodic. In addition to the intrinsic laryngeal muscles, it often involves pharyngeal and strap muscles. Lundy and colleagues found that unlike laryngeal dystonia, tremor is more often marked by fluctuations in frequency rather than just in intensity (126).

Muscle tension dysphonia, a functional dysphonia, may also mimic the strained voice quality of abductor laryngeal dystonia (83). Evidence of consistent sound-specific phonatory breaks should raise suspicion of adductor spasmodic over muscle tension dysphonia. The hyperadduction of muscle tension dysphonia is generally sustained and is unlikely to be spasmodic. Although differences between muscle tension dysphonia and adductor laryngeal dystonia have been described on fiberoptic laryngoscopy, phonatory airflow measurement, and acoustic analysis, there is currently no single diagnostic test to differentiate these two disorders (169).

Careful auditory perceptual voice evaluation can help differentiate these diagnoses. One key difference is that neither vocal tremor nor muscle tension dysphonia demonstrate task specificity, whereas laryngeal dystonia does (present with talking as opposed to laughing and singing). The voice may deteriorate with stress in all conditions. Laryngeal endoscopy helps in the differential between laryngeal dystonia, vocal tremor, and muscle tension dysphonia; however, the diagnosis may be challenging in some cases. Even among experts, there can be notable variation when diagnosing patients with laryngeal dystonia, vocal tremor, or muscle tension dysphonia. In one study, international experts were asked to classify the vocal diagnosis of 178 patients across four different sites into 11 categories (124). The experts reviewed a portion of these patients’ video-laryngeal endoscopy and speech recordings, but due to a lack of diagnostic guidelines, there was poor interrater agreement regarding patient diagnoses.

In psychogenic dysphonia, another functional dysphonia, there are often several atypical characteristics, including loss of normal shouting, yawning, and laughing. Psychogenic dysphonia also does not present with tremor (119). In psychogenic dysphonia, the vocal symptoms are more often invariant across phonetic and most phonatory variables and not associated with sound prolongations or voice arrests (119). In one study, psychogenic speech and voice disorders were found to occur in 16.5% of 182 patients with psychogenic movement disorders. Among these patients, stuttering was the most common speech abnormality (n = 16, 53.3%), followed by speech arrests (n = 4, 13.3%), foreign accent syndrome (n = 2, 6.6%), hypophonia (n = 2, 6.6%), and dysphonia (n = 2, 6.6%) (11).

Vocal cord polyps or other mass lesions of the vocal cord can cause dysphonia characterized by strain and vocal breaks. These lesions would be visualized and diagnosed on laryngeal endoscopy.

There are also reports of stridor resulting from laryngeal dystonia, and in some cases, this may be misdiagnosed as asthma (204).

A form of dysphonia similar to laryngeal dystonia has also been described in dominantly inherited ataxia with dentate calcification, currently assigned the name “spinocerebellar ataxia type 20” (107).

Table 2. Differential Diagnosis for Laryngeal Dystonia

Associated or underlying disorders

Laryngeal dystonia may occur as an isolated dystonia or as part of generalized dystonia (133; 95; 73; 03; 132; 156). Yet, most patients with laryngeal dystonia present only with the vocal dysfunction, without neurologic manifestations in other areas of the body (25). Most commonly, laryngeal dystonia occurs sporadically, and there are no associated or underlying disorders. Laryngeal dystonia less frequently occurs in the setting of segmental or generalized dystonia. The reported prevalence of extralaryngeal dystonia in patients with laryngeal dystonia varies from 5% to 14% (69; 152). In one series that included 901 patients with vocal involvement, 82.5% had primary dystonia and 17.5% had secondary dystonia (25). In another series, 15.8% of patients with laryngeal dystonia had spread of dystonia, all of whom developed cervical dystonia (19). In another study, patients with cough, disordinate breathing, paroxysmal sneezing, and hiccups were found to have a higher incidence of extralaryngeal dystonia (155).

Several causative genes have been identified in familial dystonic syndromes that cause generalized dystonia, which have risk of components of laryngeal dystonia (48). Careful clinical characterization of the dystonic syndrome allows accurate phenotype-genotype correlation and may assist in identifying an underlying genetic diagnosis. Despite these familial dystonic syndromes having components of laryngeal dystonia, genetic screening of patients with laryngeal dystonia targeted at mutations in TOR1A, THAP1, and TUBB4 has a low diagnostic yield (70; 48).

Other reported associations include neuroleptic exposure, either immediately or as part of the tardive syndrome (214; 06), mitochondrial disease (157), valproic acid administration (with improvement after discontinuation) (150), central pontine myelinosis (183), amyotrophic lateral sclerosis (168), psychogenic dysphonia (176; 11), late-onset laryngeal dystonia with low arylsulphatase A (134), essential tremor (121), palatal myoclonus (56), hereditary spastic paraplegia type 7 (71), multiple sclerosis (53), or trauma (63).

Diagnostic workup

Possibly because of the unfamiliarity of the disease, there is often a delay in diagnosis and patients are seen by multiple physicians prior to a definitive diagnosis. One study showed that patients had over a 4-year delay from initial presentation to a physician for vocal concerns to reaching a diagnosis of laryngeal dystonia (41). Another study from Japan showed that in 60% of patients, the diagnosis of laryngeal dystonia was delayed for more than 2 years (87).

Understanding of the nature of the symptoms, including onset, aggravating factors, alleviating factors, associated symptoms, duration of symptoms, and the character of symptoms is the focus of the history and helps lead to a correct diagnosis.

Table 3. Voice History and Symptoms of Laryngeal Dystonia

History, physical examination, and laryngeal stroboscopy are all critical components of the diagnostic algorithm, but the most important component is the auditory perceptual evaluation of voice (138). The primary modality to assess laryngeal dystonia is by listening to the patient speak during conversational speech and during elicited speech tasks with either vowel or voiceless consonant predominant sentences (99). Listening to the patient reading sentences that are designed specifically to elicit either adductor or abductor spasms is also helpful. One should assess the fluidity of the voice, the quality of articulation, and the quality of the vocal signal. A normal voice should be smooth, without voice breaks or spasm.

Adductor laryngeal dystonia phrases or sentences would include words with vowels or voiced sounds such as:

Abductor laryngeal dystonia phrases or sentences would include words with vowels following a voiceless consonant (such as d, f, h, p, s or t). A breathiness is heard as a speaker transitions from a voiceless consonant to a voiced sound.

Some clinicians have patients read the phonetically balanced “rainbow passage”:

Other measures of voice quality, which may provide further characterization of laryngeal dystonia, include the IINFVo (Impression, Intelligibility, Noise, Fluency, and Voicing) perceptual rating scale and the AMPEX (Auditory Model Based Pitch Extractor) acoustical analysis (186). Measurements in perceptual, acoustic, and self-assessment dimensions all demonstrate significant improvement in symptoms following botulinum toxin therapy, which is the standard of care. However, these three parameters were found to have poor intrinsic correlation; thus, a tridimensional approach may be preferable (49). Another study found that the latency between the initiation of thyroarytenoid electrical activity and the onset of phonation was significantly related to the severity of adductor laryngeal dystonia (43). The technique of airflow interruption may also provide additional quantitative information regarding laryngeal function in laryngeal dystonia (79). One study examining the perceptual structure of adductor laryngeal dystonia and the acoustic correlates of underlying perceptual factors identified a two-factor model of adductor laryngeal dystonia, characterized by hyperadduction and hypoadduction (35). Perceived ratings of roughness appeared to be most representative of the hyperadduction factor, whereas breathiness was most strongly associated with the hypoadduction factor. Onset of relative fundamental frequency measures were found to be related to perceived vocal effort in patients with adductor laryngeal dystonia in another study (57). Cepstral analysis and machine-learning algorithms have been able to distinguish between patients with laryngeal dystonia and controls and between pre- and post-botulinum toxin treated patients (198).

Although the primary modality to assess laryngeal dystonia is listening to the patient speak during conversational speech, a physical examination is essential for the evaluation. Attention should be paid to a complete neurologic examination. Laryngeal dystonia usually presents without other neurologic findings, so any tremor, weakness, or cranial nerve neuropathy should prompt further neurologic evaluation. In the setting of associated clinical features, such as segmental dystonia, tremor, or gait disturbance, careful clinical characterization of the phenotype may provide clues to an underlying genetic dystonic syndrome (see etiology and pathogenesis).

Spasms can be visualized during adductor and abductor laryngeal dystonia. Because laryngeal dystonia is a disorder of connected speech, transnasal rather than transoral laryngoscopy should be performed. In a study in which experts were provided videos, audios, and both, the diagnostic accuracy of laryngeal dystonia was 10%, 73%, and 73%, respectively (42). Based on this, laryngoscopy is most important for ruling out additional types of dysphonia diagnoses. Small vocal fold cysts and polyps may result in alteration of the voice, and stroboscopic examination may help determine the lesion’s contribution to the patient’s vocal complaints. The addition of a laryngeal stroboscopic assessment to the endoscopic imaging will allow a detailed evaluation of the vibratory function and architecture of the vocal folds, regardless of diagnosis.

Because spasms may be too quick to visualize on laryngoscopy, high-speed video endoscopy can help. Chen and colleagues were able to detect a rapid sustained adduction shortly after onset of phonation in a small sample of patients with adductor laryngeal dystonia compared to muscle tension dysphonia (38). Tsuji and colleagues described the findings of one patient with high-speed video laryngoscopy where there was a regular vibratory cycle followed by a spasm in which there was an increase in the closed phase and then a period in which the glottic cycle phases could not be identified (208).

Researchers have tried to identify modalities to diagnose laryngeal dystonia and differentiate it from muscle tension dysphonia, but these have not gained wide clinical use. One study suggested that the long-term average spectrum (LTAS), a tool that assesses the average amplitude spectrum across a selective frequency range and provides information on the spectral distribution of the speech signal over a period of time, may identify spectral noise differences between muscle tension dysphonia and adductor laryngeal dystonia in women (83). The use of neural network and support vector machine–based methods, in combination with a pattern recognition algorithm, has also been studied (179). Fine kinemetric analysis from high-speed digital imaging may assist in the clinical differentiation of adductor laryngeal dystonia and muscle tension dysphonia, although further studies are required (154).

Electromyography (EMG) measures muscle electrical activity in response to stimulation. In a study of patients with adductor laryngeal dystonia, Yang and colleagues found there were increased amplitudes of the motor unit recruitment potentials and evoked potentials of the thyroarytenoid muscles (219). Another study did not support this finding (211). When combined with acoustic channels, there may be a delay from the onset of the electrical activity on EMG with the onset of the acoustic output in laryngeal dystonia (188). A neurolaryngology study group in 2009 concluded that there is not enough evidence to support EMG being used as a diagnostic tool (29).

Management

Botulinum toxin. Botulinum toxin injections are the mainstay of treatment for laryngeal dystonia. Blitzer and colleagues performed the first botulinum toxin treatment on a patient with spasmodic dysphonia in 1986, and their work was confirmed by a subsequent double-blind study (26; 207). The American Academy of Otolaryngology-Head and Neck Surgery as well as the American Academy of Neurology endorses botulinum toxin as primary therapy for spasmodic dysphonia.

Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum that prevents the release of acetylcholine from the nerve ending at the neuromuscular junction. The result is a partial paralysis of the injected muscle. The toxin is made of a heavy and a light chain. The heavy chain allows the neurotoxin to be endocytosed into the neuron. Once within the neuron, the light chain binds to the SNARE proteins. SNARE proteins allow acetylcholine-containing vesicles to fuse at the nerve terminal to exocytose acetylcholine.

There are eight different types of toxins produced by Clostridium botulinum (A, B, C1, C2, D, E, F, and G). Type A is the most potent, and type B is the second most potent.

Five different botulinum toxin products are available on the market. Four of these toxins are botulinum toxin type A and include Botox® (Allergan, Inc., Irvine, California, United States), Dysport® (Ipsen Ltd., Slough, Berkshire, United Kingdom), Xeomin® (Merz Pharmaceuticals, United States), and CBTXA (China). Myobloc®/Neurobloc® (Solstice Neurosciences, Inc., South San Francisco, California, United States) is botulinum toxin type B. In the United States, the available preparations include Botox®, Xeomin®, and Myobloc®/NeuroBloc®.

Neutralizing antibodies to botulinum toxin can develop. Injections of botulinum toxin type B can be safely and effectively used in patients with antibodies to type A (01).

There are different techniques of laryngeal botulinum toxin injection. The most common is the EMG-guided percutaneous approach (143). Injections can also be performed using external landmarks, termed the “point-touch technique” (145). Injections under direct visualization, either by endoscopy or mirror examination, include a transoral approach (65), a percutaneous approach, and a transnasal approach (161). Others use laryngoscopic control in addition to EMG (207). A national survey of delivery methods of botulinum toxin injections for adductor laryngeal dystonia showed that an overwhelming majority (88%) of laryngologists use EMG guidance, 9% use anatomic landmarks, and very few (3%) use endoscopic guidance (185). Injections can be bilateral, unilateral, staggered, or with asymmetrical doses (136; 206; 210).

The thyroarytenoid muscle is most commonly injected for adductor laryngeal dystonia, although injections can be performed to any of the intrinsic laryngeal adductor muscles (thyroarytenoid, interarytenoid, lateral cricoarytenoid). Additionally, supraglottic injection of botulinum toxin to the false vocal folds is a treatment for adductor laryngeal dystonia (193). As there is only one muscle involved in vocal cord abduction, this muscle (the posterior cricoarytenoid) is injected for abductor laryngeal dystonia.

To perform the EMG-guided percutaneous approach to the thyroarytenoid muscle, a Teflon-coated injection needle is connected to the EMG machine. Typically, a 25-gauge needle is utilized. The needle is inserted just off midline (2–3 mm) through the space between the cricoid and thyroid cartilages, pointing towards the ipsilateral thyroarytenoid muscle. Bending the injection needle by 30 to 45 degrees can ease access to the muscle. The localization of the needle is verified by crisp motor unit potentials heard on EMG when the patient performs a long “/i/” (143; 32). The EMG activity is sustained during the phonation (75).

The EMG-guided percutaneous approach to the lateral cricoarytenoid muscle is similar to the EMG-guided percutaneous approach to the thyroarytenoid muscle. The needle is inserted further off midline in the cricothyroid space, at the junction of the cricoid cartilage and thyroid cartilage. After passing through the cricothyroid space, the needle is pointed towards the ipsilateral lateral cricoarytenoid muscle, and the location is confirmed with auditory feedback on the EMG machine during a sustained “/i/”. In this case, the EMG will show an increase and rapid drop-off in EMG activity, as the lateral cricoarytenoid muscle is responsible for the initial setting of the vocal cord position (75). A cadaver study showed that ultrasound-guided injection of the lateral cricoarytenoid muscle is feasible and precise (180).

Botulinum toxin injection into the interarytenoid muscle is additionally performed with EMG guidance. Topical anesthesia to the larynx is typically required, however. The needle is passed through the cricothyroid space and into the subglottis. A distinct air signal will be heard on the EMG when the needle is in the airway. The needle is then directed upwards towards the interarytenoid muscle. Insertional activity signal will be heard on the EMG machine when the muscle is entered, followed by recruitment activity during a sustained “/i/”.

Injections into the false vocal cords can be performed in various ways, all under direct visualization without EMG guidance. A flexible needle can be threaded through the working channel of a transnasal laryngoscope and the injection performed through this needle. However, this requires a large amount of liquid to prime the needle. Another approach is the peroral approach in which a flexible nasolaryngoscopy is performed to visualize the larynx. Then an orotracheal injector with a needle is passed perorally. The needle is visualized by the flexible laryngoscope and directed into the false vocal folds. Lastly, a thyrohyoid approach can be used in which a 25-gauge needle is advanced through the thyrohyoid membrane and under direct visualization with a flexible nasolaryngoscope; the needle is directed into the false vocal fold. In all approaches, the depth of injection is within the submucosal plane. This results in a bleb seen below the mucosa (193). Nasal anesthesia and decongestant are utilized during this procedure, in additional to laryngeal and airway anesthesia.

The injection of botulinum toxin into the posterior cricoarytenoid muscle for abductor laryngeal dystonia is more challenging. Injection techniques usually include translaryngeal EMG guidance and laryngeal rotation (27), endoscopic guidance (165), and transcricoid rostrum (136), or a combination approach. As opposed to confirming the position of the needle with a sustained “/i/”, the position within the posterior cricoarytenoid muscle is confirmed with crisp motor unit potentials heard on EMG when the patient sniffs, which further abducts the vocal cords.

In the translaryngeal EMG-guided approach to injection of the posterior cricoarytenoid, the needle is passed through the skin overlying the cricothyroid membrane, through the airway, and through the posterior cricoid plate into the posterior cricoarytenoid muscle. Visualization with laryngoscopy is often utilized to improve the accuracy of the injection. As the mucosa of the airway is violated, topical anesthesia to the glottis and subglottis is typically required.

For the laryngeal rotation technique, the physician rotates the larynx to expose the posterior aspect of the thyroid cartilage. The needle is passed posterior to the thyroid lamina, along the lower half of the thyroid cartilage/superior border of the cricoid cartilage, until the needle hits the posterior surface of the cricoid. EMG auditory feedback is used to confirm the position.

Typically, unilateral posterior cricoarytenoid muscle injections are performed. A major concern for bilateral injections is bilateral vocal fold abductor weakness and the consequent narrowing of the airway for adequate respiration. Simultaneous bilateral posterior cricoarytenoid injections have also shown success in improving vocal outcome measures (105). Successful outcomes have also been reported using an initial unilateral posterior cricoarytenoid muscle injection, followed by a contralateral injection after 2 weeks, if necessary (24).

Botulinum toxin doses. Doses of botulinum toxin used for the treatment of laryngeal dystonia vary depending on the practitioner and the brand of toxin used. In the early literature, the doses of botulinum toxin (Botox^®) into the thyroarytenoid muscle for adductor laryngeal dystonia ranged from 3.75 to 7.5 U for bilateral injections (34; 32; 33; 207) to 15 U for unilateral injections (143; 125). Up to 50 U per vocal cord has been used (96). Later literature and common practice have recommended the use of lower doses (30). In the authors’ experience, a chemodenervation-naive patient is started on botulinum toxin A at a dose of 0.5 to 1 unit in the bilateral thyroarytenoid muscle for the adductor laryngeal dystonia. This starting dose is based on Blitzer's original work (26). In one retrospective study of 126 patients, the mean dosage of onabotulinumtoxinA was 1.54 +/- 0.35 units per side (66).

Injection into the false vocal cords is typically at higher doses--anywhere from 5 to 10 units per false vocal fold (193).

The optimal dose of botulinum toxin varies between patients and does not appear to correlate with severity of laryngeal dystonia, age, or gender. In one study, BMI and overall health were correlated with a higher effective dose (220). Higher doses were required for symptom control in female patients with adductor laryngeal dystonia compared to males in one retrospective chart review, although the reasons for this observation are unclear (118). The dose of botulinum toxin required for the treatment of adductor laryngeal dystonia tends to remain stable over time (167). In one retrospective study, patients with adductor laryngeal dystonia who received long-term injections appeared to have an initial reduction followed by stabilization in their dosage (147). Those who have a fluctuating dosing trend tended to have a shorter interval between injections.

Patients are warned about potential coughing with liquids and breathy vocal quality, which typically last no more than a week. They are then instructed to return when their voice breaks start to worsen. At that time, at the authors’ institution, they are asked to judge their best voice on a scale of 0% to 100%, with 100% being a completely normal voice and 0% being no voice at all. They are then asked about any initial side effects and how long those symptoms lasted. At that point, the decision is made to increase or decrease the botulinum toxin dose or change the injection interval.

There appears to be a lower rate of resistance with botulinum toxin in laryngeal dystonia compared with other dystonias, and this may be related to the low antigen challenge associated with the low doses used (144).

Surgery. After recognition of the organic etiology of laryngeal dystonia, the development of recurrent laryngeal nerve resection confirmed the neurologic basis of the disease process. The first patient to undergo recurrent laryngeal nerve resection was a woman with a 17-year history of laryngeal dystonia who had been treated by more than 29 physicians from different specialties without improvement. Blocking of the recurrent nerve with lidocaine improved her spasm, whereas placebo injections did not improve the patient’s voice (45). After five repeated reproducible results with lidocaine, the patient underwent sectioning of the right recurrent laryngeal nerve with essentially normal voice within 1 week after the procedure, with the help of speech therapy.

Another less invasive procedure involved crushing the recurrent nerve, which initially appeared to be equally effective. Gross recurrent laryngeal nerve destruction is no longer a contemporary management for laryngeal dystonia, although this procedure is of great historical importance regarding the recognition that this disease has a neurologic and not psychiatric pathophysiology.

For adductor laryngeal dystonia, selective laryngeal adductor denervation-reinnervation (SLAD-R), first described in 1999 (18), involves selective denervation of the adductor branch of the recurrent laryngeal nerve. The distal nerve stumps are reinnervated with a nonlaryngeal nerve, generally the sternohyoid branches of the ansa cervicalis nerve (137).

Isshiki and colleagues offered an apparently mechanical solution to the problem of hyperadduction in adductor laryngeal dystonia with laryngeal framework surgery (92; 90). In this procedure, a lateralization laryngoplasty, or type II thyroplasty, is performed by means of a midline division and expansion of the thyroid cartilage.

Bilateral thyroarytenoid muscle myectomy is also used in the treatment of adductor laryngeal dystonia. Successful treatment of adductor laryngeal dystonia has also been reported in a small series of patients using selective lateral laser thyroarytenoid myotomy (86; 68). Sustained improvements in voice handicap index and GRBAS scale have been observed following endoscopic laser thyroarytenoid myoneurectomy (209; 68).

Surgical treatment for abductor laryngeal dystonia is more nuanced and has been less described in the literature. Bilateral vocal fold medialization, or type I thyroplasty, has been used by some.

Deep brain stimulation for adductor laryngeal dystonia is described for the treatment of laryngeal dystonia in a phase 1 clinical trial (81). A phase 2 clinical trial of deep brain stimulation for laryngeal dystonia is currently being conducted.

Other therapeutic modalities. Voice therapy has been reported to be helpful in conjunction with botulinum toxin treatment to retrain a long-term compensatory behavior superimposed on laryngeal dystonia (146), although this has not been consistent. Significant improvement with speech therapy may suggest an alternate diagnosis of muscle tension dysphonia (13). In a systematic review of 21 studies of voice therapy in patients with laryngeal dystonia, the adherence rate was quite low (about 60%) (131).

Although to a lesser degree than in the past, many patients with laryngeal dystonia are still subjected to psychiatric treatment. Psychotherapy is useful to help coping with social stresses, which can be considerable; the patient, however, needs to be made aware first that his or her condition is an organic disorder and to be treated accordingly either with botulinum toxin or surgery. Acupuncture has not been proven effective by expert raters, although Lee and colleagues found many patients reported subjective improvements in voice production (116). Electrical stimulation of the thyroarytenoid muscle was reported to improve symptoms in one small case series (158). An open-label study of sodium oxybate demonstrated reduced voice symptoms in alcohol-responsive laryngeal dystonia in those with and without coexistent voice tremor (170); unfortunately, the medication is expensive and only has a duration of up to 3 or 4 hours, which has limited more common clinical use (190).

Outcomes

As noted above, botulinum toxin injection is the mainstay of treatment for laryngeal dystonia, with positive outcomes. Treatment with botulinum toxin leads to a reduction in spasmodic contractions observed on video laryngoscopy (59). Yet, lower functional gain was noted in patients with dystonia in other body regions (130). A meta-analysis of 30, mostly single-blind studies, indicated moderate overall improvement as a result of botulinum toxin treatments (31). The Cochrane Collaboration Review noted that although only one study (207) out of the nearly 77 reports was double-blind and fulfilled their inclusion criteria, most of the studies had similarly positive effects (215). In one series of 131 patients, 67 of 574 injections (12%) were categorized as failures: failure was associated with injection by a new physician, the patient being a professional voice user, and a lack of breathiness in the voice after injection (221).

Improvement after injection with botulinum toxin for adductor laryngeal dystonia is realized an average of 2.4 days after injection; the average peak benefit occurs at 9 days post injection (28). For abductor laryngeal dystonia, the average onset of effect is 4.1 days, with a peak effect at 10 days.

For adductor laryngeal dystonia, the positive benefit of botulinum toxin injections lasts for approximately 15.1 weeks (28). The mean duration of benefit is 10.5 weeks for those with abductor laryngeal dystonia (28). Most insurance companies only allow for botulinum toxin injections every 3 months (four times per year). However, there are a considerable subset of patients who require short interval treatment to optimize their outcomes. In a study, 27.5% of patients required injections less than 90 days apart (short interval) while not showing an increased side effect profile (114). These patients were statistically younger than those who did not require short-interval botulinum toxin injections.

In the largest treatment series in 2010, patients with adductor laryngeal dystonia reported an improvement to 91.2% of normal with botulinum toxin injection (24). Treatment of abductor laryngeal dystonia was less satisfactory, with patients reporting an improvement to 70.3% of normal. Another study noted average subjective phonation improvement of 33% with adductor laryngeal dystonia (130). In another study examining outcomes of onabotulinumtoxinA, 88.1% of injection cycles for 328 patients with adductor laryngeal dystonia were noted to be maximally beneficial (153).

A meta-analysis showed significant improvement in several quality-of-life measures after treatment with botulinum toxin, including the Voice Handicap Index (VHI) and Voice-Related QoL scales (59; 60). Furthermore, patients on an established botulinum toxin injection routine have been shown to have high degrees of general and disease-specific self-efficacy, a concept that combines self-esteem and locus of control (85). Furthermore, the higher the self-efficacy, the lower the VHI and levels of anxiety and depression.

Possible complications from botulinum toxin injections into the thyroarytenoid musculature include breathiness, throat pain, and dysphagia. Initial functional decline following botulinum toxin injection was observed in 28.5% of cases (149). In a series of 1300 patients over 24 years of age, adductor injections were associated with a 25% risk of mild, transiently breathy voice and a 10% risk of transient coughing with drinking fluids. Breathy dysphonia has been reported to be as high as 50.9%, lasting on average 20 days (54). Local pain, bruising, and itch were reported in less than 1% of individuals (24). Rarely, bilateral abductor paralysis has been reported and is likely a result of toxin diffusion around the muscular process of the arytenoid to the posterior cricoarytenoid muscles (212).

There are some data to suggest that botulinum toxin is less effective in patients with concurrent vocal tremor (149). Patients with adductor laryngeal dystonia and associated vocal tremor may benefit from combined interarytenoid and thyroarytenoid muscle botulinum toxin injections (100). Botulinum toxin injections into the interarytenoid muscle have a 50% response rate in patients previously unresponsive to traditional injection sites (99).

Voice after supraglottic false vocal fold botulinum toxin injection for adductor laryngeal dystonia is significantly improved without the side effect of a period of a significantly breathy voice initially after injection (193).

Different protocols have been proposed for injecting botulinum toxin into the thyroarytenoid muscle, either unilaterally or bilaterally. Initial dosages of 1.25 units bilaterally of onabotulinumtoxinA resulted in a statistically significant shorter duration of breathiness without significant differences in clinical effectiveness or voice outcome in one study, compared with an initial dosage of 2.5 units bilaterally (166). Unilateral injection may result in fewer adverse events, such as breathiness or hoarseness (109; 21). Unilateral injections improve the performance ratio of strong voice interval divided by breathy voice interval (109). Upile and colleagues found that low-dose unilateral injections resulted in no significant difference in patient outcome in terms of voice duration, voice score, and complication rate when compared with bilateral injections (210). However, another study found that bilateral injections had a significantly higher proportion of patients than unilateral injections (36% vs. 33%, p=0.0228), with both greater than 3-month duration of effect and less than 2-week duration of side effects (52). Some studies have shown that the duration of benefit in men is significantly longer and with less swallowing difficulty after bilateral injections (129). Lee and colleagues found that alternating injections to the thyroarytenoid muscle was effective, with fewer side effects than bilateral injections, although the treatment effect was shorter (117). This was additionally supported by Stone and colleagues, who found that unilateral botulinum toxin injections reduce side effects without sacrificing improved voice outcomes, although with a shorter duration of improvement (196). Interestingly, they also studied bilateral injections with different doses to each side and found that this can extend the duration of effect, although with more side effects compared to a unilateral injection (196). Another study also found that the side effect profile was better for unilateral injections, but the authors concluded that bilateral injections had a better side effect/optimal effect profile (52).

Recurrent laryngeal nerve sectioning initially showed remarkable therapeutic results. Dedo reported the results of sectioning of the recurrent laryngeal nerve in 34 patients (45). Short- and mid-term results were good, with a recurrence rate of 10% to 15%, respectively (94; 46; 47). Long-term results showed a gradual decline in benefit from the procedure. Crushing of the recurrent laryngeal nerve also from widespread recurrence of symptoms had a success rate of 13% at 3 years (22).

The initial reports of selective laryngeal adductor denervation-reinnervation (SLAD-R) presented favorable results in 19 of 21 patients (18). Only one patient underwent further treatment with botulinum toxin postoperatively. Positive results using expert and untrained judge’s perceptual evaluation of the voice were also reported in a smaller series (04). Additional studies have also reported favorable results after a mean follow-up time of 7.5 years (137). Functional reinnervation of the vocal cord adductors by ansa cervicalis has been observed 10 years after successful SLAD-R surgery (44).

Isshiki reported success in a small series with informal judgments regarding voice quality by both patients and physicians after type II thyroplasty (92; 90). A further small study using laryngeal framework surgery also resulted in significant acoustic and aerodynamic improvement in adductor laryngeal dystonia (175). Follow-up after 2 to 5 years revealed unsatisfactory outcomes in 7 of 90 cases and were mainly attributed to inadequate technique and, in one case, an incorrect indication (173). Surgical mechanical faults appear to be the main cause of unsuccessful outcomes (91). Another long-term follow-up study (average of 41.3 months) following type II thyroplasty demonstrated sustained improvement in voice symptoms and quality of life (174).

One study found no difference in the postoperative Voice Handicap Index 10 score between patients who underwent bilateral thyroarytenoid muscle myectomy compared to those who received type II thyroplasty (148). Bilateral thyroarytenoid muscle myectomy appeared to improve strangulation, interruption, and tremor but worsened breathiness when compared to type II thyroplasty.

In one case series, six patients underwent vocal fold medialization via type 1 thyroplasty and demonstrated significant benefit on Voice Handicap Index (VHI) and Voice-Related Quality of Life (VR-QOL) measures. The four patients who had undergone the procedure at least 1 year prior to their survey reported a sustained benefit to their symptoms (51). One patient with staged bilateral posterior cricoarytenoid partial myoneurectomy demonstrated sustained benefit up to 8 years postoperatively (17).

Deep brain stimulation of the globus pallidus internus (GPi) resulted in improvement of segmental dystonia, including laryngeal dystonia in one patient, with maintenance of symptom control at 10-year follow-up (82). Some patients with primary dystonia with a component of laryngeal dystonia had no benefit to their laryngeal dystonia with GPi stimulation (88). One patient with essential tremor and adductor laryngeal dystonia had sustained benefit to her laryngeal dystonia with bilateral ventral intermediate (Vim) nucleus of the thalamus stimulation (127). Another patient with essential tremor and coincident adductor laryngeal dystonia treated with unilateral thalamic deep brain stimulation experienced significant improvement in vocal dysfunction with isolated Vim and combined Vim and ventral oralis anterior (Voa) nucleus of the thalamus (159). Honey and Kruger have reported promising results with bilateral thalamic deep brain stimulation (112; 81).

With regards to voice therapy, one study did not demonstrate additional benefits in patients receiving voice therapy compared to those receiving botulinum toxin alone or to those who received botulinum toxin with sham voice therapy (187). Further studies are required to confirm these results.

Laryngeal vibrotactile stimulation temporarily improved symptoms in 9 of 13 patients (102). This improvement was associated with a suppression of theta band power in the left somatosensory motor cortex, similar to what is seen during successful sensory tricks.

Special considerations

Pregnancy

Pregnancy has been associated with the sudden onset of adductor laryngeal dystonia in small studies (05). Botulinum toxin injections are not given to women who are pregnant or breastfeeding.

Anesthesia

Laryngeal spasms associated with laryngeal dystonia will relax under sedation or anesthetic; thus, there are no additional considerations for anesthesia in abductor laryngeal dystonia or adductor laryngeal dystonia.