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Insights into Focal Laryngeal Dystonia: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 3 by Jessie Wu.

Focal laryngeal dystonia (LD) is a rare, idiopathic disease affecting the laryngeal musculature with an unknown cause and clinically presented as adductor LD or rarely as abductor LD. The most effective treatment options include the injection of botulinum toxin (BoNT) into the affected laryngeal muscle. 

  • spasmodic dysphonia
  • dystonia
  • laryngeal dystonia

1. Patho- Neurophysiology of Focal Laryngeal Dystonia

1.1. Neural Structures and Function

Although the pathophysiology of focal laryngeal dystonia (LD) is not fully known, it has been suggested that LD is a functional and structural disorder involving a complex neuronal network comprising basal ganglia structures, the thalamus, and their connections with cortical areas, the cerebellum, and sensorimotor cortex [1][2][3][4][5][6][7]. Alterations in activity of speech-related areas mediating motor preparation and execution were reported in the primary motor cortex for oro-laryngeal muscle representation, the middle frontal gyrus, the inferior frontal gyrus (i.e., Broca’s area) [3][5][8][9][10][11][12], and the temporal [3] and parietal brain areas [13]. Further, the adductor and abductor laryngeal muscle movements are under the voluntary control of the corticobulbar tract projecting to the nucleus ambiguous of the brainstem. Alterations in the microstructural and functional integrity of the corticobulbar tract descending pathway from the primary motor cortex for representation of laryngeal musculature to the brain stem nuclei involved in voice/speech production might also be implicated in the pathophysiology of LD [6]. Processing of auditory and visual information during speech might also have a role in the pathophysiology of LD [10][11].

1.2. Knowledge of the Neurophysiological Basis of Focal Laryngeal Dystonia

Neurophysiological studies indicate altered inhibitory mechanisms in LD, as with cervical dystonia and focal dystonia of the hand. More precisely, cSP has been reported to be shortened in laryngeal thyroarytenoid muscle patients with adLD [14][15]. The cSP is measured as the duration of the electrical silence in the laryngeal muscle during vocalization and the simultaneous application of a single magnetic pulse with TMS at an intensity greater than the resting motor threshold (RMT) for the upper extremity hand muscle [14]. The cSP duration is a measure of GABAB-mediated inhibition of the motor cells of the primary motor cortex through the activity of inhibitory interneurons located within the superficial cortical layers of the primary motor cortex [14]. Decreased inhibition in the primary motor cortex may be due to dysfunction that may also occur in other cortical or subcortical areas that send projections to the primary motor GABAB inhibitory interneurons [14]. Thus, decreased inhibition of GABAB within the primary motor cortex may result from the dysregulation of neural circuits that consequently affect the balance of excitation and inhibition in the primary motor cortex [14]. There is no convincing and reliable evidence of changes in other neurophysiological measures such as the RMT or the active motor threshold in LD [14][15]. There are insufficient studies using TMS in patients with LD that could provide information on neurophysiological measures other than cSP, such as inhibitory measures of long-interval intracortical inhibition (LICI), short-interval intracortical inhibition (SICI), and short and long afferent latency inhibition (SAI, LAI). LICI is a paired-pulse technique with a conditioned magnetic pulse on intensity above the threshold and test stimuli (intensity below the threshold) applied in intervals between 50–200 ms leading to the suppression of cortical activity (suppression of motor evoked potential amplitude). SICI is a paired-pulse technique with a conditioned pulse below the threshold and test stimuli (above the threshold) applied in intervals between 1.5–2.1 ms leading to the suppression of cortical activity (suppression of motor evoked potential amplitude) [16][17]. There are no data for LICI and SICI in LD. SAI and LAI are techniques that can induce the suppression of motor evoked potential amplitude by applying an electrical pulse to the periphery (median nerve) followed by a magnetic pulse over the primary motor cortex (usually induced at an interstimulus interval of N20 ms + 2 for SAI and LAI is induced at an interstimulus interval of about 200 ms). SAI and LAI measures relate to GABAA transmission [16][17][18]. So far, there is evidence of reduced afferent inhibition in focal dystonia of the arm or cervical dystonia [19][20][21][22].
Decreased afferent-induced inhibition indicates abnormal sensorimotor integration within the primary motor cortices, which is not surprising as it is known that the processing of sensory (sensorimotor) information in dystonia is altered. The presence of a sensory gesture (in cervical dystonia) also suggests abnormal reliance on sensorimotor networks and a potential mechanism for alleviating dystonic contraction. Understanding the mechanisms leading to reduced afferent-induced inhibition in isolated dystonia may provide new therapeutic goals that could be explored in future research to alleviate sensorimotor symptoms. Future neurophysiological studies with transcranial magnetic stimulation (TMS) should use more homogenous cohorts of adLd and abLD subjects and publish raw data values of corticobulbar motor evoked potentials from affected and non-affected laryngeal muscles, cSP, SICI, and SAI measures.

2. Focal LD Treatment Options

2.1. Standard Treatment with Botulinum Toxin (BoNT)

Botulinum toxin is a natural neurotoxin produced by the bacteria Clostridium botulinum that causes muscular paralysis. The primary mechanism of action of the toxin is via the inhibition of calcium-dependent exocytosis and the release of acetylcholine at the neuromuscular junction [23]. The effect of botulinum toxin is reversible because the nerve terminals recover the ability to release acetylcholine into the neuromuscular junction. Two types have been developed for clinical use in humans: type A has the longest duration of effect and diffuses less from the injection point compared with type B. The dosing differs significantly between type A and type B preparations. The most common type of botulinum toxin used in LD therapy is type A (Botox, Allergan, Irvine, CA, USA; Dysport, Ipsen, Ltd., Slough, UK). Adverse effects of botulinum toxin treatment may result from over-weakening of the intended target muscle and unintended weakening of the surrounding muscles. Therefore, both appropriate dosing and the tissue distribution of the toxin are crucial. In general, the dose is proportional to the targeted muscle mass, although the range of therapeutic dosing is typically highly variable [24]. Some patients get the best results from a unilateral dose and others from bilateral treatment. For example, in bilateral injections for adLD, therapeutic doses range from 0.3–15 U per thyroarytenoid muscle, although most adLD is well controlled with doses of 0.625–2.5 U [25]. The American Academy of Otolaryngology-Head and Neck Surgery (“AAO-HNS”) considers botulinum toxin a safe and effective modality for the treatment of LD, and it may be offered as primary therapy for this disorder. The goal of treatment is to give an injection that will provide just enough weakness to relieve spasm in the target muscles for as long as possible without causing unnecessary weakness in neighboring muscles resulting in dysphagia, and prolonged breathiness (adductor), or airway compromise (abductor) [26]. There are a variety of injection approaches to deliver botulinum toxin to the larynx: percutaneous injection with EMG guidance (most traditional), percutaneous with laryngoscopic guidance, and supraglottic botulinum toxin injection with laryngoscopic guidance. For adLD, the intrinsic laryngeal injection muscles are the thyroarytenoid, lateral cricoarytenoid, and interarytenoid muscles. These muscles can all be accessed through the cricothyroid membrane. For the thyroarytenoid muscle, it is helpful to bend the needle upward to 30–45°. The needle is inserted through the skin either at or just off the midline. The needle tip is then directed superiorly and laterally, advancing towards the ipsilateral thyroarytenoid muscle. The cricothyroid membrane is palpated to inject into the lateral cricoarytenoid muscle, and the needle is placed through the cricothyroid membrane in this location and is angled superiorly. Further, the lateral cricoarytenoid muscle is more lateral than the thyroarytenoid muscle and is encountered more superficially. For abLD, the posterior cricoarytenoid muscle can be accessed anteriorly by piercing through the cricoid rostrum or laterally by rotating the larynx. The lateral approach to the cricoarytenoid muscle requires a relaxed patient, preferably with a relatively thin neck. The patient must tolerate the clinician applying moderate pressure/force on their larynx to rotate the posterior aspect of the cricoid into a position to allow access. The needle is inserted traversing the pyriform sinus and inferior constrictor, then it is further advanced until it stops abruptly against the cricoid cartilage’s rostrum [27][28].

2.2. The Long Term Effects of Botulinum Toxin

Although botulinum toxin is generally considered safe, its widespread use and the constantly expanded indications raise safety issues. In February 2008 and April 2009, the Food and Drug Administration (FDA) published an early communication regarding botulinum toxin type A and botulinum toxin type B, informing physicians that these drugs have been associated with systemic adverse reactions, including respiratory compromise and death resembling those seen with botulism, in which botulinum toxin spreads to the body beyond the injection site [29]. In 2005, the FDA raised safety issues regarding botulinum toxin in a published analysis of adverse events covering the period from 1989 to 2003. According to that publication, there were 407 adverse event reports related to the therapeutic use of botulinum toxin (median dose of 100 units), 217 of which met the FDA’s definition of serious adverse events. Few data on the long-term adverse events of botulinum toxin were identified. Most of them concern the therapeutic use of botulinum toxin. Long-term safety data indicate that toxic effects of botulinum toxin can appear at the 10th or 11th injection after prior uncomplicated injections. The longest follow-up study of 45 patients continuously treated with botulinum toxin for 12 years identified 20 adverse events in 16 patients, including dysphagia, ptosis, neck weakness, nausea/vomiting, blurred vision, marked weakness, chewing difficulties, hoarseness, edema, dysarthria, palpitations, and general weakness [30]. Diffusion of botulinum toxin to contralateral muscles has also been reported. Animal studies have shown that botulinum toxin can spread to a distance of 30–45 mm from the injection site [30]. However, generalized diffusion of botulinum toxin is possible, especially after long-term therapeutic or cosmetic use. The effects of generalized diffusion are not well studied. The mechanism responsible for the generalized diffusion of botulinum toxin is not known. Proposed hypotheses concern either a systemic spread or a retrograde axonal spread of the toxin. Systemic toxin spread can lead to adverse events suggesting botulism, including muscle weakness or paralysis, dysarthria, dysphonia, dysphagia, and respiratory arrest.
Additionally, experimental studies in rodents have shown that botulinum toxin receptors exist in the central nervous system, and a small amount of botulinum toxin crosses the blood-brain barrier [31]. This raises the possibility that botulinum toxin is transported in a retrograde manner, similar to tetanus toxin, and may cause centrally mediated side effects [32]. Davidson and Ludlow [33] studied whether physiological changes can be found in laryngeal muscles following repeated treatment with botulinum toxin injections in spasmodic dysphonia. Seven patients whose treatment consisted of multiple unilateral thyroarytenoid injections were examined more than six months following their most recent botulinum toxin injection by fiberoptic laryngoscopy and electromyography. Comparisons were made between injected and contralateral noninjected muscles’ motor unit characteristics, muscle activation patterns, and vocal fold movement characteristics. The results demonstrated that motor unit characteristics differed between injected and noninjected muscles and that these differences were more significant in patients less than 12 months since the last injection. Motor unit duration differences were reduced, and motor unit amplitude and numbers of turns were increased in muscles sampled over one year after injection. These results suggest that while the physiologic effects of botulinum toxin are reversible, the re-innervation process continues past 12 months following injection [33]. Repeated injections may eventually enhance the pathological innervation, leading to tolerance and even exacerbation of local symptoms.
Moreover, they cause muscle fibrosis after several years, though such an effect has not been shown in shorter follow-ups so far [34] Resistance to botulinum toxin due to the development of antibodies to the toxin has also been reported as a long-term adverse event of the therapeutic use of botulinum toxin [34]. Immunoresistance develops within the first years of therapy. It is unlikely to develop if immunoresistance to botulinum toxin is not noted within the first four years.

2.3. Review of the Literature on Botulinum Toxin and Deep Brain Stimulation (DBS) Treatment

Table 1 presents findings of BoNT treatments of LD and an overview of the literature on invasive brain modulation with deep brain stimulation (DBS) [35][36][37][38][39]. The efficacy and safety of BoNT were established for the treatment of LD, and this approach is considered by most to be the treatment of choice for spasmodic dysphonia/LD, particularly adLD [40]. Most studies report about 75–95% improvement in voice symptoms after BoNT [39][41]. Invasive brain stimulation with the DBS of unilateral or bilateral globus pallidus internus (GPi) or subthalamic nucleus (STN) has been approved by the FDA for the treatment of drug-refractory generalized, segmental, and cervical dystonias and hemidystonia [42][43][44], as well as for the treatment of essential tremor in adult patients whose tremor is not adequately controlled with medication. Table 1 presents patients with essential tremor and LD treated with DBS [36][37][38]. Generally, it is agreed that LD may show a poorer response to DBS [45][46].
Table 1.
 Literature overview on standard BoNT therapy and invasive brain modulation treatment effects.
Literature No

Subjects		 Age Sex (M/F) Laryngeal Dystonia (Adductor/Abductor) Clinical Presentation Medical Treatment Medical Treatment Outcome
Santos et al. [35] 1 61 F Adductor Tense voice, vocal tiredness, breathy

voice, laryngeal pain, loss of voice extension, lack

of frequency control		 5U of type A

Botulin Toxin (Botox) in the left thyroarytenoid muscle		 Increased respiratory capacity and maximum speech time
Evidente et al. [36] 3 74

71

65		 F

F

M		 Adductor Essential hand tremor with laryngeal dystonia Bilateral ventralis intermedius (VIM) DBS Could easily phonate with no vocal tremor,

improvement of USDRS scores post-DBS compared to pre-DBS, and with stimulator

on compared to stimulator off
Krüger et al. [37] 2 85

73		 F Adductor Essential limb tremor with laryngeal dystonia Bilateral ventrointermediate (VIM) nucleus DBS of the thalamus Unanticipated improvement of their SD symptom; powerful unilateral benefit in both

patients; hand dominant related probably
Poologaindran et al. [38] 1 79 F Adductor Right upper limb tremor with laryngeal dystonia Left ventral intermediate (VIM) nucleus of the thalamus Significantly improved SD vocal dysfunction compared with no stimulation (DBS off), as measured by the USDRS and VRQOL
Stewart et al. [39] 60 6078 42 F

18 M		 Adductor Roughness, strain-strangled voice quality, and increased expiratory effort BoNT Subjects reported benefit from BoNT injections, and had self-selected to return for continuing BoNT management of their voice symptoms when the benefits of the BoNT injections had diminished
Abbreviations: Unified Spasmodic Dysphonia Rating Scale (USDRS); voice-related quality of life (VRQOL).

2.4. Pharmacological Treatment Possibilities and Effectiveness in Dystonia Treatment

The most commonly used dystonia treatment, BoNT, has some limitations, e.g., it is painful for patients and can cause swallowing difficulties. Therefore, there is still an unmet need for effective dystonia pharmacological treatment [19]. The currently available pharmacological treatment involves medicines that act on gamma-aminobutyric acid (GABA), dopamine, or acetylcholine neurotransmitter pathways. Furthermore, novel treatments are also mainly focused on the same neurotransmitter pathways central in dystonia pathophysiology. However, most of the widely used drugs among dystonia patients still have low levels of efficacy evidence [47][48].
Trihexyphenidyl, one of the most commonly used anticholinergic drugs, is the treatment of choice for childhood-onset dystonia, as it has been usually well tolerated in this patient group. It could also be used in adults. The daily dose should be determined empirically but it most commonly ranges between 5–15 mg, though, if tolerated, dosages could be much higher (100 mg is the maximal daily dose recommended). The initial dosage is usually 1 mg, and then it should be increased by 2 mg every 3–7 days divided into three daily doses. The major concern regarding its use is the possibility of trihexyphenidyl to increase intraocular pressure which leads to vision blurring and possibly narrow-angle glaucoma. Other not so uncommon adverse reactions are sedation, memory impairment, psychosis, chorea, blurred vision, urinary retention, constipation, and dry mouth. Levodopa, in combination with carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a widely used dopaminergic drug in dystonia patients. The dose and titration are similar to their use in mild Parkinson’s disease (slow titration till daily doses of 300–400 mg of levodopa divided in three doses, starting with 50 mg of levodopa). The most common side effects are low blood pressure, nausea, confusion, and dyskinesia. Lastly, as adjunctive therapy, GABA agonists are used to relaxing muscles in dystonia patients. The most commonly used benzodiazepines in LD patients are clonazepam, diazepam and lorazepam [47]. A maximal recommended daily dose of clonazepam is 4 mg divided into 2–3 doses. The start is usually with 0.25–0.5 mg 2–3 times a day, and then the dosage is slowly increased every 3–5 days to 0.5 mg. The most common side effects are sedation, depression, nocturnal drooling, and behavioral disinhibition. Caution must be taken because abrupt discontinuation can trigger seizures. There are several other potential dystonia treatment alternatives described in the literature. The first one would be a medication that acts as vesicular monoamine transporter 2 inhibitors (VMAT2). The well-known representative of this medication group is tetrabenazine. Furthermore, the other medication groups are as follows: sodium oxybate; antihypertensive medication clonidine; antiepileptic’s gabapentin; zonisamide; antidepressant escitalopram, a selective serotonin reuptake inhibitor; and hypnotic medication zolpidem. Future therapies of dystonia should involve gene therapy aimed at the specific genes of dystonia patients [48][49].
Sodium oxybate is a sodium salt of g-hydroxybutyric acid used to treat narcolepsy, excessive sleepiness, and disturbed nighttime sleep. A study by Simonyan et al. [50] suggests that this medication has direct modulatory effects on abnormal neural activity of the dystonic network. This medication can raise blood pressure values due to the sodium content. However, research has shown a low frequency of cardiovascular adverse drug reactions and no association with cardiovascular risk [51]. Other than the cardiovascular risk in general, due to the symptoms of the disease, dystonia patients are prone to anxiety and depressive comorbidities, and the use of escitalopram could seem reasonable in patients with existing symptoms [52].

2.5. Future Neuromodulation Treatment Options and Vibrotactile Stimulation

The effectiveness of repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, in assessing cortical excitability and inhibition of laryngeal musculature might be one of the potential treatment options for LD. Previous neurophysiological findings demonstrated decreased intracortical inhibition in patients with adLD compared to healthy controls [14][15]. Application of low frequency (inhibitory) rTMS to the LMC might decrease the over-activation of the laryngeal muscles [53]. Given that adductor LD has been found to be associated with decreased cortical inhibition and that 1 Hz is known to increase intracortical inhibition, the purpose of the pilot study by Prudente et al. [53] was to examine the effects of 1200 pulses of 1 Hz rTMS delivered to LMC in people with adductor LD and healthy individuals. This is the first feasibility study testing effects of 1 Hz rTMS in LD. The authors tested only a single session of 1 Hz rTMS and observed acoustical measures changes pointing to beneficial effects on voice symptoms. Future studies would need to test the long-treatment duration of 1 Hz rTMS in LD. To test this hypothesis of the beneficial effects of five days of treatment of 1 Hz rTMS, a proof-of-concept, randomized study was recently registered on 27 October 2021 (ClinicalTrials.gov Identifier: NCT05095740, accessed day: 20 May 2022), and the estimated study completion date is 31 May 2025/2026.
Another non-invasive brain stimulation technique, transcranial direct current stimulation (tDCS), has not been reported in the assessment of LD according to the current state-of-the-art.
Further, a feasibility study was performed using vibrotactile stimulation (VTS) to treat LD [12]. The authors reported that 29 min of VTS in a one-day session improved the voice quality parameter (smoot cepstral peak prominence). Although a stimulation protocol by using VTS has been published, the optimal stimulation protocol for the treatment of LD is not yet known. After publishing a paper on a feasibility study of VTS, the authors started a clinical study, which is still ongoing, testing the effect of VTS for four weeks in patients with LD (ClinicalTrials.gov Identifier: NCT03746509, accessed day: 20 March 2022). The results have not yet been published, nor is their VTS stimulator commercially available. The same research group applied for a patent (the United States Patent Application Publication, Konczak et al., Pub. No. US 2019/0159953 A1, Pub. Date: 30 May 2019) where they protected the VTS solution of placing the vibrators on the laryngeal muscles over the skin in the form of a necklace placed around the neck.

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