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Spasmodic dysphonia: An overview of clinical features and treatment options

      Abstract

      Spasmodic dysphonia (SD) is considered a rare focal laryngeal dystonia characterized by task-specific voice dysfluency resulting from selective intrinsic laryngeal musculature hyperfunction. Symptoms may be attenuated by a sensory trick. Although SD can be seen at times in generalized dystonia syndrome, it is typically a sporadic phenomenon, and the involvement of the laryngeal adductor muscles is more common than that of the abductor muscles. This research reviews the literature for the pathogenesis, clinical characteristics, treatment options, and current management methods of SD. Technological advances have enabled clinicians to better understand the connection between laryngeal function and dysfunction. Refinements in imaging and genetic investigation techniques have helped better understand the underlying mechanisms of this neurolaryngology disorder. Currently, the standard of care for SD is the symptomatic management of botulinum toxin (BT) chemodenervation. This is supported by a large body of literature attesting to its efficacy in many different research studies, particularly in the uncomplicated adductor form of the disorder. Efforts towards surgical treatment predate the development of BT treatment by a decade, but the long-term efficacy has not been proven and, further research is expected. Symptom relief in patients with abductor SD and dystonia with tremors after surgical and BT treatments and those in patients remains suboptimal.

      Keywords

      1. Introduction

      This review focuses on spasmodic dysphonia (SD). SD is a task-specific focal dystonia characterized by intermittent and involuntary spasms of the intrinsic laryngeal muscles during phonation. Dystonia is a neurological disorder of the central nervous system (CNS) characterized by muscle spasms caused by task-specific movements. After the physicians recognized that SD was not a symptom related to psychiatric disorders, the initial treatment for this disease focused on surgically resolving vocal symptoms. However, the long-term results from this approach were not promising, and this procedure was largely replaced by temporary chemodenervation with botulinum toxin (BT). This was consistent with the initial surgical results and provided reproducible long-term benefits against retreatment. For most patients, BT treatment has proven to be a satisfactory means of achieving relief from symptoms. However, predictable control of voice symptoms may remain difficult in some patients, especially those with abductor SD or involuntary laryngeal movements with significant tremor.

      2. Background

      Laryngoscopic visualization of abnormal spasms in the adductor muscles of the vocal folds during speaking was first reported around 150 years ago [
      • Mackenzie M.
      Hoarseness, loss of voice, and stridulous breathing, in relation to nervo-muscular affectations of the larynx.
      ]. Abnormal vocal fold movements were characterized as dystonia in the 1980s [
      • Cannito M.P.
      • Johnson J.P.
      Spastic dysphonia: a continuum disorder.
      ]. Currently, SD is recognized as an idiopathic focal dystonia affecting the intrinsic laryngeal muscles. It is classified as a rare disease with a prevalence of 3.5 to 7.0 in 100,000 predominantly affecting women (4.1 to 4.4 times more likely to suffer from this disorder than men) [
      • Hyodo M.
      • Hisa Y.
      • Nishizawa N.
      • Omori K.
      • Shiromoto O.
      • Yumoto E.
      • et al.
      The prevalence and clinical features of spasmodic dysphonia: a review of epidemiological surveys conducted in Japan.
      ]. The age of onset is reportedly 30.9 years. SD presents with two main phenotypes: (a) adductor SD, which is the most common, and (b) abductor SD, which is relatively rare. Mixed SD involves the characteristics of both. Vocal tremors often coexist with SD.

      3. Pathogenic factors

      Robe et al. reported that, of the 10 patients diagnosed with SD, all had signs of CNS abnormalities [
      • Robe E.
      • Brumlik J.
      • Moore P.
      A study of spastic dysphonia. Neurologic and electroencephalographic abnormalities.
      ]. Further evidence suggested a neurological component when Dedo temporarily paralyzed the recurrent laryngeal nerve (RLN) and subsequently cut it open, after which half of the treated patients regained their normal voice [
      • Dedo H.H.
      Recurrent laryngeal nerve section for spastic dysphonia.
      ].
      Early electromyographic studies have indicated abnormalities in the motor control system [
      • Bielamowicz S.
      • Ludlow C.L.
      Effects of botulinum toxin on pathophysiology in spasmodic dysphonia.
      ]. Subsequently, dystonic movements were treated by injecting BT into the affected muscle. BT inhibits the release of acetylcholine from the presynaptic terminal to the neuromuscular junction, causing temporary paralysis, and early results showed that BT was effective in improving voice symptoms following injection [
      • Ludlow C.L.
      • Naunton R.F.
      • Sedory S.E.
      • Schulz G.M.
      • Hallett M.
      Effects of botulinum toxin injections on speech in adductor spasmodic dysphonia.
      ,
      • Adler C.H.
      • Bansberg S.F.
      • Krein-Jones K.
      • Hentz J.G.
      Safety and efficacy of botulinum toxin type B (Myobloc) in adductor spasmodic dysphonia.
      ]. Currently, BT is the primary treatment for SD worldwide [
      • Blitzer A.
      Spasmodic dysphonia and botulinum toxin: experience from the largest treatment series.
      ,
      • Hyodo M.
      • Nagao A.
      • Asano K.
      • Sakaguchi M.
      • Mizoguchi K.
      • Omori K.
      • et al.
      Botulinum toxin injection into the intrinsic laryngeal muscles to treat spasmodic dysphonia: a multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial.
      ].
      In recent years, SD has been considered a result of basal ganglia abnormalities, while the pathogenesis of SD is currently considered to involve genetic and environmental factors [
      • Balint B.
      • Bhatia K.P.
      Dystonia: an update on phenomenology, classification, pathogenesis and treatment.
      ].
      SD is characterized by its multifactorial etiology, and genetic variants are considered important risk factors for the development of this disorder. Additionally, 25.3% of SD patients reportedly have a family history of dystonia and 11.8% have a family history of other movement disorders [
      • Ozelius L.J.
      • Hewett J.W.
      • Page C.E.
      • Bressman S.B.
      • Kramer P.L.
      • Shalish C.
      • et al.
      The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein.
      ,
      • Klein C.
      • Brin M.F.
      • de Leon D.
      • Limborska S.A.
      • Ivanova-Smolenskaya I.A.
      • Bressman S.B.
      • et al.
      De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia.
      ,
      • Bressman S.B.
      Dystonia update.
      ]. Among other forms of dystonia-causing gene mutations that have been identified, laryngeal involvement has been reported in patients with generalized and segmental dystonia who are carriers of the DYT1, DYT4, DYT6, DYT25, and DYT28 mutations [
      • Walker R.H.
      • Shashidharan P.
      Developments in the molecular biology of DYT1 dystonia.
      ,
      • Blitzer A.
      • Brin M.F.
      • Simonyan K.
      • Ozelius L.J.
      • Frucht S.J.
      Phenomenology, genetics, and CNS network abnormalities in laryngeal dystonia: a 30-year experience.
      ,
      • Guiry S.
      • Worthley A.
      • Simonyan K.
      A separation of innate and learned vocal behaviors defines the symptomatology of spasmodic dysphonia.
      ]. Currently, only one case of adductor SD has been sequenced; the patient had the DYT25 (GNAL) mutation, with no other concomitant dystonia, and no family history of dystonia or other movement disorders has been reported [
      • Kirke D.N.
      • Frucht S.J.
      • Simonyan K.
      Alcohol responsiveness in laryngeal dystonia: a survey study.
      ]. This finding pointed to a genetic overlap between SD and other forms of dystonia, and suggested that gene mutations may underlie even sporadic SD presentation due to reduced penetrance. It was proposed that the stratification of patients into truly sporadic and familial cases would remain arbitrary, pending the discovery of causative gene mutations specific to SD [
      • Kirke D.N.
      • Frucht S.J.
      • Simonyan K.
      Alcohol responsiveness in laryngeal dystonia: a survey study.
      ].
      Previous neuroimaging studies have suggested that SD is associated with abnormal sensorimotor integration in the primary sensorimotor cortex, basal ganglia, thalamus, and cerebellum [
      • Simonyan K.
      • Ludlow C.L.
      Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study.
      ,
      • Ali S.O.
      • Thomassen M.
      • Schulz G.M.
      • Hosey L.A.
      • Varga M.
      • Ludlow C.L.
      • et al.
      Alterations in CNS activity induced by botulinum toxin treatment in spasmodic dysphonia: an H215O PET study.
      ,
      • Haslinger B.
      • Erhard P.
      • Dresel C.
      • Castrop F.
      • Roettinger M.
      • Ceballos-Baumann A.O.
      Silent event-related" fMRI reveals reduced sensorimotor activation in laryngeal dystonia.
      ]. These studies are important because they suggest that the pathogenesis of SD is an abnormality in the brain region that regulates speech production. Furthermore, Simonyan and Ludlow [
      • Simonyan K.
      • Ludlow C.L.
      Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study.
      ] deliberately trained healthy participants to 'imitate' the typical voice patterns of SD patients and measured their brain activity using functional magnetic resonance imaging (fMRI). The authors observed increased activation in the primary sensorimotor cortex, insula, superior temporal gyrus, basal ganglia, thalamus, and cerebellum in SD patients compared with that in controls. More recently, functional connectivity analysis using resting-state fMRI has been used as an alternative imaging method to overcome the inherent problems in comparing SD patients with healthy or non-SD participants. Particularly, Battistella et al. [
      • Battistella G.
      • Fuertinger S.
      • Fleysher L.
      • Ozelius L.J.
      • Simonyan K.
      Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia.
      ] showed abnormal functional connectivity within the sensorimotor and frontoparietal networks in patients compared to that observed in healthy individuals.

      4. Clinical characteristics

      Dystonia may be generalized or restricted to one functional muscle group. When involving the larynx, it is usually focal to that organ. SD, like other dystonias, is task-specific: that is, it affects only one type of activity performed by the larynx. Most patients usually experience the onset of symptoms beginning in their mid-30s and cases in women are more common [
      • Hyodo M.
      • Hisa Y.
      • Nishizawa N.
      • Omori K.
      • Shiromoto O.
      • Yumoto E.
      • et al.
      The prevalence and clinical features of spasmodic dysphonia: a review of epidemiological surveys conducted in Japan.
      ,
      • Blitzer A.
      • Brin M.F.
      • Stewart C.F.
      Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients.
      ,
      • Schweinfurth J.M.
      • Billante M.
      • Courey M.S.
      Risk factors and demographics in patients with spasmodic dysphonia.
      ]. Approximately 8 of the 10 patients have adductor SD, which causes improper glottal closure, and, consequently, strangled breaks in connected speech. Nevertheless, abductor SD causes inappropriate glottal opening, breathy breaks, etc. Because of the compensatory manipulation or mixed dystonic features, the voice patterns encountered clinically may not always be typical or easily identifiable.
      Diagnosis is based on the clinical history and examination of the larynx during various laryngeal tasks during phonation. Typical history includes deterioration of voice quality due to stress or telephone calls. Some patients find that certain tactile or proprioceptive maneuvers, so-called sensory tricks, such as chewing or supporting the head, can improve speech. The mechanism underlying this phenomenon is unknown. Singing or laughing may also improve the fluency of speech, perhaps taking advantage of the task-specific nature of dystonia. Occasionally, the diagnosis of SD can be difficult. There are no relevant signs in the SD patient's history or examination. Essential voice tremor and muscle tension dysphonia (MTD), a functional disorder, can cause voice breaks and form the most important entities in the differential diagnosis of this disease. The hyperadduction of MTD is generally persistent and spasmodic, whereas the dyskinesia of essential tremors are rhythmic and often involve the pharyngeal and strap muscles. Neither tremors nor MTD exhibits task specificity, but both disorders can be exacerbated by stress on the voice. In a pilot study, Kodama et al. demonstrated that voice therapy was useful in differentiating between adductor SD and MTD [
      • Kodama N.
      • Sanuki T.
      • Miyamoto T.
      • Tashiro J.
      Effects and differences of voice therapy on spasmodic dysphonia and muscle tension dysphonia: a retrospective pilot study.
      ]. Hyodo et al. formulated diagnostic criteria for SD based on the characteristics of clinical symptoms, response to treatment, and differential diagnosis and severity classification, using information from a nationwide epidemiological survey in Japan [
      • Hyodo M.
      • Hisa Y.
      • Nishizawa N.
      • Omori K.
      • Shiromoto O.
      • Yumoto E.
      • et al.
      The prevalence and clinical features of spasmodic dysphonia: a review of epidemiological surveys conducted in Japan.
      ,
      • Hyodo M.
      • Asano K.
      • Nagao A.
      • Hirose K.
      • Nakahira M.
      • Yanagida S.
      • et al.
      Botulinum toxin therapy: a series of clinical studies on patients with spasmodic dysphonia in Japan.
      ]. These diagnostic criteria need to be evaluated for validity and reliability, and a study using a disease registry is expected.

      5. Treatment options

      It is most likely due to Dedo's contribution that SD was again conceptualized as a medical disorder, when he proposed RLN section of the adductor form in 1976, after an attempt at a temporary lidocaine block [
      • Dedo H.H.
      Recurrent laryngeal nerve section for spastic dysphonia.
      ]. Biller et al. [
      • Biller H.F.
      • Som M.L.
      • Lawson W.
      Laryngeal nerve crush for spastic dysphonia.
      ] were the first to report a widespread recurrence of symptoms after RLN crush, which was initially thought to be equally effective, with a success rate of 13% at 3 years. Other researchers have noted recurrence in long-term follow-up, even with a complete RLN section [
      • Levine H.L.
      • Wood B.G.
      • Batza E.
      • Rusnov M.
      • Tucker H.M.
      Recurrent layngeal nerve section for spasmodic dysphonia.
      ,
      • Fritzell B.
      • Hammarberg B.
      • Schiratzki H.
      • Haglund S.
      • Knutsson E.
      • Martensson A.
      Long-term results of recurrent laryngeal nerve resection for adductor spasmodic dysphonia.
      ]. In 1983, Aronson and DeSanto [
      • Aronson A.E.
      • De Santo L.W.
      Adductor spastic dysphonia: three years after recurrent laryngeal nerve resection.
      ] reported a 64% recurrence rate at 3 years after superb initial results. Although some authors have obtained more stable long-term results, unsuccessful salvage strategies are being reported. These included ipsilateral superior laryngeal nerve transection, partial myectomy of the thyroarytenoid muscle, and more aggressive re-resection of the RLN [
      • Levine H.L.
      • Wood B.G.
      • Batza E.
      • Rusnov M.
      • Tucker H.M.
      Recurrent layngeal nerve section for spasmodic dysphonia.
      ,
      • Dedo H.H.
      • Izdebski K.
      Evaluation and treatment of recurrent spasticity after recurrent laryngeal nerve section. A preliminary report.
      ,
      • Netterville J.L.
      • Stone R.E.
      • Rainey C.
      • Zealear D.L.
      • Ossoff R.H.
      Recurrent laryngeal nerve avulsion for treatment of spastic dysphonia.
      ,
      • Schiratzki H.
      • Fritzell B.
      Treatment of spasmodic dysphonia by means of resection of the recurrent laryngeal nerve.
      ].
      Voice therapy does not result in marked improvement by itself, but may be useful when administered in addition to BT [
      • Murry T.
      • Woodson G.E.
      Combined-modality treatment of adductor spasmodic dysphonia with botulinum toxin and voice therapy.
      ], perhaps by addressing the compensatory behaviors that are superimposed on SD. Voice therapy is the principal therapy for MTD; however, it may be helpful as a diagnostic maneuver in ambiguous cases [
      • Kodama N.
      • Sanuki T.
      • Miyamoto T.
      • Tashiro J.
      Effects and differences of voice therapy on spasmodic dysphonia and muscle tension dysphonia: a retrospective pilot study.
      ].
      Because of the promising results of BT treatment for blepharospasm and torticollis, two focal dystonias affecting the periocular and cervical muscles, BT was first performed in SD patients in 1984. Blitzer's experience with laryngeal electromyography needles allowed him to deliver the BT into the intrinsic laryngeal muscles, effectively performing a chemical neurectomy and successfully relieving symptoms [
      • Blitzer A.
      • Brin M.F.
      • Fahn S.
      • Lange D.
      • Lovelace R.E.
      Botulinum toxin (BOTOX) for the treatment of "spastic dysphonia" as part of a trial of toxin injections for the treatment of other cranial dystonias.
      ]. The principle of this treatment, denervation, is the same as that of the RLN section, except that the relief of symptoms is temporary, but can be repeated indefinitely.

      5.1 Botulinum toxin

      The widespread success of BT as a treatment for focal dystonia may be due to the specificity, repeatability, and reversibility of chemodenervation. Nerve terminal recovery from poisoning is a continuous, multiphase process, beginning practically as soon as acetylcholine release is blocked [
      • de Paiva A.
      • Meunier F.A.
      • Molgo J.
      • Aoki K.R.
      • Dolly J.O.
      Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals.
      ]. The cycle of recovery and reinjection by BT may not overcome denervation because the CNS never reaches a stable plateau. The voice effects of this injection were sometimes found to be greater than expected from the observed in vitro activity of BT, suggesting that its clinical effect may be more than simple acetylcholine blockade at the neuromuscular junction. Some authors have hypothesized that BT may also affect neurotransmission in afferent systems [
      • Hallett M.
      How does botulinum toxin work?.
      ,
      • Byrnes M.L.
      • Thickbroom G.W.
      • Wilson S.A.
      • Sacco P.
      • Shipman J.M.
      • Stell R.
      • et al.
      The corticomotor representation of upper limb muscles in writer's cramp and changes following botulinum toxin injection.
      ]. In SD patients, changes in muscle activation are observed in both injected and non-injected muscles, further suggesting a central effect [
      • Bielamowicz S.
      • Ludlow C.L.
      Effects of botulinum toxin on pathophysiology in spasmodic dysphonia.
      ,
      • Gilio F.
      • Curra A.
      • Lorenzano C.
      • Modugno N.
      • Manfredi M.
      • Berardelli A.
      Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia.
      ].
      Although the treatment cycle of recovery and re-injection results in some clinical fluctuations in voice quality, the results are generally satisfactory, as seen in post-treatment clinician's assessment of voice function and, more importantly, patient self-assessment. Recent studies, measured using the Voice-Related Quality of Life questionnaire, a standardized patient-based outcome inventory, have demonstrated continued, albeit somewhat heterogeneous, benefits across multiple treatment sessions in patients with adductor SD [
      • Hogikyan N.D.
      • Wodchis W.P.
      • Spak C.
      • Kileny P.R.
      Longitudinal effects of botulinum toxin injections on voice-related quality of life (V-RQOL) for patients with adductory spasmodic dysphonia.
      ,
      • Rubin A.D.
      • Wodchis W.P.
      • Spak C.
      • Kileny P.R.
      • Hogikyan N.D.
      Longitudinal effects of Botox injections on voice-related quality of life (V-RQOL) for patients with adductory spasmodic dysphonia: part II.
      ].
      In 2002, a regimen of alternating unilateral injections has been offered as a means of controlling symptoms of glottic insufficiency, such as breathy voice or dysphagia, in patients with adductor SD by Bielamowicz et al. [
      • Bielamowicz S.
      • Stager S.V.
      • Badillo A.
      • Godlewski A.
      Unilateral versus bilateral injections of botulinum toxin in patients with adductor spasmodic dysphonia.
      ]. This study was reported based on the treatment of 45 patients. The same research group conducted a similar evaluation based on the course of treatment of 272 patients (total 4023 injections) [
      • Dharia
      • Bielamowicz S.
      Unilateral versus bilateral botulinum toxin injections in adductor spasmodic dysphonia in a large cohort.
      ]. They reported that optimal effect duration was more commonly seen in bilaterally injected patients (55%) compared to the unilaterally injected patients (47%) and the optimal side effect duration was better for the unilaterally injected patients (77%) compared to the bilaterally injected patients (73%). These results suggested that bilateral injections were more effective than unilateral injections. Hyodo et al. [
      • Hyodo M.
      • Nagao A.
      • Asano K.
      • Sakaguchi M.
      • Mizoguchi K.
      • Omori K.
      • et al.
      Botulinum toxin injection into the intrinsic laryngeal muscles to treat spasmodic dysphonia: a multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial.
      ] conducted a multicenter, placebo-controlled, randomized, double-blind, parallel-group/open-label clinical trial to gain approval for BT treatment for SD in Japan. Regarding this study, BT injections into unilateral and bilateral thyroarytenoid muscles for Adductor SD were approved in Japan.

      5.2 Evolving perspectives in surgical treatment

      SD has poor results associated with surgical neurolysis, as do other types of dystonia, such as blepharospasm or torticollis. Electromyographic and clinical evidence suggests that recurrence of the symptoms is due to reinnervation [
      • Fritzell B.
      • Hammarberg B.
      • Schiratzki H.
      • Haglund S.
      • Knutsson E.
      • Martensson A.
      Long-term results of recurrent laryngeal nerve resection for adductor spasmodic dysphonia.
      ,
      • Netterville J.L.
      • Stone R.E.
      • Rainey C.
      • Zealear D.L.
      • Ossoff R.H.
      Recurrent laryngeal nerve avulsion for treatment of spastic dysphonia.
      ,
      • Ludlow C.L.
      • Naunton R.F.
      • Fujita M.
      • Sedory S.E.
      Spasmodic dysphonia: botulinum toxin injection after recurrent nerve surgery.
      ,
      • Sulica L.
      • Blitzer A.
      • Brin M.F.
      • Stewart C.F.
      Botulinum toxin management of adductor spasmodic dysphonia after failed recurrent laryngeal nerve section.
      ]. To prevent this, Berke et al. [
      • Berke G.S.
      • Blackwell K.E.
      • Gerratt B.R.
      • Verneil A.
      • Jackson K.S.
      • Sercarz J.A.
      Selective laryngeal adductor denervation-reinnervation: a new surgical treatment for adductor spasmodic dysphonia.
      ] proposed selective sectioning of the distal branches of the RLN leading to the thyroarytenoid and sometimes the lateral cricoarytenoid muscle, with immediate reinnervation using a nonlaryngeal nerve, generally the sternohyoid branch of the ansa cervicalis. Thus, they attempted to prevent the reestablishment of abnormalities in central motor control by connecting the laryngeal musculature to a nerve supply that was not affected by the disorder. Their initial report presented favorable voice results in 21 adductor SD patients dissatisfied with BT treatment who were followed for an average of 3 years postoperatively. Most voices were markedly improved according to both professionals and patients. Only one patient required further BT injections. Most patients experienced breathiness for 3–6 months, but only one developed difficult aspiration. Berke and Blumin [
      • Berke G.S.
      • Blumin J.H.
      Spasmodic dysphonia: therapeutic options.
      ] subsequently reported formally on 50 additional patients with similar results. Conversely, repeatability is an important initial test for any new approach, and the literature contains reports of the same surgical results by another group. Allegretto et al. [
      • Allegretto M.
      • Morrison M.
      • Rammage L.
      • Lau D.P.
      Selective denervation: reinnervation for the control of adductor spasmodic dysphonia.
      ] treated six patients without complications and with generally favorable results, as rated by patients and both trained and untrained listeners. Five of the six patients no longer require BT treatment. Patients were followed up for a mean of 20 months.
      A transoral partial thyroarytenoid muscle myectomy and neurectomy has been reported [
      • Nakamura K.
      • Muta H.
      • Watanabe Y.
      • Mochizuki R.
      • Yoshida T.
      • Suzuki M.
      Surgical treatment for adductor spasmodic dysphonia–efficacy of bilateral thyroarytenoid myectomy under microlaryngoscopy.
      ,
      • Tsuji D.H.
      • Chrispim F.S.
      • Imamura R.
      • Sennes L.U.
      • Hachiya A.
      Impact in vocal quality in partial myectomy and neurectomy endoscopic of thyroarytenoid muscle in patients with adductor spasmodic dysphonia.
      ,
      • Tsuji D.H.
      • Takahashi M.T.
      • Imamura R.
      • Hachiya A.
      • Sennes L.,U.
      Endoscopic laser thyroarytenoid myoneurectomy in patients with adductor spasmodic dysphonia: a pilot study on long-term outcome on voice quality.
      ,
      • Schuering J.H.C.
      • Heijnen B.J.
      • Sjögren E.V.
      • Langeveld A.P.M.
      Adductor spasmodic dysphonia: botulinum toxin a injections or laser thyroarytenoid myoneurectomy? A comparison from the patient perspective.
      ,
      • Nomoto M.
      • Tokashiki R.
      • Hiramatsu H.
      • Konomi U.
      • Motohashi R.
      • Sakurai E.
      • et al.
      The comparison of thyroarytenoid muscle myectomy and type II thyroplasty for spasmodic dysphonia.
      ]. While this procedure is considered relatively safe, effective, and technically simple, a postoperative breathy voice was given as the greatest disadvantage of this procedure. Tsuji et al. [
      • Tsuji D.H.
      • Chrispim F.S.
      • Imamura R.
      • Sennes L.U.
      • Hachiya A.
      Impact in vocal quality in partial myectomy and neurectomy endoscopic of thyroarytenoid muscle in patients with adductor spasmodic dysphonia.
      ,
      • Tsuji D.H.
      • Takahashi M.T.
      • Imamura R.
      • Hachiya A.
      • Sennes L.,U.
      Endoscopic laser thyroarytenoid myoneurectomy in patients with adductor spasmodic dysphonia: a pilot study on long-term outcome on voice quality.
      ] evaluated the vocal quality in patients who underwent partial myoneurectomy and found a clear difference between The Voice Handicap Index (VHI) scores before and after surgery. Schuering et al. compared the long-term results of endoscopic laser thyroarytenoid myoneurectomy and BT treatment in 22 patients with the same adductor SD and observed no significant difference. However, at the postoperative follow-up, 10 of 22 patients (45%) required a second procedure after a mean of 18 months (interquartile range, 13–22 months) because of the recurrence of original voice symptoms [
      • Schuering J.H.C.
      • Heijnen B.J.
      • Sjögren E.V.
      • Langeveld A.P.M.
      Adductor spasmodic dysphonia: botulinum toxin a injections or laser thyroarytenoid myoneurectomy? A comparison from the patient perspective.
      ].
      Finally, Isshiki et al. [
      • Isshiki N.
      • Tsuji D.H.
      • Yamamoto Y.
      • Iizuka Y.
      Midline lateralization thyroplasty for adductor spasmodic dysphonia.
      ,
      • Isshiki N.
      • Haji T.
      • Yamamoto Y.
      • Mahieu H.F.
      Thyroplasty for adductor spasmodic dysphonia: further experiences.
      ] presented a mechanical solution to the problem of excessive adduction in patients with adductor SD: type 2 thyroplasty with midline division of the thyroid cartilage. Surgical success depends on maintaining a permanent left-to-right opening of the thyroid cartilage incision, and a titanium bridge was developed [
      • Isshiki N.
      • Yamamoto I.
      • Fukagai S.
      Type 2 thyroplasty for spasmodic dysphonia: fixation using a titanium bridge.
      ]. Recently, titanium bridges have been improved following clinical studies and have been commercialized as medical devices [
      • Sanuki T.
      • Nishimura T.
      • Aburada T.
      • Fukushima M.
      Titanium bridge modification for type 2 thyroplasty to improve device mechanical & safety performance.
      ]. Sanuki and Yumoto [
      • Sanuki T.
      • Yumoto E.
      Long-term evaluation of type 2 thyroplasty with titanium bridges for adductor spasmodic dysphonia.
      ] have successfully reported 47 surgical cases, employing the VHI-10 to assess the subjective symptoms of patients and the condition of the wound. The mean duration of follow-up was 41.3 months. Nomoto et al. [
      • Nomoto M.
      • Tokashiki R.
      • Hiramatsu H.
      • Konomi U.
      • Motohashi R.
      • Sakurai E.
      • et al.
      The comparison of thyroarytenoid muscle myectomy and type II thyroplasty for spasmodic dysphonia.
      ]. compared thyroarytenoid muscle myectomy with type 2 thyroplasty and found that thyroarytenoid muscle myectomy tended to improve strangulation, interruption, and tremor; however, it tended to worsen breathiness postoperatively. Postoperative VHI-10 scores did not differ significantly between the two procedures. Given the favorable improvement rates, both surgical procedures were considered effective.
      Early success and subsequent disappointment are characteristic of surgical approaches to dystonias, including SD, perhaps because the static nature of the intervention eventually allows the CNS drive to reexpress itself in the larynx over time. Against this background, any new intervention must pass a test of long-term efficacy; experience with RLN sectioning suggests that a minimum of 3 years follow-up is required. Furthermore, for the adductor SD, it would be necessary to see the postoperative voice quality compared not only to that before the operation but also to that obtained after BT treatment. This is essential if surgery is to be used as a primary treatment alternative to BT treatment, as Berke and Blumin [
      • Berke G.S.
      • Blumin J.H.
      Spasmodic dysphonia: therapeutic options.
      ] have proposed. A recent report suggests that BT treatment after RLN section can be somewhat less satisfactory than surgery [
      • Sulica L.
      • Blitzer A.
      • Brin M.F.
      • Stewart C.F.
      Botulinum toxin management of adductor spasmodic dysphonia after failed recurrent laryngeal nerve section.
      ]. The burden remains on the physician to avoid harm.
      A slightly different surgical approach intended to address abductor SD involves attachment of the posterior cricoarytenoid muscle to the arytenoid cartilage [
      • Shaw G.Y.
      • Sechtem P.R.
      • Rideout B.
      Posterior cricoarytenoid myoplasty with medialization thyroplasty in the management of refractory abductor spasmodic dysphonia.
      ]. Unlike selective adductor reinnervation, this is initially performed unilaterally to avoid airway problems, although it is sometimes combined with medialization. Shaw et al. [
      • Shaw G.Y.
      • Sechtem P.R.
      • Rideout B.
      Posterior cricoarytenoid myoplasty with medialization thyroplasty in the management of refractory abductor spasmodic dysphonia.
      ] presented three cases in which a favorable voice result was eventually obtained, as judged by counting voice breaks in a standardized voice sample 1 year postoperatively. One patient underwent simultaneous posterior cricoarytenoid muscle section with ipsilateral medialization, another followed an initial muscle section with a contralateral muscle section and medialization 5 months later, and a third underwent muscle section with contralateral BT treatment. This patient required tracheostomy until the effects of the toxin were abated. Abductor SD remains a challenge to treat both surgically and by chemodenervation.

      6. Conclusion

      SD is most likely a disorder of the basal ganglia rather than the larynx, and interventions at the end organ are unlikely to offer a true cure. The pathophysiology underlying dystonia, which was exclusively a subject for speculation when recurrent nerve sections and, later BT treatment was introduced, is becoming better understood because of discoveries in genetically based forms of the disorder. The elucidation of the function of the protein products of several genes may reveal the underlying mechanism of dystonia and offer a route to definitively relieve patient symptoms.
      Currently, the standard treatment for SD is symptomatic management through BT chemodenervation. This is supported by a large body of literature attesting to its effectiveness in many different studies, especially in the uncomplicated adductor form of the disorder. Efforts towards surgical treatment predate the development of BT treatment by a decade, but long-term efficacy has not been proven, and so further research is expected. Symptom relief in patients with abductor SD and dystonia with tremor after either surgical intervention or BT treatment remains suboptimal.

      Funding

      This research was supported by AMED under grant number JP20ek0109478, and MHLW Research Program on Rare and Intractable Diseases Program [Grant No.: JPMH20FC1001].

      Declaration of Competing Interest

      The author has no conflicts of interest directly relevant to the content of this article.

      Acknowledgments

      I thank all the staff of the Department of Otolaryngology, Head and Neck Surgery, Nagoya City University for their sincere efforts, and all members of the Registry System for Spasmodic Dysphonia research group.

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