Figure 6–1. A. Compensatory supraglottic hyperfunctional behavior in a 76-year-old patient with unilateral vocal fold paralysis. Note the medialization of the false vocal fold and the anteroposterior shortening between the petiole and interarytenoid area. B. Bowing and shortening of the left vocal fold during inspiration.

The role of voice analysis is very limited with little added value when acoustic parameters are used in isolation. In a recent cross-sectional study by Lopes et al on 279 subjects with various laryngeal pathologies, only combined acoustic measures were useful in discriminating unilateral vocal fold paralysis form normal healthy larynges.¹⁸ The incomplete closure of the vocal folds usually results in an increase in the perturbation parameters and in an increase in the first formant intensity.¹⁹ In an acoustic and aerodynamic study by Hartl et al on eight men with unilateral vocal fold paralysis, the authors have demonstrated significantly higher jitter, shimmer, high-frequency–ratio, and significantly lower Cepstral peak prominence (CPP) in affected patients compared to controls.²⁰ Acoustic analysis may also be useful in assessing the follow-up of these patients after treatment. The study by Gillespie et al on 40 patients with various vocal fold pathologies among which was unilateral vocal fold paralysis, has shown “a disorder-specific response to frequency-based acoustic measures.”²¹ Similarly, Adams et al highlighted the usefulness of acoustic analysis, in combination with perceptual and aerodynamic measures, in the evaluation of patients with unilateral vocal fold paralysis following thyroplasty. There was a significant improvement in vocal shimmer, s/z ratio, and signal-to-noise ratio.²²

Airflow measurements are also markedly useful in assessing the extent of glottal insufficiency in patients with vocal fold paralysis. Patients will invariably have a reduced maximum phonation time and an increase in the mean airflow rate as reported by Makiyama et al and Kelchner et al.^23,24 These alterations in aerodynamic measures are attributed to inefficiency in the phonatory apparatus and decreased laryngeal control as a sequel to the paralysis. Kelchner et al has also demonstrated vocal fatiguing of patients with unilateral vocal fold paralysis following prolonged reading, a finding that correlated with changes in the aerodynamic measures. Post-prolonged loud reading, patients had further reduction in the maximum phonation time and an increase in the mean airflow rate at low, comfortable, and high pitches.²⁴

Computerized tomography of the head and neck and chest is mandatory in order to rule out any central or peripheral lesions along the course of the recurrent laryngeal nerves. Based on a survey by the American Bronchoesophagological Association on the practice pattern among otolaryngologists in the workup of patients with undifferentiated unilateral vocal fold paralysis, computerized tomographic scan of neck and chest along the course of the recurrent laryngeal nerve was the most frequently requested test.²⁵ The main added value of this test has been further highlighted by two studies, one by Kang et al and another by Chin et al^26,27 where computerized tomography revealed previously unidentified causes for the paralysis in 23.5% and 15% of the cases, respectively. See Figure 6–5.

Laryngeal electromyography of the thyroarytenoid and lateral cricoarytenoid muscles is also of paramount importance in differentiating between neurogenic injury and ankylosis of the cricoaryetnoid joint.^15,28 A recent investigation by Chang et al on the quantitative electromyographic characteristics in patients with unilateral vocal fold paralysis has shown the added value of this diagnostic method in differentiating iatrogenic causes from idiopathic ones. Those that were surgically induced had less recruitment of the thyroarytenoid-LCA complex compared to those who had idiopathic etology.²⁹ Further information on laryngeal electromyography is available elsewhere.³⁰

Before a management strategy is adopted whether for unilateral vocal fold paralysis or bilateral vocal fold paralysis, three important questions need to be answered in order to adopt the best therapeutic modality and optimize the surgical outcome;

Question one: “Does the patient have a concomitant superior laryngeal nerve injury?” Superior laryngeal nerve SLN paralysis is often unrecognized as many affected patients are being diagnosed with functional voice disorders.³¹ The main reasons are the nonspecificity of the symptoms reported by the patient and the often nonconclusive laryngeal signs present on examination. Patients may complain of ill-defined vocal changes such as vocal fatigue and inability to project the voice. In professional voice users, symptoms such as loss of the high notes, lowered pitch, and contracted range are more noticeable and pronounced. These symptoms are partially attributed to the lost contraction of the cricothyroid muscle responsible for the increase in tension within the thyroarytenoid muscle, and partially to the hyperfunctional compensatory behavior and concomitant muscle tension dysphonia present in almost one out of four affected patients.³² The laryngeal signs most commonly seen in patients with superior laryngeal nerve injury include bowing and flaccidity of the affected vocal fold, rotation of the posterior glottis toward the paralyzed side, and shortening of the ipsilateral aryepiglottic fold. See Figure 6–6. A more consistent finding as reported by Sataloff is sluggish movement and fatigability of the vocal fold after repeated adduction such as /i/-hi-/i/-hi-/i/-hi.¹⁵ The presence of supraglottic constriction as a compensatory hyperfunctional behavior may also be observed and lead to delay in seeking therapy. Another reason why SLN palsy is underdiagnosed in the absence of history of neck surgery such as thyroidectomy, carotid endarterectomy, or anterior approach to cervical spine, is failure to correlate the presence of SLN palsy with other symptoms and signs of cranial polyneuropathies or recent viral infection.³² Adour et al has reported the presence of laryngeal signs of SLN palsy, namely, laryngeal rotation and shortening of the vocal fold, in patients with vestibular neuritis, migraine headaches, and globus pharyngeus, thus alluding to the high prevalence of this entity in a wider and more diverse context than that of post-thyroidectomy patients.³³ In the study by Dursun et al on 126 cases of SLN paresis, 93.6% had history of a recent viral infection prior to the development of phonatory complaints. To that end, the authors have emphasized the importance of a diligent and thorough history taking and the added value of both laryngeal videostroboscopy and laryngeal electromyography in the work-up of these patients.³² Differences in the longitudinal tension of the vocal folds is often observed when the patient is asked to slide his or her voice from the low register to the high register in a glissando fashion. More so, voice range measurements may also be useful in analyzing the effect of SLN paresis on voice range profile and subsequently in monitoring the effect of voice therapy.³⁴

Even in the presence of neck surgery, the diagnosis of SLN palsy is still being overlooked, more so in patients with unilateral or bilateral vocal fold paralysis where the main focus is on breathing and aspiration. For instance, in cases of thyroidectomy, superior laryngeal nerve paresis may be present either preoperatively or following the surgery itself. In a recent study on “Goiter and Laryngeal Sensory Neuropathy,” the authors reported a significant difference in the prevalence of laryngeal sensory neuropathy in patients with goiter versus controls, 42% versus 12%, respectively. Patients with goiter had more frequently a constellation of symptoms such as throat clearing, cough, globus, and change in voice quality.³⁵ As goiter is one of the main indications for thyroidectomy, and thyroidectomy remains one of the most common causes of vocal fold paralysis, one ought to consider the rate of preoperative laryngeal sensory neuropathy and possible SLN palsy in patients who present with vocal fold paralysis status post-thyroidectomy. This is in agreement with the report of Jansson et al where three patients out of 20 undergoing thyroidectomy had SLN paresis preoperatively.³⁶ Indeed in that same report by Jansson et al, nine patients had postoperatively SLN paresis as evident by laryngeal electromyography. Injury occurs invariably during ligature of the superior vascular bundle flush with the thyrohyoid membrane as the superior laryngeal nerve courses deep to the superior thyroid artery and vein from superolateral to inferomedial and inserts at the cricothyroid muscle medial to the superior pole of the thyroid gland.³⁶ The presence or absence of SLN injury may mandate a change in the management strategy such as less widening of the rima glottidis in patients with bilateral vocal fold paralysis with fear of exacerbating aspiration, and the possible initiation of neuromodulators such as gabapentin or pregabalin.

Question two: “Is the impaired mobility or fixed vocal fold the result of a systemic disease?” The laryngeal manifestations of systemic diseases are many and their prevalence is increasing in view of the advances in technology and increased physician’s awareness. For instance, autoimmune diseases such as systemic lupus erythematosis and rheumatoid arthritis (RA) may affect the cricoarytenoid joint leading to impaired mobility and fixation of the vocal folds. Similarly, neurogenic disorders such as Parkinson’s disease and amyotrophic lateral sclerosis may present with unilateral or bilateral vocal fold paralysis.^37–40 Diligent and early recognition of these manifestations may spare the patient unnecessary surgical intervention and morbidity. For example, the initiation of autoimmune therapy such as methotrexate in cases of advanced RA and or injecting periarticular steroids had shown promising results with regression of the pathology.⁴¹

Question three: “When to intervene, when to operate?” To answer this question there are five important factors to consider: One is the rate of spontaneous recovery which varies markedly with the etiology of the paralysis. For instance following thyroidectomy, Jatzko et al in 1994 has reported an 86% spontaneous recovery of vocal fold paralysis within a 6-month period, and as such has advocated laryngeal framework surgery at least 6 to 12 months post-surgery.⁴² Whereas in cases of idiopathic vocal fold paralysis there is complete recovery of the voice in 25% to 87% of the cases in less than a year as reported by Sulica in 2008.⁴³ The second factor to consider is the degree of insult to the recurrent laryngeal nerve, which invariably is hard to estimate be it neuropraxia, axonotmesis, or neurotmesis.^44,45 The information whether the recurrent laryngeal nerve has been injured or not as well as the extent of its injury post-surgery is not always readily available. This can be attributed partially to the imperfect communication between the surgeon who has operated and the laryngologist who is taking care of the patient, and partially to the anatomical variations in the course of the recurrent laryngeal nerve which more often than not can be misleading. To that end, there are two important deviations to consider, one is the branching of the recurrent laryngeal nerve and second is its course and angulation before entering the larynx. The most vulnerable point of injury to the RLN is at its entrance into the larynx after splitting into anterior and posterior branches, although the number of branches can reach up to 8 with trifurcation being reported in one-third to two-thirds of the cases (left vs right).⁴⁶ Another equally important anatomical variation to consider, aside from the extralaryngeal splitting of the recurrent laryngeal nerve, is the angulation along its course which is more accentuated on the right compared to the left “45 degrees versus 30 degrees.” The third important factor is the status of the cricoarytenoid joint. Although there have been debates in the literature as to whether there is fixation of the joint with time, which would mandate an adjunctive procedure to thyroplasty type I, recent reports indicate that the joint remains functional even up to 17 years after the injury to the recurrent laryngeal nerve.^47–49 The fourth important factor to consider in deciding when to operate is the position of the vocal fold at time of presentation keeping in mind that it might change. This latter is primarily determined by the synkinetic activity of the intrinsic laryngeal muscles, abductors and adductors. In an animal study by Shindo et al examining the histological and morphological changes of laryngeal muscles after sectioning the recurrent laryngeal nerve, the authors have demonstrated that denervation atrophy is only a phase following which there is reinnervation mainly from the sectioned recurrent laryngeal nerve.⁵⁰ These findings go in parallel with the shift in the topographic organization of the laryngeal motoneurons in the nucleus ambiguus following and after recurrent laryngeal nerve sectioning, as demonstrated by Flint et al.⁵¹ An equally important factor to consider in that regard is the ubiquity in the anastomosis between the superior laryngeal nerve and the recurrent laryngeal nerve. To name a few, there is the Galen anastomosis between the dorsal branch of the internal branch of the superior laryngeal nerve and the dorsal branch of the recurrent laryngeal nerve, the anastomosis between the dorsal division of the internal branch of the superior laryngeal nerve and the ventral branch of the recurrent laryngeal nerve, and the anastomosis between the descending branch of the ventral branch of the internal branch of the superior laryngeal nerve and the ascending branch of the recurrent laryngeal nerve.⁵²

Despite the difficulty in defining the exact time of intervention given the aforementioned factors, namely, the disparity in causes of denervation, the various degrees of injury and the hardship in predicting the final position of the affected vocal fold, early intervention, especially in cases of unilateral vocal fold paralysis have become common practice. The main reasons are the advances in technology that allow bedside intervention with little morbidity, and the marked improvement in quality of life following these interventions. In addition, there are few reports, namely, by Friedman et al and Prendes et al indicating that subjects who undergo early injection laryngoplasty have less need for permanent laryngeal framework surgery.^53,54 This has been attributed to the tactile stimulation of the paralyzed vocal folds which helps to improve its functional recovery. That being said, injection laryngoplasty has become the standard mode of therapy for patients with unilateral vocal fold paralysis and a viable alternative to laryngeal framework surgery. Nevertheless, there are many challenges to injection laryngoplasty, among which is the choice of material to use and the route of injection. The material used has to be biocompatible with reasonable longevity in order to serve its purpose. Teflon was commonly used in 1970s before it has been abandoned in view of the high complication rate such as extrusion and granuloma formation. Other materials used are calcium hydroxylapatite known as Radiesse, and hyaluronic acid (HA). Teflon lost its popularity in light of the increasing number of reports of inflammatory reactions and extrusion at the site of injections.⁵⁵ On the other hand, only few adverse reactions to hyaluronic acid have been reported in the literature and that is in view of its similar viscoelastic properties to the natural constituents of the lamina propria.⁵⁶ More so, experimental studies have shown that HA not only binds to water and loses less volume over time once injected, but also helps restore the vibratory malleability of the vocal fold cover. Fat has also been advocated as an alternative filling material given its long duration before it is absorbed and its high biocompatibility. With respect to the route of injection, there are many approaches performed as office-based procedures. These include the percutaneous approach, the perioral approach, the transnasal approach, and the transoral fiberoptic approach. The details of these approaches are not the subject of this chapter but it is important to note that the choice of approach is primarily determined by the surgeon’s expertise, patient’s tolerance and health, and last the patient’s orofacial morphology of the patient. For instance, an obscure neck landmark would be unfavorable for the percutaneous approach whereas a septal deviation would prohibit the transnasal approach.

Laryngeal framework surgery, namely, thyroplasty type I is an alternative to injection laryngoplasty that offers a successful and more permanent solution to patients with unilateral vocal fold paralysis. Although the surgical details of this surgery is not the topic of this chapter, positioning of the implant through a thyroid cartilage window is the most crucial step of this procedure. Based on a recent presentation by Prof. Michael Benninger, individualized implants are being tailored in order to match the exact measures for medicalization.⁵⁷ Reinnervation procedures have also gained popularity as adjunctive procedures to laryngeal framework surgery. Several reinnervation procedures have been described, the most popular are the ansa-cervicalis by Crumley⁴⁷ and the nerve-muscle pedicle transfer by Tucker.^58,59 Crumley has reported improved tension and tonicity to the paralyzed intrinsic laryngeal muscles and Tucker has reported better voice quality especially if treated early.

For patients with bilateral vocal fold paralysis, various modalities of treatment have been advocated ranging from tracheotomy to laryngeal pacing and regenerative medicine. Today the primary treatment modality is a lateralization procedure that targets the posterior glottis and is based on tissue resection. Partial arytenoidectomy and or posterior cordotomy ultimately lead to a non-physiologic state where phonation and voice quality is being traded for a better breathing. There have been numerous modifications in the lateralization technique in attempt to improve the airway and yet preserve the premorbid voice quality. This refinement in surgery of the posterior glottis had led to improvement in voice quality with restoration of adequate loudness and clarity subjectively.⁶⁰ In the study by Remacle et al in 1996, 38% of his 41 patients had a near-normal voice based on high-resolution frequency analysis with a maximum phonation time of 8 + 4 seconds and a mean vocal intensity of 61 dB.¹¹

Future Alternatives

Given the limitations in the conventional therapeutic methods for the treatment of vocal fold paralysis, new strategies have evolved over the last two decades with emphasis on gene therapy, tissue engineering, and regenerative medicine. By delivering genes that encode growth factors responsible for the promotion and sprouting of neural structures, neuronal regeneration may be stimulated and degeneration may be halted. Rubin et al has reported the injection of these factors thru viral vectors to the central nervous system via the recurrent laryngeal nerve.⁶¹ Similarly, Shiotani et al has reported reinnervation and decreased thyroarytenoid muscle atrophy after delivering IGF-I in a rat model.⁶²

Alternatively, tissue engineering and regenerative medicine address the basic histopathologic changes that occur within the vocal fold in cases of paralysis. By using cells, scaffold, or regulatory factors, the architecture and distribution of the extracellular matrix constituents are restored and the function of its primary cells, namely, fibroblasts, is improved. Among these tissue engineering strategies, stem cell therapy has gained increasing attention in laryngology in view of its promising regenerative effect and ability to alter the biologic state of the paralyzed vocal fold. Since its introduction in 2003, many studies came forward in attempt to answer three main challenges: one is the viability of the implanted or injected stem cells in both animal and human models, second is their effect on the histology and architectural components of the injected site, and third is their capacity to enhance the current function of the paralyzed vocal fold in a favorable manner. This latter is translated by an improvement in the acoustic, aerodynamic, and rheologic properties of the vocal fold.

The first study on vocal fold tissue engineering was reported by Kanemaru et al on a canine model. The injection of 3-dimensional incubated mesenchymal stem cells resulted in regeneration of the injured vocal fold.⁶³ Two years later the same author investigated the viability of the autologous bone marrow-derived stromal cells in a rat vocal fold.⁶⁴ The results showed survival of the implanted cells with expression of markers of epithelium and muscle, alluding to the potential differentiation of the stem cells in vivo. In both studies there was evidence of survival of mesenchymal cells with further differentiation of these cells into epithelial and muscle. Hertegard et al investigated the viability and effect of injected human mesenchymal stem cells on the histologic properties of a scarred vocal fold in a rabbit model. There was persistence of human mesenchymal cells with reduced scarring and improved viscoelastic properties of the treated scarred vocal fold. These changes were attributed to the decrease in collagen content in comparison to the untreated vocal fold.⁶⁵ In 2008, Ohno et al group have looked at the therapeutic potential of bone marrow–derived stromal cells in restoring the injured vocal fold. Using reverse transcription polymerase chain reaction the authors reported alterations in the gene expression of HAS 2 and MMP 1.⁶⁶ In order to obtain optimum results of the bone marrow–derived mesenchymal cells implantation in the vocal folds, atelocollagen sponge was successfully used as a scaffold in an animal model.⁶³

Among the regenerative therapeutic modes, growth factors have also been thoroughly investigated in laryngology with promising results both in the aged and paralyzed larynx.⁶⁷ The injection of βFGF has been successfully used as an alternative material to the conventional filling substances used and as an adjunctive procedure to thyroplasty as reported previously by Kanazawa et al.⁶⁸

On a different front, functional electrical stimulation is equally gaining ground as a potential option for the treatment of vocal fold paralysis. Instead of changing the position of the paralyzed vocal fold using medialization or lateralization technique, the motor function of the paralyzed vocal fold is restored. This therapeutic alternative is based on the fact that synkinetic reinnervation of the laryngeal muscles following denervation has been proven to be amenable to selective electric stimulation and hence feasible for laryngeal pacing. This theory of laryngeal reanimation using electrical stimulation was initially described in the 1970s by Zealer and Dedo after having studied the keystones for its clinical application. Following numerous animal trials, abduction of the vocal folds in paralyzed larynges using rhythmic and regulated stimulation was successfully reported.⁶⁹ More so, histochemical studies have indicated that “greater appropriate reinnervation and less inappropriate reinnervation” is present in animals who had chronic electrical stimulation compared to controls.⁷⁰ Between 1995 and 1997, seven patients were implanted with the Itrel II device with limited success.⁷¹ This has been attributed to some limitations and problems inherent to the translation of this technology to humans. These included the shift of the electrode position, electrochemical erosion, and last the lack of the sensor to align the respiratory rate with the pace of stimulation. A key element in the success of functional electrical stimulation is synchronization between an afferent input that signals inspiration and an efferent one connected to the denervated muscle through a nerve or a nerve-muscle–pedicle. To that end, human studies have been discontinued and newer animal studies using an implantable pulse generator initially designed for spinal cord stimulation have been started by numerous investigators^72–75 with emphasis on the positive impact of electrical stimulation on synkinetic reinnervation.

Essential Tremor

Essential tremor is a movement disorder initially referred to as benign familial tremor due to its benign nature and lack of significant disability. Today this term is no longer being used given the increased morbidity associated with this disease. The estimated frequency ranges between 40 and 400 per 10,000 persons, reaching a figure of 20% in the elderly.^76,77 However it is important to note that the true prevalence is unknown as the majority of affected patients do not seek medical attention.^78,79 Despite the lack of a multiethnic population study, ethnicity seems to play a role given the fact that essential tremor is less common in African Americans compared to whites. Both men and women are equally affected with no predilection to gender. Based on a review of 350 patients with essential tremor, Lou and Jankovic have reported a bimodal age distribution, namely the second and sixth decades of life.⁸⁰ A family history is present in 17% to 100% of the cases based on numerous reports.^80–82 Genetic linkage has been identified at two sites, “chromosome 2p22-25 and 3q13” as reported by Higgins et al and Gulcher et al.^83,84 This genetic cause has been further supported by the higher prevalence of essential tremor in monozygotic twins compared to dizygotic twins (60% vs 27%).⁸⁵

The pathophysiology of essential tremor remains a subject of investigation. Postmortem studies by Louis and Vonsattel indicated the presence of degenerative disease in the central nervous system.⁸⁶ As such essential tremor is considered as a central nervous system disorder that affects various sites such as the brainstem nuclei, cerebellum, and thalamus. There is growing evidence to support that the pathophysiology is heterogeneous, and many associated systemic disturbances are often overlooked by the physician whose main focus has been on tremor of the extremities.⁸⁷ Recent investigations have suggested that the Harmaline (beta-carboline) concentration was found to be high in cats with essential tremor. Montigny and Lamarre have demonstrated that Harmaline can induce rhythmic activity within the olivocerebello-bulbar system resulting in tremor.⁸⁸ This is in agreement with the study by Deuschl et al which suggests that the pathophysiology of essential tremor originates from the olivo-cerebellar circuit.⁸⁹ Another suggested pathophysiologic process is alteration in the somatosensory feedback and loop as reported by Elble et al.⁹⁰ Interestingly, Tomoda et al has also highlighted the possible impairment in the innervation of the voluntary expiratory muscles in the pathophysiology of voice tremor. In his report on two patients with voice tremor, the voice tremor was more pronounced during voluntary phonation or expiration and not during inspiration or involuntary phonation.⁹¹

The diagnosis of essential tremor is primarily made on clinical findings. Based on the diagnostic criteria set by the Movement Disorder Society on Tremor,⁹² a patient is considered to have essential tremor if he or she has “Bilateral postural or kinetic tremor of the hands and forearms; or isolated head tremor without evidence of dysphonia.” Evidently, other neurologic disorders associated with tremor such as Parkinson’s disease, and or drug-induced tremor such as beta-adrenergic agonists, thyroxin, lithium, and tricyclic antidepressants must be ruled out. The body parts most commonly affected in essential tremor are the upper limbs in 95% followed by the head in 34% and the lower extremities in 20%. The voice might be affected in almost 12% to 25% of the cases, although the true prevalence is unknown because only a minority seeks medical attention.^93,94 Thus, vocal tremor is often underdiagnosed for years and a high index of suspicion is needed to make the proper diagnosis. Many patients may be preoccupied and have overlooked their vocal tremor until it started affecting their communication. It is worth noting that a familial component may be present in almost half the patients, a fact that mandates a diligent family history taking.⁹⁵ When voice is affected, the entity is referred to as essential voice tremor or essential tremor of the voice. It is defined as “Periodic contraction of antagonistic adductor-abductor and/or superior-inferior laryngeal muscles in an alternating or synchronous fashion.”⁹⁶ In consistency with essential tremor, vocal tremor has a gradual and slow onset leading to a delay of years before a diagnosis is made. It is often precipitated by stress, emotional disturbances, and vocal fatigue, leading the patient to seek medical attention.⁹⁷ Essential vocal tremor may be either isolated or accompanied by tremor in other parts of the body. Based on a cohort study by Sulica and Louis on 34 patients with essential vocal tremor, 32.3% were aware of having arm tremor.⁹⁵ Similarly the report by Brown and Simon on 31 patients with essential vocal tremor, concomitant tremor was present in the extremities in 90%, head in 52%, and face in 10%.⁹⁷ To that end, isolated vocal tremor in the absence of tremor in other parts of the body is rare. When present in isolation, vocal tremor is more often than not misdiagnosed. In the report by Sulica and Louis, essential vocal tremor was misdiagnosed as spasmodic dysphonia in 29.4% of the cases given the high prevalence of vocal tremor (25%) in patients with spasmodic dysphonia.⁹⁵ It is important to note that dysphonia in patients with SD is provoked by phrases that contain voiced onset such as counting from 80 to 90.

The diagnosis of essential voice tremor is based primarily on listening to the patient and visualization of the larynx while the patient is asked to perform various phonatory tasks. Invariably patients report a shaking voice that is weak, diminished, and unstable. Patient-reported outcome measures such as The Voice Handicap Index, the Voice-Related Quality of Life questionnaire, or the Quality of Life in Essential Tremor questionnaire, can also be used as a self-administered tool in order to evaluate the physical, functional, and emotional impact of the disease on speech intelligibility and quality of life as a whole.⁹⁸ By listening to a patient with essential vocal tremor, the periodicity of the tremor is the most important characteristic. There is a rhythmic variation in both intensity of voice as well as pitch which ranges in frequency between 5 to 7 Hz, and which makes it perceptually pathologic and noticeable unlike the physiologic frequency range of 8 to 12 Hz.⁹⁹ Acoustic analysis may also be useful in substantiating the perceptual evaluation in these patients. Periodic oscillation in amplitude and frequency with or without voice breaks are often seen in severe cases.¹⁰⁰ Laryngeal electromyography, in particular of the thyroarytenoid and lateral cricoarytenoid muscles can be used for further confirmation of the diagnosis of essential vocal tremor. Evidence of “periodic waxing and waning of muscular activation at a rate from 4 Hz to 10 Hz is usually diagnostic,”⁹⁵ Based on laryngeal EMG studies performed on eight patients with voice tremor, the intrinsic laryngeal muscles, and in particular the thyroarytenoid muscles revealed tremulous activity during respiration and speech.¹⁰¹

Laryngeal examination is essential for making the proper diagnosis though for decades the diagnosis of essential voice tremor has been based primarily on perceptual evaluation without laryngeal examination. This could have contributed to the reports of normal laryngeal findings in early series.⁹⁷ A kinetic laryngeal tremor that extends to involve the whole phonatory apparatus is invariably seen on fiberoptic laryngeal examination as reported by Sulica et al and Bove et al.^95,102 In their report on 34 cases of essential vocal tremor, 74% had some degree of vocal during respiration.⁹⁵ Similarly, in the report by Gurey et al three-fourths of patients with essential vocal tremor had both horizontal tremor and vertical tremor although the horizontal glottic tremor was more common than the vertical one (94% vs 81%).¹⁰³ It is important to note that essential vocal tremor, when present, must be differentiated from other forms of neurogenic tremors using specific phonatory tasks. In that regard, Moraes and Biase, have developed a phonatory task-specific protocol in order to distinguish essential vocal tremor from dystonic tremor syndromes. The most significant phonatory tasks used were production of /s/, production of a whistle, and falsetto.¹⁰⁴

It is also worth noting that more than one intralaryngeal and extralaryngeal site are involved in patients with essential vocal tremor, with pharyngeal tremor being present in almost 31% of the cases.*^{101,105–107} In a study by Koda and Ludlow evaluating laryngeal muscle activities in patients with vocal tremor, the thyrohyoid, thyroarytenoid, and sternothyroid muscles were most commonly involved.¹⁰¹ Given that essential vocal tremor is not limited to the vocal folds and many anatomic areas within the vocal tract can be involved, a vocal tremor scoring system has been developed and validated by Bove et al in order to better describe the anatomical site involved and the degree of involvement.¹⁰² The “Vocal Tremor Scoring System” has also been helpful in selecting who are best candidates for injection by identifying the site of tremor. The system is being used to monitor the effect of treatment after Botulinum toxin injection as well.

The ultimate goal in the treatment of essential vocal tremor is control of symptoms. Alleviating the impact of the disease on the day-to-day activities and during a desired performance is the goal of therapy. To that end, treatment may be implemented either as needed or continuously. For intermittent usage, alcohol and or benzodiazepines can be prescribed in addition to beta-adrenergic blockers. By modulating the skeletal muscles beta-adrenergic receptors, there is improvement in 50% of the cases.^94,108,109 Justicz et al reported the use of propranolol in a group of 18 patients with essential vocal tremor. The average improvement in VRQOL score was 9.31 after taking propranolol for at least two weeks.¹¹⁰

Other medications include primidone, an anticonvulsant the efficacy of which has been reported by many despite the lack of clear understanding of its mechanism of action.^111,112 Based on a suggested algorithm by Pahwa and Lyons, if patients have insufficient improvement, other medications with potential benefits such as Gabapentin can be prescribed.⁹⁴ The study by Gironell et al has shown equal effect in controlling motor tasks using Gabapentin in comparison to propranolol.¹¹³ Other suggested medications include Topiramate which is a sulfamate-substituted monosaccharide” the usage of which has been proven to be efficacious as well.¹¹⁴

For essential vocal tremor Botulinum toxin injection remains the gold standard therapy.^115–119 It is usually given in the thyroarytenoid and lateral cricoarytenoid muscles, unilaterally or bilaterally. Nevertheless, the treatment regimen should be individualized in order to optimize the outcome. Based on the report of Gurey et al, horizontal glottic tremor is best treated by injections in the thyroarytenoid muscles whereas vertical tremor mandates additional injections in the strap muscles.¹⁰³ The recommended dose and site of injection is mostly derived from the literature on spasmodic dysphonia.^115–119 It is advisable to adjust the dose based on the patient’s response to therapy. It is important to note that Botulinum toxin injections only reduce the amplitude of the tremor but do not eliminate it. A major side effect to injection is dysphagia and breathiness which might be significant especially in elderly who have poor tolerance.

The inconsistency in the treatment of essential vocal tremor with Botulinum injection may be explained by the fact that the source of the vocal tremor is not confined to the vocal folds alone. Hence injecting the vocal folds, unilateral or bilateral, may not always be efficacious. In that regard, a crossover study of unilateral versus bilateral injection of Botulinum toxin, revealed substantial subjective improvement in most patients with essential vocal tremor at least perceptually despite the objective improvement in only a minority of patients, namely, 3 out of 10 for bilateral and 2 out of 9 for unilateral injection.⁹⁶ The disparity between the objective outcome measures and the subjective ones can be explained on the basis that the subjective reduction in vocal effort is linked to the reduction in laryngeal airway resistance.

Given the limited or focused effect of Botulinum toxin to the injected muscle and given the aforementioned side effects, alternative therapy, namely, surgical intervention in the form of thalamotomy or deep brain stimulation may be recommended.^120–122 Sataloff et al in 2002 reported the successful use of chronic stimulation of the thalamus in controlling vocal tremor in addition to upper limb tremor.¹²⁰ Recently Hagglund et al has published the effect of deep brain stimulation of Caudal Zona Incerta on voice tremor in a group of patients with essential tremor. The results indicated a reduction in vocal tremor as a group and the effect was more pronounced when the stimulation was bilateral. However, it is important to note that not all patients improved and that individual differences need to be accounted for.¹²²

Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disease that affects more than a million persons in the United States. The prevalence is estimated to be 217 in 100,000 affecting men and women in their six and seventh decades of life.^123,124 The pathophysiology lies in the depletion or reduction in dopamine secretion in the substantia nigra leading to a large array of symptoms related mainly to the motor and autonomic systems. The course of the disease is very slow and many years may lapse before functional impairment becomes an issue. The symptoms most commonly reported are mainly tremor, rigidity in movement, hypokinesia, dyskinesia, and hyperkinesia, in addition to neuropsychiatric symptoms, dementia, and depression.

Affected patients more often than not complain of speech disturbances in up to 70% of cases. Speech is described as monopitch, monoloud, with loss of intonation. These speech alterations are partially due to reduced movement of the jaw and lips, which may also affect the onset of speech, its prosodic features, and the duration of sentences. Patients may also suffer from motility disorders of both intrinsic and extrinsic laryngeal muscles as reported by Leopold and Kagel. In their study of 71 patients with Parkinson’s disease (PD) who were stratified into stages based on their disability scale, the authors have reported a delay in vertical laryngeal excursion, and a delay in opening and closure of the vocal folds during deglutition in more than 90% of the patients, more so in those with advanced disease.¹²⁵ Given the aforementioned, affected patients may present with symptoms in relation to the laryngopharyngeal complex such as dysphagia, aspiration, and change in voice quality. These laryngopharyngeal symptoms are primarily due to dysfunction in the neural pathway from nucleus ambiguus to the intrinsic laryngeal muscles.^{37,40,126,127} The depletion of dopamine in the substantia nigra pars compacta results in rigidity and alteration in laryngeal muscular control which ultimately leads to excessive tension in the phonatory system.¹²⁸ This impairment in the medullary ganglionic control results in impaired mobility, hypertonicity, and dysfunction of the laryngeal muscles.^38,129

Phonatory and swallowing dysfunction may be the primary symptom of the disease. However, their presence is often masked by the hypokinetic and hyperkinetic dysarthria in affected patients. Therefore, the concomitant presence of articulatory, resonance, and/or respiratory dysfunction in these patients mandates a diligent history taking and laryngological examination in order to make the proper diagnosis. Careful perceptual evaluation of the phonatory complaints in patients with Parkinson’s disease often reveals the presence of vocal tremor and pitch breaks in addition to impairment in voice onset and offset. Patients may also report volume disturbances with more effort to project their voice, symptoms that can be partially attributed to the higher subglottal pressure needed to produce the same vocal intensity given the inappropriate glottic closure during phonation.^130,131 Similarly, in the study by Ramig et al in 2001, the pre-treatment group of patients with PD had a weaker voice and a lower sound pressure level compared to controls.¹³² This low volume or reduced ability to regulate the speech volume especially in a noisy environment has also been linked to inattention and lack of explicit instructions as to when speak loud or soft.¹³³ In a study by Midi et al on 20 patients with Parkinson’s disease, roughness, breathiness, and asthenia were reported to be significantly higher in males compared to controls. Similarly, breathiness and asthenia were significantly higher in females compared to controls.¹³⁴ Acoustic analysis is often useful in detecting acoustic perturbations that are commensurate with the perceptual evaluation of the phonatory changes in these patients. In 1997, Gamboa et al reported the acoustic measures in 41 patients with Parkinson’s disease using the Computerized Speech Lab 4300 program and has shown higher perturbation parameters and lower harmonics to noise ratio as well as frequency and intensity variability compared to a control group.¹³⁵ In 2008, Midi et al reported the usage of the Multi-Dimensional Voice Program (MDVP) in his study on vocal abnormalities in patients with Parkinson’s disease. His results failed to show any statistically significant difference in jitter, shimmer, and fundamental frequency compared to controls.¹³⁴ On the other hand a few years later Tanaka et al in his report on the vocal acoustic characteristics of 39 patients with idiopathic Parkinson’s disease in comparison with 62 controls matched to age, indicated an increase in the perturbation parameters and noise-related measurements. The authors have also reported an increase in both fundamental frequency-tremor frequency and intensity index in males and fundamental frequency-tremor intensity index in females.¹³⁶ These gender-related vocal dysfunctions were also reported by Hertrich and Ackermann in their electrographic and acoustic analysis report in patients with Parkinson’s disease and vocal dysfunction. There were more abrupt F0 shifts and increased portions of subharmonic segments in females compared to males.¹³⁷ Many years later Bang et al analyzed the acoustic characteristics of four vowel sounds in seven female patients with Parkinson’s disease using the Praat program. His investigation revealed a significant increase in cycle-to-cycle variation in frequency and in noise-to-harmonics ratio of patients with Parkinson’s disease compared to controls. In addition there was asymmetric centralization of unrounded vowels /a/,/e/,/i/ with subsequent decrease in vowel space.¹³⁸

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