Laryngeal Tremor

The larynx is under extensive neural control, and the physiology of phonation is complex. Several mechanisms have been implicated in the etiology of laryngeal tremor, including the interaction between a central oscillatory source and peripheral reflex loops.

As a rule, tremor results from a lesion that involves the extrapyramidal system or cerebellum. Electromyographic studies show that vocal tremor can arise from the involvement of muscles at any level of the speech production mechanism.

A study by de Lima Xavier and Simonyan, using functional magnetic resonance imaging (MRI), high-resolution MRI, and diffusion-weighted imaging, found that ETV and dystonic voice tremor broadly overlap with regard to cortical alterations. This included in the primary sensorimotor, inferior/superior parietal, and inferior temporal cortices, regions in which multisensory information is integrated during speech.[9]

However, in contrast to a laryngeal dystonia such as spasmodic dysphonia, which typically affects only the intrinsic laryngeal musculature, ETV that arises from the cerebello-olivary systems often affects a greater portion of muscles of the upper aerodigestive tract.

A study by Hemmerich et al indicated that the greater the severity of vocal tremor, the more structures in the pulmonary, laryngeal, velopharyngeal, and oral regions are involved. Mild vocal tremor was found normally to involve tremor in three laryngeal structures, while moderate vocal tremor involved five structures, contained in the laryngeal area and a second region, and severe vocal tremor involved eight structures, with all regions affected. Among the 20 persons in the study with vocal tremor, all of whom were adults, the most frequently (95%) and severely affected structures were in the larynx.[10]

Approximately 50% of cases of essential tremor are inherited in an autosomal dominant fashion.

Measuring the true incidence of essential tremor is difficult because symptoms may be mild and go unnoticed in as many as 50% of affected people in the United States. Laryngeal dystonias are more prevalent in women, with a male-to-female ratio of 1:3-8.

Essential tremor is characterized by a bimodal age of onset, usually manifesting in the second and sixth decades of life. Parkinson disease is the most common movement disorder in patients older than 55 years, and dysphonia may be the initial symptom.

Often, the voice disorder present is diagnosed based on history findings alone. Onset of vocal tremor, aggravating and alleviating factors, associated neurologic symptoms, medications, and family history are important components of the patient history. A history of multiple neurologic findings may suggest that the laryngeal tremor is secondary to another disease. The patient should be asked about specific vocal symptoms, such as the following:

• Tremor

• Vocal fatigue

• Pain with speaking

• Increased effort

• Hoarseness

• Pitch breaks

Patients who are seen with concerns for vocal tremor may in fact have symptoms of adductor or abductor spasmodic dysphonia or a combination of ETV and spasmodic dysphonia. Adductor dysphonia is characterized by phonatory breaks, hoarseness, monotonal pitch, and a strained voice quality. A breathy voice quality and trouble with voiceless consonants (/p/, /t/, /l/, /h/, /f/, /s/) are associated with abductor dysphonia. This distinction must be made, as treatment and prognosis are different.

Essential tremor is often seen alongside systemic manifestations of the disease characterized by postural or kinetic tremor of the upper extremities and head. Symptoms in patients with ETV slowly worsen over months and years. Voice tremor increases with anxiety and improves after alcohol ingestion. A study by Paige et al found the median frequency of ETV to be between 4 and 5 Hz, as measured with three different techniques (the perceptual, computerized peak detection, and laryngeal electromyography methods).[11]

Patients with Parkinson disease may experience the following symptoms in addition to a soft, breathy voice with or without a laryngeal tremor:

• Limb tremor

• Bradykinesia

• Rigidity

• Poor articulation

• Difficulty initiating speech

A thorough physical examination, including otolaryngologic and neurologic components, should be performed, with special attention paid to the neurologic examination of the mouth, pharynx, and larynx, as well as the evaluation of the voice. The assessment of vocal quality during conversational speech may enable the examiner to make a working diagnosis based only on the history and the sound of the patient’s voice.[12]

A neurolaryngeal examination, at rest and during phonation, is performed with a flexible laryngoscope (see Dynamic Voice Evaluation Using Flexible Endoscopy). Spontaneous rhythmic muscular activity of the laryngeal, supraglottic, and pharyngeal muscles while at rest is characteristic of tremor due to both Parkinson disease and ETV. However, tremor may also occur during sustained phonation in the case of ETV. Tremor should be differentiated from myoclonus, which is jerky and arrhythmic.

Full evaluation of the voice should include measures of fluidity, articulation, and voice quality (raspiness, breathlessness, strain). Phonatory tasks that isolate the abductor, adductor, and tensor muscle groups of the larynx allow the examiner to assess for paralysis, fatigability, and agility.

Bove et al developed a vocal tremor scoring system that standardized the evaluation and scaling of vocal tremor.[13] Furthermore, this system determined which patients were likely to benefit from botulinum toxin A (BTA) injection therapy. BTA injections are most helpful if the muscles causing the tremor are few and the injection would be focused. Global tremor involving the pharynx, tongue, and larynx is not often helped by BTA injections.

Workup in laryngeal tremor includes the following:

• Laboratory tests - A complete blood count (CBC) and chemistry panel, thyroid function test, erythrocyte sedimentation rate, liver function test, and serum ceruloplasmin are indicated studies but are often low yield

• Flexible laryngoscopy with videostroboscopy - Enables an assessment of the extent of the tremor and its location in the pharynx and larynx; videostroboscopy may demonstrate the vibratory function and architecture of the vocal folds but is often difficult to obtain in severe tremor cases due to supraglottic compensatory hyperfunction

• Electromyography - May reveal tremor or increased muscle activity in patients with a confusing vocal picture and when spasmodic dysphonia is suspected in addition to tremor

Imaging studies

Imaging studies are not likely to be needed. The use of computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be reserved for patients who present with focal neurologic findings or acute onset and stepwise progression.

Acoustic analysis

Acoustic analysis may be used to monitor the patient’s response to treatment. The following components of the voice are analyzed (patients with laryngeal dystonias usually have higher frequency, amplitude, and voice breaks):

• Fundamental frequency changes

• Jitter

• Voice breaks

• Shimmer

• Signal-to-noise ratio

Aerodynamic analysis

Aerodynamic analysis is used to evaluate airflow and air pressure during voice production. Patients with adductor spasmodic dysphonia have higher than normal subglottic pressures and lower airflow rates, and aerodynamic analysis may help to differentiate ETV from a mixed case. Greater than normal airflow rates are seen during abductor spasms.

The treatment of vocal tremor depends on the etiology of the tremor. In Parkinson disease, for example, behavioral therapy can produce speech and voice improvements, while in adductor spasmodic dysphonia, botulinum toxin A (BTA) is the mainstay of treatment. BTA can also be used to treat essential tremor of the voice (ETV), although the results of this treatment in ETV have been mixed. While systemic tremor symptoms can improve, the efficacy of other pharmacologic interventions for ETV is typically poor.[8]  Vocal fold augmentation for ETV does not always relieve the tremor but can improve other symptoms, such as effort, strain, and fatigue, and can ameliorate social restrictions; this treatment may offer a permanent option for symptom alleviation, but rarely symptom elimination.

Follow-up

The patient’s response to treatment needs to be periodically evaluated and, if needed, the medication dosage adjusted. Acoustic analysis or perceptual analysis may be used to monitor treatment response. The benefits of BTA injections for treatment of laryngeal tremor last approximately 3-4 months, so frequent follow-up is needed.

Standard levodopa (L-dopa) treatment has had limited and mixed results on laryngeal tremor. Some authors have found decreased jitter and increased fundamental frequency; other researchers have found no statistical improvement. Another therapy, the use of vocal fold injections, has had mixed results.

Patients with Parkinson disease gain a sustained benefit and improvement of speech and voice functions after behavioral therapy, specifically Lee Silverman voice therapy.

Deep-brain stimulation has been used to treat Parkinson vocal tremor, with mixed results. Side effects of this procedure include paresthesia, dysarthria, disequilibrium, and localized pain.

BTA injections and other pharmacologic treatments have been used to treat ETV. First-line treatment in patients who have other associated manifestations of essential tremor is pharmacologic. Propranolol and primidone have proven to be efficacious for essential tremor, with both of these medications decreasing the amplitude of tremor in about 50% of patients. These agents are not usually successful in treating ETV. Studies of a small number of patients have shown no improvement of vocal symptoms with either propranolol or primidone. On the other hand, a study by Nida et al found improvement in essential vocal tremor in 14 of 26 patients treated with primidone, with the investigators suggesting that this agent can be used as an alternative to botulinum toxin.[14]

Methazolamide, a carbonic anhydrase inhibitor, showed promising results in the treatment of laryngeal tremor when studied in a small, open trial, but these results were not supported in a subsequent placebo-controlled, blinded investigation of 9 patients by Busenbark et al.[15]

BTA injections have shown mixed results in the literature. The recently described vocal tremor scoring system was able to predict favorable treatment outcomes with BTA injections.

Vocal fold augmentation in the setting of vocal fold atrophy and comorbid ETV has been shown to offer some sustained improvement in patient symptoms.[16]

Additionally, newer voice therapy techniques have shown promise with the behavioral management of ETV.[17]

As previously stated, botulinum toxin A (BTA) is the mainstay of treatment for spasmodic dysphonia (SD) and has also been used to treat essential tremor of the voice (ETV), albeit with mixed results.[8, 18]

The benefits of propranolol, primidone, and methazolamide in the treatment of ETV are not known. Although propranolol and primidone have been used successfully against essential tremor, research has not yet indicated that they can effectively treat ETV. Methazolamide showed promising results in the treatment of laryngeal tremor when studied in a small, open trial, but these results were not supported in a subsequent placebo-controlled, blinded investigation of 9 patients by Busenbark et al.[15]

Class Summary

These agents compete with beta-adrenergic agonists for available beta-receptor sites.

Propranolol (Inderal, InnoPran XL)

Propranolol is often the first choice for tremor control in essential tremor and can be used as adjunctive medical therapy.

Class Summary

These agents are used to manage severe muscle spasm.

Primidone (Mysoline)

The low-dose form of primidone is the traditional second choice for the treatment of essential tremor. It is also possibly effective as an adjunct in the treatment of prominent tremor.

Class Summary

Methazolamide showed promising results in a small, open trial but not in a double-blind study.[15]

Methazolamide (Neptazane)

Methazolamide reduces aqueous humor formation by inhibiting the enzyme carbonic anhydrase, in this way decreasing intraocular pressure.

Class Summary

These agents block neuromuscular transmissions.

OnabotulinumtoxinA A (BOTOX)

OnabotulinumtoxinA A (BOTOX)

This is one of several toxins produced by Clostridium botulinum. It blocks neuromuscular transmission through a 3-step process.

Step 1

BOTOX® binds to the motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals.

Step 2

BOTOX® is internalized via receptor-mediated endocytosis, a process in which the plasma membrane of the nerve cell invaginates around the toxin-receptor complex, forming a toxin-containing vesicle inside the nerve terminal. After internalization, the light chain of the toxin molecule, which has been demonstrated to contain the transmission-blocking domain, is released into the cytoplasm of the nerve terminal.

Step 3

BOTOX® blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction. The toxin does not affect the

synthesis or storage of acetylcholine or the conduction of electrical signals along the nerve fiber.

Typically, a 24- to 72-hour delay occurs between the administration of toxin and the onset of clinical effects, which terminate in 2-6 months. This purified neurotoxin complex is a vacuum-dried form of purified botulinum toxin A, which contains 5ng of neurotoxin complex protein per 100U. It treats excessive, abnormal contractions associated with blepharospasm.

BOTOX® must be reconstituted with 2mL of 0.9% sodium chloride diluent. With this solution, each 0.1 mL results in a 5-U dose. The patient should receive 5-10 injections per visit.

BOTOX® must be reconstituted from vacuum-dried toxin into 0.9% sterile saline without preservative, using the manufacturer's instructions, to provide an injection volume of 0.1mL. It must be used within 4 hours of storage in a refrigerator at 2-8°C. Preconstituted dry powder must be stored in a freezer at below 5°C.