Essential Tremor

Etiology

The etiology of essential tremor is mostly unexplained. Approximately half of the cases of essential tremor appear to result from a genetic mutation; however, no specific gene has been identified. Familial tremor is an autosomal dominant disorder. The variability in age of onset, the presence of sporadic cases, and incomplete concordance of essential tremor among monozygotic twins suggest that environmental factors play a role.[5][6][7][8]

The Movement Disorders Society diagnostic criteria include:

• Bilateral, symmetrical, and postural tremor
• Tremor involves the forearms and hands
• Persistent and visible tremor
• May be associated with isolated head tremor

Epidemiology

Essential tremor is the most common neurologic disorder that affects postural or action tremor. The worldwide estimated prevalence is up to 5% of the population. Family history can be found in nearly 50% of cases, with 90% concordance in monozygotic twins. The incidence of essential tremor increases with age, although the disorder often affects young individuals, especially when familial.

Pathophysiology

Some reports suggest that the neuropathology of essential tremor is localized to the brainstem (locus coeruleus) and cerebellum, but the presence of cerebellar pathology remains controversial. However, evidence suggests that essential tremor is a risk factor for the development of Parkinson disease. In addition, an association has been reported between essential tremor and dystonic movements.

History and Physical

Essential tremor most often affects the hands and arms bilaterally and is symmetric, but cases of asymmetric essential tremor have also been reported. In cases of asymmetric essential tremor, the tremor was more severe in the nondominant arm. Essential tremor can also affect the head and voice and, uncommonly, the face, legs, and trunk. The presentation ranges from a low-amplitude, high-frequency postural tremor of the hands to a larger-amplitude tremor triggered by specific postures and actions. In most cases, the tremor frequency of essential tremor is 6 to 12 Hz. Essential tremor becomes apparent in the arms when they are held outstretched; the tremor typically increases at the end of goal-directed movements, such as drinking from a glass or finger-to-nose testing. Amplitude tends to increase with age, whereas frequency tends to decrease. Although tremor amplitude and disability vary widely among patients with essential tremor, the disorder is disabling for a substantial proportion of affected individuals. Results from reports suggested that functional disability in essential tremor is associated with the amplitude of kinetic tremor in the upper extremities. Some patients with essential tremor develop enhanced physiologic tremor due to anxiety or other adrenergic mechanisms, thereby aggravating the underlying tremor. On physical examination, essential tremor can be elicited during examination under 2 circumstances: with the arms suspended against gravity in a fixed posture and during goal-directed activity. Essential tremor is usually relieved by small amounts of alcohol (60% to 70%) but, in contrast to physiologic tremor, is not usually aggravated by caffeine. In some cases, additional cerebellar signs can be found, such as abnormal tandem walking and mild ataxia.

A tremor in the legs is unusual with essential tremor. Parkinsonian tremor is more likely if resting tremor is present in the legs. A tremor of the neck may be vertical (yes-yes) in approximately 25% of patients or horizontal (no-no) in approximately 75% of patients and is usually associated with a tremor of the hand or voice. A tremor of the head rarely occurs in isolation in essential tremor. When head tremor occurs in isolation, the possibility of cervical dystonia with dystonic head tremor should be considered. Additionally, results from preliminary studies suggested that very mild cognitive deficits, with reduced performance on tests of memory and frontal executive function, may be more common in patients with essential tremor than in age-matched controls and that essential tremor may be associated with an increased risk of dementia and Parkinson disease.

Evaluation

The diagnosis of essential tremor is based on clinical features and exclusion of alternative diagnoses. The core criteria require bilateral action tremor of the hands and forearms and the absence of other neurologic signs. Additional features strongly suggestive of essential tremor include long duration (longer than 3 years) of the tremor, a positive family history of essential tremor, and a beneficial response to alcohol.[9]

The evaluation relies on a detailed neurologic examination to identify specific features of the tremor, including its frequency, amplitude, pattern, and distribution, as well as other neurologic findings, if present. Precipitating, aggravating, or relieving factors, such as caffeine, alcohol, medications, exercise, fatigue, or stress, should be elicited. A complete list of all medications should be reviewed to exclude the possibility of enhanced physiologic tremor.

No specific biomarkers, neuroimaging findings, or other ancillary investigation findings confirm the diagnosis of essential tremor, but testing may be appropriate to exclude other causes of tremor. Laboratory evaluation may include tests of thyroid function, urinary copper, and ceruloplasmin to exclude Wilson disease, with screening for heavy metal poisoning, such as lead testing, if any of these causes are suspected.

Brain imaging can be useful in patients clinically suspected of having a structural cause of tremor, such as Wilson disease, brain trauma, stroke, or a mass lesion, but otherwise brain imaging is not indicated. Striatal dopamine transporter imaging using ioflupane I-123 injection single-photon emission CT can reliably distinguish patients with Parkinson disease and other parkinsonian syndromes associated with nigrostriatal degeneration, such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration, from patients with essential tremor.[10]

Treatment / Management

Patients with less functional impairment may choose to defer treatment altogether. Some patients who are not functionally impaired desire treatment because their tremor is a significant source of embarrassment. Options for patients with significant functional impairment include nonpharmacologic, medical, and interventional therapy.

Nonpharmacologic Therapy

In some patients, tremors can be reduced by weighting the extremity, typically with wrist weights. In a small proportion of patients, this strategy can dampen the tremor enough to provide some relief or improve functioning. Because anxiety and stress classically worsen tremor, nonpharmacologic relaxation techniques and biofeedback can be effective in some patients. Medications known to worsen tremors should be eliminated or minimized when possible. Patients with tremor also may benefit from avoiding dietary stimulants, such as caffeine. Several commercially available technologies may help stabilize utensil use, such as weighted utensils or active tremor-cancellation technology to dampen tremor, and may be helpful for some patients.

Medical Therapy

The therapeutic approach to essential tremor often follows a trial-and-error approach, and patients should try several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first-line, second-line, and third-line therapies.

First-line therapy: First-line therapy is either approved by the US Food and Drug Administration (FDA) or supported by double-blind, placebo-controlled studies that meet criteria for class 1 evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

Second-line therapy: Second-line therapy is supported by double-blind, placebo-controlled trials that do not meet other requirements for class 1 evidence studies. This category includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam and alprazolam), β-blockers (atenolol and metoprolol), and zonisamide.

Third-line therapy: These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

Interventional Therapy

For patients who do not respond to pharmacologic treatment with the above drugs or are unable to tolerate the adverse effects, surgical options include deep brain stimulation (DBS), focused ultrasonography, or radiosurgical Gamma Knife thalamotomy to treat persistently disabling extremity tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.

Botulinum neurotoxin injections: In some patients with severe head or hand tremors, injection with botulinum toxins can be helpful. Botulinum neurotoxin should be considered a treatment option for essential hand tremor in patients who do not respond to treatment with oral agents. Results from a recent evidence-based review found insufficient evidence to conclude that botulinum neurotoxin is effective for treating head and voice tremors.

Deep brain stimulation: Deep brain stimulation is the most common surgical treatment for essential tremor. Most series report 70% to 90% hand tremor control. In DBS, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. DBS is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. DBS can be done unilaterally or bilaterally, depending on the patient's symptoms. Bilateral procedures carry an increased risk of speech and balance difficulties. If the tremor significantly affects both hands, the dominant hand is targeted, and bilateral procedures may be considered.

Thalamotomy: Stereotactic surgical techniques can create a lesion in the VIM of the thalamus.

Focused ultrasonography: Approved by the FDA in 2016, magnetic resonance imaging–guided high-intensity focused ultrasonography thalamotomy is an innovative method for treating essential tremor. Although this procedure is transcranial and does not require an incision, skull penetration, or an implanted device, high-intensity focused ultrasonography is an invasive therapy that produces a permanent thalamic lesion.

Radiosurgical Gamma Knife thalamotomy: Gamma Knife thalamotomy focuses high-energy gamma rays on the VIM, resulting in neuronal death. Gamma Knife thalamotomy is an unproven treatment that has not generally been adopted due to concerns about potential radiation adverse effects, including a theoretical, long-term risk of secondary tumor formation.

Differential Diagnosis

Conditions to consider in the differential diagnosis of essential tremor include the following:

• Physiologic tremor: Predominantly bilateral, symmetric action tremor. Physiologic tremor is high-frequency (10 to 12 Hz) and is associated with a known cause (eg, medications, hyperthyroidism, or hypoglycemia).
• Parkinson disease tremor: Predominantly resting and asymmetric. Parkinson disease tremor usually does not produce head tremor. The frequency is 4 to 6 Hz.
• Orthostatic tremor: Postural tremor in the torso and lower extremities while standing; orthostatic tremor may also occur in the upper extremities. The tremor is suppressed by walking. Orthostatic tremor is high frequency (14 to 20 Hz) and synchronous among ipsilateral and contralateral muscles.
• Cerebellar tremor: Postural, intention, or action tremor. Cerebellar tremor has a relatively low frequency (3 to 4 Hz). The tremor is associated with ataxia and dysmetria.
• Writing tremor (task-specific): Writing tremor is not evident in other tasks requiring coordination and occurs only during writing. Task-specific writing tremor is considered a variant of focal hand dystonia (writer’s cramp).
• Psychogenic tremor: not a diagnosis of exclusion. Symptoms vary in severity, depending on the patient’s emotional state and association with stressful life events. Several clues help differentiate the psychogenic nature of tremor, including sudden onset and spontaneous remission, greater variability in amplitude and frequency, and lower severity. The tremors disappear with distractions, such as alternating digit tapping, mental concentration on the serial 7s, or a healthcare professional applying a vibrating tuning fork to a patient’s forehead and incorrectly informing the patient that this maneuver can stop the tremor or achieve entrainment. Entrainment is a change in tremor frequency in response to voluntary movements, such as regular movement of the contralateral extremity.

Prognosis

Although prospective longitudinal data are limited, the usual course of essential tremor is slow, gradual progression. Essential tremor may remain stable in a minority of patients. However, a stable course should raise suspicion for an alternative diagnosis, such as enhanced physiologic tremor or drug-induced tremor, rather than essential tremor. While prospective data are limited, essential tremor may be associated with an increased risk of developing Parkinson disease. Survival in essential tremor does not differ from survival in the general population. Overall quality of life is poor.