Essential Tremor

Etiology

The etiology of essential tremor is mostly unexplained. About half of the cases of essential tremor appear to result from a genetic mutation; although, a specific gene has not been identified. This form is referred to as familial tremor and 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:

• Tremor is bilateral, symmetrical, and postural
• The tremor involves the forearms and hand
• Is persistent and visible
• It may be associated with isolated head tremor

Epidemiology

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

Pathophysiology

Some reports suggest that the neuropathology of essential tremor is localized in the brainstem (locus coeruleus) and cerebellum, but the presence of cerebellar pathology is controversial. However, it is believed that essential tremor is a risk factor for the development of Parkinson disease. In addition, there has also been an association between essential tremors 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 non-dominant arm. It can also affect the head and voice and, uncommonly, the face, legs, and trunk. It varies from a low amplitude, high-frequency postural tremor of the hands to a much larger amplitude, a tremor that is activated by particular 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; it 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, while frequency tends to decrease with age. Although there are large variations in tremor amplitude and disability among patients with essential tremor, it is a disabling condition for a substantial proportion of affected individuals. A number of reports suggest that functional disability in essential tremor is associated with the amplitude of kinetic tremor in the upper limbs. Some patients with essential tremor develop enhanced physiologic tremor due to anxiety or other adrenergic mechanisms, thereby aggravating the underlying tremor. On a physical exam, 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 with physiologic tremor, is not usually aggravated by caffeine. In some cases, additional cerebellar signs can be found, like abnormal tandem walking and mild ataxia.

A tremor in the legs is unusual with essential tremor. Parkinsonian tremor is more likely if the resting tremor is present in the legs. A tremor of the neck may be vertical ("yes-yes") near 25%  or horizontal ("no-no") near 75% 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 it does, the possibility of cervical dystonia with dystonic head tremor should be considered.

Also, preliminary studies suggest 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 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 upon clinical features and exclusion of alternative diagnosis. The core criteria require either a bilateral action tremor of the hands and forearms and the absence of other neurologic signs. Other information strongly suggestive of essential tremor includes long duration (more than 3 years) of the tremor, a positive family history of essential tremor, and beneficial response to alcohol.[9][10]

The evaluation relies on a detailed neurologic examination to identify specific features of the tremor, including its frequency, amplitude, pattern, and distribution, and to identify 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.

There are no specific biomarkers or findings from neuroimaging or other ancillary investigations for confirming 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, screening for heavy metal poisoning such as lead if any of these causes are suspected.

Brain imaging can be useful in patients suspected clinically of having a structural cause for tremors, such as Wilson disease, brain trauma, stroke, or mass lesion, but otherwise is not indicated. Striatal dopamine transporter imaging using ioflupane I123 injection single-photon emission tomography can reliably distinguish patients with Parkinson disease and other parkinsonian syndromes associated with nigrostriatal degeneration, for example, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration from patients with essential tremor.

Treatment / Management

Less impaired patients may choose to skip treatment altogether. Some patients that are not functionally impaired desire treatment because their tremor is a significant source of embarrassment. Options for patients with significant functional impairment include non-medical, medical, or interventional therapy.

Non-Medical Therapy

In some patients, tremors can be reduced by weighting the limb, usually by applying wrist weights. In a small proportion of patients, this can dampen the tremor enough to provide some relief or improve functioning. Since anxiety and stress classically make the tremor worse, non-medical relaxation techniques and biofeedback can be effective in some patients. Medications known to make tremors worse should be eliminated or minimized when possible. People with tremors also may benefit from avoiding dietary stimulants, such as caffeine. There are several commercially available technologies to help stabilize the use of utensils, like weighted utensils or active cancelation of tremor technology to dampen tremor, which could be helpful for some patients.

Medical Therapy

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

First-line therapy: It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet criteria for the class I 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-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-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 fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.

Botulinum neurotoxin (BoNT) injections: In some patients with severe head or hand tremors, injection with botulinum toxins can be helpful. BoNT should be considered a treatment option for essential hand tremor in those patients who fail treatment with oral agents. [Level B] A recent evidence-based review reported insufficient evidence to conclude the use of BoNT in the treatment of head and voice tremors.

Deep-brain stimulation: This is the most common surgical treatment for essential tremor. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This 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. Deep-brain stimulation can be done unilaterally or bilaterally, depending on the patient's symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.

Thalamotomy: Stereotactic surgical techniques can create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

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

Radio-surgical gamma knife thalamotomy: Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side 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, symmetrical action tremor. High frequency (10 to 12 Hz), the presence of known cause (e.g., medications, hyperthyroidism, hypoglycemia)
• Parkinson Disease Tremor: Predominantly at rest, asymmetrical.  Usually does not produce head tremor. Frequency 4 to 6 Hz.
• Orthostatic tremor: Postural tremor in the torso and lower limbs while standing; may also occur in the upper limbs. Suppressed by walking. Tremor is high frequency (14 to 20 Hz) and synchronous among ipsilateral and contralateral muscles.
• Cerebellar tremor: Postural, intention, or action tremor. Relatively low frequency (3 to 4 Hz). Associated with ataxia and dysmetria.
• Writing tremor (task-specific): Not evident in other tasks requiring coordination, only during writing. It is considered a variant of focal hand dystonia (writer’s cramp).
• Psychogenic tremor: It is not an exclusion diagnosis. Symptoms vary in severity, depending on the subject’s emotional state associated with stressful life events. Several clues are helpful to differentiate the psychogenic nature and include sudden onset and spontaneous remission, larger variations of amplitude and frequency, and less severity. The tremors disappear with distractions such as alternate finger tapping, mental concentration on serial 7s, or the healthcare professional applying a vibrating tuning fork to a patient’s forehead and informing the patient (wrongly) that this can stop the tremor and entrainment. Entrainment is a change in frequency of the tremor in adaptation to voluntary movements, such as a regular movement in the contralateral limb.

Prognosis

Although prospective longitudinal data are limited, the usual course of essential tremor is one of 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 an enhanced, physiologic tremor or drug-induced tremor rather than an essential tremor. While prospective data are limited, essential tremors may be associated with an increased risk for developing Parkinson disease. Survival in essential tremor does not differ from the general population. The overall quality of life is poor.