Essential tremor

Definition

Tremor is derived from the Latin "to shake." It is an involuntary, rhythmic, back and forth oscillation or shaking of a part of the body, resulting from alternating or irregularly synchronous contractions of antagonist muscles. Essential tremor (ET) is the most common movement disorder. It is a syndrome characterized by a slowly progressive postural and/or kinetic tremor of certain body parts, most commonly the arms, hands, and head when the respective body part is maintained in a constant position.

Description

James Parkinson in 1817 was the first to describe and differentiate ET from the tremor seen in Parkinson's disease . ET is also called benign essential tremor or familial tremor. ET is called benign as it does not increase an individual's risk of mortality, and is called essential as the cause was initially unknown. Two genes for ET were discovered in 1997. ET is caused by abnormal communication between certain areas of the brain, including the cerebellum, thalamus, and brainstem. In most cases, the tremor is mild and non-progressive, whereas a minority of people has a slowly progressive condition with the tremor eventually involving the voice box, tongue, legs, and trunk. There can be several periods when the symptoms do not worsen and remain stable. ET can be quite disabling if the tremor is severe and widespread and can substantially affect a person's quality of life.

Demographics

ET is probably the most common neurologic movement disorder of adults and affects about 10 million people in the United States alone. Various estimates indicate that about 5% of patients older than 60 years of age have ET and that it is more prevalent than Parkinson's disease or Alzheimer's disease . The incidence is bimodal with the first peak occurring in an individual's early 20s and the second peak in the 60s. It can even occur in children, although onset is rare before age 10. Sometimes, ET appears in adolescence and can go into remission, only to surface later in life. There is no major ethnic or gender differences, although males tend to have more severe extremity tremor and females have more severe head tremor. The actress Katherine Hepburn is one of the well-known personalities who had ET involving the head and voice.

Genetic profile

ET can occur either as a truly sporadic form or more commonly as an autosomal dominant inheritance with variable penetrance. Some cases appear to be sporadic, but this could be due to decreased penetrance in certain families, which means that all persons who inherit the gene need not express symptoms. In familial ET, 50% of patients develop symptoms by 40 years of age and this differentiates it from truly sporadic ET, which has a later age of onset. Most studies indicate that 50–70% of ET is familial and first-degree relatives are five times more likely to develop ET than a person without an affected relative. Children of affected individuals have a 50% risk of inheriting the gene and expression of this is nearly complete by 70 years of age.

Two susceptibility genes have been identified in ET. One is a familial essential tremor gene (FET1 or ETM1), found on the long arm of chromosome 3. The second one is ETM2 on the short arm of chromosome 2. It is not clear if the phenomenon of anticipation occurs in ET, whereby symptoms occur earlier with each successive generation. A third mutation in chromosome 4p may also cause postural tremor.

No structural lesions in the brain have been detected using sophisticated brain imaging techniques like computerized tomography (CT) or magnetic resonance imaging (MRI). Positron emission tomography (PET), which examines the biochemistry in various parts of the brain, and functional MRI (fMRI) scans have shown increased activity in the cerebellum and olivo-cerebellar pathways. It is postulated that certain circuits in the brain may become unstable and drive muscle contractions. These are called central oscillators, and one such oscillating generator/pacemaker is a part of the brainstem near the inferior olivary nucleus, which becomes unmasked in ET. Other possible generators include the red nucleus, globus pallidus, and cerebellum. Disturbances in neural transmission involving the amino acid gamma amino butyric acid (GABA) are thought to be important in ET.

Signs and symptoms

Tremor is usually the only symptom seen in ET. There are three types of tremor that can be observed in ET.

The most common is postural tremor is seen when the patient is voluntarily maintaining a fixed anti-gravity position of a limb (e.g., outstretched hands). This resembles a physiologic tremor that is present in everyone, but is more severe in an affected individual. The postural tremor appears as a fine to moderate tremor with a frequency of 4–12 Hertz (Hz). This usually begins in both hands simultaneously, but 10–15% patients notice tremor onset in the dominant hand. A mild degree of asymmetry in tremor severity is not unusual. Tremor usually moves from the hands to the arms over time. Initially the tremor may be noticeable only during periods of fatigue or anxiety, but it becomes more constant over time. The severity of tremor varies considerably even from day to day. Tremor amplitude worsens with emotion, cold, hunger, and fatigue, and tends to increase with age. Changing the angle of the limb position can significantly alter the magnitude of the tremor. Handwriting becomes shaky and rounded letters take on a sharp angularity. There is a component of the tremor that can be voluntarily suppressed. The tremors can range from being mild and a minor annoyance in one individual to severe and disabling in another family member.

Some patients have worsening of tremor while performing goal-directed tasks, such as writing, buttoning a shirt, or drinking from a cup, and this is called intention tremor, or kinetic tremor. This type of tremor is higher in amplitude than positional tremor and is the major cause of disability. The third type of tremor is a feeling of general shakiness or a sensation of vibration inside the body referred as internal tremor.

In about 30% of patients, the tremor involves the head region. Head tremor (titubation) is the second most common body part to be affected and can occur either in isolation or with hand tremors. Head tremor is mostly a horizontal sideways pattern, as if indicating no. Voice and tongue tremor causes dysarthria (difficulty in articulating words) and causes quavering or shaky speech and is usually seen with advancing age above 65.

Tremor generally disappears during sleep and is minimal during periods of rest. Although the typical picture is that of gradually increasing postural and kinetic tremor of the hands and forearms, there exists considerable variation among patients. Muscle tone and strength are usually not affected. Memory, intellect, strength, and muscle tone remain intact. Some associated symptoms like ataxia (unsteady and uncoordinated gait) and dystonia can also be seen. It is still controversial if there is a higher-than-chance incidence of Parkinson's disease among people with ET.

Diagnosis

Although ET is a common condition seen in general medical practice, diagnosis may be difficult and treatment challenging. Correct diagnosis is crucial to implement early treatment and to avoid unnecessary anxiety about a misdiagnosis of more severe neurological conditions like Parkinson's disease or other neurodegenerative disorders. It is best diagnosed and treated by a neurologist or a physician trained in movement disorders. No biomarkers, blood tests, or imaging tools is available to assist in diagnosis. Thyroid disease, excess caffeine consumption, and medication side effects should be excluded as these can mimic ET. MRI scans are used only to exclude other causes of tremor, such as multiple sclerosis .

Diagnosis is mainly clinical and depends on recognizing the postural tremor, absence of rest tremor that is seen in Parkinson's disease, presence of tremor for more than three years, a decrease in tremor with alcohol consumption, and a family history of similar tremor. Clinical tremor questionnaires and rating scales can be helpful in the diagnosis and in assessing response to treatment. During the neurological assessment, the physician may use simple tests like spiral or line drawing, handwriting, tasks such as taking a water-filled cup to the mouth, articulating vowels, etc., to determine the extent and severity of ET. Accelerometer is a simple device attached to the fingers that measures tremor frequency.

Diagnostic criteria

Inclusion criteria include the following symptoms:

• Bilateral, largely symmetrical postural, or kinetic tremor in hands/forearms that is visible and persistent.
• Isolated head tremor may occur, but without abnormal posturing.

Exclusion criteria include the following symptoms:

• Prominent dystonia
• Known causes of enhanced physiologic tremor
• Psychogenic origin of tremor
• Primary orthostatic tremor
• Isolated voice tremor
• Isolated position or task-specific tremor
• Isolated tongue or chin tremor
• Isolated leg tremor

Treatment and management

Various population-based studies have found that only about 15% of patients with ET seek treatment, mostly because of lack of awareness of the disease and treatment options. Treatment is based on how disabling the symptoms are to the patient, as early treatment has not been shown to stop or delay the disease progression. There is a 50% chance that the tremor will respond to currently available medications without undue side effects. Sometimes, trials with multiple medications may have to be done before the tremor responds. Depending on coexisting medical conditions and neurological diseases, treatment must be individualized.

Lifestyle changes, including elimination of caffeinated foods like sodas, coffee, and chocolates, and other stimulants like cigarettes, are the first step in treatment. Biofeedback, acupuncture, yoga, tai-chi, and guided imagery are techniques that can be used in patients in whom the tremor worsens with stress and anxiety. In 50% of patients, alcohol may reduce tremor for up to two hours, but this is not to be considered as therapy. Excessive alcohol consumption can worsen tremor as a rebound phenomenon. Adaptive devices like wrist weights and plate guards can help to minimize tremor and interference with daily activities. Specially designed utensils (such as rocker knives and utensils with large handles) and electrical appliances (such as can openers and toothbrushes) can make daily activities easier. Certain simple precautions can enable many people to continue their normal daily activities. For example, objects should be grasped firmly but comfortably and held close to the body. Cylinders of foam can be placed around handles to make them easier to hold. Other helpful measures include using straws, button hooks, Velcro fasteners, zipper pulls, and shoe horns. Counseling may be needed to help patients deal with social isolation resulting from severe tremor.

The most commonly used medication to treat ET is propranolol, which is a beta blocker. It prevents the action of adrenaline and reduces tremor amplitude. It is available in a short- and long-acting form. The effect of the short-acting form lasts for 3–4 hours and is suitable for taking prior to a specific task, such as giving a speech, attending a social gathering, etc. It is rare for the tremor to completely disappear with treatment, but about 60% of patients respond to it. The medication works best for hand tremor. Side effects include lowering of blood pressure and heart rate, aggravation of asthma and depression , fatigue, and impotence. Primidone is a barbiturate and is the second most commonly used medication. It was originally developed as an anti-seizure medication and is taken once a day at night in order to minimize the side effects of drowsiness and fatigue. It can be used for long periods of time with minimal side effects. Other medications include gabapentin and benzodiazepines like Valium and clonazepam. A combination of propranolol and primidone can be used in resistant cases. Newer therapeutic approaches include botulinum toxin injection into the muscles, such as neck muscles to treat head tremor. Transient weakness may be experienced, but the therapeutic effect lasts for 3–6 months.

Invasive surgical intervention is usually reserved for patients with severe disabling unilateral tremor, bilateral tremor, head and voice tremor, functional disability that interferes with the activities of daily living, or tremor that is unresponsive to the highest tolerated doses of medications.

The thalamus is a paired structure deep inside the brain and its ventral intermediate nucleus (VIM) is intimately involved in movement regulation. In thalamotomy, a small pea-sized hole is made in the thalamus on the side opposite to the tremor to disrupt faulty circuits. As the thalamus is close to vital brainstem structures, the surgery has to be done only by an experienced neurosurgeon. Postoperatively, some temporary side effects like confusion, weakness, and speech difficulty may occur. Bilateral thalamotomy is not advised as it may cause loss of speech and other permanent neurologic problems. Thalamotomy is especially helpful in patients with severe unilateral hand, arm, and leg tremor and is effective in up to 80% of patients with either decrease or cessation of medications. In a similar method using gamma knife, a small burn is made in the thalamus without a hole or operation being necessary.

Thalamic stimulation, or deep brain stimulation (DBS), is an alternative to thalamotomy. Unilateral DBS for tremor was approved by the Food and Drug Administration (FDA) in 1997. It involves implanting an electrode (a fine wire) deep in the VIM nucleus of the thalamus. The electrode is connected to a stimulation device (implantation pulse generator), similar to a pacemaker, which is placed under the skin below the collarbone. By sending painless, high-frequency electrical currents through the electrode, it interrupts communication between tremor cells and helps the thalamus rebalance the tremor control messages. Patients may turn the pulse generator off and on by passing a hand-held magnet over the device. The batteries that power the pulse generator need to be surgically replaced every 3–5 years. Tremor reduction occurs within seconds of activation and can be quite dramatic. Significant or complete tremor reduction occurs in approximately 80% of people with this procedure and, thus far, efficacy has continued for 6–7 years. The main advantages of this procedure are that implantation on both sides of the brain is possible, the device can be adjusted for optimal effect, and it may be removed if desired. Other potential targets for DBS in ET include globus pallidus and sub-thalamic nucleus.

There are two ongoing clinical trials sponsored by the National Institute of Neurological Diseases and Stroke (NINDS). One of these measures the reduction of tremor by a substance called Octanol. The other looks at

KEY TERMS

Yoga

—An exercise that combines relaxation and breathing techniques to combat stress and help circulation and movement of the joints; yoga has its origin in ancient Indian medicine.

tremor reduction by Botox (botulinum toxin). The Essential Tremor Organization is also conducting a trial looking at the efficacy of a medication called topiramate. Fetal neural implant (or nigral implant) is an experimental technique that involves transplanting fetal tissue into the brain to replace degenerated nerves. Many issues are still unresolved, such as the source of embryonic tissue, the amount of tissue required, the number of brain penetrations needed, and rejection of transplanted tissue.

Prognosis

ET does not increase a person's risk of mortality, but can result in varying levels of functional difficulty and disability depending on how severe the tremor is. With advancing age, the amplitude of the tremor worsens and it is this feature that results in major disability. The patient with ET is disabled either due to physical limitations or from the resulting social embarrassment, which can lead to social withdrawal and depression. Everyday tasks that need fine motor skills and manipulation become difficult, such as writing, using utensils, drinking from a glass, applying makeup, etc. Several patients even opt for early retirement or change jobs due to the severity of tremor. Patients should be educated about the disease and emphasized that it is not life-threatening or a forerunner of a neurodegenerative disorder like Parkinson's disease.

Resources

BOOKS

Bradley, Walter G., Robert B. Daroff, Gerald M. Fenichel, and Joseph Jankovic. Neurology in Clinical Practice, 4th ed. Philadelphia: Butterworth Heinemann, 2004.

PERIODICALS

Louis, Elan D. "Essential Tremor". Lancet Neurology 4 (February 2005): 100–110.

Sullivan, Kelly L., Robert A. Hauser, and Theresa A. Zesiewicz. "Essential Tremor". The Neurologist 10 (September 2004): 250–258.

ORGANIZATIONS

International Essential Tremor Foundation. P.O.Box 14005, Lenexa, Kansas 66285-4005. (888) 387 3667. (April 4, 2005.) <http://www.essentialtremor.org>.

National Institutes of Health/National Institute of Neurological Disorders and Stroke Brain Resources and Information Network. PO Box 5801, Bethesda, MD 20824. (301) 496 5751. (April 4, 2005.) <http://www.ninds.nih.gov>.

Worldwide Education and Awareness for Movement Disorders (WE MOVE). 204 West 84th Street, New York, NY 10024. (April 4, 2005.) <http://www.wemove.org>.

OTHER

Medtronic Neurological Patient Services. LN 360, 710 Medtronic Parkway NE, Minneapolis, MN 55432-5604. (800) 325-2518. (April 4, 2005.) <http://www.medtronic.com>.

National Institute of Neurological Disorders and Stroke, Patient Recruitment and Public Liaison Office. 9000 Rockville Pike, Bethesda, MD 20892. (800) 411-1222. (April 4, 2005.) <http://www.clinicaltrials.gov>.

Tremor Action Network. PO Box 5013, Pleasanton, CA 94566-0513. (952) 462-0111. (April 4, 2005.) <http://www.tremoraction.org>.

Chitra Venkatasubramanian, MBBS, MD