NORD gratefully acknowledges Elan D. Louis, MD, MS, Professor of Neurology and Epidemiology, Yale University, who was consulted in the preparation of this report.
Essential tremor (ET) is a progressive, neurological disease characterized by tremor, most often of the hands or arms. A tremor is an involuntary, rhythmic, movement of a body part. Tremor may be seen as involuntary shaking or trembling of the affected area. In individuals with ET, other motor symptoms may be present including an unsteady manner of walking due to an inability to coordinate voluntary movements (ataxia). In some cases, affected individuals may also develop a variety of non-motor symptoms including cognitive impairment, depression or anxiety. ET can occur in childhood or adulthood. The exact, underlying cause of ET is not fully understood. In some cases, the disorder runs in families; in others, it occurs in individuals with no previous family history. The causes of ET are most likely many, which means that several factors, such as genetic and environmental ones, may each play a role in the development of the disorder.Introduction
Traditionally, ET was viewed as a relatively benign disorder characterized by one symptom, tremor. However, ET can be associated with a variety of psychosocial issues and it can potentially significantly disrupt daily activities and social interactions. Consequently, the term benign was dropped from the name. In addition, researchers have determined that additional motor and non-motor symptoms can be associated with the disorder. Some researchers now believe that ET may actually represent a group of similar, yet distinct, diseases sharing the common trait of kinetic tremor.
ET is a highly variable disorder. Age of onset, progression, tremor distribution, and severity can vary greatly from one individual to another. The characteristic symptom of ET is tremor, which most often occurs as involuntary shaking or trembling of the hands and/or arms. In some cases, tremor of the hands or arms occurs as an isolated finding. Usually, both of the hands or arms are affected, although one side of the body is generally affected more than the other. Tremor can also affect the head (i.e., neck), voice, jaw, or tongue.
In many cases, tremor affecting the hands or arms can slowly progress to affect other areas, most often the head. Although generally progressive, the rate of progression is slow on average. Recent studies have demonstrated that the average rate of progression of arm tremor severity is approximately 1.5 to 5% per year.
A tremor can be fast or slow and its breadth of range or degree (amplitude) can be dramatic and easily noticeable or so mild as to be nearly imperceptible. Tremor in individuals with ET usually begins gradually, slowly worsening as an affected individual ages. Tremor often worsens with movement. It can also be aggravated by stress, fever, fatigue, a heightened emotional state, low blood sugar, and caffeine.
Different tremor types can be associated with ET. In most cases, tremor occurs when individuals attempt to make voluntary movements (kinetic tremor). Such movements can include simple tasks such as pouring a drink, drinking from a cup, using utensils, tying shoelaces, drawing, or writing.
Postural tremor is also common in individuals with ET. Postural tremor refers to a tremor that occurs while an individual attempts to maintain a fixed position against gravity, such as when holding ones arms outstretched in front of the body as when holding a newspaper.
Some individuals with ET have an “internal tremor,” which is described as a general feeling of shakiness in the body. These tremors cannot be seen by observers.
In advanced cases, a rest tremor may occur. Rest tremors occur when the body is relaxed and at rest against gravity as when resting one’s arm on a chair.
Some affected individuals also have an impaired ability to coordinate voluntary movements (ataxia) affecting the muscles of the legs. This can cause an uncoordinated or clumsy manner of walking (abnormal gait).
In recent years, researchers have determined that non-motor symptoms develop in individuals with ET more commonly than in individuals within the general population. Such symptoms include cognitive deficits, personality changes, and depression. Hearing impairment and an altered sense of smell (mild olfactory dysfunction) have also been reported in some studies. Cognitive dysfunction appears to be more likely to occur in individuals with an older age of onset of the disorder.
ET is often associated with a variety of social and psychological consequences. The disorder can cause difficulty with normal daily activities and can potentially dramatically impact an individual’s quality of life. Affected individuals may avoid social or stressful situations due to anxiousness and frustration.
Recent epidemiological studies indicate that individuals with ET are at slightly increased risk of developing dementia (particularly Alzheimer’s disease) compared to their age-matched counterparts without ET. Similar studies also show that persons with ET have a more than four-times increased risk of developing Parkinson’s disease. The mechanisms for these associations are currently under study.
In some affected individuals, ET appears to occur spontaneously for unknown reasons (sporadically) and there is no previous family history of the disorder. However, in many cases, the disorder runs in families. First degree relatives of an individual with ET are just under five times more likely to develop a tremor than the general population. The exact percentage of familial cases of ET is unknown, with estimates ranging from 17% to more than 50% of cases.
In familial cases, ET has traditionally been viewed as being inherited as an autosomal dominant trait, although other modes of inheritance are increasingly being considered. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
In ET, there is evidence of reduced penetrance and gene expression, meaning that individuals vary within families in terms of their clinical manifestations. This suggests that additional factors, most likely environmental or additional genetic (e.g. modifier genes) ones are necessary for the development the disorder in an individual (multifactorial development).
Investigators believe that as-yet-unidentified genes located on the long arm (q) of chromosome 3 (3q13.31), the short arm (p) of chromosome 2 (2p25-p22), and the short arm of chromosome 6 (6p23) may be involved in some cases of ET. Aside from this, a small number of specific genes seem to play a role in a few ET families, but further confirmatory work is needed. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q13.31” refers to band 13.31 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The exact underlying cause of ET is not fully understood, although recent research suggests that ET may be a neurodegenerative disorder. Controlled postmortem studies have demonstrated a variety of degenerative changes within the cerebellum affecting the Purkinje cell population, and some patients have other degenerative changes, including Lewy bodies. Additional work remains to be performed and more research is necessary to determine the complex, underlying mechanisms that cause ET.
ET is the most prevalent tremor disorder and is one of the most common neurological disorders among adults. ET is often misdiagnosed as Parkinson’s disease, making it difficult to determine the disorder’s true frequency in the general population. An estimated 7 million Americans have ET. The incidence of ET increases with age and more than 4% of the population over the age of 40 has ET. Although the disorder is most common in older adults, it can affect individuals of any age including middle-aged or young adults and children. In rare cases, it has been reported during infancy. Individuals with a family history of ET tend to experience earlier onset of tremor. ET affects both men and women and individuals of every race or ethnicity.
A diagnosis of ET is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. There is no specific test to diagnose ET. A neurological exam and other tests to evaluate the tremor may be conducted to rule out other causes of tremor.
The treatment of ET is directed toward the specific symptoms that are apparent in each individual. Some individuals with a mild form of the disorder may not require treatment. Drug therapy is the first-line therapy for individuals who do require treatment and is usually begun when ET starts to interfere with daily activities or is causing significant embarrassment. Response to various drug therapies is highly individualized; what provides relief for one person may not help at all in another person.
Two common medications used to treat the disorder are propranolol (Inderal®) and primidone (Mysoline®). These drugs can be used alone or in combination.
Propranolol is classified as a beta blocker and is one of the most widely used anti-tremor medications available. It is also used to treat high blood pressure. Propranolol is the only drug approved by the Food and Drug Administration (FDA) for the treatment of individuals with ET. Approximately 50-70% of individuals receive symptomatic relief from tremor when treated with propranolol.
Primidone is an anti-seizure drug (antiepileptic) and has also been effective in treating some individuals with ET. Some individuals have had difficulty tolerating primidone.
Additional drugs have been to treat individuals with ET when propranolol and primidone are ineffective or cannot be tolerate (i.e. second line therapies). These drugs include additional beta blockers, atenolol (Tenormin®) and sotalol (Betapace®); the anti-seizures medications topiramate (Topamax®) and gabapentin (Neurontin®); and the benzodiazepine alprazolam (Xanax®).
Other medications that have been used to treat individuals with ET include inconclusive or inconsistent results include the anti-seizure medication levetiracetam (Keppra®) and benzodiazepines such as diazepam (Valium®), lorazepam (Ativan®), and clonazepam (Klonopin®). The antidepressant drug, mirtazapine (Remeron®), has been used to treat individuals with ET. However, this drug has generally proved ineffective for most individuals.
Botulinum toxin injections have been used to treat some individuals with head and voice tremors in whom other medications were ineffective. It has also sometimes been used to treat individuals with hand and arm tremor. Botulinum toxin is a neurotoxin that is injected into muscles in very small doses. After injection into a muscle, the action of botulinum toxin is to interrupt nerve messages to the muscles. Temporary muscle weakness may be a side effect of this treatment.
Individuals with severe cases of ET that do not respond to other treatment options may undergo a procedure known as thalamic deep brain stimulation. Thalamic refers to the thalamus, a portion of the brain that relays motor and sensory information. It is believed that some types of tremors occur due to abnormal brain activity that is processed in the thalamus. During this procedure, an electrode is placed into the thalamus and a thin wire is passed under the skin. This wire is connected to a small battery pack (which is also placed underneath the skin). The electrode is used to send electrical impulses (stimulate) to the brain and interrupt aberrant nerve signals that contribute to tremors. Many individuals who undergo thalamic deep brain stimulation have experienced significant relief from tremor symptoms. This procedure is effective for all tremors associated with ET. In 1997, the FDA approved unilateral (one-sided) thalamic stimulation with a device from Medtronics Corporation for control of ET.
Thalamic deep brain stimulation has replaced thalamotomy as the treatment of choice in severe cases that have not responded to other therapies. Thalamotomy refers to the surgical removal or destruction of targeted parts of the brain such as thalamus. This surgical procedure is generally effective in controlling tremor but carries high risk of complications.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. For example, psychological support and counseling can help individuals cope with depression or other psychological issues associated ET. Physical devices, including stabilizing and weighted utensils, may reduce shaking while eating.
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