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Essential tremor (ET) is a degenerative disorder of the central nervous system whose most recognizable feature is a tremor of the arms or hands during voluntary movements such as eating and writing. In many respects it resembles Idiopathic Parkinson's disease. Essential tremor is commonly described as an action tremor (it intensifies when one tries to use the affected muscles) rather than a resting tremor; rigidity, such as is seen in Parkinson’s, is usually not included among its symptoms. In practice, however, there is far less difference between Essential Tremor and Parkinson's Disease than is often assumed.
Varieties and incidence
This type of tremor is often referred to as "kinetic tremor." The tremor may also occur in the head (neck), jaw and voice as well as other body regions, with the general pattern being that the tremor begins in the arms and then spreads to these other regions in selected patients. Women are more likely to develop the head tremor than are men. Other types of tremor may also occur, including postural tremor of the outstretched arms, intentional tremor of the arms and rest tremor in the arms. Some patients may have unsteadiness and problems with gait and balance, as well as symptoms of neuropathy, rigidity, dystonia, and dysautonomia (with symptoms such as, changes in heart rate and blood pressure, heat/cold intolerance, oily skin, & even dandruff or Seborrhoeic dermatitis) as well as neuropsychiatric disturbances (forgetfulness, mood swings, confusion, and even dementia) similar to those seen in Parkinson's disease.It has even been suggested that ET is simply a variant of Parkinson's.
In addition to these motor problems, a variety of non-motor symptoms have recently been linked with ET. These include anxiety and depression as well as cognitive difficulty. Recent studies have demonstrated that late-onset ET (onset > age 65) may be associated with an increased risk of developing dementia.
ET is one of the most common neurological diseases, with a prevalence of approximately 4% in persons age 40 and older and considerably higher among persons in their 60s, 70s, 80s, and 90s. Aside from enhanced physiological tremor, it is the most common type of tremor and one of the most commonly observed movement disorders. Essential tremor was also previously known as "benign essential tremor", but the adjective "benign" has been removed in recognition of the sometimes disabling nature of the disorder. Although essential tremor is often mild, patients with severe tremor have difficulty performing many of their routine activities of daily living.
Signs and symptoms
Essential tremor generally presents as a rhythmic tremor (4–12 Hz) that ocurs only when the affected muscle is exerting effort. Any sort of physical or mental stress will tend to make the tremor worse, often creating the false impression that the tremor is of psychosomatic origin. The prevalence of Parkinson's Disease in people with Essential Tremor is greater than in the general population. The overlap of symptoms suggests that rather than being separate disorders, they are actually different aspects of the same medical disorder. Parkinson's Disease and Parkinsonism can also occur simultaneously with Essential Tremor. In those cases the degree of tremor, rigidity, and functional disability does not differ from those people with idiopathic Parkinson's Disease. Hand tremor predominates (as it does in Parkinson’s Disease), and occurs in nearly all cases, followed by head tremor, voice tremor, neck, face, leg, tongue and trunk tremor. Most other tremors occur in association with hand tremor. Walking difficulties in Essential Tremor are common. About half of patients have associated dystonia, including cervical dystonia, writer's cramp, spasmodic dysphonia, and cranial dystonia, and 20% of the patients had associated parkinsonism. Olfactory dysfunction (loss of sense of smell) is common in Parkinson’s Disease, and has also been reported to occur in patients with Essential Tremor. A number of Patients with essential tremor also suffer from dysautonomia, and exhibit many of the same neuropsychiatric disturbances & skin problems seen in idiopathic Parkinson's disease.
Tremor & disease activity & intensity can worsen in response to fatigue, strong emotions, low blood sugar, cold, & heat caffeine, lithium salts, some antidepressants or other factors. It is typical for the tremor to worsen in "performance" situations, such as when writing a cheque for payment at a store or giving a presentation.
ET-related tremors do not occur during sleep, but patients sometimes complain of an especially coarse tremor upon awakening that becomes noticeably less coarse within the first few minutes of wakefulness.
In mild cases, ET can manifest as the inability to stop the tongue or hands from shaking, the ability to sing only in vibrato, and difficulty to do small precise tasks such as threading a needle. Even simple tasks like cutting in a straight line or using a ruler can range from difficult to impossible, depending on the severity of the condition. In disabling cases, ET can interfere with a person's ability to perform tasks of daily living, including feeding, dressing, and activities of personal hygiene.
People with ET can sometimes have problems with finding words and can't articulate themselves effectively even with preparation. A person with ET may become shy, withdrawn, pessimistic, anxious and have difficulties concentrating. It is common for those with ET to be embarrassed by the condition even though it is out of their control.
The underlying etiology is not clear but many cases seem to be familial. It has been estimated that approximately one-half of the cases are due to a genetic mutation and the pattern of inheritance is most consistent with autosomal dominant transmission. No genes have been identified yet but genetic linkage has been established with several chromosomal regions. A number of environmental factors, including toxins, are also under active investigation and these may play a role in disease etiology. In terms of pathophysiology, clinical, physiological and imaging studies point to an involvement of the cerebellum and/or cerebellothalamocortical circuits. Recent postmortem studies have demonstrated the presence of degenerative changes, including Purkinje cell axonal swellings and Purkinje cell loss in the majority of cases and brainstem Lewy bodies in the remainder. These studies suggest that the disease is both heterogeneous and degenerative. In other words, ET might be a family of degenerative diseases rather than a single disease.
However, emerging research based on brain autopsies of 50 deceased ET patients (as of December 2009), showed clear degenerative and pathological abnormalities, including "messy" neurofilaments which can impede nerve impulses. Research by Dr. Elan Louis and colleagues revealed that 80% of autopsied brains also exhibited changes within the cerebellum particularly to neurons that produce GABA, a major inhibitory neurotransmitter. Further analysis showed elevated levels of two neurotoxins, lead and harmane, a heterocyclic amine. Heterocyclic amines (HCA) are chemicals found in some foods. Harmane has been detected in coffee and cigarettes (see: http://www.ncbi.nlm.nih.gov/pubmed/21776263), but is especially prevalent in meats that have been barbecued or exposed to high heat.
Another research indicates there is a strong link between essential tremor in males and the amount of meat consumed, but the exact mechanism is yet unknown.
Changes in the cerebelleum could also be mediated by alcohol consumption. Purkinje cells are especially susceptible to ethanol excitotoxicity. The impairment could lead to the abnormal cerebellar circuitry seen in essential tremor and suggests that alcohol may also work as an exacerbating agent in the pathology of this disease.
Chronic ethanol consumption results in a loss of Purkinje cell synapses. However, these synapses are regained following a period of recovery that includes gradual weaning off of ethanol. Continued consumption of ethanol inhibits the recovery of synapses. This impairment of Purkinje synapses is a component of cerebellar degradation that could underlie essential tremor.
Usually the diagnosis is established on clinical grounds. Tremors can start at any age, from birth through advanced ages (senile tremor). Any voluntary muscle in the body may be affected, although the tremor is most commonly seen in the hands and arms and slightly less commonly in the neck (causing the patient's head to shake), tongue, and legs. A resting tremor of the hands is sometimes present. Tremor occurring in the legs might be diagnosable as Orthostatic Tremor.
ET does sometimes occur in combination with other neurological disorders such as dystonia, neuropathy, & dysautonomia. In addition, there may be a link between ET and Parkinson's disease, with one study showing ET patients having an approximately 4 times greater likelihood of developing Parkinson's disease. Essential tremor also tends to co-occur with Orthostatic Tremor.
There is no recognised cure for essential tremor. Many of the treatments available are to lower the severity of the condition. These may include:
This is where Essential tremor & Parkinson's disease probably differ the most. As PD, is generally treated with levodopa or dopamine agonists.Essential tremor is usually treated with medications such as: the beta-blockers propranolol & Nadolol and the antiepileptics primidone & Neurontin.
Self-medication with small amounts of alcohol has been shown to give short term relief from tremor, although this form of self-medication is not recommended due to an increased risk of alcohol dependence or abuse. However other alcohol groups such as 1-octanol are being researched to provide relief from essential tremor without providing the intoxication or toxicity that ethanol does.
Topiramate has also been cited as a possible pharmaceutical treatment.
Memantine is a drug that is currently being researched for its potential ameliorative effects on essential tremor. Memantine is not as potent as ethanol at decreasing tremor intensity or locomotion. However, memantine exhibits neuroprotective effects. Memantine treatment results in a significantly higher reduction in caspase-3 positive neurons.
Minor cases of ET can be treated with physical therapy and development of the muscles in the sections of the body that are severe in their shaking.
Mild cases of ET which are not affecting activities of daily life may not require any treatment. Use of wrist weights and avoiding triggers such as caffeine may be helpful.
The International Essential Tremor Foundation (IETF) provides information, services and support to individuals and families affected by essential tremor (ET). The organization encourages and promotes research in an effort to determine the causes, treatment and ultimately the cure for ET. The IETF is a worldwide organization dedicated to meeting the needs of those whose daily lives are challenged by ET. IETF, an international non-profit 501(c)(3) organization that derives its support entirely from its membership and the general public, was founded in 1988 and is guided by a board of directors and a medical advisory council. The organization's membership consists of patients, physicians, educators, parents, relatives and volunteers who provide education, community services and funding to help support tremor research.
The National Tremor Foundation (NTF), founded in 1992, is a British friendly organisation based in Essex, England, an affiliate of the International Tremor Foundation, which was founded in 1988. The organisation's primary work is production of a quarterly informational newsletter. The NTF also maintains a list of ITF medical advisors, and facilitates the formation of self-help groups. NTF was granted charitable status in 1994.
Harmaline is a widely used model of essential tremor (ET) in rodents. Harmaline is thought to act primarily on neurons in the inferior olive(IO). Olivocerebellar neurons exhibit rhythmic excitatory action when harmaline is applied locally. Additionally, when harmaline is administered to lesioned IOs, little to no tremors are observed, reinforcing harmalines’ specificity for inferior olive connections. The treatment of harmaline results in higher levels of caspase-3 immunoreactivity in Purkinje, granule and inferior olive cells, suggestive of harmaline-mediated apoptosis. Harmaline also increases the concentration of glutamate in cerebellar nuclei which disrupts normal NMDA-mediated down-regulation of glutamate release. Together, these interferences likely give rise to essential-tremor like behavior that is likely a result of diseregulation of glutamatergic circuitry within the cerebellum.
Ethanol is effective at decreasing tremor intensity and locomotion. Ethanol-mediated effects are not observed on tremor frequency and peak location. Additionally, ethanol is able to reduce caspase-3 induced apoptosis though not without an increased loss of neurons in the cerebellum and olivary nucleus. Ethanol has been shown to decrease levels of glutamate in the cerebellar nuclei which had been pre-treated with harmaline. Furthermore, ethanol directly reduces hyperactivity of the climbing fiber-Purknije cell synapse by acting on glutamatergic receptors. Ethanol may reduce tremor by dampening the overexcitation of glutamatergic pathways involving deep cerebellar nuclei which may also reduce levels of caspase-3 induced apoptosis.
Different alcohols exert similar ameliorative effects on harmaline-induced tremors, though to different degrees. Different isomers of octanol vary in efficacy when it comes to antagonizing harmaline-mediated tremors. These effects are likely mediated in the inferior olive, specifically at low-threshold calcium channels (LTCC) which have been shown to modulate the rhythmic firing of cells in this area. Octanol, specifically by binding to LTCCs of IOs, behaves in an antagonistic fashion on the spike discharges from Purkinje cells. The most potent isomers: (+)2-octanol, (-)2-octanol and 4-octanol, followed by 4-octanol, and lastly, 1-octanol. Both the magnitude and duration of the tremor are dependent on the octanol isomer. Differences in solubility does not appear to account for the disparity between isomers. The first clinical trial of 1-Octanol in essential tremor was first conducted by Bushara etal and published in 2002, 2004. This showed the safety of 1-octanol and its efficacy in reducing tremor in patients diagnosed with essential tremor.
Genetic animal models of essential tremor utilize GABAA receptor α1 -/- mice because of the major role GABA plays in inhibiting motor activity. Moreover, GABAA receptor α1 -/- mice produce essential-like tremors and motor impairment as seen in ET patients.
Alcohol is implicated as a therapeutic agent for GABAA receptor α1 -/- mice because of its interaction with Purkinje cells which mediate their actions via GABA transmission. GABAA receptor α1 -/- mice respond positively to ethanol treatment. Ethanol reduces tremor activity in GABAA receptor α1 -/- mice in a dose dependent manner. An optimum dose of 2.5 g/kg of ethanol completely suppresses tremors in GABAA receptor α1 -/- mice. Purkinje cells in these knockout mice also exhibit a lack of GABAergic inhibitory postsynaptic potentials in response to both exogenous and endogenous GABA. The loss of GABAergic inhibition in purkinje cells likely underlies the pathological tremors observed. These ameliorative effects are thought to involve inhibition of glutamatergic transmission, though the numerous targets of ethanol make it difficult to determine the exact underlying mechanism.
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- International Essential Tremor Foundation (USA)
- Tremor Action Network (USA)
- National Tremor Foundation (UK)
- Association APTES (France)
- Leonid L. Rubchinsky et al. (2007) Tremor. Scholarpedia 2(10):1379
- Brain Autopsies Reveal Abnormalities
- Essential Tremor Centralized Brain Repository
- Essential Tremor Info