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'''Essential tremor''' ('''ET''') is a slowly progressive [[neurological disorder]] whose most recognizable feature is a tremor of the [[arm]]s that is apparent during voluntary movements such as eating and writing.<ref>Benito-Leon J, Louis ED. Clinical update: Diagnosis and treatment of essential tremor. The Lancet 2007;369:1152-1153.</ref> 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.<ref>Hubble JP, Busenbark KL, Pahwa R, Lyons K, Koller WC. Clinical expression of essential tremor: Effects of gender and age. Mov Disord 1997;12:969-972.</ref><ref>Louis ED, Ford B, Frucht S. Factors associated with increased risk of head tremor in essential tremor: A community-based study in northern manhattan. Mov Disord 2003;18:432-436.</ref> Other types of tremor may also occur, including postural tremor of the outstretched arms, [[Intention tremor|intentional tremor]] of the arms and rest tremor in the arms.<ref>Louis ED. Clinical Practice: Essential tremor. N Engl J Med 2001;345:887-891.</ref> Some patients may have unsteadiness and problems with gait and balance that are above and beyond that due to normal aging.<ref>Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain. November 2001;124(Pt 11):2278-2286.</ref><ref>Singer C, Sanchez-Ramos J, Weiner WJ. Gait abnormality in essential tremor. Mov Disord. March 1994;9(2):193-196.</ref> In addition to these motor problems, a variety of non-motor features have recently been linked with ET. These include anxiety and depressive symptoms as well as cognitive difficulty.<ref>Tan EK, Fook-Chong S, Lum SY, et al. Non-motor manifestations in essential tremor: use of a validated instrument to evaluate a wide spectrum of symptoms. Parkinsonism Relat Disord. September 2005;11(6):375-380.</ref> Recent studies have demonstrated that late-onset ET (onset > age 65) may be associated with an increased risk of developing dementia.<ref>Bermejo-Pareja F, Louis ED, Benito-Leon J. Risk of incident dementia in essential tremor: A population-based study. Mov Disord 2007;22:1573-1580.</ref> 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.<ref>Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder?: Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13:5-10.</ref><ref>Dogu O, Sevim S, Camdeviren H, Sasmaz T, Bugdayci R, Aral M, Kaleagasi H, Un S, Louis ED. Prevalence of essential tremor: Door-to-door neurological exams in Mersin Province, Turkey. Neurology 2003;61:1804-1807.</ref> Aside from enhanced physiological tremor, it is the most common type of [[tremor]] and one of the most commonly observed movement disorders.<ref>Benito-Leon J, Louis ED. Essential tremor: emerging views of a common disorder. Nat Clin Pract Neurol 2006;2:666-678.</ref> 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 often mild, patients with severe tremor have difficulty performing many of their routine [[activities of daily living]].<ref>Bain PG, Mally J, Gresty M, Findley LJ. Assessing the impact of essential tremor on upper limb function J Neurol 1993;241:54-61.</ref><ref>Louis ED, Barnes LF, Albert SM, Cote L, Schneier F, Pullman SL, Yu Q. Correlates of functional disability in essential tremor. Mov Disord 2001;16:914-920.</ref>
'''Essential tremor''' ('''ET''') is a slowly progressive [[neurological disorder]] whose most recognizable feature is a tremor of the [[arm]]s that is apparent during voluntary movements such as eating and writing.<ref>Benito-Leon J, Louis ED. Clinical update: Diagnosis and treatment of essential tremor. The Lancet 2007;369:1152-1153.</ref> 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.<ref>Hubble JP, Busenbark KL, Pahwa R, Lyons K, Koller WC. Clinical expression of essential tremor: Effects of gender and age. Mov Disord 1997;12:969-972.</ref><ref>Louis ED, Ford B, Frucht S. Factors associated with increased risk of head tremor in essential tremor: A community-based study in northern manhattan. Mov Disord 2003;18:432-436.</ref> Other types of tremor may also occur, including postural tremor of the outstretched arms, [[Intention tremor|intentional tremor]] of the arms and rest tremor in the arms.<ref>Louis ED. Clinical Practice: Essential tremor. N Engl J Med 2001;345:887-891.</ref> Some patients may have unsteadiness and problems with gait and balance that are above and beyond that due to normal aging.<ref>Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain. November 2001;124(Pt 11):2278-2286.</ref><ref>Singer C, Sanchez-Ramos J, Weiner WJ. Gait abnormality in essential tremor. Mov Disord. March 1994;9(2):193-196.</ref> In addition to these motor problems, a variety of non-motor features have recently been linked with ET. These include anxiety and depressive symptoms as well as cognitive difficulty.<ref>Tan EK, Fook-Chong S, Lum SY, et al. Non-motor manifestations in essential tremor: use of a validated instrument to evaluate a wide spectrum of symptoms. Parkinsonism Relat Disord. September 2005;11(6):375-380.</ref> Recent studies have demonstrated that late-onset ET (onset > age 65) may be associated with an increased risk of developing dementia.<ref>Bermejo-Pareja F, Louis ED, Benito-Leon J. Risk of incident dementia in essential tremor: A population-based study. Mov Disord 2007;22:1573-1580.</ref> 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.<ref>Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder?: Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13:5-10.</ref><ref>Dogu O, Sevim S, Camdeviren H, Sasmaz T, Bugdayci R, Aral M, Kaleagasi H, Un S, Louis ED. Prevalence of essential tremor: Door-to-door neurological exams in Mersin Province, Turkey. Neurology 2003;61:1804-1807.</ref> Aside from enhanced physiological tremor, it is the most common type of [[tremor]] and one of the most commonly observed movement disorders.<ref>Benito-Leon J, Louis ED. Essential tremor: emerging views of a common disorder. Nat Clin Pract Neurol 2006;2:666-678.</ref> 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 often mild, patients with severe tremor have difficulty performing many of their routine [[activities of daily living]].<ref>Bain PG, Mally J, Gresty M, Findley LJ. Assessing the impact of essential tremor on upper limb function J Neurol 1993;241:54-61.</ref><ref>Louis ED, Barnes LF, Albert SM, Cote L, Schneier F, Pullman SL, Yu Q. Correlates of functional disability in essential tremor. Mov Disord 2001;16:914-920.</ref>


⚫
==Cause==
⚫
The underlying etiology is not clear but many cases seem to be familial.<ref>Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain. June 2007;130(Pt 6):1456-1464.</ref> It has been estimated that approximately one-half of the cases is due to a genetic mutation and the pattern of inheritance is most consistent with autosomal dominant transmission. As of yet, no genes have been identified but genetic linkage has been established with several chromosomal regions.<ref>Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord. 1997;12:859-864</ref><ref>Gulcher JR, Jonsson P, Kong A et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nature Genetics 1997;17:84-87.</ref> A number of environmental factors, including toxins, are also under active investigation and these may play a role in disease etiology.<ref>Louis ED. Etiology of essential tremor: Should we be searching for environmental causes? Mov Disord 2001;16:822-829.</ref> In terms of pathophysiology, clinical, physiological and imaging studies point to an involvement of the cerebellum and/or cerebellothalamocortical circuits.<ref>Louis ED, Vonsattel JP. The emerging neuropathology of essential tremor. Mov Disord 2007;23:174 - 182.</ref> Recent postmortem studies have demonstrated the presence of degenerative changes in the ET brain, with these changes including [[Purkinje cell]] axonal swellings and Purkinje cell loss in the majority of cases and brainstem [[Lewy body|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.<ref>Louis ED, Faust PL, Vonsattel JPG, Honig LS, Rajput A, Robinson CA, Rajput A, Pahwa R, Lyons KE, Ross W, Borden S, Moskowitz CB, Lawton A, Hernandez N. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130:3297-3307.</ref><ref>Shill HA, Adler CH, Sabbagh MN, Connor DJ, Caviness JN, Hentz JG, Beach TG: Pathologic findings in prospectively ascertained essential tremor subjects. Neurology 2008;70:1452-1455.</ref>

⚫
However, emerging research based on brain autopsies of fifty deceased ET patients (as of Dec. 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 [[Gamma-Aminobutyric acid|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<ref>{{cite journal|last=Louis|first=Elan D.|coauthors=Keating, Garrett A., Bogen, Kenneth T., Rios, Eileen, Pellegrino, Kathryn M., Factor-Litvak, Pam|title=Dietary Epidemiology of Essential Tremor: Meat Consumption and Meat Cooking Practices|journal=Neuroepidemiology|date=1 January 2008|year=2008|volume=30|issue=3|pages=161–166|doi=10.1159/000122333|url=http://academiccommons.columbia.edu/catalog/ac:130000|accessdate=25 July 2011}}</ref> 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 cell]]s are especially susceptible to ethanol excitotoxicity <ref>{{cite pmid| 20721919}}</ref>. 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 [[synapse]]s. However, these synapses are regained following a period of recovery that includes gradual weaning of off ethanol. Continued consumption of ethanol inhibits the recovery of [[synapse]]s <ref>{{cite pmid| 9105510}}</ref> . This impairment of Purkinje synapses is a component of cerebellar degradation that could underlie essential tremor <ref>{{cite pmid| 20721919}}</ref>.

⚫
Chronic alcohol abuse has also been linked to other movement disorders such as [[myoclonus]], [[ataxia]], and [[dyskinesia]] <ref>{{cite pmid| 20721919}}</ref>.

⚫
==Diagnosis==
⚫
Usually the diagnosis is established on clinical grounds. Tremors can start at any age, from [[childbirth|birth]] through advanced ages (senile tremor).<ref>Louis ED, Dure L, Pullman S. Essential tremor in childhood. Mov Disord 2001;16:921-923.</ref><ref>Bain PG, Findley LJ, Thompson PD, et al. A study of hereditary essential tremor. Brain. August 1994;117 ( Pt 4):805-824.</ref> Any voluntary muscle in the body may be affected, although the tremor is most commonly seen in the [[hands]] and [[arm]]s 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.<ref>Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in essential tremor patients: Prevalence, clinical correlates, and electrophysiological characteristics. Arch Neurol 2003;60:405-410.</ref><ref>Rajput AH, Rozdilsky B, Ang L, Rajput A. Significance of Parkinsonian manifestations in essential tremor. Can J Neurol Sci 1993;20:114-117.</ref>

⚫
ET does sometimes occur in combination with other neurological disorders such as [[dystonia]]. 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.<ref>{{citejournal|author=Minen M, Louis ED|title=Emergence of Parkinson’s disease in essential tremor: A study of the clinical correlates in 53 patients|journal=Mov Disord|volume=23|issue=11|pages=1602–1605|year=2008|pmid=18618664|pmc=2683412|doi=10.1002/mds.22161}}</ref><ref>{{citejournal|doi=10.1016/S1353-8020(02)00057-3|author=Yahr MD, Orosz D, Purohit DP.|title=Co-occurrence of essential tremor and Parkinson’s disease: a clinical study of a large kindred with autopsy findings.|journal=Parkinsonism Relat Disord|year=2003|volume=9|issue=4|pages=225–231|pmid=12618058}}</ref><ref>{{citejournal
⚫
|author=Benito-Leon J, Louis ED, Permejo-Pareja F.|title=Risk of incident Parkinson's disease and parkinsonism in essential tremor: a population-based study.|journal=J Neurology Neurosurgery Psychiatry|year=2009|month=April|volume=80|issue=4|pages=423–5|pmid=19289477|doi=10.1136/jnnp.2008.147223}}</ref>


==Signs and symptoms==
==Symptoms==
Essential tremor generally presents as a rhythmic tremor (4–12 [[Hertz|Hz]]) that is present only when the affected [[muscle]] is exerting effort (in other words, it is not present at rest). Any sort of physical or mental [[stress (medicine)|stress]] will tend to make the tremor worse, often creating the false impression that the tremor is of [[psychosomatic]] origin.
Essential tremor generally presents as a rhythmic tremor (4–12 [[Hertz|Hz]]) that is present only when the affected [[muscle]] is exerting effort (in other words, it is not present at rest). Any sort of physical or mental [[stress (medicine)|stress]] will tend to make the tremor worse, often creating the false impression that the tremor is of [[psychosomatic]] origin.


Line 50: Line 32:
Though it is not directly a result of the condition, a high number of people with ET develop a dependence on alcohol. This is due to the fact alcohol helps alleviate the tremor, making things like social gatherings much more enjoyable for the sufferer. However the next day it is common to suffer from a "rebound tremor" where the tremor is more noticeable than normal. This leads to many people "chasing the tail" and leading to a problem far worse than the symptoms listed.
Though it is not directly a result of the condition, a high number of people with ET develop a dependence on alcohol. This is due to the fact alcohol helps alleviate the tremor, making things like social gatherings much more enjoyable for the sufferer. However the next day it is common to suffer from a "rebound tremor" where the tremor is more noticeable than normal. This leads to many people "chasing the tail" and leading to a problem far worse than the symptoms listed.


⚫
==Cause==
==Essential Tremor Models==
⚫
The underlying etiology is not clear but many cases seem to be familial.<ref>Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain. June 2007;130(Pt 6):1456-1464.</ref> It has been estimated that approximately one-half of the cases is due to a genetic mutation and the pattern of inheritance is most consistent with autosomal dominant transmission. As of yet, no genes have been identified but genetic linkage has been established with several chromosomal regions.<ref>Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord. 1997;12:859-864</ref><ref>Gulcher JR, Jonsson P, Kong A et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nature Genetics 1997;17:84-87.</ref> A number of environmental factors, including toxins, are also under active investigation and these may play a role in disease etiology.<ref>Louis ED. Etiology of essential tremor: Should we be searching for environmental causes? Mov Disord 2001;16:822-829.</ref> In terms of pathophysiology, clinical, physiological and imaging studies point to an involvement of the cerebellum and/or cerebellothalamocortical circuits.<ref>Louis ED, Vonsattel JP. The emerging neuropathology of essential tremor. Mov Disord 2007;23:174 - 182.</ref> Recent postmortem studies have demonstrated the presence of degenerative changes in the ET brain, with these changes including [[Purkinje cell]] axonal swellings and Purkinje cell loss in the majority of cases and brainstem [[Lewy body|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.<ref>Louis ED, Faust PL, Vonsattel JPG, Honig LS, Rajput A, Robinson CA, Rajput A, Pahwa R, Lyons KE, Ross W, Borden S, Moskowitz CB, Lawton A, Hernandez N. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130:3297-3307.</ref><ref>Shill HA, Adler CH, Sabbagh MN, Connor DJ, Caviness JN, Hentz JG, Beach TG: Pathologic findings in prospectively ascertained essential tremor subjects. Neurology 2008;70:1452-1455.</ref>


⚫
However, emerging research based on brain autopsies of fifty deceased ET patients (as of Dec. 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 [[Gamma-Aminobutyric acid|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.
⚫
====Harmaline-induced tremor====
⚫
[[Harmaline]] is a widely used model of [[essential tremor]] (ET) in rodents <ref>{{cite pmid| 17366267 }}</ref>. [[Harmaline]] is thought to act primarily on neurons in the [[inferior olivary nucleus | inferior olive ]](IO). Olivocerebellar neurons exhibit rhythmic excitatory action when [[harmaline]] is applied locally <ref>{{cite pmid| 17366267 }}</ref>. Additionally, when harmaline is administered to [[lesion]]ed IOs, little to no tremors are observed, reinforcing harmalines’ specificity for inferior olive connections <ref>{{cite pmid| 2542888 }}</ref>. The treatment of harmaline results in higher levels of [[caspase-3]] immunoreactivity in Purkinje, granule and inferior olive cells, suggestive of harmaline-mediated [[apoptosis]] <ref>{{cite pmid| 21640732 }}</ref>. [[Harmaline]] also increases the concentration of [[glutamic acid | glutamate]] in cerebellar nuclei which disrupts normal [[N-Methyl-D-aspartic acid | NMDA ]]-mediated down-regulation of glutamate release <ref>{{cite pmid| 18445025}}</ref>. Together, these interferences likely give rise to essential-tremor like behavior that is likely a result of diseregulation of glutamatergic circuitry within the [[cerebellum]] <ref>{{cite pmid| 18445025}}</ref>.


⚫
Another research<ref>{{cite journal|last=Louis|first=Elan D.|coauthors=Keating, Garrett A., Bogen, Kenneth T., Rios, Eileen, Pellegrino, Kathryn M., Factor-Litvak, Pam|title=Dietary Epidemiology of Essential Tremor: Meat Consumption and Meat Cooking Practices|journal=Neuroepidemiology|date=1 January 2008|year=2008|volume=30|issue=3|pages=161–166|doi=10.1159/000122333|url=http://academiccommons.columbia.edu/catalog/ac:130000|accessdate=25 July 2011}}</ref> indicates there is a strong link between essential tremor in males and the amount of meat consumed, but the exact mechanism is yet unknown.
⚫
=====Ethanol mechanisms in harmaline-induced tremor=====
⚫
[[Ethanol]] is effective at decreasing tremor intensity and locomotion <ref>{{cite pmid| 21640732 }}</ref>. [[Ethanol]]-mediated effects are not observed on tremor frequency and peak location <ref>{{cite pmid| 21640732 }}</ref>. Additionally, ethanol is able to reduce [[caspase-3]] induced apoptosis though not without an increased loss of [[neuron]]s in the [[cerebellum]] and olivary nucleus <ref>{{cite pmid| 21640732 }}</ref>. [[Ethanol]] has been shown to decrease levels of glutamate in the cerebellar nuclei which had been pre-treated with [[harmaline]] <ref>{{cite pmid| 18445025}}</ref>. Furthermore, [[ethanol]] directly reduces hyperactivity of the [[climbing fiber]]-Purknije cell synapse by acting on glutamatergic receptors <ref>{{cite pmid| 16481422}}</ref>. [[Ethanol]] may reduce tremor by dampening the overexcitation of [[glutamate receptor | glutamatergic]] pathways involving deep cerebellar nuclei which may also reduce levels of [[caspase-3]] induced [[apoptosis]].


⚫
Changes in the cerebelleum could also be mediated by alcohol consumption. [[Purkinje cell]]s are especially susceptible to ethanol excitotoxicity <ref>{{cite pmid| 20721919}}</ref>. 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.
⚫
=====Octonal mechanism in harmaline-induced tremors=====
⚫
Different alcohols exert similar ameliorative affects on [[harmaline]]-induced tremors, though to different degrees. Different [[isomer]]s 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 <ref>{{cite pmid| 7310722 }}</ref>. [[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 <ref>{{cite pmid| 2542888 }}</ref>. 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 <ref>{{cite pmid| 2542888 }}</ref>.


⚫
Chronic ethanol consumption results in a loss of Purkinje cell [[synapse]]s. However, these synapses are regained following a period of recovery that includes gradual weaning of off ethanol. Continued consumption of ethanol inhibits the recovery of [[synapse]]s <ref>{{cite pmid| 9105510}}</ref> . This impairment of Purkinje synapses is a component of cerebellar degradation that could underlie essential tremor <ref>{{cite pmid| 20721919}}</ref>.
⚫
====Genetically-induced tremor====
⚫
Genetic animal models of essential tremor utilize [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice because of the major role [[gamma-Aminobutyric acid | GABA]] plays in inhibiting motor activity. Moreover, GABAA receptor α1 -/- mice produce essential-like tremors and motor impairment as seen in ET patients <ref>{{cite pmid| 15765150}}</ref>.


⚫
Chronic alcohol abuse has also been linked to other movement disorders such as [[myoclonus]], [[ataxia]], and [[dyskinesia]] <ref>{{cite pmid| 20721919}}</ref>.
⚫
=====Ethanol mechanisms in genetically-induced tremors=====

⚫
Alcohol is implicated as a therapeutic agent for [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice because of its interaction with Purkinje cells which mediate their actions via [[gamma-Aminobutyric acid | GABA]] transmission <ref>{{cite pmid| 17366267 }}</ref>. [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice respond positively to ethanol treatment. [[Ethanol]] reduces tremor activity in [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice in a dose dependent manner. An optimum dose of 2.5 g/kg of ethanol completely suppresses tremors in [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice <ref>{{cite pmid| 15765150}}</ref>. Purkinje cells in these knockout mice also exhibit a lack of GABAergic inhibitory postsynaptic potentials in response to both exogenous and endogenous [[gamma-Aminobutyric acid | GABA]]. The loss of GABAergic inhibition in purkinje cells likely underlies the pathological tremors observed <ref>{{cite pmid| 15765150}}</ref>. 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 <ref>{{cite pmid| 15765150}}</ref>.
⚫
==Diagnosis==
⚫
Usually the diagnosis is established on clinical grounds. Tremors can start at any age, from [[childbirth|birth]] through advanced ages (senile tremor).<ref>Louis ED, Dure L, Pullman S. Essential tremor in childhood. Mov Disord 2001;16:921-923.</ref><ref>Bain PG, Findley LJ, Thompson PD, et al. A study of hereditary essential tremor. Brain. August 1994;117 ( Pt 4):805-824.</ref> Any voluntary muscle in the body may be affected, although the tremor is most commonly seen in the [[hands]] and [[arm]]s 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.<ref>Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in essential tremor patients: Prevalence, clinical correlates, and electrophysiological characteristics. Arch Neurol 2003;60:405-410.</ref><ref>Rajput AH, Rozdilsky B, Ang L, Rajput A. Significance of Parkinsonian manifestations in essential tremor. Can J Neurol Sci 1993;20:114-117.</ref>

⚫
ET does sometimes occur in combination with other neurological disorders such as [[dystonia]]. 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.<ref>{{citejournal|author=Minen M, Louis ED|title=Emergence of Parkinson’s disease in essential tremor: A study of the clinical correlates in 53 patients|journal=Mov Disord|volume=23|issue=11|pages=1602–1605|year=2008|pmid=18618664|pmc=2683412|doi=10.1002/mds.22161}}</ref><ref>{{citejournal|doi=10.1016/S1353-8020(02)00057-3|author=Yahr MD, Orosz D, Purohit DP.|title=Co-occurrence of essential tremor and Parkinson’s disease: a clinical study of a large kindred with autopsy findings.|journal=Parkinsonism Relat Disord|year=2003|volume=9|issue=4|pages=225–231|pmid=12618058}}</ref><ref>{{citejournal
⚫
|author=Benito-Leon J, Louis ED, Permejo-Pareja F.|title=Risk of incident Parkinson's disease and parkinsonism in essential tremor: a population-based study.|journal=J Neurology Neurosurgery Psychiatry|year=2009|month=April|volume=80|issue=4|pages=423–5|pmid=19289477|doi=10.1136/jnnp.2008.147223}}</ref>


==Treatment==
==Treatment==
Line 91: Line 75:
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 caffieine may be helpful.
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 caffieine may be helpful.


==Support groups==
===Support groups===
The [http://www.essentialtremor.org/ 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 [http://www.essentialtremor.org/ 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 [http://www.tremor.org.uk/ 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.
The [http://www.tremor.org.uk/ 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.


==Research==
==Help with technology==
⚫
===Harmaline-induced tremor===
Tunic Software has released software to help people with essential tremor, [[Parkinson's disease]], and other causes of hand tremor control their [[computer mouse]]. The software, MouseCage, automatically smooths mouse cursor motion to reduce the effects of unsteady or shaky hands.
⚫
[[Harmaline]] is a widely used model of [[essential tremor]] (ET) in rodents <ref>{{cite pmid| 17366267 }}</ref>. [[Harmaline]] is thought to act primarily on neurons in the [[inferior olivary nucleus | inferior olive ]](IO). Olivocerebellar neurons exhibit rhythmic excitatory action when [[harmaline]] is applied locally <ref>{{cite pmid| 17366267 }}</ref>. Additionally, when harmaline is administered to [[lesion]]ed IOs, little to no tremors are observed, reinforcing harmalines’ specificity for inferior olive connections <ref>{{cite pmid| 2542888 }}</ref>. The treatment of harmaline results in higher levels of [[caspase-3]] immunoreactivity in Purkinje, granule and inferior olive cells, suggestive of harmaline-mediated [[apoptosis]] <ref>{{cite pmid| 21640732 }}</ref>. [[Harmaline]] also increases the concentration of [[glutamic acid | glutamate]] in cerebellar nuclei which disrupts normal [[N-Methyl-D-aspartic acid | NMDA ]]-mediated down-regulation of glutamate release <ref>{{cite pmid| 18445025}}</ref>. Together, these interferences likely give rise to essential-tremor like behavior that is likely a result of diseregulation of glutamatergic circuitry within the [[cerebellum]] <ref>{{cite pmid| 18445025}}</ref>.


⚫
====Ethanol mechanisms in harmaline-induced tremor====
IBM created a peripheral device that filters out tremoring movements of the hand. The hardware adapter, termed AMA, is connected between the computer and the input device. It is switched on or off and adjusted on the device for tremor severity.
⚫
[[Ethanol]] is effective at decreasing tremor intensity and locomotion <ref>{{cite pmid| 21640732 }}</ref>. [[Ethanol]]-mediated effects are not observed on tremor frequency and peak location <ref>{{cite pmid| 21640732 }}</ref>. Additionally, ethanol is able to reduce [[caspase-3]] induced apoptosis though not without an increased loss of [[neuron]]s in the [[cerebellum]] and olivary nucleus <ref>{{cite pmid| 21640732 }}</ref>. [[Ethanol]] has been shown to decrease levels of glutamate in the cerebellar nuclei which had been pre-treated with [[harmaline]] <ref>{{cite pmid| 18445025}}</ref>. Furthermore, [[ethanol]] directly reduces hyperactivity of the [[climbing fiber]]-Purknije cell synapse by acting on glutamatergic receptors <ref>{{cite pmid| 16481422}}</ref>. [[Ethanol]] may reduce tremor by dampening the overexcitation of [[glutamate receptor | glutamatergic]] pathways involving deep cerebellar nuclei which may also reduce levels of [[caspase-3]] induced [[apoptosis]].


⚫
====Octonal mechanism in harmaline-induced tremors====
IBM also offers a free [http://www.alphaworks.ibm.com/tech/mousesmoothing smoothing mouse driver] for Windows 2000 and XP which uses the same technology that helps steady the image in a handheld [[camcorder]].
⚫
Different alcohols exert similar ameliorative affects on [[harmaline]]-induced tremors, though to different degrees. Different [[isomer]]s 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 <ref>{{cite pmid| 7310722 }}</ref>. [[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 <ref>{{cite pmid| 2542888 }}</ref>. 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 <ref>{{cite pmid| 2542888 }}</ref>.


⚫
===Genetically-induced tremor===
Another free software application, [http://www.steadymouse.com SteadyMouse], filters mouse movement to remove tremors. Additionally it provides a mechanism for ignoring accidental right clicks which are a common problem for patients suffering from essential tremor. The software supports Windows 2000, XP, Vista, Windows 7 32-bit and Windows 7 64-bit.
⚫
Genetic animal models of essential tremor utilize [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice because of the major role [[gamma-Aminobutyric acid | GABA]] plays in inhibiting motor activity. Moreover, GABAA receptor α1 -/- mice produce essential-like tremors and motor impairment as seen in ET patients <ref>{{cite pmid| 15765150}}</ref>.


⚫
====Ethanol mechanisms in genetically-induced tremors====
Other tools have also been adapted for people with tremors; for example, eating utensils which are weighted to help damp out tremor.
⚫
Alcohol is implicated as a therapeutic agent for [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice because of its interaction with Purkinje cells which mediate their actions via [[gamma-Aminobutyric acid | GABA]] transmission <ref>{{cite pmid| 17366267 }}</ref>. [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice respond positively to ethanol treatment. [[Ethanol]] reduces tremor activity in [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice in a dose dependent manner. An optimum dose of 2.5 g/kg of ethanol completely suppresses tremors in [[GABA receptor | GABA<sub>A</sub> receptor]] α1 -/- mice <ref>{{cite pmid| 15765150}}</ref>. Purkinje cells in these knockout mice also exhibit a lack of GABAergic inhibitory postsynaptic potentials in response to both exogenous and endogenous [[gamma-Aminobutyric acid | GABA]]. The loss of GABAergic inhibition in purkinje cells likely underlies the pathological tremors observed <ref>{{cite pmid| 15765150}}</ref>. 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 <ref>{{cite pmid| 15765150}}</ref>.


==References==
==References==

Revision as of 11:46, 13 January 2012

Essential tremor
SpecialtyNeurology Edit this on Wikidata

Essential tremor (ET) is a slowly progressive neurological disorder whose most recognizable feature is a tremor of the arms that is apparent during voluntary movements such as eating and writing.[1] 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.[2][3] 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.[4] Some patients may have unsteadiness and problems with gait and balance that are above and beyond that due to normal aging.[5][6] In addition to these motor problems, a variety of non-motor features have recently been linked with ET. These include anxiety and depressive symptoms as well as cognitive difficulty.[7] Recent studies have demonstrated that late-onset ET (onset > age 65) may be associated with an increased risk of developing dementia.[8] 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.[9][10] Aside from enhanced physiological tremor, it is the most common type of tremor and one of the most commonly observed movement disorders.[11] 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 often mild, patients with severe tremor have difficulty performing many of their routine activities of daily living.[12][13]


Signs and symptoms

Essential tremor generally presents as a rhythmic tremor (4–12 Hz) that is present only when the affected muscle is exerting effort (in other words, it is not present at rest). 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.

Tremor intensity can worsen in response to fatigue, strong emotions, low blood sugar, cold, 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 word finding and can't articulate themselves effectively even with preparation. A person with ET may become shy, withdrawn, pessimistic, anxious and also have difficulties concentrating. It is common for those with ET to be embarrassed by the condition even though it is out of their control.

ET is generally progressive in most cases (sometimes rapidly, sometimes very slowly), and can be disabling in severe cases.[14][15][16]

Though it is not directly a result of the condition, a high number of people with ET develop a dependence on alcohol. This is due to the fact alcohol helps alleviate the tremor, making things like social gatherings much more enjoyable for the sufferer. However the next day it is common to suffer from a "rebound tremor" where the tremor is more noticeable than normal. This leads to many people "chasing the tail" and leading to a problem far worse than the symptoms listed.

Cause

The underlying etiology is not clear but many cases seem to be familial.[17] It has been estimated that approximately one-half of the cases is due to a genetic mutation and the pattern of inheritance is most consistent with autosomal dominant transmission. As of yet, no genes have been identified but genetic linkage has been established with several chromosomal regions.[18][19] A number of environmental factors, including toxins, are also under active investigation and these may play a role in disease etiology.[20] In terms of pathophysiology, clinical, physiological and imaging studies point to an involvement of the cerebellum and/or cerebellothalamocortical circuits.[21] Recent postmortem studies have demonstrated the presence of degenerative changes in the ET brain, with these 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.[22][23]

However, emerging research based on brain autopsies of fifty deceased ET patients (as of Dec. 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[24] 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 [25]. 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 of off ethanol. Continued consumption of ethanol inhibits the recovery of synapses [26] . This impairment of Purkinje synapses is a component of cerebellar degradation that could underlie essential tremor [27].

Chronic alcohol abuse has also been linked to other movement disorders such as myoclonus, ataxia, and dyskinesia [28].

Diagnosis

Usually the diagnosis is established on clinical grounds. Tremors can start at any age, from birth through advanced ages (senile tremor).[29][30] 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.[31][32]

ET does sometimes occur in combination with other neurological disorders such as dystonia. 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.[33][34][35]

Treatment

There is no cure for essential tremor. Many of the treatments available are to lower the severity of the condition. These may include:

Medication

The two most recommended medications are: the beta-blockers propranolol and the antiepileptic primidone.[36]

Self medication with small amounts of alcohol has been shown to give short term relief from tremor,[37] although this form of self-medication is not recommended due an increased risk of alcohol dependence or abuse.[38] 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.[39]

Gabapentin may be helpful in the treatment of essential tremor.[40]

A trial of the benzodiazepine-anticonvulsant Clonazepam (Klonopin, Rivotril) was found not to be an effective treatment;[41] however, it is still recommended in some cases.[42]

Topiramate has also been cited as a possible pharmaceutical treatment.

Other

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 [43].

Surgical treatments (which are generally reserved for the most severe cases) include thalamotomy and deep brain stimulation.[44][45][46]

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 caffieine may be helpful.

Support groups

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.

Research

Harmaline-induced tremor

Harmaline is a widely used model of essential tremor (ET) in rodents [47]. Harmaline is thought to act primarily on neurons in the inferior olive (IO). Olivocerebellar neurons exhibit rhythmic excitatory action when harmaline is applied locally [48]. Additionally, when harmaline is administered to lesioned IOs, little to no tremors are observed, reinforcing harmalines’ specificity for inferior olive connections [49]. The treatment of harmaline results in higher levels of caspase-3 immunoreactivity in Purkinje, granule and inferior olive cells, suggestive of harmaline-mediated apoptosis [50]. Harmaline also increases the concentration of glutamate in cerebellar nuclei which disrupts normal NMDA -mediated down-regulation of glutamate release [51]. Together, these interferences likely give rise to essential-tremor like behavior that is likely a result of diseregulation of glutamatergic circuitry within the cerebellum [52].

Ethanol mechanisms in harmaline-induced tremor

Ethanol is effective at decreasing tremor intensity and locomotion [53]. Ethanol-mediated effects are not observed on tremor frequency and peak location [54]. Additionally, ethanol is able to reduce caspase-3 induced apoptosis though not without an increased loss of neurons in the cerebellum and olivary nucleus [55]. Ethanol has been shown to decrease levels of glutamate in the cerebellar nuclei which had been pre-treated with harmaline [56]. Furthermore, ethanol directly reduces hyperactivity of the climbing fiber-Purknije cell synapse by acting on glutamatergic receptors [57]. 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.

Octonal mechanism in harmaline-induced tremors

Different alcohols exert similar ameliorative affects 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 [58]. 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 [59]. 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 [60].

Genetically-induced 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 [61].

Ethanol mechanisms in genetically-induced tremors

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 [62]. 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 [63]. 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 [64]. 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 [65].

References

  1. ^ Benito-Leon J, Louis ED. Clinical update: Diagnosis and treatment of essential tremor. The Lancet 2007;369:1152-1153.
  2. ^ Hubble JP, Busenbark KL, Pahwa R, Lyons K, Koller WC. Clinical expression of essential tremor: Effects of gender and age. Mov Disord 1997;12:969-972.
  3. ^ Louis ED, Ford B, Frucht S. Factors associated with increased risk of head tremor in essential tremor: A community-based study in northern manhattan. Mov Disord 2003;18:432-436.
  4. ^ Louis ED. Clinical Practice: Essential tremor. N Engl J Med 2001;345:887-891.
  5. ^ Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain. November 2001;124(Pt 11):2278-2286.
  6. ^ Singer C, Sanchez-Ramos J, Weiner WJ. Gait abnormality in essential tremor. Mov Disord. March 1994;9(2):193-196.
  7. ^ Tan EK, Fook-Chong S, Lum SY, et al. Non-motor manifestations in essential tremor: use of a validated instrument to evaluate a wide spectrum of symptoms. Parkinsonism Relat Disord. September 2005;11(6):375-380.
  8. ^ Bermejo-Pareja F, Louis ED, Benito-Leon J. Risk of incident dementia in essential tremor: A population-based study. Mov Disord 2007;22:1573-1580.
  9. ^ Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder?: Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13:5-10.
  10. ^ Dogu O, Sevim S, Camdeviren H, Sasmaz T, Bugdayci R, Aral M, Kaleagasi H, Un S, Louis ED. Prevalence of essential tremor: Door-to-door neurological exams in Mersin Province, Turkey. Neurology 2003;61:1804-1807.
  11. ^ Benito-Leon J, Louis ED. Essential tremor: emerging views of a common disorder. Nat Clin Pract Neurol 2006;2:666-678.
  12. ^ Bain PG, Mally J, Gresty M, Findley LJ. Assessing the impact of essential tremor on upper limb function J Neurol 1993;241:54-61.
  13. ^ Louis ED, Barnes LF, Albert SM, Cote L, Schneier F, Pullman SL, Yu Q. Correlates of functional disability in essential tremor. Mov Disord 2001;16:914-920.
  14. ^ Critchley M. Observations on essential (heredofamilial) tremor. Brain. 1949;72:113-139.
  15. ^ Busenbark KL, Nash J, Nash S, Hubble JP, Koller WC. Is essential tremor benign? Neurology. December 1991;41(12):1982-1983.
  16. ^ Louis ED, Ford B, Barnes LF. Clinical subtypes of essential tremor. Arch Neurol 2000;57:1194-1198.
  17. ^ Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain. June 2007;130(Pt 6):1456-1464.
  18. ^ Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord. 1997;12:859-864
  19. ^ Gulcher JR, Jonsson P, Kong A et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nature Genetics 1997;17:84-87.
  20. ^ Louis ED. Etiology of essential tremor: Should we be searching for environmental causes? Mov Disord 2001;16:822-829.
  21. ^ Louis ED, Vonsattel JP. The emerging neuropathology of essential tremor. Mov Disord 2007;23:174 - 182.
  22. ^ Louis ED, Faust PL, Vonsattel JPG, Honig LS, Rajput A, Robinson CA, Rajput A, Pahwa R, Lyons KE, Ross W, Borden S, Moskowitz CB, Lawton A, Hernandez N. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130:3297-3307.
  23. ^ Shill HA, Adler CH, Sabbagh MN, Connor DJ, Caviness JN, Hentz JG, Beach TG: Pathologic findings in prospectively ascertained essential tremor subjects. Neurology 2008;70:1452-1455.
  24. ^ Louis, Elan D. (1 January 2008). "Dietary Epidemiology of Essential Tremor: Meat Consumption and Meat Cooking Practices". Neuroepidemiology. 30 (3): 161–166. doi:10.1159/000122333. Retrieved 25 July 2011. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: date and year (link)
  25. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20721919, please use {{cite journal}} with |pmid= 20721919 instead.
  26. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 9105510, please use {{cite journal}} with |pmid= 9105510 instead.
  27. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20721919, please use {{cite journal}} with |pmid= 20721919 instead.
  28. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20721919, please use {{cite journal}} with |pmid= 20721919 instead.
  29. ^ Louis ED, Dure L, Pullman S. Essential tremor in childhood. Mov Disord 2001;16:921-923.
  30. ^ Bain PG, Findley LJ, Thompson PD, et al. A study of hereditary essential tremor. Brain. August 1994;117 ( Pt 4):805-824.
  31. ^ Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in essential tremor patients: Prevalence, clinical correlates, and electrophysiological characteristics. Arch Neurol 2003;60:405-410.
  32. ^ Rajput AH, Rozdilsky B, Ang L, Rajput A. Significance of Parkinsonian manifestations in essential tremor. Can J Neurol Sci 1993;20:114-117.
  33. ^ Minen M, Louis ED (2008). "Emergence of Parkinson's disease in essential tremor: A study of the clinical correlates in 53 patients". Mov Disord. 23 (11): 1602–1605. doi:10.1002/mds.22161. PMC 2683412. PMID 18618664.
  34. ^ Yahr MD, Orosz D, Purohit DP. (2003). "Co-occurrence of essential tremor and Parkinson's disease: a clinical study of a large kindred with autopsy findings". Parkinsonism Relat Disord. 9 (4): 225–231. doi:10.1016/S1353-8020(02)00057-3. PMID 12618058.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  35. ^ Benito-Leon J, Louis ED, Permejo-Pareja F. (2009). "Risk of incident Parkinson's disease and parkinsonism in essential tremor: a population-based study". J Neurology Neurosurgery Psychiatry. 80 (4): 423–5. doi:10.1136/jnnp.2008.147223. PMID 19289477. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  36. ^ Zesiewicz, TA (2011 Nov 8). "Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology". Neurology. 77 (19): 1752–5. PMID 22013182. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  37. ^ Lou JS, Jankovic J (1991). "Essential tremor: clinical correlates in 350 patients". Neurology. 41 (2 ( Pt 1)): 234–8. PMID 1992367. {{cite journal}}: Unknown parameter |month= ignored (help)
  38. ^ http://www.nlm.nih.gov/medlineplus/ency/article/000762.htm
  39. ^ http://neurology.jwatch.org/cgi/content/full/2004/923/1
  40. ^ http://www.uwo.ca/cns/ebn/PDFCATs/move-tremor-gabapentin-therapy.pdf
  41. ^ Thompson C, Lang A, Parkes JD, Marsden CD (1984). "A double-blind trial of clonazepam in benign essential tremor". Clin Neuropharmacol. 7 (1): 83–8. doi:10.1097/00002826-198403000-00004. PMID 6367975.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ^ http://www.aafp.org/afp/20051101/practice.html
  43. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21640732 , please use {{cite journal}} with |pmid= 21640732 instead.
  44. ^ Zesiewcz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey RB, Ondo WG, Gronseth GS, Weiner WJ. Practice parameter: Therapies for essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64:2008-2020.
  45. ^ Schuurman PR, Bosch DA, Bossuyt PM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med. February 17, 2000;342(7):461-468.
  46. ^ Rana A.Q. An Introduction to Essential Tremor.iUniverse, Bloomington, IN 2010.
  47. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17366267 , please use {{cite journal}} with |pmid= 17366267 instead.
  48. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17366267 , please use {{cite journal}} with |pmid= 17366267 instead.
  49. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 2542888 , please use {{cite journal}} with |pmid= 2542888 instead.
  50. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21640732 , please use {{cite journal}} with |pmid= 21640732 instead.
  51. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18445025, please use {{cite journal}} with |pmid= 18445025 instead.
  52. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18445025, please use {{cite journal}} with |pmid= 18445025 instead.
  53. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21640732 , please use {{cite journal}} with |pmid= 21640732 instead.
  54. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21640732 , please use {{cite journal}} with |pmid= 21640732 instead.
  55. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21640732 , please use {{cite journal}} with |pmid= 21640732 instead.
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External links

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