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Essential Tremor—Not Just A Shake
Essential Tremor—Not Just A Shake Arif Dalvi, MD, MBA, and Michael G. Mercury, PhD Essential tremor (ET) is the most common pathologic tremor in humans.1 Analogous to the term essential hypertension, the term ET was coined to describe tremor as an isolated symptom without a secondary etiology.2 However, recent observations suggest that it may be a neurodegenerative process with additional symptoms developing over time with specific genetic etiologies in some cases.3 There is an increasing recognition that additional neurologic symptoms may accompany tremor, such as ataxia and cognitive impairment.4
Pathology and Pathophysiology of Essential Tremor In 1912, Ferdinand Lewy described the presence of hyaline intracellular inclusions within neurons from the substantia nigra of brains with Parkinson’s disease (PD). These Lewy bodies have become the pathognomonic hallmark of PD, although they are not exclusive to PD and are also seen in Diffuse Lewy Body disease as well as Alzheimer’s disease.5 Unlike PD, where the pathology of nigral cell loss and Lewy body formation has been well studied, information on the pathologic processes underlying ET has been fairly limited. The Essential Tremor Centralized Brain Repository was established in 2003 at Columbia University (New York, NY) and has helped improve the understanding of the pathology of ET. A recent report6 examined 33 brains of patients with ET and 21 controls. Two broad categories of pathology were seen. The first was the presence of prominent cerebellar changes seen in about 75% of the ET brains. These changes included a significant decline in the number of Purkinje cells and a marked increase in the number of swollen Purkinje cell axons called torpedoes. The remaining 25% of brains showed Lewy bodies confined, for the most part, to the locus ceruleus. These 2 pathologic subtypes appear to be mutually exclusive with the former type, called cerebellar ET, and the latter, the Lewy body variant of ET. The presence of 2 distinct pathologic subtypes further casts doubt on the concept of ET as a homogenous clinicopathologic entity.7 It remains to be Dis Mon 2011;57:127-134 0011-5029/2011 $36.00 ⫹ 0 doi:10.1016/j.disamonth.2011.02.005 DM, March 2011
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established how Lewy bodies in locus ceruleus can lead to a kinetic tremor. Norepinephrine is the principal neurotransmitter in the locus ceruleus, and axons from the locus ceruleus project to cerebellar Purkinje cells. A locus ceruleus lesion may thus result in reduced stimulatory output from the locus ceruleus to the inhibitory Purkinje cells with a net reduction in ␥-aminobutyric acid-mediated output from the Purkinje cells.7 In terms of pathophysiology, ET may be considered a cerebellar disorder. Pathologic changes in ET occur either in the cerebellum itself or in neurons that synapse with the Purkinje cells of the cerebellum. Functional imaging studies corroborate the idea of cerebellar dysfunction in ET.8,9 The location of the central oscillator in ET is a matter of debate. The cerebellum and the olivopontocerebellar pathways are favored as the likely location. However, the ventral intermediate nucleus of the thalamus may be an alternative site. Of note, the ventral intermediate nucleus is the preferred surgical target for ET.10
Genetics of Essential Tremor ET is often inherited in a manner suggesting an autosomal-dominant genetic pattern. The incidence of inherited ET ranges from 17% to 100% depending on the study methodology and defining characteristics used in the study.11 Two loci with linkage to ET have been reported on chromosome 3q13 (ETM1) and 2p22-25 (ETM2)12,13 with additional linkage suggested at 6p23.14 However, a putative gene remains to be found. In a population-based twin study high concordance was observed among elderly monozygotic twins, suggesting that the ET phenotype has a high heritability and is a good candidate for linkage studies.15 Recently, a large sample of familial ET in Iceland revealed an association with the LINGO1 gene using genome-wide association methods. The LINGO1 gene is required for proper myelination and is also important in regulating central nervous system axon regeneration and oligodendrocyte maturation.16 A subsequent study has replicated this finding in a Caucasian population in North America, with young-onset ET patients more likely to have this association.17 In a family from Iowa, referred to as the Iowa kindred, members presented with either symptoms of PD, ET, or dementia. The genetic variant for this family was labeled PARK4 in accordance with current nomenclature for the genetics of PD. However, subsequent research revealed that this family had a variation of the ␣-synuclein (PARK1) mutation with a triplication of the gene locus. The reason for the varying phenotypes despite the same genotype is unclear.18,19 Abnormalities in the number of triplet repeats in the fragile X gene have 128
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also been identified in the setting of ET.20 The normal number of CGG repeats in this region is less than 50. When more than 200 repeats occur, the presentation is one of learning disability, with the fragile X syndrome being the most common cause of inherited mental retardation. Patients with a repeat number between 55 and 200 show a postural tremor that is identical with typical ET. In addition, they also show mild ataxia of gait and cognitive impairment that may be mild but may progress to the level of dementia. This presentation is referred to as the fragile X tremor ataxia syndrome.21
Epidemiology of Essential Tremor ET is one of the most common movement disorders and one of the most common neurologic disorders among adults.22 Examination of the epidemiology of ET is limited by several methodologic issues, which suggest it may be underrecognized. It is common for a patient with mild tremor to go undiagnosed as many families and physicians mistakenly believe that tremor is a normal age-related condition.23 It is estimated some 90% of patients with ET do not see their physician24 despite the finding in population-based studies that test-detectable tremor may occur in as high as 98% of the older population.25 Therefore, it is likely that patients who are socially or functionally impacted by the tremor are those who are most likely to seek out help and be identified while the others are not identified. Another issue is the difficulty of case definition in a monosymptomatic disorder. Unlike PD, which has more than 1 cardinal feature, the defining feature of ET is the postural tremor. However, an identical tremor may be seen in some cases of PD and other disorders of the central and peripheral nervous system. ET also must be distinguished from enhanced physiologic tremor. Consensus criteria have been defined for ET26 that improve case identification, but these as well rely on a clinical diagnosis in the absence of a biomarker. Population-based studies attempt to eliminate biases involved with patient selection and referral. A large population-based study from central Spain examined 5278 subjects and found 256 prevalent ET cases. A follow-up evaluation of 3942 individuals revealed 83 incident ET cases.23 The adjusted annual incidence rate (per 100,000 person-years) in the population aged 65 years and older was 616 (95% CI: 447-784). Of note, 64 of the 83 incident cases (77%) had not been previously diagnosed, suggesting that epidemiologic results from studies that are not population based may significantly underestimate the prevalence and incidence of ET. A pooled analysis of 28 population-based epidemiologic studies in ET from 9 countries calculated a crude prevalence across all ages of 0.4%. DM, March 2011
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Prevalence increased markedly with age and was found to be 4.6% in those aged 65 or over, and 21.7% in those aged 95 or over. Greater than a third of the studies showed gender differences with the prevalence being more common among men.27 A bimodal pattern has been reported for ET with a smaller peak in the second decade and a larger peak in the sixth decade.28 Retrospective studies from subspecialty movement disorder clinics indicate that childhood-onset ET is usually hereditary, begins at a mean age of 6 years, and affects boys 3 times as often as girls.29 A study of ethnic differences in ET examined a random sample of 2117 Medicare recipients residing in Washington Heights, Inwood, NY. Prevalence was higher in whites than African Americans and intermediate in Hispanics.30
Clinical Presentation of Essential Tremor The most common clinical presentation of ET is that of a monosymptomatic tremor disorder.31 The tremor is an action tremor with mixed postural and kinetic elements. The postural tremor is most commonly seen in the hands when they are held outstretched. Holding objects in the hands may bring out tremor, with heavier objects more likely to bring out the tremor. The kinetic tremor is brought out by actions, such as pouring a cup of water, eating with utensils, or handwriting. Having the patient draw an Archimedes spiral can help demonstrate ET and can help distinguish ET from PD. The typical spiral in ET is jagged but not micrographic, in contrast to PD, where the micrographia is more prominent. There may be a significant positional component. For example, a patient may have a mild tremor when the hands are held outstretched in front but the tremor may increase when the hands are held in front of the chest with the elbows bent. There may also be a component of terminal or intention tremor. This refers to the increase in tremor on finger to nose testing as the fingertip approaches the intended target at the terminus of the action.32 While the hands are most commonly affected, many patients may have a head tremor as well. The upper limbs are affected in about 95% of patients, followed by head (34%), lower limbs (20%), voice (12%), and face and trunk (5%).33 Occasionally, the tremor may present as an isolated head tremor. In this case ET will need to be distinguished from cervical dystonia or spasmodic torticollis. In the latter syndrome there is a distinct directional component to the head tremor. In addition sustained abnormal posturing of the head is a hallmark of cervical dystonia. Asymmetrical hypertrophy of the cervical muscles, especially the sternocleideomastoid, may be observed in cervical dystonia that is very unusual in ET.34 Given that in many cases of cervical dystonia head tremor may 130
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precede the dystonic component by many years, some investigators refer to pure head tremor as probable ET rather than definite ET.35 Some patients may also present with a voice tremor. This is best demonstrated by asking the patient to sustain a note for a minute with a wavering voice seen in some patients with ET. At times the voice tremor of ET may be confused with spasmodic dystonia. However, in the latter case the voice is strained and tight, not breathy like in ET. It is important to note that laryngeal tremor and spasmodic dysphonia can coexist.36 Videostroboscopic examination of the vocal cords can help distinguish the 2 presentations where a clinical diagnosis is difficult. Essential voice tremor is more common in women. One third to one half of affected individuals have a family history of tremor. Videostroboscopic examination reveals a kinetic laryngeal tremor extending beyond the larynx to involve the phonatory apparatus globally.37
Diagnostic Criteria and Rating Scales for Essential Tremor Although the diagnosis of ET is clinical, there are no universally accepted criteria for the diagnosis. The Movement Disorders Society has proposed consensus criteria for ET. More recently, core and secondary criteria have been proposed to facilitate a diagnosis of ET. Core criteria include bilateral action tremor of hands and forearms, absence of other neurologic signs, and isolated head tremor without signs of dystonia. Secondary criteria include long duration (greater than 3 years), positive family history, and a beneficial response to alcohol.26 The most widely used rating scale is the Fahn, Tolosa, and Marine tremor rating scale (TRS). The TRS quantifies rest, postural, and action/intention tremors, and the severity of body parts is rated from 0 (none) to 4 (severe). The scale is divided into 3 parts: assessing tremor location/severity, ability to perform specific motor tasks/functions, and patient-reported disability due tremor. Although useful, the interobserver variability of the TRS is fair, and thus it is important to maintain the same observer to assess for change in tremor severity.38
Cognitive Symptoms Associated With Essential Tremor In the realm of movement disorders, more attention is now being focused on the nonmotor aspects of the disorder. As the most common of the movement disorders, ET has been found to carry with it risk for cognitive deficits. A population-based case-control study of cognitive DM, March 2011
131
function in ET revealed mini-mental state examination scores declined at a rate that was 7 times faster in ET cases compared with controls over a 3-year follow-up.39 Several studies have found executive functioning deficits in ET.40,41 The study by Gasparini and coworkers41 was especially intriguing as it found a continuum of normals, familial ET, ET with a family history of PD, and patients with PD, suggesting a common dysregulation of dopamine pathways. Patients with ET may also show changes in personality. A crosssectional study that used the Tridimensional Personality Questionnaire showed patients with ET had higher scores in comparison with controls in the domain of harm avoidance, implying a personality with increased levels of pessimism, fearfulness, and shyness. Tremor severity and harm avoidance scores were not correlated, suggesting that the personality profile was a primary feature of the disease rather than a reactive psychologic consequence of severe and disabling tremor.42 The term “Essential Tremor Plus” has been used analogous to the Parkinson-plus syndromes as has the term “Indeterminate Tremor Syndrome” to describe a category of ET where additional signs and symptoms are noted in addition to the primary presentation of tremor.43 However, increasing evidence from clinicopathologic studies suggests that these symptoms should be recognized as part of the primary symptom complex of ET.44
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6. 7. 8. 9.
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Louis ED, Thawani SP, Andrews HF. Prevalence of essential tremor in a multiethnic, community-based study in northern Manhattan, New York, N.Y. Neuroepidemiology 2009;32:208-14. Critchley M. Observations on essential (heredofamial) tremor. Brain 1949;72: 113-39. Deuschl G, Elble R. Essential tremor--neurodegenerative or nondegenerative disease towards a working definition of ET. Mov Disord 2009;24(14):2033-41. Louis ED. Essential tremor as a neuropsychiatric disorder. J Neurol Sci 2010;289: 144-8. Schulz-Schaeffer WJ. The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol 2010;120:131-43. Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130:3297-307. Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurol 2010;9:613-22. Bucher SF, Seelos KC, Dodel RC, et al. Activation mapping in essential tremor with functional magnetic resonance imaging. Ann Neurol 1997;41:32-40. Louis ED, Shungu DC, Chan S, et al. Metabolic abnormality in the cerebellum in patients with essential tremor: a proton magnetic resonance spectroscopic imaging study. Neurosci Lett 2002;333:17-20. DM, March 2011
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Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337: 403-6. Louis ED, Ottman R. How familial is familial tremor? The genetic epidemiology of essential tremor. Neurology 1996;46:1200-5. Gulcher JR, Jónsson P, Kong A, et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet 1997;17:84-7. Higgins JJ, Loveless JM, Jankovic J, et al. Evidence that a gene for essential tremor maps to chromosome 2p in four families. Mov Disord 1998;13:972-7. Shatunov A, Sambuughin N, Jankovic J, et al. Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23. Brain 2006;129:2318-31. Lorenz D, Frederiksen H, Moises H, et al. High concordance for essential tremor in monozygotic twins of old age. Neurology 2004;62:208-11. Stefansson H, Steinberg S, Petursson H, et al. Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat Genet 2009;41:277-9. Clark LN, Park N, Kisselev S, et al. Replication of the LINGO1 gene association with essential tremor in a North American population. Eur J Hum Genet 2010; 18:838-43. Farrer M, Gwinn-Hardy K, Muenter M, et al. A chromosome 4p haplotype segregating with Parkinson’s disease and postural tremor. Hum Mol Genet 1999; 8:81-5. Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science 2003;302:841. Leehey MA, Munhoz RP, Lang AE, et al. The fragile X premutation presenting as essential tremor. Arch Neurol 2003;60:117-21. Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. J Investig Med 2009;57(8):830-6. Benito-León J. How common is essential tremor? Neuroepidemiology 2009;32: 215-6. Benito-León J, Bermejo-Pareja F, Louis ED. Neurological Disorders in Central Spain (NEDICES) Study Group. Incidence of essential tremor in three elderly populations of central Spain. Neurology 2005;64:1721-5. 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. Louis ED, Wendt KJ, Ford B. Senile tremor. What is the prevalence and severity of tremor in older adults? Gerontology 2000;46:12-6. Bain P, Brin M, Deuschl G, et al. Criteria for the diagnosis of essential tremor. Neurology 2000;54(Suppl 4):S7. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord 2010;25:534-41. Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234-8. Ferrara J, Jankovic J. Epidemiology and management of essential tremor in children. Paediatr Drugs 2009;11:293-307.
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Louis ED, Marder K, Cote L, et al. Differences in the prevalence of essential tremor among elderly African Americans, whites, and Hispanics in northern Manhattan, NY. Arch Neurol 1995;52:1201-5. Elble RJ. Essential tremor is a monosymptomatic disorder. Mov Disord 2002;17: 633-7. Benito-León J, Louis ED. Essential tremor: emerging views of a common disorder. Nat Clin Pract Neurol 2006;2:666-78. Elble RJ. Diagnostic criteria for essential tremor and differential diagnosis. Neurology 2000;54(Suppl 4):S2-6. Pal PK, Samii A, Schulzer M, et al. Head tremor in cervical dystonia. Can J Neurol Sci 2000;27:137-42. Jankovic J. Essential tremor: a heterogenous disorder. Mov Disord 2002;17:638-44. Wolraich D, Vasile Marchis-Crisan C, Redding N, et al. Laryngeal tremor: co-occurrence with other movement disorders. ORL J Otorhinolaryngol Relat Spec 2010;72:291-4. Sulica L, Louis ED. Clinical characteristics of essential voice tremor: a study of 34 cases. Laryngoscope 2010;120:516-28. Stacy MA, Elble RJ, Ondo WG, et al. Assessment of interrater and intrarater reliability of the Fahn-Tolosa-Marin Tremor Rating Scale in essential tremor. Mov Disord 2007;22:833-8. Louis ED, Benito-León J, Vega-Quiroga S, et al. Neurological Disorders in Central Spain (NEDICES) Study Group. Faster rate of cognitive decline in essential tremor cases than controls: a prospective study. Eur J Neurol 2010;17:1291-7. Benito-León J, Louis ED, Bermejo-Pareja F. Neurological Disorders in Central Spain (NEDICES) Study Group. Population-based case-control study of cognitive function in essential tremor. Neurology 2006;66:69-74. Gasparini M, Bonifati V, Fabrizio E, et al. Frontal lobe dysfunction in essential tremor: a preliminary study. J Neurol 2001;248:399-402. Chatterjee A, Jurewicz EC, Applegate LM, et al. Personality in essential tremor: further evidence of non-motor manifestations of the disease. J Neurol Neurosurg Psychiatry 2004;75:958-61. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13(Suppl 3):2-23. Louis ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol 2009;66:1202-8.
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Pathology and Pathophysiology of Essential Tremor In 1912, Ferdinand Lewy described the presence of hyaline intracellular inclusions within neurons from the substantia nigra of brains with Parkinson’s disease (PD). These Lewy bodies have become the pathognomonic hallmark of PD, although they are not exclusive to PD and are also seen in Diffuse Lewy Body disease as well as Alzheimer’s disease.5 Unlike PD, where the pathology of nigral cell loss and Lewy body formation has been well studied, information on the pathologic processes underlying ET has been fairly limited. The Essential Tremor Centralized Brain Repository was established in 2003 at Columbia University (New York, NY) and has helped improve the understanding of the pathology of ET. A recent report6 examined 33 brains of patients with ET and 21 controls. Two broad categories of pathology were seen. The first was the presence of prominent cerebellar changes seen in about 75% of the ET brains. These changes included a significant decline in the number of Purkinje cells and a marked increase in the number of swollen Purkinje cell axons called torpedoes. The remaining 25% of brains showed Lewy bodies confined, for the most part, to the locus ceruleus. These 2 pathologic subtypes appear to be mutually exclusive with the former type, called cerebellar ET, and the latter, the Lewy body variant of ET. The presence of 2 distinct pathologic subtypes further casts doubt on the concept of ET as a homogenous clinicopathologic entity.7 It remains to be Dis Mon 2011;57:127-134 0011-5029/2011 $36.00 ⫹ 0 doi:10.1016/j.disamonth.2011.02.005 DM, March 2011
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established how Lewy bodies in locus ceruleus can lead to a kinetic tremor. Norepinephrine is the principal neurotransmitter in the locus ceruleus, and axons from the locus ceruleus project to cerebellar Purkinje cells. A locus ceruleus lesion may thus result in reduced stimulatory output from the locus ceruleus to the inhibitory Purkinje cells with a net reduction in ␥-aminobutyric acid-mediated output from the Purkinje cells.7 In terms of pathophysiology, ET may be considered a cerebellar disorder. Pathologic changes in ET occur either in the cerebellum itself or in neurons that synapse with the Purkinje cells of the cerebellum. Functional imaging studies corroborate the idea of cerebellar dysfunction in ET.8,9 The location of the central oscillator in ET is a matter of debate. The cerebellum and the olivopontocerebellar pathways are favored as the likely location. However, the ventral intermediate nucleus of the thalamus may be an alternative site. Of note, the ventral intermediate nucleus is the preferred surgical target for ET.10
Genetics of Essential Tremor ET is often inherited in a manner suggesting an autosomal-dominant genetic pattern. The incidence of inherited ET ranges from 17% to 100% depending on the study methodology and defining characteristics used in the study.11 Two loci with linkage to ET have been reported on chromosome 3q13 (ETM1) and 2p22-25 (ETM2)12,13 with additional linkage suggested at 6p23.14 However, a putative gene remains to be found. In a population-based twin study high concordance was observed among elderly monozygotic twins, suggesting that the ET phenotype has a high heritability and is a good candidate for linkage studies.15 Recently, a large sample of familial ET in Iceland revealed an association with the LINGO1 gene using genome-wide association methods. The LINGO1 gene is required for proper myelination and is also important in regulating central nervous system axon regeneration and oligodendrocyte maturation.16 A subsequent study has replicated this finding in a Caucasian population in North America, with young-onset ET patients more likely to have this association.17 In a family from Iowa, referred to as the Iowa kindred, members presented with either symptoms of PD, ET, or dementia. The genetic variant for this family was labeled PARK4 in accordance with current nomenclature for the genetics of PD. However, subsequent research revealed that this family had a variation of the ␣-synuclein (PARK1) mutation with a triplication of the gene locus. The reason for the varying phenotypes despite the same genotype is unclear.18,19 Abnormalities in the number of triplet repeats in the fragile X gene have 128
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also been identified in the setting of ET.20 The normal number of CGG repeats in this region is less than 50. When more than 200 repeats occur, the presentation is one of learning disability, with the fragile X syndrome being the most common cause of inherited mental retardation. Patients with a repeat number between 55 and 200 show a postural tremor that is identical with typical ET. In addition, they also show mild ataxia of gait and cognitive impairment that may be mild but may progress to the level of dementia. This presentation is referred to as the fragile X tremor ataxia syndrome.21
Epidemiology of Essential Tremor ET is one of the most common movement disorders and one of the most common neurologic disorders among adults.22 Examination of the epidemiology of ET is limited by several methodologic issues, which suggest it may be underrecognized. It is common for a patient with mild tremor to go undiagnosed as many families and physicians mistakenly believe that tremor is a normal age-related condition.23 It is estimated some 90% of patients with ET do not see their physician24 despite the finding in population-based studies that test-detectable tremor may occur in as high as 98% of the older population.25 Therefore, it is likely that patients who are socially or functionally impacted by the tremor are those who are most likely to seek out help and be identified while the others are not identified. Another issue is the difficulty of case definition in a monosymptomatic disorder. Unlike PD, which has more than 1 cardinal feature, the defining feature of ET is the postural tremor. However, an identical tremor may be seen in some cases of PD and other disorders of the central and peripheral nervous system. ET also must be distinguished from enhanced physiologic tremor. Consensus criteria have been defined for ET26 that improve case identification, but these as well rely on a clinical diagnosis in the absence of a biomarker. Population-based studies attempt to eliminate biases involved with patient selection and referral. A large population-based study from central Spain examined 5278 subjects and found 256 prevalent ET cases. A follow-up evaluation of 3942 individuals revealed 83 incident ET cases.23 The adjusted annual incidence rate (per 100,000 person-years) in the population aged 65 years and older was 616 (95% CI: 447-784). Of note, 64 of the 83 incident cases (77%) had not been previously diagnosed, suggesting that epidemiologic results from studies that are not population based may significantly underestimate the prevalence and incidence of ET. A pooled analysis of 28 population-based epidemiologic studies in ET from 9 countries calculated a crude prevalence across all ages of 0.4%. DM, March 2011
129
Prevalence increased markedly with age and was found to be 4.6% in those aged 65 or over, and 21.7% in those aged 95 or over. Greater than a third of the studies showed gender differences with the prevalence being more common among men.27 A bimodal pattern has been reported for ET with a smaller peak in the second decade and a larger peak in the sixth decade.28 Retrospective studies from subspecialty movement disorder clinics indicate that childhood-onset ET is usually hereditary, begins at a mean age of 6 years, and affects boys 3 times as often as girls.29 A study of ethnic differences in ET examined a random sample of 2117 Medicare recipients residing in Washington Heights, Inwood, NY. Prevalence was higher in whites than African Americans and intermediate in Hispanics.30
Clinical Presentation of Essential Tremor The most common clinical presentation of ET is that of a monosymptomatic tremor disorder.31 The tremor is an action tremor with mixed postural and kinetic elements. The postural tremor is most commonly seen in the hands when they are held outstretched. Holding objects in the hands may bring out tremor, with heavier objects more likely to bring out the tremor. The kinetic tremor is brought out by actions, such as pouring a cup of water, eating with utensils, or handwriting. Having the patient draw an Archimedes spiral can help demonstrate ET and can help distinguish ET from PD. The typical spiral in ET is jagged but not micrographic, in contrast to PD, where the micrographia is more prominent. There may be a significant positional component. For example, a patient may have a mild tremor when the hands are held outstretched in front but the tremor may increase when the hands are held in front of the chest with the elbows bent. There may also be a component of terminal or intention tremor. This refers to the increase in tremor on finger to nose testing as the fingertip approaches the intended target at the terminus of the action.32 While the hands are most commonly affected, many patients may have a head tremor as well. The upper limbs are affected in about 95% of patients, followed by head (34%), lower limbs (20%), voice (12%), and face and trunk (5%).33 Occasionally, the tremor may present as an isolated head tremor. In this case ET will need to be distinguished from cervical dystonia or spasmodic torticollis. In the latter syndrome there is a distinct directional component to the head tremor. In addition sustained abnormal posturing of the head is a hallmark of cervical dystonia. Asymmetrical hypertrophy of the cervical muscles, especially the sternocleideomastoid, may be observed in cervical dystonia that is very unusual in ET.34 Given that in many cases of cervical dystonia head tremor may 130
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precede the dystonic component by many years, some investigators refer to pure head tremor as probable ET rather than definite ET.35 Some patients may also present with a voice tremor. This is best demonstrated by asking the patient to sustain a note for a minute with a wavering voice seen in some patients with ET. At times the voice tremor of ET may be confused with spasmodic dystonia. However, in the latter case the voice is strained and tight, not breathy like in ET. It is important to note that laryngeal tremor and spasmodic dysphonia can coexist.36 Videostroboscopic examination of the vocal cords can help distinguish the 2 presentations where a clinical diagnosis is difficult. Essential voice tremor is more common in women. One third to one half of affected individuals have a family history of tremor. Videostroboscopic examination reveals a kinetic laryngeal tremor extending beyond the larynx to involve the phonatory apparatus globally.37
Diagnostic Criteria and Rating Scales for Essential Tremor Although the diagnosis of ET is clinical, there are no universally accepted criteria for the diagnosis. The Movement Disorders Society has proposed consensus criteria for ET. More recently, core and secondary criteria have been proposed to facilitate a diagnosis of ET. Core criteria include bilateral action tremor of hands and forearms, absence of other neurologic signs, and isolated head tremor without signs of dystonia. Secondary criteria include long duration (greater than 3 years), positive family history, and a beneficial response to alcohol.26 The most widely used rating scale is the Fahn, Tolosa, and Marine tremor rating scale (TRS). The TRS quantifies rest, postural, and action/intention tremors, and the severity of body parts is rated from 0 (none) to 4 (severe). The scale is divided into 3 parts: assessing tremor location/severity, ability to perform specific motor tasks/functions, and patient-reported disability due tremor. Although useful, the interobserver variability of the TRS is fair, and thus it is important to maintain the same observer to assess for change in tremor severity.38
Cognitive Symptoms Associated With Essential Tremor In the realm of movement disorders, more attention is now being focused on the nonmotor aspects of the disorder. As the most common of the movement disorders, ET has been found to carry with it risk for cognitive deficits. A population-based case-control study of cognitive DM, March 2011
131
function in ET revealed mini-mental state examination scores declined at a rate that was 7 times faster in ET cases compared with controls over a 3-year follow-up.39 Several studies have found executive functioning deficits in ET.40,41 The study by Gasparini and coworkers41 was especially intriguing as it found a continuum of normals, familial ET, ET with a family history of PD, and patients with PD, suggesting a common dysregulation of dopamine pathways. Patients with ET may also show changes in personality. A crosssectional study that used the Tridimensional Personality Questionnaire showed patients with ET had higher scores in comparison with controls in the domain of harm avoidance, implying a personality with increased levels of pessimism, fearfulness, and shyness. Tremor severity and harm avoidance scores were not correlated, suggesting that the personality profile was a primary feature of the disease rather than a reactive psychologic consequence of severe and disabling tremor.42 The term “Essential Tremor Plus” has been used analogous to the Parkinson-plus syndromes as has the term “Indeterminate Tremor Syndrome” to describe a category of ET where additional signs and symptoms are noted in addition to the primary presentation of tremor.43 However, increasing evidence from clinicopathologic studies suggests that these symptoms should be recognized as part of the primary symptom complex of ET.44
REFERENCES 1.
2. 3. 4. 5.
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