The new england journal of medicine Clinical Practice Caren G. Solomon, M.D., M.P.H., Editor Essential Tremor Dietrich Haubenberger, M.H.Sc., M.D., and Mark Hallett, M.D., D.M.​​ This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors’ clinical recommendations. From the Clinical Trials Unit, Office of the A 62-year-old woman presents with a tremor that affects both of her hands, which Clinical Director (D.H.), and the Human started in her early 50s. She reports that the tremor started slowly and symmetri- Motor Control Section, Medical Neurol- ogy Branch (M.H.), National Institute of cally and has progressed gradually. The tremor affects her fine-motor movements Neurological Disorders and Stroke Intra- and results in impaired handwriting, which is often illegible, and difficulty in such mural Research Program, National Insti- activities as eating soup and putting on a necklace. The tremor gets worse with tutes of Health, Bethesda, MD. Address reprint requests to Dr. Hallett at the stress. Her mother had a similar tremor. She has a more recent history of depression, Human Motor Control Section, Medical which is now well controlled with fluoxetine and bupropion. The neurologic exami- Neurology Branch, National Institute of nation shows a postural and action tremor of both hands in the medium (4 to 8 Hz) Neurological Disorders and Stroke Intra- mural Research Program, National Insti- frequency range with postural tremor amplitudes of 1 to 3 cm bilaterally; the exami- tutes of Health, 9000 Rockville Pike, Bldg. nation is otherwise unremarkable. How would you evaluate and treat the patient? 10, Rm. 7D37, Bethesda, MD 20892-1428, or at hallettm@ ninds . nih . gov. N Engl J Med 2018;378:1802-10. The Clinical Problem DOI: 10.1056/NEJMcp1707928 Copyright © 2018 Massachusetts Medical Society. ssential tremor is one of the most common movement disorders and affects approximately 1% of the population worldwide. The incidence increases with advancing age, with the majority of population-based studies E 1 showing no difference in prevalence between men and women. The age of onset can be as early as childhood and has a bimodal distribution, with age peaks in the second and sixth decades of life.2 The natural history of essential tremor is char- acterized by a slow progression of tremor intensity with age, with a higher rate of physical and cognitive coexisting conditions among patients who have a later age of onset (≥65 years).3 The term “essential” implies that the tremor is of unknown cause, as in essential hypertension; it also suggests that there is only tremor and that tremor is the critical aspect of the disorder. However, the term has often been applied more broadly, including in cases in which there are obvious other clinical features, such as dystonia, or isolated tremors of the head or voice. Recently, a task force of the International Parkinson and Movement Disorder Society proposed a new formal definition of essential tremor (see text box)4 as a syndrome of isolated tremor of both upper limbs with a duration of at least 3 years, with or without tremor in other locations, such as head, larynx (voice tremor), or lower limbs. “Isolated” in this context means that tremor is the only abnormal sign, in contrast to “combined” tremor, in which other signs are present in addition to tremor. Another syndrome, “essential tremor plus,” includes addi- tional “soft” neurologic signs so mild as to be of uncertain clinical significance Videos showing (e.g., impaired tandem gait, questionable dystonic posturing, or impaired memory) “essential tremor plus” are available that do not suffice for an additional or alternative diagnosis (see videos, available at NEJM.org with the full text of this article at NEJM.org). Defining essential tremor as a syn- 1802 n engl j med 378;19 nejm.org May 10, 2018 The New England Journal of Medicine Downloaded from nejm.org by KEVIN ROSTEING on September 6, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Clinical Practice Key Clinical Points Essential Tremor • Essential tremor is considered to be a tremor syndrome characterized by isolated bilateral upper-limb action tremor with a duration of at least 3 years, with or without tremor in other locations, such as head, larynx (voice tremor), or lower limbs. • Essential tremor frequently manifests with additional mild neurologic signs of diagnostic uncertainty, such as mild ataxia, questionably abnormal posturing of the limbs, or impaired memory. This presentation is classified as “essential tremor plus.” • The diagnosis is generally based on a comprehensive history taking and neurologic examination. Routine laboratory testing, including the measurement of thyrotropin and electrolyte levels and liver and kidney function, is reasonable to rule out abnormalities that can confer a predisposition to enhanced physiologic tremor. • First-line treatment of essential tremor involves pharmacotherapy with propranolol or primidone. • Interventional treatment approaches for essential tremor that is refractory to pharmacotherapy and that causes substantial disability include deep-brain stimulation or focused ultrasound thalamotomy guided by magnetic resonance imaging. drome and not as a single disease, while con- Whether there are defined pathophysiological comitantly narrowing its phenotypic scope to in- features of essential tremor is controversial. How- crease its homogeneity, recognizes that there are ever, several lines of evidence point to cerebellar multiple possible causes, which may facilitate dysfunction. Magnetic resonance spectroscopy progress in understanding the pathogenesis. has revealed decreased levels of N-acetylaspar- Essential tremor is often familial, with a typi- tate in the cerebellum, a finding that indicates cally autosomal dominant pattern. Mutations have loss or dysfunction of neurons.7 Some,8,9 although been found in some families but not others, and not other,10 pathological studies have shown a not in patients who fit the current definition of loss of Purkinje’s cells in the cerebellum; studies essential tremor.5 Genomewide association stud- with this finding have also shown an increased ies have shown that several single-nucleotide poly- number of so-called torpedoes, thought to be morphisms are associated with essential tremor, swollen axons of Purkinje’s cells, and loss of but the only one that has been well replicated is dendritic arborization of Purkinje’s cells. Increased associated with the gene that encodes LINGO1,6 LINGO1 levels11 and γ-aminobutyric acid (GABA) a protein that appears to inhibit cell differentia- dysfunction12 have also been reported in the tion during development as well as axonal regen- cerebellum of persons with essential tremor. In eration and synaptic plasticity. addition, quantitative clinical testing of gait and limb movement has shown mild incoordination Criteria for Essential Tremor and Essential Tremor Plus similar to that observed in patients with ataxia.13,14 of the International Parkinson and Movement Disorder Society (2017). The pathophysiology of essential tremor almost certainly involves rhythmic activity in the cortico– Essential tremor ponto–cerebello–thalamo–cortical loop, although • Isolated tremor syndrome characterized by bilateral upper-limb action tremor the origin of the oscillation is unknown (Fig. 1). • Duration of at least 3 years Cerebellar metabolism is high at rest, increases • With or without tremor in other locations (e.g., head, with arm extension,15 and decreases with admin- voice, or lower limbs) • Absence of other neurologic signs, such as dystonia, istration of ethanol (which suppresses essential 16 ataxia, or parkinsonism tremor). Cellular bursts in the cerebellar receiv- Essential tremor plus ing zone of the thalamus (ventral intermediate • Tremor with the characteristics of essential tremor nucleus) correlate strongly with the tremor itself.17 and additional neurologic signs of uncertain clinical significance such as impaired tandem gait, question- able dystonic posturing, memory impairment, or other mild neurologic signs that do not suffice to make an Strategies and Evidence additional syndrome classification or diagnosis Assessment • Essential tremor with additional tremor at rest should be classified as essential tremor plus A history taking and neurologic examination pro- vide a phenotypic characterization of the tremor n engl j med 378;19 nejm.org May 10, 2018 1803 The New England Journal of Medicine Downloaded from nejm.org by KEVIN ROSTEING on September 6, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Cerebral cortex Reticular nucleus VIM thalamus VIM thalamus Prelemniscal radiation Red Zona Prelemniscal nucleus incerta radiation Thalamic Globus fasciculus H1 pallidus Cerebellar cortex Ansa lenticularis Subthalamic nucleus Pons Substantia Red nigra nucleus Lenticular fasciculus H2 Cerebellum Dentate Inferior Guillain–Mollaret nucleus olivary nucleus triangle Figure 1. Schema of the Presumed Pathways Involved in the Pathophysiology of Essential Tremor and Targets for Surgical Treatment. Shown are the anatomical structures related to essential tremor, the circuits thought to underlie tremor,