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-

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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

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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, and the targets for surgical treatment. There are two circuits implicated in tremor generation: the cortico–ponto–cerebello–thalamo–cortical loop (in dark blue) and the Guillain–Mollaret triangle, dentate nucleus to red nucleus to inferior olivary nucleus to dentate nucleus (via the cerebellar cor- tex) (in light blue). Some dentate fibers form synapses in the red nucleus, and others go around it. The two circuits interact in the cere- bellum. The targets for surgical treatment are the ventral intermediate (VIM) nucleus of the ventrolateral thalamus, the zona incerta, and the prelemniscal radiation. The prelemniscal radiation is the end of the dentatothalamic tract going to the VIM nucleus (dark blue). The zona incerta is the ventral continuation of the reticular nucleus of the thalamus and gets input from the prelemniscal radiation and the thalamic fasciculus (which is composed of the ansa lenticularis fibers and the lenticular fasciculus fibers) (red). The ventrolateral thalamus includes the VIM nucleus, the target of cerebellar output, and the ventralis oralis anterior and ventralis oralis posterior nuclei (not depicted), the main targets of the basal ganglia output (via the thalamic fasciculus).

syndrome. The history taking should include examination should assess the distribution of information about age of onset, family history, tremor and activation condition (i.e., whether temporal evolution, and any exposure to poten- tremor appears during rest, posture [defined as tially tremor-inducing drugs (e.g., valproate, se- isometric extension of a body part, such as a lective serotonin-reuptake inhibitors, sympatho- limb, against gravity], or goal-directed move- mimetic agents, or lithium) and toxins (e.g., ment), include a visual estimation of the tremor mercury, lead, or manganese). The neurologic frequency range (low [<4 Hz], medium, [4 to 8 Hz],

1804 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 or high [>8 Hz]), and assess any signs to suggest rhythmicity, and frequency, may be helpful to systemic illness or other neurologic disease. (See distinguish essential tremor from rhythmic cor- text box for diagnostic criteria and characteristic tical myoclonus (cortical tremor), functional presentation of essential tremor and Table 1 for tremor, and enhanced physiologic tremor. How- differential diagnoses.) Rating scales are useful ever, such testing is not performed in routine to assess severity and effect of tremor on activi- practice, and availability is limited to specialized ties of daily living (the Essential Tremor Rating centers.22 Assessment Scale [TETRAS], detailed in the Sup- plementary Appendix) as well as health-related Treatment quality of life in patients with essential tremor.18-20 Treatments for essential tremor can be broadly According to the classification by the Interna- grouped into three categories: pharmacologic, tional Parkinson and Movement Disorder Society surgical, and other nonpharmacologic or non- (see text box), if a workup reveals a cause for surgical treatment approaches. essential tremor, the diagnosis is “essential trem- or due to that [cause].” Other conditions causing Pharmacotherapy tremor must be considered. The differential di- Propranolol and primidone are the two com- agnoses of isolated tremor syndromes without pounds with the highest level of evidence to other neurologic signs include enhanced physi- treat essential tremor by reducing the severity of ologic tremor, isolated focal tremors (e.g., isolat- upper-limb symptoms.23 The nonselective beta- ed tremors of head, voice, or palate), and ortho- blocker propranolol has been shown to be an static tremors. Tremor syndromes with prominent effective treatment in randomized, controlled additional neurologic signs include dystonic trials at doses ranging from 120 to 240 mg per tremors, tremors combined with parkinsonism, day.24-26 Across randomized, controlled trials, intention tremor syndromes, Holmes tremor tremor amplitudes that were measured by ac- (combined low-frequency rest, posture, and in- celerometry were reduced by a mean of 55%.27 tention tremor due to lesions in the cerebellar Adverse effects include bradycardia and broncho- outflow tract), and myorhythmia (Table 1). spasm. In one small, randomized, controlled trial, long-acting propranolol had efficacy simi- Laboratory Testing lar to that of the short-acting formulation in A comprehensive medical history and neurologic reducing the amplitude of essential tremor.28 examination are often sufficient to make a diag- Primidone, which is metabolized to phenyle- nosis. Ancillary laboratory testing is infrequent- thylmalonamide and phenobarbital, has been ef- ly indicated if the clinical presentation is sugges- fective in doses ranging from 250 to 750 mg per tive of other relevant diagnoses (Table 1). In day, with reductions of 60% in tremor ampli- particular, early Parkinson’s disease with pre- tudes, similar to reductions observed with pro- dominant action tremor and little or no resting pranolol monotherapy.27 These effects on tremor tremor or bradykinesia can reliably be distin- amplitudes translated to benefits in patient evalu- guished from essential tremor by single-photon- ations of disabilities related to eating and dress- emission computed tomography using the tracer ing and assessment of the performance of 123I-ioflupane, which gives a measure of the manual tasks.29 Early adverse effects — includ- striatal presynaptic dopamine-transporter den- ing dizziness, fatigue, and malaise — occurred sity. Alternatively, patients may be followed over in 23 to 32% of patients on initiation of treat- time to determine whether more definitive signs ment with primidone (vs. in 8% taking proprano- of parkinsonism arise.21 Routine laboratory tests lol) but typically resolved within 1 to 4 days, and should be performed to rule out metabolic or the majority of patients who had such effects hormonal disturbances that may cause enhanced continued therapy.29,30 A randomized, controlled physiologic tremor, which may mimic mild es- trial of propranolol–primidone combination ther- sential tremor (Table 1). apy versus placebo showed a treatment effect of Additional electrophysiological testing, includ- up to a 70% difference in tremor amplitude.31 ing surface electromyography and accelerometry However, despite efficacy, in a survey of persons to evaluate muscle-activation characteristics, who received propranolol or primidone for es-

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GNAL PPARGC1A , and pesti - and VPS13C ( DYT6 ) THAP1 STK32B , Unknown ) and ( DYT24 ) ANO3 , or LRRK2 , Causal Correlates SLC1A2 , GBA , ; environmental risk factors risk environmental CTNNA3 ; ) and TOR1A ( DYT1 ) LINGO1 , ism, hypoglycemia, hyperparathyroidism, hypoglycemia, ism, hypocal - hypomagnesemia, hyponatremia, failure; kidney and failure, hepatic cemia, caffeine, including drugs, to exposure amphet - theophylline, cocaine, ­ nicotine, antidepres - hormones, thyroid amines, or SSRIs, tricyclics, (especially sants amioda - acid, valproic lithium, SNRIs), immunosup - and glucocorticoids, rone, tacrolimus) and A (cyclosporine pressants predom ­ a with manifest may that causes include phenotype tremor dystonic inant in mutations other in present be also may ( DYT25 ); mutations by caused dystonias, ­ genetic in and beta-carbo - to exposure higher include may that harmine) and (harmane alkaloids line meat overcooked in present are factors for Parkinson’s disease (e.g., vari - (e.g., disease Parkinson’s for factors in ants exposure) cide symptom - or (ADCME) and epilepsy nus, myoclonus cortical atic Genetic risk variants have been described in described been have variants risk Genetic Metabolic disturbances, such as hyperthyroid - as such disturbances, Metabolic genetic of examples genetic; or Idiopathic Environmental or genetic causes of and risk and of causes genetic or Environmental myoclo - tremor, cortical dominant Autosomal -

Other Features yes”), left–right rotation (“no–no”), or mixed or (“no–no”), rotation left–right yes”), dystonia cervical of signs out rule directions; by relief symptom or posture abnormal (e.g., head than elsewhere tremor or trick) sensory signs (e.g., dystonia, ataxia, or parkinsonism); or ataxia, dystonia, (e.g., signs clini - uncertain of signs neurologic additional if tan - impaired (e.g., present are significance cal or posturing, dystonic questionable gait, dem “es - is classification the impairment), memory plus” tremor sential (involuntary movement mitigated by touch ontouch by mitigated movement ­ (involuntary pears without other symptoms; may be trig - be may symptoms; other without pears exposure or fatigue, anxiety, stress, gered by temperature cold to acti (involuntary dystonia overflow part), body a vol - during groups muscle additional of vation (in ­ dystonia mirror and movement), untary part body dystonic the in dystonia of duction the of side other the of movement voluntary by focal, with patients in occur can tremor body); dystonia generalized segmental, and multifocal that help essential tremor; marked by cortical by marked tremor; essential help that poten - somatosensory giant with excitability, EEG back-averaging on spikes cortical and tials motion from rest to posture and reemerges and posture to rest from ­ motion delay brief ­ after Tremor may be present in flexion–extension (“yes– flexion–extension in present be may Tremor Duration of ≥3 yr and absence of other neurologic other of absence and yr ≥3 of Duration Typical signs of dystonia include sensory trick sensory include dystonia of signs Typical An isolated tremor syndrome, which typically ap - typically which syndrome, tremor isolated An May coexist with epilepsy; is refractory to therapies to refractory is epilepsy; with coexist May Tremor characteristically pauses during limb during pauses characteristically Tremor <7 Hz <7 2–5 Hz 2–5 4–7 Hz 4–7 4–12 Hz 4–12 4–12 Hz 4–12 9–18 Hz 9–18 Frequency Typical Tremor Head with or without or with other in tremor head,(e.g., ­ locations larynx [voice tremor], limbs) lower or hands, arms, or arms, hands, parts body other limbs; may also may limbs; voice, head, ­ affect face or tongue, lateral involvement) lateral tremor), lower tremor), tongue, jaw, limbs, foot or Body Area Affected Upper limbs bilaterally, limbs Upper Head, face, jaw, voice, jaw, face, Head, Predominantly upper Predominantly Arms (unilateral or bi - or (unilateral Arms Hands (asymmetric Hands Condition Activation movement head; subsides head; head is when rested nia in same in nia area body “dys - (termed tremor”) tonic body other in or (“tremor areas with associated dystonia”) movement movement present during present ki - and posture movement netic Posture and kinetic and Posture Posture of the of Posture Occurs with dysto - with Occurs Posture and kinetic and Posture Posture and kinetic and Posture Rest; may also be also may Rest;

tremor logic tremor logic with parkin ­ with sonism Characteristics of Essential Tremor and Conditions to Be Distinguished from Essential Tremor.* Essential from Distinguished Be to Conditions and Tremor Essential of Characteristics 1. Table Tremor Syndrome Essential tremor Essential Isolated head Isolated Dystonic tremor Dystonic Enhanced physio - Enhanced Cortical tremor Cortical Tremor combined Tremor This list is not comprehensive; see Table S1 in the Supplementary Appendix, available at NEJM.org, for a comprehensive version. Posture describes isometric extension of body part (e.g., a limb) against gravity. EEG denotes electroencephalography, SNRI serotonin–norepinephrine reuptake inhibitor, and SSRI selective serotonin-reuptake inhibitor. * 

1806 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 sential tremor, approximately half reported that (MRI) guidance resulted in a significantly greater they had eventually discontinued the drugs.32 reduction in hand tremor and better quality of The most likely reasons for discontinuation are life over a period of 12 months than a sham limited efficacy and unacceptable side effects. intervention. The most common adverse events Limited data from randomized, controlled with focused ultrasound thalamotomy were in- trials are available to support the use of other traprocedural discomfort, as well as postopera- medications in essential tremor, including topi- tive paresthesia or numbness (in 38% of par- ramate, alprazolam, gabapentin, and other beta- ticipants) and gait disturbance (in 36%). At 12 blockers besides propranolol (e.g., atenolol, nado- months after the intervention, the rate of pares- lol, and sotalol).23,27 Randomized, controlled trials thesia or numbness was 14%, and the rate of have shown no significant benefit for several gait disturbance was 9%.41 other agents for essential tremor, including leve- tiracetam, amifampridine, flunarizine, trazodone, Areas of Uncertainty pindolol, acetazolamide, mirtazapine, nifedipine, and verapamil.23 The relationship between pathological, neuro- physiological, and genetic factors in essential Neurostimulation and Ablative Therapies tremor requires further study. The extent of de- Deep-brain stimulation (unilateral and bilateral) generative processes in the cerebellum in affected and thalamotomy (only unilateral) targeting the patients and their relevance to the broad spec- thalamic nucleus ventralis intermedius are used trum of essential tremor remain unclear.8 for the treatment of medically intractable upper- More data are needed from randomized trials limb tremor in essential tremor. Although con- to provide information regarding the effective- ventional stereotactic thalamotomy was the first ness and risks of treatments for essential tremor. available interventional treatment of tremor, its Clinical rating scales and transducer-based meth- application is limited to unilateral interventions ods to objectively quantify tremor have been owing to the high risk of irreversible dysarthria developed for use in clinical trials as well as in or ataxia after bilateral thalamotomy.33,34 In a routine practice.18,22 However, the clinical mean- randomized trial involving patients with tremor ingfulness of observed changes in these in­ (with essential tremor in the minority), deep- struments is uncertain, and data are needed on brain stimulation resulted in greater functional patient-reported outcomes and quality of life. improvements than thalamotomy and fewer ad- Potential molecular targets for treatment of verse events, such as dysarthria, sensory distur- essential tremor include the T-type calcium bances, and gait disturbances.35 At a 5-year fol- channel42 and GABA type A receptors.43 On the low-up, half the patients with essential tremor basis of the tremor-suppressing effect of ethanol who were assigned to deep-brain stimulation and its presumed molecular action on these tar- reported a diminished effect, which has been gets,44 the long-chain alcohol 1-octanol and its attributed to disease progression or the develop- metabolite octanoic acid have been proposed for ment of tolerance to stimulation.36,37 Adverse treatment of essential tremor; preliminary data events are more common with bilateral than have suggested benefit,45 although further study unilateral deep-brain stimulation.37,38 Adverse is needed. effects of deep-brain stimulation may include Although the ventral intermedius nucleus of reversible stimulation-induced ataxia, dysarthria, the thalamus has been the primary target for paresthesias, tonic muscle contractions, and surgical treatment of tremor, two regions below impaired balance.39 the thalamus — the zona incerta and the white- In 2016, the Food and Drug Administration matter tract of cerebellothalamic fibers (the approved a focused ultrasound device to treat prelemniscal radiation) — have been proposed essential tremor that is refractory to medical as alternative targets (Fig. 1), with uncontrolled therapy.40 The approval was based on the results studies suggesting a potentially greater effect of a randomized, controlled trial involving 76 than with the conventional target.46-48 However, participants with essential tremor, in which uni- controlled trials are needed to confirm efficacy. lateral thalamic thermoablation using focused New developments in stimulation therapies ultrasound with magnetic resonance imaging for essential tremor include closed-loop stimula-

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tion using sensors to monitor tremor activity to ologic tremor, which can be induced by meta- trigger and adjust stimulation in real time and bolic disturbances or certain medications (in- “on demand.” 49 A tremor-cancelling spoon, which cluding fluoxetine, which the patient is taking). uses tremor sensors that drive micro-motors to We would recommend routine laboratory stud- counteract the tremor and stabilize the utensil, ies, including tests of liver and kidney function has been developed.50 More data are needed to and measurement of blood levels of electrolytes inform the efficacy of this and other assistive and thyrotropin. However, the long-standing devices for essential tremor. course and positive family history of tremor make essential tremor more likely. Guidelines Because the patient has not yet received any therapy for essential tremor and reports that The 2017 consensus statement on tremor of the tremor interferes with daily life tasks, we would International Parkinson and Movement Disorder recommend treatment initiation with either pro- Society represents a major update in the classifi- pranolol or primidone, with a gradual dose cation scheme of tremor disorders, since it de- adjustment to target doses (propranolol, 120 to fines essential tremor as a tremor syndrome and 240 mg per day; primidone, 250 to 750 mg per includes the recommendation to classify pa- day). The choice of first-line therapy should be tients with tremor according to both clinical made after assessment for any contraindications characteristics and cause.4 The American Acad- (e.g., symptomatic bradycardia or hypotension emy of Neurology (AAN) published guidelines in when beta-blocker therapy is considered) and 2011 summarizing recommendations for medi- may also take the patient’s preference into ac- cal and surgical approaches.23 The AAN has de- count after education regarding short-term and veloped an Essential Tremor Quality Measure- long-term effects of these drugs, such as dizzi- ment Set that aims to ensure the quality of ness, hypotension, and sedation. After the pa- diagnosis and the identification of appropriate tient is taking a dose of either drug that provides pharmacologic and surgical treatment options, sufficient benefit without unacceptable side with attention to quality-of-life measures, coex- effects, we recommend annual assessments of isting depression and anxiety, and education of tremor severity with the use of rating scales such patients.51 Recommendations in the present as TETRAS. For second-line treatment, we would article are generally consistent with guideline recommend switching to the other first-line recommendations for evaluation and treatment, agent, if not contraindicated; if neither was ef- with the exception that data to support MRI- fective alone, combination therapy with both guided focused ultrasound thalamotomy for propranolol and primidone could be considered. treatment-refractory essential tremor were not For patients whose symptoms cause substantial available at the time these guidelines were pub- disability and who do not have an adequate re- lished. sponse to pharmacotherapy, which may also in- clude treatments with lower levels of evidence of Conclusions and efficacy (e.g., topiramate, alprazolam, or gaba- Recommendations pentin), we would discuss the option of deep- brain stimulation or MRI-guided focused ultra- The patient described in the vignette presented sound thalamotomy with the patient, weighing with approximately a 10-year history of a slowly possible risks of the surgical intervention and progressive bibrachial tremor during action and potential benefit. posture, such as limb extension against gravity. Dr. Haubenberger reports receiving devices for use in re- On the basis of the history taking and the neu- search studies from Cala Health; and Dr. Hallett, receiving devices for use in research studies from and serving on an un- rologic examination (including the observed fre- paid scientific advisory board for Cala Health and holding a quency and amplitude of tremor), a diagnosis of patent (US 7,407,478), licensed to Brainsway, for the H-coil. No essential tremor is most likely. In the absence of other potential conflict of interest relevant to this article was reported. any other abnormal neurologic signs, the main Disclosure forms provided by the authors are available with differential diagnosis would be enhanced physi- the full text of this article at NEJM.org.

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1810 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.