News and controversies regarding essential tremor.

NEUROL-1489; No. of Pages 11 revue neurologique xxx (2015) xxx–xxx

Available online at

ScienceDirect www.sciencedirect.com

General review

News and controversies regarding essential tremor Actualite´s et controverses concernant le tremblement essentiel E. Boutin a,b,*, M. Vaugoyeau a,b, A. Eusebio a,b, J.-P. Azulay a,b, T. Witjas a,b a

Service de Neurologie et Pathologie du Mouvement, Poˆle de Neurosciences cliniques, CHU de La Timone, 264, rue Saint-Pierre, 13385 Marseille Cedex 05, France b CNRS-AMU, LNC UMR 7291, 3, place Victor-Hugo, 13331 Marseille, France

info article

abstract

Article history:

Essential tremor is the most common movement disorder in adults. It is characterized by

Received 29 October 2014

a postural and kinetic tremor affecting the arms, but it can also affect other body parts. It

Received in revised form

evolves gradually and can be responsible for a functional impairment in activities of

1 February 2015

daily living. Its pathophysiology remains poorly understood and effective therapeutic

Accepted 2 February 2015

options are limited. There are significant semiological variations between patients,

Available online xxx

and the term ‘‘essential tremor’’ seems to encompass a wide range of heterogeneous

Keywords:

Furthermore, there is a current debate concerning the etiology of this affection, as to

Essential tremor

whether essential tremor is a complex degenerative disorder or a functional reversible

clinical phenotypes. The diagnostic criteria presented in 1998 are now challenged.

Pathophysiology

disorder of neuronal oscillation. In this review, we summarize some aspects of clinical,

Cerebellum

etiologic and therapeutic news, to better address the questioning on unravelling the clinical presentation and examine the current pathophysiological controversy in this disorder. # 2015 Elsevier Masson SAS. All rights reserved.

r e´ s u m e´ Mots cle´s :

Le tremblement essentiel est le plus fre´quent des mouvements anormaux de l’adulte. Il est

Tremblement essentiel

caracte´rise´ par un tremblement postural et d’action affectant les membres supe´rieurs, mais

Physiopathologie

pouvant aussi atteindre d’autres parties du corps. Il e´volue de façon lentement progressive

Cervelet

et peut eˆtre responsable d’un handicap fonctionnel dans les activite´s de la vie quotidienne. Sa physiopathologie demeure mal connue, et les options the´rapeutiques efficaces sont limiteés. Il existe des variations se´miologiques importantes entre les patients, et le terme de tremblement essentiel englobe un ensemble he´te´roge`ne de pheńotypes cliniques. Les crite`res diagnostiques dećrits en 1998 sont aujourd’hui remis en cause. Par ailleurs, il existe actuellement un de´bat concernant l’e´tiologie de cette affection, qui oppose l’hypothe`se

* Corresponding author at: Service de neurologie et Pathologie du Mouvement, Poˆle de Neurosciences Cliniques, 264, rue Saint-Pierre, 13385 Marseille Cedex 05, France. E-mail address: [email protected] (E. Boutin). http://dx.doi.org/10.1016/j.neurol.2015.02.007 0035-3787/# 2015 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Boutin E, et al. News and controversies regarding essential tremor. Revue neurologique (2015), http:// dx.doi.org/10.1016/j.neurol.2015.02.007

NEUROL-1489; No. of Pages 11

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revue neurologique xxx (2015) xxx–xxx

neurode´geńe´rative a` celle d’une origine plutoˆt fonctionnelle. Cet article reprend quelques aspects des actualite´s cliniques, e´tiologiques et the´rapeutiques, afin de mieux aborder le questionnement du de´membrement clinique, et la controverse physiopathologique dans le tremblement essentiel. # 2015 Elsevier Masson SAS. Tous droits re´serve´s.

Tremor is an involuntary rhythmic motor activity by which a body part exhibits a regular oscillatory movement. Tremor is defined by the movement’s frequency, localization and mode of activation, at rest, during an ongoing action or when maintaining an attitude. Many causes of tremor have been described. Among them, essential tremor (ET) corresponds to the most common movement disorder observed in adults. Nevertheless, our current knowledge about the underlying pathophysiology remains sparse, and effective treatments are limited. This article resumes some of the new data that has become available concerning the clinical, etiological and therapeutic aspects of ET in order to better examine the current controversy about the degenerative or functional etiology of this pathological condition.

1. Definition of essential tremor: towards new clinical criteria? ET is characterized by a postural and kinetic tremor of the upper limbs, sometimes involving the head (30%) and more rarely the face, voice, trunk and legs. Age, family history of tremor and Caucasian ethnic background are risk factors for ET [1–3]. Age of onset has a bimodal distribution, with a first peak in the 20–40 years age range and a second higher peak after 65 years [4]. Prevalence estimates have been quite variable, mainly because of difficult diagnosis and access to care. In the most reliable epidemiology studies, the estimated prevalence of ET is around 400 per 100,000 inhabitants, rising sharply with age to exceed 4600 per 100,000 inhabitants over the age of 65 years [5]. Despite its prevalence, less than onethird of affected people seek medical care [6]. Patients attending neurology clinics or tertiary centers probably have atypical or more severe forms of ET. The diagnostic criteria set forward in 1998 in the Consensus Statement on Tremor describe ‘‘a bilateral, largely symmetric postural or kinetic tremor involving hands and forearms, that is visible and persistent’’, excluding other abnormal neurological signs, notably a dystonic component or task-specific tremor [7]. The course is slowly progressive, the intensity increasing with age, and in general potentially extending from the peripheral areas to the central axis. The tremor can have a functional impact impairing activities of daily living such as writing, drinking, or dressing. Characteristically, the tremor worsens with physiological or emotional stress, receding temporarily after ingestion of alcohol in half of patients. The diagnosis is essentially clinical. Polygraphic electromyography (EMG) using surface electrodes to record several muscles simultaneously can be coupled with a continuous accelerometric recording of the movement. Polygraphic recordings of ET display a 6–10 Hz postural tremor with an additional

intentional component [8]. The rhythm is slower in the elderly subject and for more proximal muscles. The diagnosis of ET requires a duration of at least 5 years, and formal exclusion of differential diagnoses: exacerbation of physiological tremor; iatrogenic, cerebellar or psychogenic tremor; dystonic tremor. In clinical practice, presentations are quite variable depending on age of onset, extension beyond the upper limbs or to the voice, frequency of head tremor, responsiveness to alcohol, and association with cerebellar motor symptoms or non-motor symptoms. The current diagnostic criteria are not precise and lead to including a number of heterogeneous conditions under the term of ET. Two studies have reported high rates of misdiagnosis of ET, reaching 37% and 50%, respectively [9,10], most often in patients with Parkinsonism or dystonia. Dystonic tremor is defined as a postural or kinetic tremor appearing in a body part that is affected by dystonia, with irregular amplitude, variable frequency (generally < 7 Hz), and disappearance with complete rest [7]. When head or voice tremor predominates, it can be difficult to distinguish between different variants of ET, or between ET and dystonia (tremulous spasmodic torticollis, laryngeal dystonia). The presence of an antagonist movement is an argument in favor of dystonia [11]. Tremor associated with dystonia occurs in patients with a focal dystonia, but in a part of the body not affected by dystonia; for example a patient with spasmodic torticollis also presenting postural tremor of the upper limbs. Task-specific tremor, such as primary writing tremor (tremor appearing solely when writing), could be a form of dystonic tremor. It is highly important to have precise limits for the definition of ET: is dystonic tremor a form of ET or an entirely different entity? Can patients with isolated neck or voice tremor or with a very asymmetrical tremor of the upper limbs be considered to have ET or must we insist on finding some dystonic component? In this situation, using clinical criteria alone seems to be insufficient; other electrophysiological explorations are needed to analyze the tremor to determine whether it has an irregular amplitude or frequency, included myoclonic elements, or is associated with cocontraction of agonist/antagonist muscles suggestive of dystonia. Several recent studies show that tremor may not be the only clinical manifestation of ET and that there is a more diffuse underlying neurological process.

1.1.

Cognitive deficits

Gasparini et al. were the first to demonstrate, in 2001, significant abnormalities in cognitive function, e.g. frontal function, in patients with ET; they showed that in comparison with healthy controls, these patients exhibit lower performance levels on



attention and conceptualization tasks, and on a verbal fluency test [12]. Subsequent studies have confirmed the low performance on lexical and categorical verbal fluency, naming, anterograde verbal memory, working memory and mental flexibility tests, as well on tests of verbal and visual attention and inhibition (STROOP test), immediate recall of a word list, and visuospatial tests [13–15]. Taken together, these studies reveal a special dysexecutive neuropsychological pattern in patients with ET, sometimes associated with a lesser degree of visuospatial dysfunction. This pattern recalls the subcorticofrontal syndrome described in Parkinson’s disease, although ET is not associated with patently deficient psychomotor performance or visuospatial dysfunction, and the frontal deterioration is less marked. This cognitive pattern is also close to the ‘‘cerebellar cognitive affective syndrome’’ described in 1998 by J. Schmahmann in pure cerebellar lesions [16]. This pattern of cognitive disorders in ET suggests the implication of subcorticofrontal circuits, and specially a dysfunction of the cerebello-thalamo-cortical pathway, whose etiology remains to be clarified. It should however be noted that all of these studies were conducted with small cohorts (27–101 patients), had potential biases (patient age, multiple medications, mood disorders, different educational levels) and were not always controlled. Moreover, the incidence of dementia would be higher in patients with late onset ET than in an age-matched control population, although it is not known what would be the underlying pathophysiological mechanism [17,18].

1.2.

Mood and personality disorders

Patients with ET would have a more pessimistic, fearful, timid and anxious, easily tired personality [19]. This would occur with no correlation with the severity of the tremor or the functional disability it causes, indicating that this personality profile is not a consequence of the tremor-related disability. Anxiety, depression and social phobia are psychiatric symptoms that have a higher prevalence in ET than in control populations [20,21]. Some authors report severe depression in 8% of questioned patients [6]. Although depression can be a consequence of the tremor-related disability, mood disorders could also be a manifestation associated with the pathogenic process and aggravate the functional impact of the disease. One-third of patients with ET report significant impairment of their occupational and personal quality of life [6].

1.3.

Olfactory deficit

Data in the literature concerning potential olfactory disturbance are rather scarce and contradictory. Three studies analyzing olfaction using the University of Pennsylvania Smell Identification Test (UPSIT) found normal olfactory function in patients with ET but a significantly altered smell in patients with Parkinson’s disease [22–24]. One single UPSIT study involving 37 patients with ET found significant moderate olfactory deficits in the ET cohort compared with controls. This alteration of olfactory function was not correlated with the severity of the disease nor with its duration and there is so far no evidence supporting the usefulness of smell tests as a diagnostic tool for ET. It has been

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suggested that the cerebellum may play a role in human olfaction, hence such olfactory dysfunction could relate to cerebellar dysfunctions reported in ET [25]. Alternatively, the involvement of olfactory pathways in ET is considered by some authors as evidence for a continuum with degenerative disorders such as PD [26].

1.4.

Hearing impairment

One population-based study including patients aged over 65 years showed that 38.7% of ET patients had impaired hearing compared with 29.4% in controls (P = 0.002) [27]. Audiometric tests in tremor patients have shown a hearing loss involving the high frequencies that would be correlated with the severity of the tremor [28]. However, due to the lack of controls for age, co-morbidity, treatments and ENT history, these data do not allow any conclusion concerning the presence of specific disorders.

1.5.

Abnormal eye movements

The abnormal eye movements described in ET are slow initiation of smooth pursuit (correlated with the presence of intention tremor) and abolition of the oculo-vestibular reflex [29]. This could indicate a dysfunction of the caudal vermis. There appears to be an increased latency and slower speed of horizontal and vertical saccades, as well as a clear increase in square-waves [30]. These anomalies, suggestive of cerebellar dysfunction are not correlated with the severity of the tremor nor with its duration or with treatment. They correspond to a pattern distinct from other movement disorders (particularly Parkinson’s disease), potentially providing a guide for differential diagnosis [30].

1.6.

Disorders of motor-timing programming

Several studies have found an alteration of motor-timing movements in ET, leading to irregular rhythmic movements and rapidly alternating movements. As shown by the index finger taping test, ET patients have difficulty synchronizing repeated movements in response to an external auditory stimulus, exhibiting greater temporal variability than controls [31,32]. Repetitive transcranial magnetic stimulation (rTMS) at 1 HZ for 10 minutes placing the coil over the ipsilateral cerebellum hemisphere corrects the motor rhythm disorders, confirming the implication of cerebellar loops [32]. Lower motor performance during rapid repetitive movements and longer visual reaction time suggest some degree of bradykinesia in ET [33]. Furthermore, Deuschl et al. have individualized a subgroup of patients presenting ET with frank intentional tremor. When performing fine movement cinematic tasks involving the upper limb, these patients exhibit abnormal target-directed movements, dissymmetry, and abnormal temporal programming of ballistic movements very similar to those observed in patients with a cerebellar syndrome [34]. Motor-timing and movement precision appear to be improved after deep brain stimulation and thalamotomy of the ventral intermediate nucleus (VIM) nucleus [35]. The VIM nucleus is an important part of the cerebello-thalamo-cortical



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network and thus participates in temporal regulation of rhythmic movements. All these studies converge toward a dysfunction of the cerebellum of unknown origin.

1.7.

Gait and balance disorders

Over the last two decades, a growing number of studies have demonstrated the presence of gait and balance disorders in ET. These disorders can be observed on bedside examinations with tandem gait, but can also be recorded quantitatively using force platform and treadmill setups. The rate of unsteady steps is greater in ET patients, especially after the age of 70 years and in patients with a duration of tremor longer than 5 years [36–39]. Other anomalies included reduced gait speed, mainly related to shortened step length rather than cadence, longer phase of bipedal stance, and a larger support polygon [40,41]. Age over 70 years and the presence of head tremor have been proposed as factors predictive of posturolocomotor disorders. Gait impairment is not correlated with the severity of upper limb postural tremor [36,38]. The presence of gait disturbances suggestive of ataxia is a further argument favouring the hypothesis of cerebellar dysfunction in ET. Increasingly precise descriptions of these abnormal locomotor patterns raise the question of their inclusion in the diagnostic criteria of ET.

2. New developments in the pathophysiology of essential tremor Although many elements of the pathophysiology of ET remain unclear, research over the last decade has greatly affected our underlying approach to this disorder; some advances have been made in unraveling the different symptomatic and etiological aspects. Two opposing pathophysiological concepts can be described, one based on the hypothesis of a single-symptom disease arising from a functional disorder related to a neuronal oscillator [42] and the other considering ‘‘tremor syndrome’’ to be a more complex, heterogeneous, potentially neurodegenerative, disorder [43]. The notion that ET is a benign condition is also questioned since the tremor has a tendency to worsen progressively, becoming a serious disability affecting the quality of life of many patients. The goal of this review is to summarize our current knowledge and describe the arguments put forward to support each of these hypotheses. The co-existence of heterogeneous genetic patterns, sporadic cases and variations in age of onset as well as severity of the tremor observed within a given family suggest the influence of environmental factors, and could also be due to modificator genes.

2.1.

Environmental factors

Several neurotoxic agents have been incriminated, such as the b-carboline alkaloids (harmane, harmine), GABA receptor antagonists that provoke severe tremor in intoxicated animal models and lead to Purkinje cell death. Significantly, higher blood levels of alkaloids and lead have been observed in ET patients compared with healthy subjects [44,45].

2.2.

Genetic factors

A family history of ET, defined as ET in at least two first-degree relatives diagnosed before the age of 65 years, is found in 50–70% of patients [46]. Twin concordance studies confirm higher concordance in monozygous twins (60–93%) than dizygous twins (27–29%) [47,48]. Despite this strong suspicion of inherited transmission, it is very difficult to identify causal mutations, in part because of potential diagnostic error (studies including patients with dystonic tremor or Parkinson’s disease), and also because of ET’s incomplete penetrance, high prevalence (hiding the true pattern of heredity), and variable clinical presentation (especially concerning age-at-onset). Three potential loci, ETM 1, 2 and 3 have been identified in European or American families [49–51], but with inconsistent results [52]. More recently, two genome-wide association studies (GWAS) demonstrated a significant association between ET and a variant of the leucine-rich repeat and Ig domain containing 1 (LINGO-1) gene and the solute carrier family 1, member 2 (SLC1A2) gene [53,54]. A nonsense mutation of the FUS (fused in sarcoma) gene demonstrated in 2012 by exome sequencing could also play a role in ET [55]. It is generally accepted that genetic determinants can explain at least the familial cases of ET, potentially via multifactorial inheritance or linkage to susceptibility genes.

2.3.

Degenerative versus functional hypothesis

It is commonly accepted that the cerebellum is implicated in the pathophysiology of ET, but the exact nature of the anomalous cerebellar function is poorly understood, remaining a subject of debate. Recent imaging, electrophysiological and pathological data would suggest that a degenerative etiology can be opposed to a functional etiology. There is also a more global hypothesis suggesting defective gamma-amino-butryic acid (GABA) transmission. Classically, routine neuroimaging is normal in ET but technological advances in neuroimaging have demonstrated some structural, functional and metabolic alterations. Voxelbased morphometry (VBM) magnetic resonance imaging (MRI) has provided contradictory data. Daniels et al. were unable to find any atrophy of the cerebellum in ET [56]. Several other VBM studies have on the other hand demonstrated structural anomalies in the gray and white matter of the cerebellum, and also in brain regions in the frontal and parietal cortex, suggesting the presence of rather diffuse atrophy affecting the cerebello-thalamo-cortical network [57–59]. Most of the diffusion MRI studies show a loss of integrity in the cerebellocortical white fibers, yet Martinelli et al. did not find any anomaly in the apparent diffusion coefficient in their patient with ET [60–62]. Two MNR spectroscopy studies have shown a reduction in the NAA/creatine ratio in the cerebellar cortex of ET patients compatible with neuronal loss [63,64]. Regarding metabolic imaging, PET studies have provided evidence of bilateral cerebellar hyperactivation during tremor attitude while SPECT studies show increased brain blood flow [65,66]. Two PET studies using 11C-flumazenil specific for a GABA receptor subunit as the radiotracer show increased tracerreceptor binding reflecting underlying GABAergic dysfunction in the cerebello-thalamic pathways [67,68]. Morphometric



and diffusion studies are thus globally in favor of cerebellar, or even diffuse, atrophy. The metabolic imaging data suggest a more functional involvement of the cerebello-thalamocortical loops. It must be noted that all of these studies were conducted with small cohorts (7–50 subjects), and that the alterations noted were not detectable clinically on standard brain computed tomography or MRI scans. Very few pathology studies on ET were published before 2004. None found notable changes. In 2004, two pathology studies including 24 and 11 patients respectively failed to find any significant pathological result [69,70]. During the following decade, two large-scale autopsy studies nevertheless provided evidence of neuropathological anomalies mainly involving the cerebellum and the brain stem. Louis et al. published several studies including a study of the entire brain in 33 patients [71]. Twenty-five percent of the brains displayed Lewy body inclusions in the brain stem, mainly in the locus cœruleus; 75% had cerebellar anomalies: loss of Purkinje cells and torpedo formation. From these findings, the authors proposed to define two pathology patterns of ET: ‘‘cerebellar ET’’ and ‘‘Lewy body variant of ET’’. These two subgroups would present different phenotypic and epidemiological characteristics. In 2008, Shill et al. also described a series of 24 patients with cerebellar anomalies (loss of Purkinje cells, sclerosis of the cerebellar cortex, Bergmann astrogliosis), but did not find any significant increase in Lewy bodies [72]. These results favouring degenerative remodeling of the cerebellum have not however been confirmed throughout the literature [73,74]. It must be emphasized that incidental Lewy bodies are found in less than 10% of asymptomatic elderly persons so that it is difficult to conclude about any specificity in ET. The same is true for torpedoes, axonal swellings of Purkinje cells, and for Bergmann astrogliosis, both of which can be found in other cerebellar diseases. Concerning the loss of Purkinje cells, it is difficult to determine whether they are the result or consequence of longstanding ET. Two recent pathology-biochemistry studies reported the presence of GABA receptor anomalies in the cerebello-thalamic pathways in ET. In one autopsy series of 10 ET patients compared with 16 controls, Paris-Robidas et al. showed a 35% and 22% reduction in GABAa and GABAb receptors respectively in the cerebellar dentate nucleus that was inversely correlated with duration of ET [75]. This suggested that this loss of GABA receptors followed the progression of the disease. The authors proposed that this loss of GABA receptors in the dentate nucleus would lead to disinhibition of the efferent pacemaker activity of the cerebellum that would propagate along the cerebellothalamo-cortical pathways generating tremor. Shill et al. showed in another series of 23 autopsy patients that the concentration of parvalbumin, a marker of GABAergic neurons, is significantly reduced in the locus cœruleus in patients compared with controls, but not in the cerebellum [76]. The authors suggest that the locus cœruleus, a noradrenalin source for the cortex, thalamus and cerebellum, could be a primary promoter of tremogenic oscillations in the motor networks. Electrophysiology evidence is generally in favor of a dysfunction of a central oscillator and GABAergic transmission in ET. One of the supposed mechanisms giving rise to tremor is the presence of a central neuronal oscillating pacemaker. The

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rhythmic oscillatory activity would be generated by a group of neurons called the oscillator that is not necessarily an isolated anatomic structure but rather a system composed of several structures linked together by functional connections. These electrophysiological arguments have led to suspect that abnormal rhythmic activities would be generated by the olivocerebellar complex, then, would propagate through the cerebello-thalamo-cortical network [77]. GABA is the main inhibiting neurotransmitter in the brain. It is present in high concentrations in Purkinje cells, allowing the cerebellum to regulate and coordinate motor schemes via its inhibitory efferents. The cells of the dentate nucleus are sensitive to the Purkinje cells’ GABAergic tonic efferents that could control the rhythmic oscillatory activity of the deep cerebellar nuclei [78]. The inferior olive is an interesting candidate for this hypothetical central generator. In animal models, it has been shown that cells of the inferior olive have an autonomous synchronous oscillatory activity and that this rhythmic activity is transmitted via the cerebellum and the reticulospinal projections to motoneurons [79]. A similar mechanism might be operating in ET: rhythmic discharge from the olivocerebellar system could cause a dysregulation of the control functions of the cerebellum on limb movement. Furthermore, abolishing tremor by stimulation or by thalamic lesion suggest that the thalamic neurons would play a role in the genesis or propagation of rhythmic oscillations. In vivo studies after thalamotomy show that microinjections of muscimol, a GABA agonist, into the VIM of the thalamus lead to a transient reduction in tremor in the contralateral limb [80]. Spectral analysis of coherence confirms the linear correlation between EMG muscle activity and the rhythmic activity of thalamic neurons in tremor [81,82]. The cerebellum could play a role in propagating a generated rhythmic oscillatory activity. It has been recently shown by analysis of coherence that the oscillatory activity recorded in the cerebellum with magnetoencephalography correlates with the tremor frequency recorded by the EMG [83]. The oscillatory circuits do not appear to be pathological per se, but rather would correspond to dysregulated preexisting physiological motor circuits submitted to an exaggerated synchronization [84]. Structural remodeling of the cerebellum suggesting neuronal loss in some imaging and pathological studies are in agreement with the hypothesis of a degenerative origin of ET. However, conflicting data argue against this concept. The hypothesis that dysfunctional GABAergic transmission would give rise to ET appears to be an interesting proposition since it would link together the degenerative and functional concepts. From this point of view, the cerebellum degenerationrelated loss of Purkinje cells would lead to decreased GABAergic activity in the cerebellar dentate nuclei, which in turn would give rise to disinhibition of efferent oscillatory rhythmic activity of the deep cerebellar nuclei, subsequently propagating this abnormal oscillatory rhythmic activity to the cerebellothalamo-cortical loops [78]. There are however arguments opposing this hypothesis; for instance, while knockout mice models devoid of the a1-subunit of the GABA receptor develop postural and kinetic tremor and disordered motor coordination mimicking the characteristics of human ET [85], none of the



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subsequent genetic studies has been able to demonstrate a link between a mutation of the known GABA transporter and receptor genes and ET [86,87]. Moreover, despite in vitro and in vivo arguments supporting the hypothesis of a GABA neurotransmission anomaly in ET, several therapeutic controlled trials using GABA analogs such as gabapentin or pregabalin have not been conclusive, and efficacy of GABAergic drugs in tremor is modest, indicating that isolated increase in GABAergic neurotransmission is not a solution to the problem [88]. The effect of changes in GABAergic tonus on tremor genesis has not been perfectly established.

3. What is the link between essential tremor and Parkinson’s disease? The presence of a link between ET and idiopathic Parkinson’s disease (PD) remains highly controversial. The co-existence of these two commonly encountered disease states in the same patient could be incidental. There are however epidemiological, genetic and pathological data suggesting that ET could be a risk factor for developing PD [89]. It is not rare that patients with longstanding ET develop clinical manifestations of resting tremor. This tremor generally occurs alone, with no other sign of the Parkinsonian triad. It is a resting tremor always associated with a predominant postural tremor and does not affect the lower limbs. The underlying mechanism is not clear. It remains to be known whether this tremor corresponds to an extension of the pathophysiological mechanism of ET involving the pathway from the cerebello-thalamo-cortical circuits to the basal nuclei during the course of the disease, or if it is actually a first clinical sign of early-stage PD. It is also possible to find postural tremor in patients with patent PD. This is generally called reemergent tremor since it occurs most often after several seconds of maintaining a given posture and has classically the same frequency as in resting tremor. A recent epidemiological study in the general population of patients aged over 65 years found a 4-fold higher incidence of PD in patients with ET compared with controls, with a 2.3% increase in the absolute risk of developing PD compared with the control population [90]. This study did not however provide any evidence favouring an increased risk of PD in ET subjects under the age of 65 years. These results should be balanced against the high rate of diagnostic confusion between ET and PD, making it even harder to come to any firm conclusion about a link between these two diseases [10]. Fekete et al. found a history of prior ET more than 5 years before the onset of Parkinson symptoms in 12.2% of the patients followed for PD [91]. However, a longitudinal retrospective study over 45 years showed that only 2% of the incident cases of ET later developed PD [92]. The existence of common pathogenic processes in these two diseases has been suggested by some teams, mainly based on anatomopathological data. As mentioned above, work by Louis et al. demonstrated the presence of Lewy bodies in the brain stem in a subgroup of ET patients, suggesting a degenerative pathophysiological mechanism similar to the PD process in this subgroup of patients [71]. An initial common pathophysiological pathway leading to Lewy body formation

could produce an ET phenotype or a PD phenotype depending on the brain regions initially implicated: brain stem or subcortical structures. Inversely, it should also be noted that no anomalous cerebello-thalamic pathways as found in ET have been described in pure PD. Data from the most recent genetic studies do not provide any evidence confirming the common pathophysiological hypothesis; no genetic study has found evidence of a link between ET and genetic mutations common to the hereditary forms of Parkinson’s disease such as LRRK2 and PARKIN. Possible evidence of a genetic link between ET and PD has been suggested by the finding of association of LINGO1 variants with both ET and PD, thus representing a common genetic risk factor, However, there is conflicting data and recent studies argue against the involvement of this gene in PD [53,93,94]. In addition, morphological and functional imaging studies disagree on the presence of degeneration in the nigrostriatal pathway or the hyperechogenicity of the substantia nigra in ET, and to date have been unsuccessful in proving a link between ET and PD [89]. DATscan, which uses a marker of the dopamine transporter as a tracer, is usually considered normal in ET; it can be used as a tool for differential diagnosis between ET and PD [95]. Nevertheless, certain studies have demonstrated less marked striatal dopaminergic denervation on the DATscan in ET than in PD, suggesting a continuum between these two diseases [96]. It is also interesting to recall that pharmacological strategies used in ET and PD are quite different, levodopa not being effective on kinetic tremor, emphasizing the existence of different mechanisms generating the abnormal movement in these two diseases. Finally, although epidemiological arguments tend to underscore the frequent association of these two disease entities in patients, there remains a lack of formal evidence in favor of a pathophysiological link, and factors determining the course of ET towards PD remain unknown. Some authors emphasize the existence of an overlapping ‘‘ET-PD’’ syndrome that would correspond to the phenotype of patients with a predominantly tremulous form of Parkinson’s disease, with a history of preexisting or associated ET, with a slower progression and a better long-term prognosis than classical PD [97]. Nevertheless, prospective studies will be necessary to answer the unresolved questions, particularly to study factors influencing the onset of Parkinson’s syndrome in patients with ET; in this type of study, a clear definition of the diagnostic criteria for ET is of major importance.

4.

Treatments

4.1.

Drug therapy

While there is no curative treatment for ET, several drug regimens are available that provide relief for about half of treated patients. First-intention drug therapy is based on two main compounds: propanolol and primidone. Both have proven efficacy demonstrated with double-blind randomized controlled trials, with a 50–60% reduction in tremor (88%). Propanolol is a non-selective beta-adrenergic blocker: symptom improvement is observed in 50–70% of patients taking a



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Several studies have evaluated the efficacy and tolerance of type A botulinum toxin in ET. Only two were double-blind randomized controlled trials versus placebo. The effect of type A bolulinum toxin on arm tremor is significant but moderate and of short duration. It is associated with hand weakness that is dose-dependent [109]. Use of botulinum toxin can also be interesting for the management of head and voice tremor that often remains unresponsive to drug therapy. Injections of botulinum toxin in the neck muscles can lead to moderate improvement in head tremor [110,111]. For voice tremor, two class II studies report subjective improvement after bilateral injections of botulinum toxin in the vocal cords although there are adverse effects such as dyspnea, hypophonia, cough, and swallowing disorders after this type of major treatment that requires close surveillance [112,113].

technique of deep brain stimulation (DBS) in 1987 [114]. DBS has since progressively become the gold standard surgical procedure in this indication [115]. This ‘‘functional’’ surgery is modular and reversible. The target in this indication is usually the VIM. DBS has proven efficacy and provides a 70–80% reduction in tremor in more than 70% of patients [116] as well as significant improvement in quality of life [117,118]. Adverse effects reported have included paresthesia (19% of complications), dysarthria (9%), and balance disorders (4%) that can in general be improved by modifying the stimulation parameters [116]. In patients receiving a bilateral stimulation, dysarthria and balance and gait disorders appear to be more frequent than in patients receiving unilateral stimulation [119]. Hardware complications (infections, electrode fracture, cable-related pain, skin problems) occur in 25% of patients [120]. Although the long-term efficacy of DBS may decrease over time in some patients, the beneficial effect is generally sustained but may require adjustments of the stimulation parameters [121,122]. Over the last 15 years, thalamotomy has returned as an important element of the therapeutic armamentarium for ET. This has been made possible by the development of gamma knife stereotaxic radiosurgery. The principle is to converge narrow ionizing beams radiation onto a unique focus. The current recommendations propose the delivery of a single dose (130–140 Gray) with a 4-mm isocenter. This technique has the advantage of being a closed skull procedure avoiding the risk of hemorrhagic, infectious, and neurological damage of the surrounding non-target tissue observed with conventional neurosurgery techniques and DBS. Open cohort studies published in the literature have reported clear clinical improvement in the tremor scores (50–60% improvement) in 70–80% of patients treated with Gamma Knife [123,124]. The beneficial effect is usually delayed 3–12 months after radiosurgery. The reported complications are sensorial and motor disorders affecting the contralateral hemibody and dysarthria. Most of these events are transient; they concern about 7% of procedures [123,124]. This technique is currently proposed for patients with a contraindication for DBS or who decline this procedure. Although there is a rather general consensus considering that VIM is the best target for stereotaxic surgery in ET, several recent publications have suggested an efficacy when stimulating other targets such as the zona incerta, the prelemniscal radiation or the posterior subthalamic area (PSA). The zona incerta and the prelemniscal radiation are neighboring areas. Stimulation of the zona incerta leads to a 60% reduction in the overall tremor score on the Fahn-Tolosa scale [125]. PSA stimulation also improves ET in non-controlled trials [126,127]. These trials were not controlled and require confirmation. The long-term efficacy of stimulation or lesion of these new targets is unknown.

4.3.

4.4.

daily dose of 240–320 mg, with a mean 50–60% reduction of tremor [98]. Sustained release formulation of propanolol is also effective [99]. Prescription of beta-adrenergic blockers is limited by contraindications (asthma, sinusal bradycardia, complete or high-grade atrioventricular block, cardiogenic shock, concomitant use of calcium channel inhibitors) as well as by the development of adverse effects: fatigue, bradycardia, weight gain, nausea, diarrhea, skin rash, erectile dysfunction, mood disorders. Other beta-blockers as atenolol and sotalol can be used but with limited efficacy on tremor [88]. Primidone is an anticonvulsant drug metabolized to phenylethylmalonamide and phenobarbital: the mechanism of action remains uncertain. Taken at daily doses of 50–1000 mg, primidone has proven effect versus placebo [100,101]. On average, primidone reduces tremor by 50% [101]. No significant difference has been found with propanolol in a comparative study by Gorman et al. [100], but in practice, primidone is often less well tolerated and must be started carefully with very low dose. The secondary effects are more common and include somnolence, nausea and vomiting, balance disorders, vertigo, confusion, and acute allergic reactions. If the clinical benefit is insufficient, the two drugs can be combined. Other compounds can also be used but do not have marketing approval in France for this indication, as alprazolam or topiramate. Topiramate is an anticonvulsant that potentiates GABA activity, and has been shown to reduce tremor in monotherapy in three controlled studies for doses up to 400 mg/day. Gabapentin, a GABA structural analog used for its antiepileptic effect, showed relatively modest improvement in only one blinded study when given alone (1200 mg/d) versus placebo [102]. All other therapeutic trials using GABA structural analogs (pregabalin, tiagabin) were non-conclusive and insufficient to recommend these compounds for ET [103–108].

4.2.

Current use of botulinum toxin

Surgical strategies

Patients with severe ET that is unresponsive to medical treatment may be candidates for stereotaxic surgery. Historically, the first procedures involving the thalamus (thalamotomy) were performed in the 1950s by Irving Cooper to treat Parkinsonian tremor. They were then used later for ET. For three decades, thalamotomy was the surgical procedure of choice for the treatment of refractory ET until Benabid popularized the

New therapeutic approaches

Magnetic resonance-guided focused ultrasound transcranial stereotaxic thalamotomy has been the topic of recent publications on the treatment of ET [128,129]. The procedure is monitored with magnetic resonance thermometry; the correct position of the target is first confirmed by applying a sublesional quantity of energy to the VIM, temporarily blocking neuronal transmission, before executing the thermal



8


lesion. The results have been promising, showing a mean reduction of 75–81% in the tremor score. Regarding the side effects, four patients had persistent paresthesia of lip or fingers at 12 months, which could be consistent with the extension of the lesion beyond the thalamic target, or with a lack of precision in the targeting [128]. These results are however obtained with very small cohorts (15 and 4 patients, respectively) and short follow-up. They will have to be confirmed with larger populations. Two teams have also studied low-frequency (1 Hz) repetitive transcranial magnetic stimulation of the cerebellar cortex and showed a prolonged efficacy of up to 3 weeks on tremor [130,131].

5.

Conclusion

Despite many unknowns, research advances over the last 20 years have provided us with a better understanding of the complex pathophysiology of ET. Evidence is pointing towards dysfunctional cerebello-thalamo-cortical loops, although the underlying cause remains unknown. Recent imaging, electrophysiological, and anatomopathological data have led to the emergence of two highly-debated pathophysioloical concepts: one supports a neurodegenerative origin of the disorder; the other proposes the existence of dynamic functional perturbations within the olivo-cerebellothalamo-cortical network. These two hypotheses may not be incompatible: cerebellar degeneration could be the cause of GABAergic neurotransmission dysfunction, in turn leading to dysregulation of the oscillatory rhythmic activity of the cerebello-thalamo-cortical loops. One of the main problems encountered in all studies is the difficult diagnostic challenge and the risk of erroneous classification. Many study cohorts have been heterogeneous, not only in terms of age of onset, but also concerning the clinical presentation of tremor. It is becoming increasingly obvious that ET is not a single nosological entity but rather a larger category including several different phenotypes and probably different pathological conditions. Deuschl and Elble have proposed to define three categories of ET: hereditary ET, sporadic ET, and senile ET (symptom onset after 65 years). This emphasizes the notion that early onset and late onset ET probably result from two different pathophysiological mechanisms [42]. Diagnostic criteria for ‘‘tremor syndromes’’ will have to be updated to establish a more precise phenotypic definition. This will enable not only improved treatment for patients, but also increased power for pathophysiological studies in this field.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

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Essential tremor.

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Controversies regarding neonatal inguinal hernia.

Pharmacotherapy of essential tremor.

Tremor in the elderly: Essential and aging-related tremor.

The nature of tremor circuits in parkinsonian and essential tremor.

Metoprolol tartrate for essential tremor.

Challenges in essential tremor genetics.

Beta-blockers in essential tremor.

Re-Emergent Tremor of Parkinson's Disease Masquerading as Essential Tremor.

Correlation between essential tremor and migraine headache.

Diurnal variation of essential and physiological tremor.

Magnetic resonance support vector machine discriminates essential tremor with rest tremor from tremor-dominant Parkinson disease.

Focused ultrasound thalamotomy improves essential tremor.

Is there cerebellar pathology in essential tremor?

Trazodone is ineffective in essential tremor.

Effects of Cerebellothalamic Tractotomy on Cognitive and Emotional Functioning in Essential Tremor: A Preliminary Study in 5 Essential Tremor Patients.

Eye movement abnormalities in essential tremor.

Stereotactic thalamotomy for medically intractable essential tremor.

Essential tremor-Parkinson's disease: A double whammy.

Treatment of essential tremor with methazolamide.

Essential tremor associated with paroxysmal kinesigenic dystonia.

Resetting tremor by single and paired transcranial magnetic stimulation in Parkinson's disease and essential tremor.

Differential Diagnosis of Parkinson Disease, Essential Tremor, and Enhanced Physiological Tremor with the Tremor Analysis of EMG.