The balance and gait disorder of essential tremor: what does this mean for patients?

Transcription

1 471415TAN Therapeutic Advances in Neurological DisordersD Arkadir and E Louis 2012 Therapeutic Advances in Neurological Disorders Review The balance and gait disorder of essential tremor: what does this mean for patients? David Arkadir and Elan D. Louis Ther Adv Neurol Disord (2013) 6(4) DOI: / The Author(s), Reprints and permissions: journalspermissions.nav Abstract: Essential tremor (ET), once considered a monosymptomatic disease, is now viewed as a syndrome characterized by action tremor as well as a variety of other neurological features. These features include deficits of both balance (i.e. the ability to maintain the body within its base of support) and gait. Balance and gait abnormalities in ET have been studied most extensively in the laboratory, with the disability and burden on life, as experienced by patients with ET, being a subject of relatively less scrutiny. In this paper, we review the data on balance and gait impairment in ET. These include data both from objective assessments (bedside examination or laboratory gait analysis) and subjective assessments (patients reports of imbalance). We discuss the clinical implications of the current data, and suggest a tiered approach to begin to address the still unanswered questions in this field. This tiered approach starts with an attempt to isolate a subpopulation of patients who are at greatest risk of difficulty with balance and gait, and then later focuses on this subgroup to assess the burden of any balance and gait impairments as well as the impact of potential therapeutic interventions. Keywords: balance, clinical, essential tremor, falls, gait Introduction Essential tremor (ET) is a neurological disorder characterized primarily by action tremor. The diagnosis, a clinical one, is based on history and neurological examination. Until recently, ET was considered a simple, monosymptomatic disorder with a benign course. This view is reflected in commonly used diagnostic criteria, which specify that the presence of other abnormal findings on neurological examination are exclusionary of ET [Nahab et al. 2007]. In more recent years, however, this traditional view of ET has been challenged, with the accumulation of evidence that tremor is not the sole feature of ET, but rather, the most initially obvious one in a syndrome that can include cognitive and psychiatric features as well as impairments of balance and gait [Chandran and Pal, 2012; Louis and Okun, 2011]. This and other issues are among the core topics in a debate over disease diagnosis and definition [Benito-Leon et al. 2007; Bermejo-Pareja, 2011; Deuschl and Elble, 2009]. Impairments of balance and gait in patients with ET were anecdotally reported by clinicians long before a more formal association was explored [Critchley, 1972]. Initially, however, the presence of such impairments was considered to be very uncommon and simply age related. Greater awareness of subtle balance and gait deficits in ET emerged later, when gait and balance were assessed in case control studies [Singer et al. 1994]. Thus, a series of studies followed that expanded our knowledge by defining the nature of impaired gait in ET, the relation between impaired gait and specific characteristics of the tremor, and the risk factors for developing such balance and gait deficits in ET. Still, until now, most studies in this field have been restricted to bedside examinations and laboratory settings. How to translate objective findings from these artificial environments to daily disabilities is still somewhat elusive. Therefore, after more than a decade of investigations, many gaps in our knowledge exist. The true impact of balance and gait impairments on the quality of life in patients with ET and on their risk for falls is not well defined, the potential benefit of therapeutic interventions to improve balance and gait has only scarcely been studied, and the anatomical correlates for these impairments is currently only speculative. Correspondence to: Elan D. Louis, MD, MSc Neurological Institute, 710 West 168th Street, New York, NY 10032, USA edl2@columbia.edu David Arkadir, MD, PhD Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA 229

2 Therapeutic Advances in Neurological Disorders 6 (4) Table 1. List of studies of balance and gait in essential tremor. First author, year Singer, Hubble, Stolze, Lim, Bove, Ondo, Parisi, Earhart, Kronenbuerger, 2009 ET (n) Control (n) Fasano, Louis, Rao, Hoskovcova, Louis, Mean age (years) Exclusion Method Main positive results 69.9 Abnormal routine gait examination NE More mis-steps during tandem gait Deficit increased with age (>70 years) and disease duration (>5 years) 68 NE More mis-steps during tandem gait Deficit increased with age 50.3 NE, GA Reduced speed and enlarged step width during normal walk Increased step variability and more mis-steps during tandem walk among patients with intention tremor 60.9 NE Patients older than 70 years had higher number of mis-steps during tandem walk 64.1 P Impaired balance only in the group of patients with ET with head tremor 72.8 P Balance was impaired in a variety of static conditions but improved when thalamic DBS was turned on 58 ET medications Q, P Lower scores on both SS and OS except β blockers Deficit increased in the presence of head tremor 61.6 Q, NE Lower scores on both SS and OS GA Lower cadence and longer double limb support. No significant effect of thalamic DBS on gait 46.3 DBS- 64 DBS+ ET medications except β blockers 69.8 Abnormal mobility NE, GA P NE, GA Shorter stride and more mis-steps during tandem gait Impaired postural control, mainly among patients with cerebellar signs Slower tandem walk, more mis-steps and increased step variability that were correlated with intention tremor Improvement with DBS on 64.9 Cane assistance NE The number of mis-steps during tandem walk increased with age, age of onset and the presence of cranial tremor 86 NE, GA More mis-steps during tandem walk, lower velocity and cadence during normal walk Deficits increased with age 55.8 Q, GA More mis-steps during tandem walk and lower velocity Increased step width during normal gait Deficits more pronounced in the elderly and in the presence of midline tremor 71.2 Q, NE Lower scores on SS More near-falls and assistance by walking aids Deficits were more pronounced if head tremor was present ET, essential tremor; GA, gait analysis; NE, bedside neurological exam; OS, objective scale (performance based); P, posturography; Q, questionnaire; SS, subjective scale (questionnaire based). In this review, we summarize current knowledge regarding balance and gait impairments in ET. We review objective findings from the bedside studies to more sophisticated gait analysis. Current evidence for the presence or absence of subjective impairments in daily life is then reviewed. The implications of these data on clinical practice will be discussed and, based on the questions that are still open in this field, we suggest several future questions for investigation. Physical findings: from the naked eye to three-dimensional gait analysis A number of diverse methods have been used to assess the association between balance and gait impairment and ET (Table 1). The simplest of them, the tandem, or heel-to-toe walk, is a sensitive, quick and easy-to-apply, bedside test that can even detect minor impairments of balance and gait. In general, increased number of mis-steps 230

3 D Arkadir and ED Louis (out-of-line steps) during tandem walk is a risk factor for future falls [Nevitt et al. 1989]. This numeric value was used to compare the performance of patients with ET with that of agematched healthy controls. The finding that patients with ET had more mis-steps during tandem walk served as initial evidence for the presence of balance and gait abnormalities among patients with ET [Singer et al. 1994]. In that study, half of the patients with ET had at least two missteps out of 10 consecutive tandem steps compared with only a quarter of the healthy controls. A similar finding has been consistently replicated in different studies [Hoskovcova et al. 2012; Hubble et al. 1997; Lim et al. 2005; Louis et al. 2010; Stolze et al. 2001]. The subsequent use of other performance-based scales (see Box 1) to study balance and gait in ET revealed the presence of deficits in patients with ET. Some of these scales have been validated to predict falls [Lajoie and Gallagher, 2004] but were never validated for this purpose in ET. Their main disadvantage is that they are time consuming, and therefore, are less suitable for use in routine clinical settings. Patients with ET received lower scores on the Berg Balance Scale (BBS), which rates balance during static and dynamic activities [Earhart et al. 2009; Louis et al. 2012; Parisi et al. 2006], and on the Dynamic Gait Index (DGI), in which the patient s gait is assessed under different conditions [Parisi et al. 2006]. Patients with ET also received lower scores in scales that were less specific for imbalance and could easily be influenced by other neurological impairments. These include the Timed Up & Go test (TUG) (the mean TUG score was 18 23% longer in patients with ET than controls) [Earhart et al. 2009; Parisi et al. 2006] and the International Cooperative Ataxia Rating Scale (ICARS), which incorporates assessments of a range of cerebellar signs involving gait, speech and ocular movements [Fasano et al. 2010; Hoskovcova et al. 2012; Kronenbuerger et al. 2009]. Impairments of balance and gait in ET, which were initially observed using the above-mentioned bedside methods, were later studied and quantified using a variety of laboratory devices [Bove et al. 2006; Earhart et al. 2009; Fasano et al. 2010; Hoskovcova et al. 2012; Kronenbuerger et al. 2009; Ondo et al. 2006; Parisi et al. 2006; Rao et al. 2011; Stolze et al. 2001]. Laboratory devices, either motor-driven treadmills or sensor-embedded free-walking surfaces (e.g. GaitRite, Footscan), Box 1. Scales that have been used for studying balance and gait in essential tremor. Berg Balance Scale (BBS): this performance-based scale consists of 14 items that cover a range of mobility tasks from simple ones such as transfers and standing unsupported to more difficult ones such as tandem standing, turning 360 and single-leg stance. The highest score is 56. A score lower than 41 is correlated with increased risk for falls [Earhart et al. 2009; Louis et al. 2012; Parisi et al. 2006] Dynamic Gait Index (DGI): a performance-based scale that assesses gait in eight different conditions with varying demands, such as walking at different speeds, walking with head turns, ambulating over and around obstacles, ascending and descending stairs, and making quick turns. The highest score is 24. A score below 19 is associated with falls [Parisi et al. 2006] Timed Up & Go Test (TUG): a performance-based scale in which the time it takes a patient to stand up from an armchair, walk a distance of 3 m, turn, walk back to the chair, and sit down is measured. A time longer than 14 s is associated with high risk for falls [Earhart et al. 2009; Parisi et al. 2006] International Cooperative Ataxia Rating Scale (ICARS): this physical exam-based scale quantifies signs of cerebellar impairment. These include postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders. The highest score of 100 reflects maximal severity. This scale was not developed to predict falls [Fasano et al. 2010; Hoskovcova et al. 2012; Kronenbuerger et al. 2009] Activities-specific Balance Confidence scale (ABC): a 16-item self-administered questionnaire that scores the level of confidence in performing different activities, such as standing on the tiptoes in order to reach for an object or walking outside on icy sidewalks, without losing balance or becoming unsteady. Each activity is scored between 0 (minimal confidence) and 100% and all the results are averaged. A cutoff score of 67% was found to be optimal to separate fallers from nonfallers [Earhart et al. 2009; Hoskovcova et al. 2012; Parisi et al. 2006]. ABC-6 is a shortened six-item version of this scale [Louis et al. 2012] 231

4 Therapeutic Advances in Neurological Disorders 6 (4) enabled investigators to assess physiological parameters of balance and gait that were harder to assess with the naked eye. These parameters included body sway, step variability and joint kinematics. The different laboratory methodologies that were used to study gait in ET largely yielded similar and complementary results. During normal walking, gait abnormalities were mild among patients with mild to moderate ET. These abnormalities included wider step, more variable stride and mildly reduced speed [Stolze et al. 2001], probably due to reduced stride and not to reduced number of steps per minute (cadence). A more severely affected population also had lower cadence [Earhart et al. 2009; Fasano et al. 2010; Rao et al. 2011] and longer phase of gait cycle with double-limb support, even during standard walking [Earhart et al. 2009]. By comparison, during tandem gait, abnormalities were more obvious and included slower speed [Earhart et al. 2009; Fasano et al. 2010; Hoskovcova et al. 2012; Rao et al. 2011] and, similar to patients with cerebellar ataxia, a broad and dysmetric gait [Stolze et al. 2001]. Balance was assessed through the use of posturography, which measures body sway under different conditions [Bove et al. 2006; Hoskovcova et al. 2012; Kronenbuerger et al. 2009; Parisi et al. 2006]. Conclusions regarding balance in ET have covered the whole spectrum, ranging from normal among patients without head tremor [Bove et al. 2006] to severely impaired [Kronenbuerger et al. 2009]. Apparent contradictory findings are probably the result of differences in the populations that have been sampled (mildly versus severely affected patients with ET), diagnostic criteria used (i.e. inclusion versus exclusion of patients with intention tremor or other signs of cerebellar dysfunction) and the wide differences between study conditions (e.g. less versus more challenging conditions). Overall, it seems that balance impairments are more obvious among the more severely affected patients under more challenging conditions [Kronenbuerger et al. 2009]. Therefore, the balance of patients with mild disease was found to be normal during natural stance [Bove et al. 2006; Hoskovcova et al. 2012], only minimally impaired during tandem stance [Hoskovcova et al. 2012; Parisi et al. 2006] and severely affected with large increases in sway area, even leading to more falls (in ET versus control comparisons) during highdemanding tasks such as combined moving platform with moving visual surround [Kronenbuerger et al. 2009]. Do balance and gait deficits impact on patients? A patient-centered approach requires a direct estimation of the burden that the aforementioned deficits impose on the lives of patients with ET. To estimate this burden, the Activitiesspecific Balance Confidence (ABC) scale was used [Earhart et al. 2009; Louis et al. 2012; Parisi et al. 2006]. In this self-administered questionnaire patients are asked to rate their level of confidence in performing different activities without losing their balance or becoming unsteady. Their score can predict the risk for future falls [Lajoie and Gallagher, 2004]. In several studies, patients with ET received lower scores [Earhart et al. 2009; Louis et al. 2012; Parisi et al. 2006] and therefore were subjectively less stable. For community-recruited ET cases with relatively mild tremor, the average ABC scale value was only minimally reduced (i.e. a 10-point mean difference) and did not cross the suggested threshold for increased risk for falls [Parisi et al. 2006]. However, patients with moderate to severe ET who required bilateral thalamic deep brain stimulation (DBS) surgery had even lower ABC values (patients with ET 66% ± 20.1%, healthy controls 95.8% ± 5.1%) [Earhart et al. 2009]. Both of these studies reported the statistics for the study sample, yet information regarding the percentage of ET patients with an ABC score that crosses a predictive threshold for falls is needed in order to estimate the prevalence of clinically significant balance and gait impairment in the ET population. This information was not provided. A more direct approach to assess the risk that balance and gait deficits imposes on patients with ET, beyond their subjective feelings of unsteadiness, was taken by asking patients how many falls or near misses they experienced in the previous year [Louis et al. 2012; Parisi et al. 2006]. Two studies showed that the number of actual falls was not significantly different when patients with ET were compared with a healthy control group. The number of near misses was, however, significantly higher among patients with ET in one of the studies [Louis et al. 2012]. In that study, patients with ET had 26 near misses per year compared with only six in the healthy controls, and patients with ET with head tremor had even more near misses (67 per year). This finding implies that subpopulations of patients may be at higher risk of falls or near misses

5 D Arkadir and ED Louis Are some patients with essential tremor more prone to balance and gait impairment? A variety of studies have tried to assess the findings on neurological examination that can predict balance and gait impairments among patients with ET. Intention tremor, a subtype of kinetic tremor that typically increases as the limb moves closer to a target during visually guided movements, is found in about one-third of the patients with ET [Deuschl et al. 2000; Louis, 2009]. One group reported that this type of tremor was a significant risk factor for balance and gait impairments in ET [Fasano et al. 2010; Stolze et al. 2001]; but another group was not able to replicate those results [Louis et al. 2010]. Tremor of the head (i.e. neck) [Louis et al. 2012; Parisi et al. 2006] and other cranial tremors, namely voice and jaw, are also clear predictors in some studies for balance and gait impairments among patients with ET [Bove et al. 2006; Hoskovcova et al. 2012; Louis et al. 2010]. Interestingly, the hallmarks of ET, postural and simple kinetic tremor of the upper extremities, were not found to correlate with deficits in balance and gait [Hubble et al. 1997; Kronenbuerger et al. 2009; Louis et al. 2010; Singer et al. 1994]. Also, the presence of leg tremor was not found to be correlated with these impairments [Fasano et al. 2010; Louis et al. 2010; Singer et al. 1994; Stolze et al. 2001]. Small studies that examined the contribution of ET medications (propranolol and primidone) to instability did not report any relation to gait and balance difficulties [Fasano et al. 2010; Stolze et al. 2001]. Older age (>70 years) was consistently found to increase risk of balance and gait disturbances in ET [Hoskovcova et al. 2012; Hubble et al. 1997; Louis et al. 2010; Rao et al. 2011; Singer et al. 1994]. An older age of onset was associated with higher risk for deficits in one study [Louis et al. 2010] and duration of tremor longer than 5 years in another [Singer et al. 1994]. Yet whether age of tremor onset or tremor duration is a risk factor for the development of balance and gait disturbances in ET is still under debate [Hubble et al. 1997; Louis et al. 2012, 2012; Singer et al. 1994]. Contradictory findings could reflect some difficulty in retrospectively assessing age of onset in an accurate way. Potential therapies to improve balance and gait in essential tremor: where do we stand? A variety of symptomatic therapies for the treatment of arm tremor in ET are considered effective in evidence-based reviews [Zesiewicz et al. 2011]. These include both pharmacological agents, the most effective and commonly used of which are propranolol and primidone, and surgical procedures. A much smaller amount of attention has been paid to possible therapeutic approaches for balance and gait impairment in ET. Ethanol, an agent that is known to transiently suppress arm tremor in ET, was reported to improve gait parameters in ET in a single study [Klebe et al. 2005]. This unexpected temporary improvement in the number of mis-steps (30% reduction), step width and step variability occurred with a mean blood ethanol level of 0.45%. No other studies, to our knowledge, have tested a potential positive effect of other pharmacological agents on gait in ET. The role of physical therapy is unexplored. Currently, the most common surgical procedure for ET is DBS, with electrodes that are targeted to the thalamic ventralis intermedius nucleus. Few studies tested the potential benefit of this procedure for balance and gait. Impaired gait was conventionally considered a potential side effect of bilateral thalamic DBS and was reported by more than 50% of patients following this procedure [Pahwa et al. 2006]. Surprisingly, the studies that directly addressed the effect of stimulation, by examining each patient with ET during an on and off state of the DBS stimulator, did not show aggravation of balance and gait impairments when the stimulator was on. Moreover, while two studies were equivocal [Earhart et al. 2009; Kronenbuerger et al. 2009] others indicated a certain benefit of stimulation [Fasano et al. 2010; Ondo et al. 2006]. Fasano and colleagues found thalamic stimulation to be beneficial when the conventional therapeutic stimulation parameters were used, but not when supratherapeutic stimulation was applied [Fasano et al. 2010]. In this therapeutic range, the velocity of both routine walking and balance-assisted tandem gait improved, the number of mis-steps in tandem gait was lowered by half and step variability was reduced. The improvement, however, was only partial, and in all tested conditions, patients with ET performed more poorly than healthy controls. Implications for the clinical assessment of patients with essential tremor The combination of action tremor and severe gait ataxia should always raise an alternative diagnosis such as the possibility of fragile X-associated 233

6 Therapeutic Advances in Neurological Disorders 6 (4) tremor/ataxia syndrome (FXTAS) due to CGG expansion in the FMR1 gene or a form of spinocerebellar ataxia. With this cautionary caveat aside, physicians who care for patients with ET should keep in mind that balance and gait deficits are part of the syndrome and might be clinically significant in some of their patients. Imbalance could cause the patient to avoid daily activities that require mobility and could lead to injuries as a result of falls. Since arm or head tremor is often the major symptom that concerns both the patient and their physician, these balance and gait impairments could be overlooked in office settings, especially because balance and gait impairments are not correlated with the severity of postural and kinetic tremor of the arms in ET. During clinical assessments, patients with ET should routinely be asked about balance and gait problems, near misses and actual falls. Balance and gait should be directly examined by assessing the patient s normal and tandem walks and by pulling the patient backward to test their recovery. During the physical examination, findings that predict balance and gait deficits should be assessed. Emphasis should be given to the type of tremor (e.g. intention tremor) and its location (e.g. cranial). Clinicians should also be careful to distinguish ET from orthostatic tremor, which may be accompanied by feelings of unsteadiness and imbalance. Open questions and future directions In this last section, we raise a number of currently unanswered questions (see Box 2). Box 2. Open questions. Should future ET diagnostic criteria include mild gait and balance deficits? What degree of ataxia is compatible with ET diagnosis? Are clinically significant balance and gait impairments more prevalent in a subpopulation of patients with ET? What is the true risk for falls in that group? What are the therapeutic approaches to improve balance and gait deficits in ET? ET, essential tremor. Should current diagnostic criteria be revised to incorporate a mild gait and balance impairment in essential tremor? Exclusion of neurological signs aside from action tremor is a feature of all of the currently utilized diagnostic schemes for ET [Deuschl and Elble, 2009; Nahab et al. 2007]. The presence of a growing number of studies that point to the presence of other cerebellar signs in patients with ET suggests that the current diagnostic schemes should be reconsidered and perhaps revised to incorporate some of these additional neurological features. Are clinically significant balance and gait impairments more prevalent in a subpopulation of patients with essential tremor? Evidence to date suggests that clinically significant balance and gait impairments are not likely to be equally distributed in the ET population, but rather, they likely effect a subpopulation of patients. There is some preliminary evidence that patients with cerebellar signs and midline tremors may be at higher risk of developing these gait and balance problems. Yet the number of studies has been small and further attempts at identification are needed. If and when such a subpopulation is identified, future studies of balance and gait in ET should focus on this subpopulation. Only after isolating this subpopulation will we be able to efficiently answer additional questions. Does essential tremor impose a real risk for falls or only cause a subjective imbalance? Impaired tandem gait on neurological examination and mild ataxia in gait analysis are well established, but the burden of these deficits on the lives of the patients is less clear. The majority of studies in this field did not aim to clarify this issue. Some studies that investigated balance and gait in patients with ET even excluded patients who had clear gait deficits [Louis et al. 2010; Singer et al. 1994] or those who took medications that might affect gait [Kronenbuerger et al. 2009; Parisi et al. 2006] and therefore underestimated a true risk. A systematic study that will uncover the frequency of falls in the high-risk ET subpopulation will enable us to test different therapeutic approaches. What therapeutic approaches improve balance? After isolating a subpopulation at risk for falling, and assessing this risk, different therapeutic 234

7 D Arkadir and ED Louis approaches can be tested. The use of this tiered approach is more likely to result in studies that demonstrate a proven benefit of therapy with a reasonably low number of test patients. Therapeutic approaches should include physical therapy, pharmacological agents (including those that are currently in common use for the treatment of ET, see below) and optimal DBS settings. Ethanol was reported to improve gait parameters of ET in a single study [Klebe et al. 2005] but the possibility of clinically significant effect was never assessed. Obviously, chronic daytime consumption of ethanol cannot be recommended, even if a significant benefit would be found. The importance of this finding, however, lays in the fact that gait can be symptomatically improved by a chemical agent, and therefore, the search for an appropriate drug is not futile. This is especially encouraging in the absence of large-scale evidenced-based symptomatic therapies in other types of ataxia. Symptomatic benefit of propranolol and primidone, the most frequently used agents in ET, should be assessed first. Clinical trials aiming to study these two agents could be performed with relative ease as these are generic drugs which are in common use. Sodium oxybate (Xyrem) was found to be an effective treatment for the ethanol-responsive tremor of ET, as well as for other ethanol-responsive movement disorders [Frucht et al. 2005]. The improvement of gait parameters with ethanol in ET calls for testing this drug as a symptomatic agent in patients with ataxic ET. Experimental symptomatic therapies that were tested in small studies in other types of ataxia, such as varenicline and riluzole, could be tested next. Varenicline, a partial nicotinic acetylcholine agonist that is used for smoking cessation, was tested against placebo in a double-blind study of 20 patients with spinocerebellar ataxia type 3 and was found to improve gait ataxia within 8 weeks [Zesiewicz et al. 2012]. The improvement of gait, stance and 25 ft walk was mild (~15%) but statistically significant. Riluzole was tested in a doubleblind study in 40 patients with cerebellar ataxia due to various etiologies. The mean improvement in the gait score was approximately 14% [Ristori et al. 2010]. Summary The association between ET and deficits in gait and balance is well established. However, the true burden of these deficits on patients is not totally clear. We showed here that bedside testing and laboratory gait analysis have served to identify and then quantify the balance and gait impairments in ET, and have exposed some of the risk factors to develop these impairments, but the implication of these data in clinical settings is not entirely clear. Understanding the true impact of these deficits on the life of patients with ET and isolating a subpopulation of patients who are prone to these impairments are crucial steps on the way to fully understand and address these deficits. Funding David Arkadir and Elan D. Louis are supported by the Parkinson s Disease Foundation (PDF). Elan D. Louis is supported by the National Institutes of Health (NIH R01 NS and NS042859). Conflict of interest statement The authors declare that there are no conflicts of interest and no competing financial interests. References Benito-Leon, J., Louis, E. and Bermejo-Pareja, F. and Neurological Disorders in Central Spain Study Group (2007) Reported hearing impairment in essential tremor: a population-based case-control study. Neuroepidemiology 29: Bermejo-Pareja, F. (2011) Essential tremor a neurodegenerative disorder associated with cognitive defects? Nat Rev Neurol 7: Bove, M., Marinelli, L., Avanzino, L., Marchese, R. and Abbruzzese, G. (2006) Posturographic analysis of balance control in patients with essential tremor. Mov Disord 21: Chandran, V. and Pal, P. (2012) Essential tremor: beyond the motor features. Parkinsonism Relat Disord 18: Critchley, E. (1972) Clinical manifestations of essential tremor. J Neurol Neurosurg Psychiatry 35: Deuschl, G. and Elble, R. (2009) Essential tremor neurodegenerative or nondegenerative disease towards a working definition of ET. Mov Disord 24: Deuschl, G., Wenzelburger, R., Loffler, K., Raethjen, J. and Stolze, H. (2000) Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain 123: Earhart, G., Clark, B., Tabbal, S. and Perlmutter, J. (2009) Gait and balance in essential tremor: variable effects of bilateral thalamic stimulation. Mov Disord 24:

8 Therapeutic Advances in Neurological Disorders 6 (4) Visit SAGE journals online SAGE journals Fasano, A., Herzog, J., Raethjen, J., Rose, F., Muthuraman, M., Volkmann, J. et al. (2010) Gait ataxia in essential tremor is differentially modulated by thalamic stimulation. Brain 133: Frucht, S., Houghton, W., Bordelon, Y., Greene, P. and Louis, E. (2005) A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor. Neurology 65: Hoskovcova, M., Ulmanova, O., Sprdlik, O., Sieger, T., Novakova, J., Jech, R. et al. (2012) Disorders of balance and gait in essential tremor are associated with midline tremor and age. Cerebellum 26 April (Epub ahead of print). Hubble, J., Busenbark, K., Pahwa, R., Lyons, K. and Koller, W. (1997) Clinical expression of essential tremor: effects of gender and age. Mov Disord 12: Klebe, S., Stolze, H., Grensing, K., Volkmann, J., Wenzelburger, R. and Deuschl, G. (2005) Influence of alcohol on gait in patients with essential tremor. Neurology 65: Kronenbuerger, M., Konczak, J., Ziegler, W., Buderath, P., Frank, B., Coenen, V. et al. (2009) Balance and motor speech impairment in essential tremor. Cerebellum 8: Lajoie, Y. and Gallagher, S. (2004) Predicting falls within the elderly community: comparison of postural sway, reaction time, the Berg balance scale and the Activities-specific Balance Confidence (ABC) scale for comparing fallers and non-fallers. Arch Gerontol Geriatr 38: Lim, E., Seo, M., Woo, S., Jeong, S. and Jeong, S. (2005) Relationship between essential tremor and cerebellar dysfunction according to age. J Clin Neurol 1: Louis, E. (2009) Factor analysis of motor and nonmotor signs in essential tremor: are these signs all part of the same underlying pathogenic process? Neuroepidemiology 33: Louis, E. and Okun, M. (2011) It is time to remove the benign from the essential tremor label. Parkinsonism Relat Disord 17: Louis, E., Rao, A. and Gerbin, M. (2012) Functional correlates of gait and balance difficulty in essential tremor: balance confidence, near misses and falls. Gait Posture 35: Louis, E., Rios, E. and Rao, A. (2010) Tandem gait performance in essential tremor: clinical correlates and association with midline tremors. Mov Disord 25: Nahab, F., Peckham, E. and Hallett, M. (2007) Essential tremor, deceptively simple. Pract Neurol 7: Nevitt, M., Cummings, S., Kidd, S. and Black, D. (1989) Risk factors for recurrent nonsyncopal falls. A prospective study. JAMA 261: Ondo, W., Almaguer, M. and Cohen, H. (2006) Computerized posturography balance assessment of patients with bilateral ventralis intermedius nuclei deep brain stimulation. Mov Disord 21: Pahwa, R., Lyons, K., Wilkinson, S., Simpson, R., Jr, Ondo, W., Tarsy, D. et al. (2006) Long-term evaluation of deep brain stimulation of the thalamus. J Neurosurg 104: Parisi, S., Heroux, M., Culham, E. and Norman, K. (2006) Functional mobility and postural control in essential tremor. Arch Phys Med Rehabil 87: Rao, A., Gillman, A. and Louis, E. (2011) Quantitative gait analysis in essential tremor reveals impairments that are maintained into advanced age. Gait Posture 34: Ristori, G., Romano, S., Visconti, A., Cannoni, S., Spadaro, M., Frontali, M. et al. (2010) Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology 74: Singer, C., Sanchez-Ramos, J. and Weiner, W. (1994) Gait abnormality in essential tremor. Mov Disord 9: Stolze, H., Petersen, G., Raethjen, J., Wenzelburger, R. and Deuschl, G. (2001) The gait disorder of advanced essential tremor. Brain 124: Zesiewicz, T., Elble, R., Louis, E., Gronseth, G., Ondo, W., Dewey, R., Jr, et al. (2011) Evidencebased guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology. Neurology 77: Zesiewicz, T., Greenstein, P., Sullivan, K., Wecker, L., Miller, A., Jahan, I. et al. (2012) A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 78: