Year: 2017
Type: article
Abstract: The term essential tremor (ET) was originally used as a diagnostic label for patients with abnormal action tremor, frequently familial, and no other neurologic signs.1 Clinicians ultimately recognized that most patients exhibited a common distribution of tremor in the upper limbs and frequently in the head, voice, and elsewhere. Epidemiologic studies revealed that ET, so defined, is the most common movement disorder, excluding drug-induced conditions.2, 3 However, clinicians commonly disagree on the diagnosis of ET.4-6 Despite its high prevalence and frequent familial occurrence, ET has no known etiology except possibly a mutation in the fused in sarcoma gene, which was discovered in a single family but not replicated in other ET cohorts.7 Therefore, ET is a syndrome, not a specific disease with known etiology. Syndromes like ET are generally defined and used to facilitate the discovery of underlying etiologies and effective therapies. To these ends, the syndrome of ET has failed; therefore, it is reasonable to question its usefulness. No candidate gene has been replicated, and no consistent or specific pathology has been found. No pharmaceutical treatment has emerged from our limited knowledge of the pathophysiology of ET, and no drug therapy produces more than modest benefit in the average patient. All existing drug therapies were discovered serendipitously or by trial and error. Perhaps ET is defined too broadly. Marsden and coworkers8 reasoned that ET is not a single entity and proposed 4 types of ET: (1) enhanced physiologic tremor, (2) benign ET, (3) severe ET, and (4) symptomatic ET. This proposal was made before it was discovered that enhanced physiologic tremor has the electrophysiologic properties of mechanical-reflex oscillation, and the other 3 types are produced by central neurogenic oscillation.9 Therefore, Type 1 should be excluded as a form of ET. Type 2 is by far the most common. Most individuals with Type 2 have not seen a physician for their tremor,10 probably because it is mild or self-diagnosed as a relatively mild (“benign”), slowly progressive familial condition. Nevertheless, most individuals with Type 2 ET are bothered by their tremor, however mild.11 Type 3 ET is severe and unmistakably disabling. Some of these patients progressed from Type 2, but many have a short history of tremor, older age of onset, and no family history of tremor, suggesting that Type 3 is often distinct from Type 2. Type 4 ET is tremor that resembles Type 2 or Type 3 but that occurs in association with acquired or hereditary neuropathies, dystonia, or cerebellar ataxia. Thus, Type 4 defies the original concept of ET being tremor with no other neurologic signs. Type 4 tremor resembles ET; but, by most definitions, Type 4 is not ET. Marsden and coworkers acknowledged that a prospective longitudinal study was needed to examine the validity of these subtypes. It is estimated that thousands of patients will be needed to fully understand the heterogeneity of those diagnosed with ET.7 One may question the definition of ET, which is admittedly somewhat arbitrary, but ET must be defined and used consistently to be useful. The Tremor Investigation Group (TRIG), the International Parkinson and Movement Disorder Society (MDS), and the National Institute of Neurologic Disorders and Stroke (NINDS) research criteria are incompatible,12 and the variable and repeated redefinition of ET has been an unproductive exercise that has produced nothing more than a moving target for clinicians and researchers. ET is not a useful syndrome if we cannot agree on its definition and successfully use this syndrome to discover specific etiologies, pathophysiology, and effective treatment. Because ET is a syndrome, it makes no sense to hypothesize that ET causes dystonia, Parkinson disease (PD), ataxia, dementia, etc. It does make sense to ask whether ET is associated with other medical conditions. Patients with the syndrome of ET may develop other neurologic signs (e.g., parkinsonism, dystonia, ataxia, or dementia), and it is then necessary to determine whether these new signs are coincidental or etiologically/pathophysiologically related. For example, absent ankle reflexes and sensory loss in the lower limbs could be signs of the etiology of tremor (neuropathic tremor) or could be signs of a comorbidity (diabetes mellitus) that has little or no bearing on the clinical expression of tremor. A big problem with ET and other syndromic labels is that they often oversimplify a particular patient's condition. The pursuit of patients who fulfill the criteria for ET can lead to the biased dismissal of other signs and symptoms as insignificant or irrelevant. Once labeled, there is a risk of overlooking clinical characteristics that make a patient or family unique. There is arguably too much emphasis on the definition of ET and not enough emphasis on the discovery of other signs and symptoms that may reveal more specific and useful tremor syndromes. The MDS Task Force on Tremor proposes to call ET with neurologic signs of uncertain significance “ET plus.” These “soft” signs include memory loss, hyporeflexia, impaired tandem gait, and suspicious limb or head posturing. These signs and others should be sought in all studies of ET, and there should be no assumption of clinical significance or relevance. Careful follow-up is needed to determine the significance of these signs. All of these subtypes fall within the definition of ET, but experimental results obtained from 1 of these subtypes may not be true for the entire ET population. For example, there is increasing evidence that data from individuals with late-onset ET are not applicable to those who develop ET earlier in life.13-15 Furthermore, ET should not be conflated with other isolated tremor syndromes (e.g., primary orthostatic tremor, primary writing tremor, isolated rest tremor, and isolated head and voice tremor). Patients with long-standing ET occasionally develop a neurologic comorbidity that may or may not be relevant to the etiology and pathophysiology of the original tremor. For example, a patient might have had ET since adolescence and develops PD at age 62 years. There should be no assumption that ET and PD are etiologically related. In the so-called Iowa Parkinson kindred, ET and PD appeared to be genetically related,16 but the genetic abnormality for PD was ultimately shown to be α-synuclein gene triplication, and the gene for ET was never found.17 When patients with ET develop another neurological disorder that is possibly related etiologically, they should be classified by their current diagnosis (e.g., PD) and noted to have a pre-existing ET syndrome. Such a patient no longer has ET unless other neurologic signs can be shown (not assumed) to be unrelated. Patients with ET and signs of uncertain significance are classified as having ET plus. Longitudinal studies of carefully defined patient cohorts are needed to understand the natural history of ET.7 The heterogeneity and ambiguities of ET should not deter us from exploring new therapies. The corticobulbocerebellothalamocortical loop plays an important role in all tremor disorders, and our success with stereotactic thalamotomy and deep-brain stimulation suggests that drug therapies targeting ventrolateral thalamocortical oscillation are a logical approach to treating ET.18 Effective treatments are clearly possible, despite our poor understanding of ET. However, we must remain mindful of the possibility that heterogeneity in underlying etiology or pathophysiology of ET may produce variability in the response to pharmacologic and surgical treatments. In conclusion, the concept of ET is useful if its ambiguities are recognized and if we can all agree on and abide by a definition of ET. These criteria for usefulness have never been achieved. The definition of ET syndrome is admittedly somewhat arbitrary, contentious, and probably too nonspecific to lead to the discovery of specific etiologies or pathophysiologies. Therefore, more restrictive subtypes of ET should be examined within a large, prospective, longitudinal study of individuals with ET and ET plus. A cohort of 10,000 has been recommended,7 and this will require an international collaborative effort. This should be a priority of the new MDS Tremor Study Group. Ethical Compliance Statement: I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: Rodger Elble is funded by the Spastic Paralysis Research Foundation of Kiwanis International, Illinois-Eastern Iowa District. He is chair of the Movement Disorder Society Task Force on Tremor. Financial disclosures of author for the preceding 12 months: The author reports consultancies for Cavion, Sage, and InSightec; service on the advisory boards of the International Essential Tremor Foundation and the Spastic Paralysis Research Foundation of Kiwanis International, Illinois-Eastern Iowa District; grants from the Spastic Paralysis Research Foundation of Kiwanis International, Illinois-Eastern Iowa District; and employment at SIU HealthCare.
DOI: 10.1002/mdc3.12514
Author: Rodger J. Elble
Institution: SIU Medicine
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2622548680