The diagnosis and management of essential tremor appears deceptively simple. However, isolated mild tremor may be difficult to classify, and if the patients have any additional features the diagnosis is more difficult. Management can be challenging, despite the numerous treatments available, because so many patients are not benefited adequately and some not at all. However, as we gain a better understanding of the disorder, more effective therapies with fewer adverse effects are sure to follow.
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Essential tremor is a very common movement disorder.1 It is characterised by rhythmic shaking of the arms in 95% of cases, but may also involve tremor of the head (34%), tongue and lower limbs (30%), voice (12%) and face (5%).2,3 Although generally described as a “benign” disorder, about three quarters of the patients have significant disability and decreased quality of life.4 It is recognised as a heritable disorder with apparent Mendelian autosomal dominant transmission, though no disease-causing genes are yet certain. The treatment is based primarily on pharmacological agents, although surgical intervention may be an option in the most disabling cases.
Although difficult to trace back, it is possible that one of the earliest descriptions of essential tremor may have been by the Greek physician Galen in his essay entitled De tremore written some time between 169 and 180 CE*.5 He attempted to differentiate tremor from other movements including palpitations, convulsions and rigors. In describing the features of tremor, Galen writes, “For no one trembles who does not choose to move his limb … moreover, tremor is an affection of one part [of the body].” In addition to identifying action and posture as provoking tremor and noting that it could be very localised, Galen also provided an exhaustive list of features to differentiate these different movements from one another. Very little more of the relevant features of essential-type tremors seems to have been recognised until the late 19th century when the first report of essential tremor, credited to C L Dana (1887),6 described the characteristic features in three different families: “The affection in question consists of a fine tremor, constantly present in typical cases during waking hours, voluntarily controlled for a brief time, affecting nearly all the voluntary muscles, chronic, beginning in early life, not progressive, not shortening life, not accompanied with paralysis or any other disturbances of nervous function. It resembles to some extent the tremor of paralysis agitans, still more a simple neurasthenic tremor. A most striking clinical feature is its marked hereditary or family type, and its transmission along with other nervous diseases”.
Although essential tremor can rarely begin in early childhood, the incidence increases dramatically with age and most individuals become symptomatic in mid to late adulthood. Overall, there is no gender difference, although childhood cases do show a male predominance.7 Based on reports from a variety of nations, essential tremor appears to occur in all ethnic groups. However, estimates of prevalence are difficult because the symptoms are frequently mild and do not necessarily require, and so come to, medical attention. Dogu and colleagues8 studied a random sample of 2253 Turkish adults over the age of 40 using door-to-door screening interviews and tremor examinations of all participants by study neurologists; the prevalence was 4% in people over the age of 40 years. Prevalence increased to 14% in people over the age of 65 who were similarly screened in a Canadian population.9 On the other hand, a retrospective study in Rochester, Minnesota spanning 45 years10 identified only 24 cases per 100,000, while a population-based survey of Spanish adults over age 65 found 616 cases per 100,000.11
There have been limited epidemiological studies to identify environmental factors which may be associated with essential tremor. Geographic clusters, where essential tremor is found in much higher numbers, suggest at least some impact of local environmental pressures, such as toxins for example. To date, elevations in blood harmane, a tremorogenic β-carboline normally found in the body,12 and small elevations in blood lead levels13 are the only chemicals to have been associated with essential tremor when compared with unaffected controls.
Once considered a monosymptomatic benign movement disorder of Mendelian autosomal dominant inheritance, the situation is now turning out to be rather more complex. Although 50–70% of cases are believed to be hereditary, over 50% of cases reported in the literature have not had an affected family member. This point highlights a common concern for many patients about the risk of a family member inheriting tremor.
Based on the Washington Heights-Inwood Genetic Study of essential tremor, first-degree relatives of essential tremor cases were 4.7 times more likely to have essential tremor as compared with controls. Linkage studies have identified at least three loci for familial essential tremor (ETM1 on 3q13, ETM2 on 2p24.1, and a locus on 6p23),14 in addition to a polymorphism (Ser9Gly) in the gene coding for the dopamine D3 receptor15,16 that appears to convey increased risk of developing essential tremor.
Recent observations have noted that essential tremor seems to occur along with other movement disorders more often than one would expect. This provides further evidence that essential tremor may be a heterogeneous condition and is not the pure tremor disorder as previously thought. Disorders which appear to co-segregate with essential tremor include Parkinson’s disease, dystonia, myoclonus, ataxia, hearing abnormalities and cognitive impairment.17 Further epidemiological and genetic studies are needed to better define this phenotypic diversity.
PATHOPHYSIOLOGY AND PATHOLOGY
A number of direct and indirect neurophysiological studies have implicated a neuronal network involving the thalamus (especially nucleus ventralis intermedius (Vim)), the sensorimotor cortex, the inferior olivary nuclei, and cerebellum in the production of essential tremor. This is supported by an animal model using harmaline, that induces a reversible essential tremor-like state where there are abnormal tremor-specific oscillations in the olivocerebellar pathway. Additionally, ablation or lesions of the Vim thalamus, subthalamic nucleus or cerebellum can reduce essential tremor.
Despite the high frequency in the general population, few autopsy studies have systematically looked for and identified pathological abnormalities in essential tremor brains. Louis and colleagues reported an increased density of brainstem α-synuclein positive Lewy bodies in the locus ceruleus, dorsal vagal nucleus, and substantia nigra pars compacta, although only two of the 10 patients studied met pathological criteria, and none the clinical criteria, for Parkinson’s disease.18 Additional observations showed an increased number of torpedoes and Bergmann glia suggesting cerebellar injury in cases compared with controls.18
A number of different criteria have been proposed for making the diagnosis, the current ones combining the guidelines of the Tremor Investigation Group and the Consensus Statement of the Movement Disorder Society on Tremor (table 1). Additional criteria developed for the WHIGET study (Washington-Heights-Inwood Genetic Study of Essential Tremor) can also be useful for office-based tremor evaluation and monitoring; these involve five specific tasks—pouring water from cup to cup, using a spoon to drink water, drinking water, finger to nose testing and drawing a spiral.19
Although the symptoms and signs of essential tremor appear straightforward, isolated tremor can still be a diagnostic dilemma for the clinician. Specific causes of tremor should be sought including the initiation or withdrawal of various drugs (commonly beta-2 agonists, valproic acid, lithium, steroids, thyroxine and certain antidepressants; see table 2), and metabolic disorders including hyperthyroidism, hyperparathyroidism and hypoglycaemia. Decreased levels of magnesium, calcium and sodium can also cause tremor. Withdrawal from alcohol or cocaine is an additional consideration.21,22 Also, with the increasing use of energy drinks, over-the-counter diet pills and supplements to combat fatigue, physiological tremor may be exacerbated as it is by caffeine, anxiety and stress.
On neurological examination, essential tremor patients should have normal tone, strength and coordination (table 3). However, despite this normal examination, with the exception of the tremor, patients with advanced essential tremor may have impairments in tandem gait without other disturbances in walking, impaired smooth pursuit eye movements, and abnormal initiation and suppression of the vestibulo-ocular reflex (to test this, patients are seated in a chair and rotated in a dark room).23 These gait and eye movement abnormalities are predominantly cerebellar in type, and add to the evidence that there is some cerebellar dysfunction in essential tremor.
DIFFERENTIAL DIAGNOSIS OF ESSENTIAL TREMOR
In cases of suspected essential tremor, it is important to consider a broad differential diagnosis (table 4). Those disorders most commonly confused with essential tremor are discussed below and summarised in table 5.
Enhanced physiological tremor
Enhanced physiological tremor requires special consideration because it is probably the most commonly confused tremor with essential tremor. It is usually of low amplitude and high frequency, predominantly a postural tremor and—by definition—an exaggeration of the normal physiological tremor. It is generally caused by exogenous factors such as drugs, metabolic syndromes or anxiety, and it is reversible. This tremor can be difficult to differentiate from essential tremor because it too responds well to first line agents given for essential tremor and is often alcohol responsive. In difficult cases, tremor physiology can be especially helpful in distinguishing the two types of tremor and is discussed further below.
Parkinson’s disease is the second most common cause of tremor in adults (after essential tremor). Patients usually have a 4–6 Hz “pill rolling” rest tremor that begins on one side of the body (in contrast to essential tremor which is generally bilateral in onset). In addition, parkinsonian patients have additional neurological signs including bradykinesia, rigidity and postural instability. However, the situation is not always so straightforward. There is a growing body of evidence that essential tremor may precede the onset of Parkinson’s disease, especially if it starts in childhood, and patients with Parkinson’s disease have an increased frequency of other family members with essential tremor. To add to the confusion, there is an “essential tremor-Parkinson’s disease syndrome” that includes a subset of essential tremor patients that go on to develop a parkinsonian disorder with overlapping features of tremor, olfactory deficit, dopaminergic deficit and Lewy bodies on pathological examination.25
Cerebellar tremor has a lower frequency (<5 Hz) than essential tremor. It is seen with lesions affecting the dentate nucleus or superior cerebellar peduncle, such as a stroke or multiple sclerosis. It is predominantly thought of as an intention type tremor, but can occur with posture. However, this tremor does not occur at rest. On examination, the tremor can affect one or both sides depending on which side of the cerebellum is affected.21 Other findings include dysmetria, dysrhythmia and dyssynergia when the patient performs coordination tasks, such as rapid alternating movements of the hands, heel-knee-shin testing, and the finger chase test. A common additional finding is a slow frequency oscillation—titubation—of the head or trunk.
Dystonic tremor is usually a focal tremor in an area that is also affected by dystonia, such as the head with cervical dystonia. The frequency is variable, but is usually less than 7 Hz and the amplitude is irregular.22 Cervical dystonia is an important consideration when the clinical presentation is of an isolated head tremor and little or no hand tremor. Look for the subtle head deviation that suggests dystonia, or a position of the head where the tremor disappears. Unlike essential tremor, the patients may have a sensory trick (for example, touching the face) to dampen the tremor. When considering cervical dystonia look for other forms of focal dystonia including blepharospasm, oromandibular dystonia and focal hand dystonia. A point to watch out for is that patients with essential tremor may also have a tremor of their jaw and/or voice.
Psychogenic tremor may present in a variety of ways. The onset is usually sudden and the tremor can occur at rest, with a posture, intention, or any combination. The frequency and amplitude are variable and the tremor may completely disappear when the patient is distracted. The tremor can be present in any body part and may become more pronounced as the patient stands and walks.22 The tremor may appear bizarre and have a very large amplitude. In our experience, psychogenic tremor can be a great source of fatigue for the patient, unlike for essential tremor patients
Orthostatic tremor is a characteristic high frequency tremor (13–18 Hz) which occurs in the lower extremities with standing and improves when the patient walks. The patients may just describe a feeling of unsteadiness with standing which goes away when they begin to walk. On examination, there may be a fine rippling of the gastrocnemius or quadriceps muscles,21 which can be heard by auscultation over the muscles as a characteristic thumping sound.26 Although it is most prominent in the lower extremities, it can usually be picked up by tremor physiology in the arms and trunk. An important distinction on tremor physiology studies is that orthostatic tremor is highly coherent throughout the whole body. Some of these patients have essential tremor-like tremor in their upper extremities.
Task specific tremor
Task specific tremors are unique because they occur only during a specific motor task, the most common being writing—when it is called primary writing tremor. This form of tremor has also been reported in musicians and athletes. The cause is unknown but there may be at least two forms: one, a distinct entity, and the other, a variant of task specific dystonia.
When the clinical picture is confusing, physiological studies can be very helpful in distinguishing different types and causes of tremor, but these are only available in specialised laboratories. The standard procedure is to record EMG in tremor–producing muscles at rest, with a posture, during a kinetic task, with weighting, and while tapping at a certain frequency to evaluate for entrainment (fig 1). Based on the tremor frequency and its presence in certain positions, the differential diagnosis can be narrowed down. Further evaluation of the tremor can be addressed with the following questions:
Does the tremor amplitude decrease with weighting? For this procedure, small weights of 0.25–1.5 lbs are applied to the patient’s most affected hand and the tremor frequency recorded with EMG. The frequency in enhanced physiological tremor will decrease whereas in essential tremor and Parkinson’s disease the frequency does not change.
Does the tremor entrain? To test for entrainment, the patient listens to a metronome and taps the least affected hand along with the beat, at a range of frequencies from 2–6 Hz. It is important to choose a frequency that is lower and higher (if possible) than the resonant frequency to see if the underlying tremor entrains to the metronome frequency. At higher frequencies (above 5 Hz), this may become difficult for the patient to perform voluntarily. Psychogenic tremor commonly entrains but often the patient is unable to perform the tapping task accurately. Although the frequency may shift slightly in essential tremor and Parkinson’s disease (by 0.2–1 Hz), the tremor does not entrain.
Is the same frequency present in all limbs (coherence)? Tremor in different affected limbs is not exactly the same in essential tremor and Parkinson’s disease. Orthostatic tremor especially, and sometimes psychogenic tremor, is highly coherent in different body parts.
The management of essential tremor should be tailored to the patient’s level of disability. It is important to recognise that many patients seeking medical evaluation are primarily concerned that they have an underlying neurodegenerative disorder such as Parkinson’s disease. Patients may be counselled that although their tremor severity may gradually worsen over time, having essential tremor is unlikely to shorten their life and numerous treatment options are available if needed.
For patients with mild symptoms where tremor does not significantly limit their daily activities or cause major embarrassment, lifestyle modifications such as limiting caffeine, nicotine or other tremorogenic agents (table 2) may be adequate. For some patients who require only occasional treatment, perhaps on special occasions, small amounts of alcohol can be highly effective (fig 2), although the tremor-suppressive effects are generally brief (30–60 min) while the intoxicating effects may last for hours (and because alcohol is known by most patients to be helpful, all patients should be asked about their alcohol use and monitored for signs of overuse). Propranolol when required is also effective in situations where alcohol use is unwanted or contraindicated.
For individuals with moderate to severe tremor, a variety of medical and surgical therapies are available. Despite this seeming diversity, it is important that the clinician take a pragmatic approach to educating the patient and making treatment recommendations because 25–55% of patients gain no benefit from medical therapy.27
Essential tremor is an action tremor characterised by rhythmic shaking of the arms in almost every case; it may also involve tremor of the head, tongue, lower limbs, voice and face.
Essential tremor is commonly autosomal dominant, so a family history is important.
Enhanced physiological tremor is commonly misdiagnosed as essential tremor.
The neurological examination in essential tremor is usually normal, apart from the tremor itself, but there can sometimes be gait or eye movement abnormalities suggesting a mild cerebellar component.
Clinical neurophysiological studies can help differentiate essential tremor from enhanced physiological tremor, and from psychogenic tremor as well.
Essential tremor may be an independent risk factor for the development of Parkinson’s disease, and both conditions can be seen in the same patient.
Wilson’s disease should be considered in a patient presenting with tremor under the age of 40 years.
First-line agents for the treatment of essential tremor include propranolol and primidone; other agents have been less well studied and appear to be less effective.
Deep brain stimulation of the Vim nucleus of the thalamus should be considered in patients with severe essential tremor that is refractory to standard medical therapy.
Table 6 summarises the various agents which were reviewed by the Quality Standards Subcommittee of the American Academy of Neurology.28 Among them, propranolol and primidone are the first-line agents with the long-acting propranolol formulation being preferred due to its once-daily dosing and more favourable adverse effect profile compared with primidone. Of course, any treatment strategy should consider the patient’s other medical conditions and various risk factors. For example, a β-blocker is not recommended in patients with depression, asthma or diabetes mellitus, and any agents that can cause sedation should be used cautiously in patients at risk of falling.
For patients who do not respond to adequate trials of first-line agents or have intolerable adverse effects, a number of alternatives may be tried, based on the individual patient and the adverse effect profile (table 6). Botulinum toxin for reducing tremor amplitude may also be considered; agonist-antagonist muscles contributing to the tremor should be injected with doses which cause subclinical weakness without limiting the patient’s ability to effectively use the limb. However, in our experience, the effects are not consistent across successive treatments, which must be repeated every three months, and the patients are rarely satisfied enough to warrant the cost and inconvenience of numerous injections.
In cases of disabling medication-resistant essential tremor, deep brain stimulation of the thalamic Vim nucleus has been shown to be safe and effective in long-term studies. At five-year follow-up, patients receiving unilateral or bilateral deep brain stimulation showed improvements in mean tremor motor scores of 46% and 78%, respectively.29 Adverse effects of unilateral stimulation include paraesthesias, disequilibrium, cognitive problems and asthenia, while bilateral stimulation can cause dysarthria and balance problems. Based on the increased risk of adverse events with bilateral stimulation, implantation on both sides should be considered cautiously.
The tremor-suppressive effects of alcohol in many, but not all, patients make it the most effective agent currently available, although it has obvious limitations because of its short half-life, its intoxicating effects, and the ethical implications of recommending an agent with significant abuse potential. These limitations have encouraged the search for agents which have alcohol-like benefits but without its limitations. For example, 1-octanol decreases tremor amplitude for up to 90 minutes without intoxicating adverse effects,30,31 the main problem being an unpleasant taste when swallowing the medication, or later with a belch. Sodium oxybate is another agent with alcohol-like action, and was originally approved for the treatment of cataplexy accompanying narcolepsy; a recent single-blind, open-label trial in patients with alcohol responsive myoclonus and tremor found it improved their symptoms, and after completing the study, more than half the patients chose to continue the treatment.32
An additional investigational compound is barbiturate t2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid). Two brief, randomised, placebo-controlled, parallel-group, double-blind trials showed improvements in the Fahn-Tolosa-Martin tremor scale.33
This article was reviewed by Richard Davenport, Edinburgh, UK.
↵* CE stands for “Common Era” or “Current Era” and is the preferred—by these authors and others—religiously neutral substitute for AD (Anno Domini). Of course, CE could also stand for Christian Era, which rather destroys the point. With this notation BC becomes BCE (Before Current/Common Era). Editor