Clinical Characteristics

The predominant finding in patients with ET is a kinetic tremor (i.e., a tremor that occurs during voluntary movement), as shown in the two spirals, drawn by ET patients, in Figure 1 below. The frequency of this tremor is between 4 and 12 Hz, and is inversely related to age, with older patients tending to have tremor frequencies that are at the lower end of this spectrum [28]. The kinetic tremor occurs during a variety of different voluntary movements such as writing, pouring, drinking from a cup, eating, putting in eye drops, and other daily activities. Patients with severe ET also have a postural tremor, which can be elicited by asking the patient to hold their arms outstretched in front of the body [28]. The literature abounds in statements that define ET as a postural tremor; this is incorrect [28]. The tremor is predominantly kinetic.

The tremor most commonly affects the arms, but it may also affect additional regions of the body, especially the head (i.e., neck), voice, or both and occasionally the trunk, lower extremities, tongue, and other facial musculature [5]. The proportion of subjects with both head and arm tremor ranges from 34% to 53%, depending on the study sample [14,29-32]. In most studies, however, isolated head tremor (head tremor without accompanying arm tremor) is rare, occurring in 1-10% of patients [32].

A characteristic feature of ET is the somatotopic spread of tremor over time, from the arms to the head. Head tremor typically evolves several years after the onset of arm tremor, but the converse (arm tremor developing after the onset of isolated head tremor) is unusual and should call the diagnosis into question [32].

The hallmark feature of ET is a kinetic tremor, and this probably results from an abnormality in the cerebellum or cerebellar-thalamic outflow pathways. In addition, recent work has demonstrated that, as in other neurodegenerative diseases (e.g., Parkinson disease [PD], Alzhemier disease, and Huntington disease), involvement of the central nervous system may be diffuse, having the tendency to evolve over

FIGURE 1 Archimedes spirals drawn by patients with mild (left) and severe (right) essential tremor.

time. Therefore, ET patients who are sampled at different times during their disease are likely to have different clinical characteristics. There is considerable evidence that the pathological process in some patients, which in ET remains to be identified, ultimately results in diffuse cerebellar involvement, signs referable to the basal ganglia, cognitive abnormalities that may be referable to cerebellar-frontal connections, changes in personality whose basis and localization are unclear, olfactory deficits, and perhaps changes in the peripheral nervous system. Each of these clinical areas will be outlined in the succeeding paragraphs.

Several studies [6-8] have demonstrated postural instability and ataxic gait in a large proportion of patients with ET, suggesting that the cerebellar involvement can become more widespread, though not as widespread as that occurring in the spinocerebellar ataxias. The diagnostic differentiation between (1) the ET patient with severe tremor who later develops gait ataxia and (2) the patient with spin-ocerebellar ataxia can be difficult, although the current dogma is that patients with ET do not exhibit nystagmus or scanning or dysarthric speech.

It is well known that some patients with ET develop a tremor at rest [9,33]. In one study [10], investigators studied the prevalence and clinical correlates of this tremor in a sample of ET patients who were referred to a tertiary referral center. In that study [10], 18.8% of the ET patients had a rest tremor (i.e., approximately one in five ET cases), which suggests that this type of tremor is not uncommon in ET patients who are seen at tertiary referral centers. When compared to the ET patients without rest tremor, those with rest tremor had a disease of longer duration and of greater severity. Also, their ET was more widely disseminated as evidenced by a larger proportion with head tremor. None had clinical signs of bradykinesia or rigidity, but on electro-physiological testing, they had electrophysiological features consistent with mild Parkinsonism (e.g., slow spiral speed, increased decrement of spiral speed with radius) [10]. The basis for rest tremor in patients with ET is not clear, although several possibilities exist. First, in patients with severe, longstanding, and disseminated disease, the pathological process that caused their ET may have spread into motor systems outside of the cerebellum/cerebellar outflow connections. That is, the basal ganglia and/or their connections could be involved. Interestingly, in a fluorodopa positron emission tomography (PET) study [34], uptake in the basal ganglia in ET patients was 10%-13% below that of controls, but the difference was not significant in that small study sample. A second possibility is that rest tremor may be the only clinically detectable sign of co-existing Lewy body PD that developed in these ET patients with rest tremor. Against this possibility is the observation [9] that pathological findings compatible with idiopathic PD were absent in three cases of ET with isolated rest tremor (i.e., rest tremor without other features of Parkinsonism). Second, in the PET study [34], while fluorodopa uptake in the basal ganglia was

10%-13% below normal in patients with ET, it was well above the range seen in patients with idiopathic PD, suggesting that these patients did not have PD. Finally, the severe olfactory deficit that is an early feature of patients with PD is not seen in many of the ET patients with rest tremor, suggesting that they do not have an early form of PD [35].

As in other neurodegenerative diseases, patients with ET appear to have cognitive problems. Several recent studies have demonstrated mild cognitive abnormalities in ET, and, more specifically, problems with verbal fluency, recent memory, working memory, and mental set-shifting, suggesting that the frontal cortical or frontal cortical-cerebellar pathways are involved [11,12,36-38]. These cognitive problems appear to be mild and sub-clinical.

The emerging picture of ET suggests that the pathological process involves a number of different higher order cortical domains. In addition to cognitive changes, personality changes may also occur. In one study [39], investigators administered the Tridimensional Personality Questionnaire to patients with ET and to controls. Patients with ET had higher scores on one of the three subscales of this test, namely, the harm avoidance subscale. A high harm avoidance score defines a person who is pessimistic, fearful, shy, anxious, and easily fatigued. This is an intriguing initial finding and suggests that, as in several other movement disorders (Parkinson and Huntington diseases), personality may be involved.

As in other degenerative disorders, an olfactory deficit occurs in patients with ET, which appears milder than that seen in patients with PD, although the University of Pennsylvania Smell Identification Test scores overlap in the two conditions [40]. The deficit seems to be unrelated to disease duration or severity, suggesting that, as in PD, the deficit occurs early in the disease process.

Interestingly, several studies have suggested abnormalities might occur outside of the central nervous system in patients with ET. These include a study of hearing loss in patients with ET. In that study [41], patients with ET had significantly more hearing disability, as measured by the Nursing Home Hearing Handicap Resident and Staff Assessment, than did patients with PD or normal controls. Also, a higher percentage of ET patients (16.6%) wore hearing aids than patients with PD (1.6%) or normal controls (1.6%). The authors concluded that the basis for the hearing loss might be cochlear-vestibular involvement. In another study [42], the authors showed that the peripheral silent period was shorter in patients with ET compared to normal individuals, indicating a possible role for peripheral modulation of the tremor.

Several studies have now demonstrated a mild loss of body mass index (BMI) in patients with ET [43,44]. In one study [43], investigators compared seventy-eight ET patients at a tertiary referral center to 242 controls of similar age. BMI in ET patients was 26.5 ± 5.0kg/m2 vs. 28.2 ±

4.8kg/m2 in controls, which was on average a 6% reduction (p = 0.008). Mean daily caloric intake was similar in patients and controls, suggesting that lower BMI was not due to a reduction in calories and perhaps due to increased energy expenditure in ET. In the second study [44], which was population-based, investigators compared eighty-nine ET patients who lived in the Mersin province of Turkey to eighty-nine controls in the same province. Most of the ET cases had not been previously diagnosed with ET and few were taking medications for tremor. There was a similar 5.5% reduction in BMI in these ET cases.

In summary, the old view of ET, as a simple mono-symptomatic syndrome characterized by action tremor, is beginning to change. It is being replaced by a view of this entity as a disease with a complex set of clinical characteristics that evolve in a prescribed manner over time. The study of these patterns will provide clues about the underlying pathogenesis of this disease, which remains poorly understood.

A. Functional Sequelae

In the past, investigators often used the term "benign essential tremor," but this term is controversial. The large majority (as many as 90-99.5%) of ET cases who live in the population [45,46] do not seek health care, and this suggests that their tremor is of little consequence. In reality, the majority of these cases experience some functional disability resulting from their tremor. In a study of community-dwelling ET cases, the large majority (73%) reported disability, with most experiencing this disability in multiple functional domains [1]. In general, the tremor in ET is progressive [5], eventually producing disabilities with basic daily activities such as eating, writing, body care, and driving [14,47]. More than 90% of patients who come for medical attention report disability [1], and severely affected end-stage patients are physically unable to feed or dress themselves. In these patients, the tremor prevents any normal activity, resulting in a substantial loss of indepen-ence and even incapacitation [48]. Between 15% and 25% of clinic patients are forced to retire prematurely, and 60% choose not to apply for a job or promotion because of uncontrollable shaking [14,47].

B. Prognosis

As noted above, ET is clinically progressive. Clinicians have long recognized among many of their ET patients a progressive increase in tremor severity with advancing age and disease duration [2,3,5]. In our cross-sectional study of the functional correlates of tremor among ET cases [1], the correlation between tremor severity (assessed clinically using a 36-point total tremor score) and disease duration was significant (r = 0.66, p < 0.001). Also, all of the ET cases who had tremor of long duration also had high tremor scores, sug gesting that longstanding disease inexorably results in a severe tremor. There have been few longitudinal studies of ET and few attempts to quantify the extent to which the tremor worsens over time. One notable exception is a prospective four-year study of ET, in which tremor amplitude was assessed electrophysiologically, and that demonstrated a 29.4% increase in tremor amplitude during the study period [49].

Although the current dogma is that the risk of mortality is not increased in patients with ET, investigators have made few attempts to study the mortality of ET. In one case-control study [24], a longitudinal retrospective study of ET patients in Rochester, Minnesota, investigators selected 266 patients and abstracted their medical records. The survival after diagnosis of ET was comparable to the expected survival for persons of similar age and sex from the West North Central region of the U.S.A (i.e., a group of historical controls) [24]. In that study, the mean age at diagnosis was fifty-eight years, and the mean length of follow-up after diagnosis was 9.7 years, suggesting that some of the cases may not have been followed into advanced age. At these advanced ages the risk of mortality in ET may rise. Further work is needed in this important area.

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