Correspondence *Móstoles General Hospital, Avenida de la Constitución 73, portal 3, 7^° Izquierda, E-28820 Coslada, Madrid, Spain

Email jbenitol@meditex.es

Introduction

Essential tremor (ET) is one of the most common neurological disorders among adults, and is the most common tremor disorder.^{1, 2, 3} It is estimated that 30–50% of supposed ET cases are misdiagnosed as parkinsonian or other forms of tremor.^{4, 5} ET has traditionally been viewed as a benign monosymptomatic disorder, characterized mainly by a kinetic arm tremor. The emerging view, however, is that ET might be a family of diseases unified by the presence of kinetic tremor, but also showing etiological, pathological and clinical heterogeneity.^{2, 3}

Epidemiology

Pathophysiology

A fundamental question about the biology of any neurological disorder is whether there are histopathological changes in the brain. Until recently, only 25 reports of postmortem examinations in ET were available, many of which were published 50–100 years ago, and few of which described relevant brain structures in detail. The pathological picture was unclear, although mild to diffuse loss of Purkinje cells was reported in four isolated cases.³¹ A further problem was the absence of any age-matched control brains for comparison. The Essential Tremor Centralized Brain Repository at Columbia University (New York, NY) was established in 2003 to prospectively collect and study in detail the brains of individuals with ET, and to compare them with matched control brains.⁴⁸ An initial report (10 ET cases vs 12 controls) demonstrated that pathological findings were present in all 10 brains from patients with ET, and that the findings were heterogeneous.⁴⁹ ET cases clustered into two groups: those with cerebellar degenerative changes (n = 4) and those with brainstem Lewy bodies ('Lewy body variant of ET'; n = 6).⁴⁹

In the ET cases with cerebellar degenerative changes, the cerebellum contained significantly larger numbers of Bergmann glial cells and torpedoes, with the number of torpedoes being 10 times higher in ET than in control brains.^{49, 50} Bergmann astrocytes are a nonspecific pathological response to injury. A torpedo is a fusiform swelling of the proximal segment of the Purkinje cell axon (Figure 1), and consists of massive accumulations of disoriented neurofilaments.⁴⁹ Torpedoes occur in degenerating—and possibly in regenerating—Purkinje cells, and have been described in other disease processes involving destruction of cerebellar tissue.⁴⁹ A fifth ET case demonstrated further cerebellar abnormalities, with extensive changes in the dentate nucleus (Figure 2), including marked neuronal loss, neuronal atrophy, microglial clusters, and pallor of the white matter (hilum).⁵⁰ The presence of pathological changes in the cerebellum in patients with ET is not unexpected. Clinical^{17, 18, 51} and imaging^{52, 53, 54, 55} studies have consistently pointed to cerebellar involvement in ET; indeed, the tremor itself it believed to be mediated by a neuronal loop involving cerebellothalamocortical fibers. Moreover, recent magnetic resonance spectroscopic imaging studies demonstrated a reduction in the cerebellar N-acetyl-aspartate:creatine ratio, indicating that there is neuronal loss in the cerebellum.^{53, 54} Emerging pathological studies are providing additional evidence for cerebellar degeneration in some forms of ET.^{49, 50}

Figure 1 Section of cerebellar folium from a patient with essential tremor, showing two torpedoes (arrows).

The section was stained with Luxol^® fast blue (Rohm and Haas Chemicals LLC Ltd, West Philadelphia, PA)–hematoxylin and eosin (200 magnification). Permission obtained from American Medical Association © Louis ED et al. (2006) Arch Neurol 63: 1189–1193.

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Figure 2 Section of the dentate nucleus from an individual with essential tremor, showing neuronal loss.

The neurons that remain are small and angular. One normal, rounded dentate neuron remains in the center (arrow). The section was stained with Luxol fast blue^® (Rohm and Haas Chemicals LLC Ltd)–hematoxylin and eosin (200 magnification). Permission obtained from American Medical Association © Louis ED et al. (2006) Arch Neurol 63: 1189–1193.

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Six of 10 ET cases studied at the Essential Tremor Centralized Brain Repository exhibited a distinctive pattern of Lewy bodies in the brainstem.^{49, 56} Patients with this Lewy body variant of ET exhibited many Lewy bodies in the locus ceruleus, rare Lewy bodies in the substantia innominata and dorsal vagal nucleus, and rare or absent Lewy bodies in the substantia nigra (see Figure 3 for a section stained with luxol fast blue–hematoxylin and eosin, and reference 49 for -synuclein-stained sections).^{49, 56} This pattern of Lewy body distribution has not been observed in patients with subclinical or clinically manifest PD, in whom involvement of the dorsal vagal nucleus (in subclinical PD) and substantia nigra pars compacta (in clinically manifest PD) are prominent.^{49, 56} In addition, this pattern has not been observed in normal, aged controls—Lewy bodies are observed rarely in the normal aged locus ceruleus and, when present, are not abundant—or in the matched control brains that were studied.⁴⁹ Other investigators have also preliminarily reported increased numbers of Lewy bodies in patients with presumed ET.⁵⁷

Figure 3 Multiple Lewy bodies (arrows) are seen in a section of the locus ceruleus from a patient with essential tremor.

The section was stained with Luxol^® (Rohm and Haas Chemicals LLC Ltd) fast blue–hematoxylin and eosin (200 magnification). Permission obtained from AAN Enterprises, Inc. © Louis ED et al. (2006) Neurology 66: 1756–1759.

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The spectrum of Lewy body disease includes entities other than PD, such as diffuse Lewy body disease and Alzheimer's disease with Lewy bodies.⁴⁹ The possibility that a significant proportion of ET cases could have a form of Lewy body disease lends support to the literature indicating a link between ET and Lewy body disease.^{58, 59} Although it is known that patients with ET can eventually develop PD, it remains to be demonstrated that the ET patients with Lewy bodies in the locus ceruleus are the ones who go on to develop more-widespread (e.g. nigral) Lewy bodies and PD.

The mechanism whereby Lewy bodies confined mainly to the locus ceruleus could result in kinetic tremor in ET is unclear. The locus ceruleus is the principal source of norepinephrine in the CNS, and axons from the locus ceruleus project to and synapse on cerebellar Purkinje cells.⁴⁹ A locus ceruleus lesion could result in a diminution of stimulatory output from the locus ceruleus to the inhibitory Purkinje cells, resulting in a net reduction in inhibitory -aminobutyric acid (GABA)-mediated output from the Purkinje cells.⁴⁹ Many of the mainstays of treatment in ET, as we will discuss later, might help to restore GABAergic tone to the CNS, and a GABA_A receptor ₁ subunit knockout mouse has been proposed as an animal model for ET.⁶⁰

Clinical manifestations

General characteristics

Tremor is a movement that is rhythmic (regularly recurrent) and oscillatory (alternating around a central axis).^{2, 3} Kinetic tremor—tremor occurring during voluntary movements—of the arms is the most recognized feature of ET (Figure 4).^{2, 3} The tremor is usually apparent in both arms, although as a rule it is slightly asymmetric, with the tremor being of greater amplitude in one arm than in the other.⁶¹ The frequency of this tremor (range 4–12 Hz) is inversely related to age.⁶² Kinetic tremor can occur during any voluntary movement, including pouring water into a cup, drinking from a cup, eating with utensils, or writing.^{2, 3} The kinetic tremor in ET often has an intentional component; for example, during visually guided movements such as the finger-to-nose maneuver, the amplitude of the tremor increases as the target is approached.¹⁷ This characteristic provides further support for an abnormality of cerebellar function in ET. Patients with ET can also have postural arm tremor (e.g. when holding their arms horizontally extended in front of the body), although the amplitude of kinetic tremor is usually greater than that of postural tremor.⁶² Tremor in ET is most frequently seen in the arms, but other regions of the body might also be affected—in particular the head (or, more accurately, the neck), but also the voice, jaw, tongue and legs.^{2, 3, 35, 63, 64, 65, 66, 67} The proportion of patients with head tremor ranges from 34 to 53%, and with jaw tremor from 7.5 to 18.0%.^{35, 63, 64, 65, 66, 67} In the familial form of tremor, considerable heterogeneity in terms of tremor distribution, age of onset and rate of progression has been described.^{68, 69, 70}

Figure 4 Archimedean spirals drawn by individuals with and without essential tremor.

(A) A spiral drawn by a patient with severe essential tremor. (B) A spiral drawn by an individual without tremor.

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Between 75 and 99% of patients with ET detected through population-based studies are previously undiagnosed and untreated,^{7, 11, 68, 69} although approximately three-quarters of such population-dwelling patients report tremor-related disability.¹⁴ Furthermore, more than 90% of ET patients who seek medical attention for tremor report disability,¹⁴ and patients with severely advanced ET are unable to perform basic daily activities such as feeding or dressing themselves.⁷⁰ Almost a quarter of patients who come to treatment centers are forced to quit their profession, and 60% decide not to apply for jobs or promotions because of disabling shaking.^{35, 68}

ET is generally considered to be a slowly progressive disorder,^{70, 71} with disease duration and age each being independent contributors to tremor severity.⁷² With the passage of time, tremor might spread from the arms to previously unaffected body regions. Most typically, this spread involves the head; the converse (initial involvement of the head with subsequent spread to the arms) should raise suspicions with regard to the diagnosis.^{15, 66, 70, 73}

Diagnostic evaluation

Treatment

Although there is no cure for ET, several treatments can ease the condition for some patients. Medications should be used to reduce functional disability or embarrassment and to improve quality of life. Hence, treatment generally begins when the tremor begins to interfere with the patient's ability to perform daily activities, or if the tremor is embarrassing to the patient. Surgery should be limited to those disabling cases that fail to benefit from several different medications.

For patients who require symptomatic treatment, medications should be introduced at a low dose and increased slowly until sufficient benefit is achieved or the maximum attainable dosage is reached (Table 1). If insufficient benefit is seen, the patient should be weaned off the medication. If the benefit is only partial, a second medication should be added and slowly increased until sufficient benefit is achieved or the maximum attainable dosage is reached. Some patients require only intermittent tremor reduction, such as when attending a social event or when engaged in a meeting. For these patients, oral propranolol (10–40 mg) approximately half an hour before the event might be useful.

Table 1 Pharmacological agents for the treatment of essential tremor.¹¹⁰

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Recently, the therapies for ET were reviewed by a Quality Standards Subcommittee of the American Academy of Neurology (Table 1).¹¹⁰ Propranolol and primidone remain the cornerstone therapies. Propranolol is a nonselective -adrenoceptor antagonist that, in doses of 120 mg or more daily, results in significant reduction in tremor compared with placebo.¹¹¹ This drug is relatively contraindicated in patients with asthma, diabetes mellitus or atrioventricular block, and absolutely contraindicated in patients with unstable heart failure.¹¹² Propranolol formulated as a long-acting once-daily preparation is as effective as conventional propranolol.¹¹³ Primidone, an anticonvulsant medication, has resulted in significant reduction in tremor compared with placebo;^{114, 115, 116, 117} tolerability is a frequent problem, however, even at low starting doses of 2.5 mg in suspension¹¹⁸ or 62.5 mg daily,^{114, 115} requiring withdrawal of the agent in approximately 20% of patients.¹¹⁴ Propranolol and primidone seem to be equally efficacious,^{116, 119} although long-term tolerability of primidone might be superior to that of propranolol.¹²⁰

Other medications have been used with varying efficacy in the treatment of ET (Table 1). Among these agents, atenolol (dose ranging from 50 to 150 mg/day), a selective ₁-adrenoceptor antagonist, might have anti-tremor efficacy in patients with ET, but less than that of the -adrenoceptor antagonist sotalol or propranolol.¹²¹ Sotalol (75–200 mg/day) and another -adrenoceptor antagonist nadolol (120–240 mg/day) have both been shown to reduce tremor compared with placebo.^{122, 123} In one study nimodipine, a calcium channel blocker, reduced tremor at a dose of 30 mg four times daily.¹²⁴ Clozapine, an atypical neuroleptic, was found to reduce tremor at doses of 6–75 mg/day.^{125, 126} Gabapentin, an anticonvulsant structurally similar to the inhibitory neurotransmitter GABA,¹²⁷ resulted in significant reduction in tremor compared with placebo in some but not all studies (at doses ranging from 1,200 to 3,600 mg daily).^{128, 129, 130} A recent multicenter, double-blind, randomized trial in 208 patients found that topiramate was more effective than placebo in the treatment of ET.¹³¹ Benzodiazepines are known to enhance GABAergic tone in the CNS; one of these agents, alprazolam (dose ranging from 0.75 to 2.75 mg daily), was more effective than placebo at reducing tremor.¹³² Clonazepam significantly reduced kinetic tremor in one study using doses ranging from 0.5 to 6 mg/day;¹³³ in another study, however, the results were negative, and the completion rate was only 40% owing to drowsiness.¹³⁴ Recent preliminary studies indicate that levetiracetam (1,000 mg/day),¹³⁵ olanzapine (20 mg/day),¹³⁶ 1-octanol (an alcohol currently used as a food flavoring agent),¹³⁷ and zonisamide¹³⁸ might be useful for alleviating tremor in patients with ET. Intramuscular botulinum toxin A is indicated in the treatment of neck tremor, as oral medications are less effective in treating neck tremor than arm tremor.³ This medication is also effective in hand tremor;¹³⁹ although the improvement was compromised by extensor finger weakness, reduction of dosage into the extensors usually eliminates this adverse effect.¹³⁹

An abnormal cerebellothalamocortical loop might be responsible for ET. Thalamic stimulation (i.e. continuous deep brain stimulation through an electrode implanted in the ventral intermediate nucleus of the thalamus) and thalamotomy are equally effective for the suppression of drug-resistant tremor, but thalamic stimulation has fewer adverse effects and has replaced thalamotomy as the surgical treatment of choice in ET.¹⁴⁰ Recent studies indicate that gamma knife thalamotomy provides relief from tremor equivalent to that provided by radiofrequency thalamotomy or deep brain stimulation, but its safety is not as well established.¹⁴¹

The anti-tremor effects of ethanol are well known.^{74, 75} Ethanol binds to the GABA_A receptor, thereby facilitating GABAergic neurotransmission. Ethanol intake is not, however, an appropriate maintenance therapy for patients who seek tremor reduction throughout the day, mainly because of its cognitive and soporific effects, as well as its deleterious effects on general health.

The future of ET therapy will benefit greatly from a better understanding of the pathogenesis of the disorder. If ET is indeed a neurodegenerative disorder, then consideration must also be given to neuroprotective strategies, as have been tested in other diseases such as PD, Alzheimer's disease, and motor neuron disease.

Conclusions

ET is one of the most common neurological disorders. Although ET has been traditionally viewed as a unidimensional condition, recent studies indicate that the disorder is characterized by a number of previously unrecognized motor and non-motor problems. The new paradigm presents ET as a more complex entity. As with other progressive neurological disorders of later life (e.g. motor neuron disease and parkinsonism), ET might represent a family of related diseases that show heterogeneity at etiological, clinical and pathological levels. A better understanding of the anatomical and pathological bases of these disorders will lead to advances in the development of symptomatic treatments, and also possibly neuroprotective treatments.

Acknowledgments

ED Louis is supported by grants R01 NS39422, R01 NS42859 and P30 ES09089 from the National Institutes of Health, Bethesda, MD, USA. No funding source was involved in the preparation of this article.

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Subject areas under which this article appears: Movement disorders