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Essential tremor (ET) is the most common adult movement disorder. Traditionally considered as a benign disease, it can cause an important physical and psychosocial disability. Drug treatment for ET remains poor and often unsatisfactory. Current therapeutic strategies for ET are reviewed according to the level of discomfort caused by tremor. For mild tremor, nonpharmacological strategies consist of alcohol and acute pharmacological therapy; for moderate tremor, pharmacological therapies (propranolol, gabapentin, primidone, topiramate, alprazolam and other drugs); and for severe tremor, the role of functional surgery is emphasised (thalamic deep brain stimulation, thalamotomy). The more specific treatment of head tremor with the use of botulinum toxin is also discussed. Several points are discussed to guide the immediate research into this disease in the near future. Dystonic tremor is a common symptom in dystonia. Diagnostic criteria for dystonic tremor and differential diagnosis with psychogenic tremor and ET are described. Treatment of dystonic tremor matches the treatment of dystonia. In cases of symptomatic dystonic tremor similar to ET, therapeutic strategies would be the same as for ET.
Essential tremor (ET) is not only the most common movement disorder in the elderly but it is also one of the neurological disorders most frequently seen by general neurologists and specialists within neurology [Louis, 2005; Gironell et al. 2001]. Effective treatment options for the disorder are limited (Figure 1). The traditional view of ETas a benign, familial, monosymptomatic disorder is being replaced by one of ET as a disease or family of diseases with aetiological, clinical and pathological heterogeneity [Louis, 2005].
ET is characterised by the presence of postural and kinetic tremor. In classic ET, upper limbs (95% of patients) and less commonly the head (34%), lower limbs (30%), voice (12%), tongue (7%), face (5%), and trunk (5%) exhibit postural or kinetic tremor [Elble, 2006]. It has traditionally been considered a benign condition because of the perception that it does not reduce life expectancy or cause symptoms other than tremor and impaired tandem walking. However, this disorder may cause substantial physical and psychosocial disability. Tremor amplitude increases gradually over time and patients frequently face growing difficulties with writing, drinking, eating, dressing, speaking, and other fine motor tasks.
ET is a clinical diagnosis. Criteria for definite and probable ET include abnormal bilateral postural or kinetic tremor of the hands in the absence of other neurological signs. The clinical criteria were comprehensively reviewed by the Consensus Statement of the Movement Disorder Society on Tremor [Deuschl et al. 1998]. Six routine neurophysiological criteria (EMG and accelerometer) have recently been described [Gironell et al. 2004]: (1) rhythmic burst of postural tremor on EMG; (2) tremor frequency superior or equal to 4 Hz; (3) absence of rest tremor or, if present, frequency 1.5Hz lower than the postural tremor; (4) absence of tremor latency from rest to postural position; (5) changes of the dominant frequency peak less or equal to 1 Hz after the weight load test; and (6) no changes in tremor amplitude after mental concentration.
There are several recent excellent reviews on ET treatment [Elble, 2006; Zesiewich et al. 2005]. This paper includes evidence-based medicine observations together with reviewer experience in this field. It is structured according to the severity of patient symptoms.
There are to date no neuroprotective therapies for ET. A genetic locus will likely be found in the future. With the aid of genetic engineering, it will then be possible to replace the causative mutation into the wild-type allele. This would be a presymptomatic and curative therapy for the disease.
In milder cases of ET, drug treatment benefits are insufficient to justify continuous chronic treatment. Physicians should explain to patients that psychostimulants such as coffee, tea and cola drinks may have tremoric effects and that anxiety and stress also worsen tremor amplitude. Nonpharmacological anxiolytic measures may be beneficial in milder cases.
Ethanol is a potent suppressant of ET in many patients, but it has obvious limitations in the chronic treatment of the disorder. It has been reported that alcohol reduces tremor amplitude in 50–90% of cases, but tremor may temporarily worsen after the effects of alcohol have worn off [Koller and Biary, 1984]. The mechanism of ethanol in tremor suppression is uncertain. Other alcohols appear to have similar efficacy. Octanol and sodium oxybate were beneficial in pilot studies, but larger double-blind placebo-controlled trials are needed to test the safety, tolerability and efficacy of long-term treatment with these drugs. Sodium oxybate has been approved with restrictions in the United States and several European countries for the treatment of cataplexy [Frucht et al. 2005]. In mild cases of tremor, the physician may suggest an occasional alcoholic beverage (i.e. a beer) approximately 30 minutes prior to a tremor discomfort activity.
Another possibility in patients with mild tremor is the use of pharmacological treatment a short time prior to a concrete tremor discomfort activity. The drug should have a rapid absorption and antitremoric action. The most commonly used of such treatments is propranolol (the characteristics of which are discussed later). A dose of 20–40mg propranolol about 30–60 minutes prior to specific actions disrupted by tremor can be used.
The patient should be informed that no drug is yet available to entirely eliminate tremor. Antitremoric drugs only ameliorate tremor amplitude. As these drugs may have adverse effects, chronic treatment should be prescribed only if there is some functional disability. Most physicians would agree that drugs should not be prescribed for aesthetic reasons. Common sense is basic in ET treatment. Oral medication commonly used in ET is described in Table 1.
Propranolol is a nonselective beta-adrenergic receptor antagonist. Twelve controlled studies found it to be efficacious in treating limb tremor in ET (accelerometry was reduced by approximately 50%). The dose in these studies ranged from 60 to 320 mg/day. Side effects occurred in 12–66% of patients and included fatigue, impotence, bradycardia and lightheaded-ness [Koller and Vetere-Overfield, 1989; Cleeves and Findley, 1988; Jefferson et al. 1979; Tolosa and Loewnson, 1975]. Although propranolol is generally well tolerated, it should be administered with caution in view of contraindications, which include asthma, congestive heart failure, diabetes mellitus and atrioventricular block. Several beta blockers, including sotalol and atenolol, seem to be effective in the management of ET, but propranolol, a nonselective antagonist, has been the most consistently studied and it is more effective that relative selective beta-1 antagonists. Sustained-release propranolol is as effective as conventional propranolol, although patients usually prefer the classical propranolol formulation because its effects are more evident and rapid. Only 25% of patients maintain their initial good response at 2 years [Koller and Vetere-Overfield, 1989].
In our experience, beta blockers are the best pharmacological treatment for ET and two-thirds of patients improve. We usually start with nadolol rather than propranolol because of its more convenient posology (two 40mg doses per day). As stated above, the major problem with beta blockers is the contraindications, which are very common in older ET patients.
Primidone is an anticonvulsant agent that is metabolised to phylethylmalonamide and phenobabital. Its efficacy in treating ET has been examined in several articles [Chakrabarti and Pearce, 1981; Gorman et al. 1986; Findley et al. 1985; Sasso et al. 1990] in which doses from 50 to 1000 mg/day were useful. The mean reduction in tremor magnitude by accelerometry was approximately 50%. Primidone has been associated with a moderate to high frequency of adverse events that were more severe at treatment initiation. These include sedation, drowsiness, fatigue, nausea, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo and an acute toxic reaction. One study showed that slow titration did not improve tolerability to the drug. Another study showed no significant differences in tremor improvement with doses ranging from 250 to 750 mg/day. Prospective, randomised clinical trials indicate that propranolol and primidone reduce limb tremor in ET. Magnitudes of effect of primidone and propranolol were approximately similar [Gorman et al. 1986]. In our experience, the main drawback with primidone is the high prevalence of adverse effects, especially in older patients. For this reason it can be considered a second-line drug, at a similar level to gabapentin.
Gabapentin is an anticonvulsant that is structurally similar to the inhibitory neurotransmitter GABA. There is some evidence that there is a disturbance in the GABAergic system in ET. In two of three clinical trials, gabapentin (doses ranging from 1200 to 3600mg daily) resulted in a significant reduction in tremor compared with placebo, and in one of the two, its effect was similar to that of propranolol [Ondo et al. 2000; Gironell et al. 1999; Pahwa et al. 1998]. Gabapentin is generally well tolerated.
In our experience approximately one-third of patients improve with gabapentin. Its main drawback is this low efficacy rate; however, it is well tolerated and there are very few contraindications. It is a suitable therapy for older patients (the majority of ET patients). If beta blockers are not tolerated or are contraindicated, it is thus a valid option prior to primidone.
Topiramate is an anticonvulsant that blocks sodium channels and potentiates GABA activity. Several studies, including one double-blind placebo-controlled trial, reported an 18–23% improvement in clinical rating scales with topiramate use. The dropout rate was approximately 40% due to appetite suppression, weight loss, paresthesias, anorexia and concentration difficulties [Connor et al. 2008].
In our experience, the efficacy of topiramate is similar to gabapentin, but titration is long and difficult, and tolerance is poor compared to gabapentin. In view of these limitations it is mainly used as a third-line therapy.
Alprazolam is a short-acting benzodiazepine. Several studies have found that doses of 0.125-3 mg/day reduce limb tremor (25-34%) as compared with placebo [Huber and Paulson, 1988]. Side effects range from none to 50% in these studies and include mild sedation and fatigue. Alprazolam is probably efficacious in treating ET, but caution with its use is recommended due to its abuse potential. Alprazolam is usually used as a coadjuvant therapy associated with other drugs in cases of severe tremor.
The following agents possibly reduce limb tremor associated with ET
Pharmacologic management of essential head and voice tremor is less efficient than that of hand tremor. Propranolol and primidone, alone or in combination, have been recommended for essential head tremor. Clonazepam is often recommended, but controlled studies are not available. A promising therapy for head tremor is the local injection of botulinum toxin, but further studies are needed to confirm this [Pahwa et al. 1995]. Deep brain stimulation is also effective for head and voice tremor, but bilateral ventralis intermedius (VIM) stimulation is usually necessary. In our experience, the response to botulinum toxin is good in head tremor and we usually prefer this treatment before other oral pharmacological therapies in patients with predominant moderate and severe head tremor.
This is of limited aid in cases of severe tremor, especially when beta blockers cannot be used. In these cases, we usually propose surgery, especially in patients less than 70 years old. The age is a relative criterion. In patients aged 70–75 years, unilateral surgery may be performed to minimise the risk of pseudobulbar and cognitive sequelae. Patients with severe tremor are usually treated with polytherapy that includes a combination of beta blockers, primidone, gabapentin or topiramate, and benzodiazepines.
VIM nucleus thalamotomy and deep brain stimulation (DBS) produce marked (475%) or complete suppression of limb tremor in 70–90% of patients. Surgery is therefore the most effective treatment for ET [Vaillancourt et al. 2003]. Thalamotomy and DBS are reserved for drug-resistant tremor that warrants surgery. DBS is the procedure of choice at most centres because it is associated with fewer adverse events than thalamotomy, particularly when bilateral procedures are performed. In a multicentre European study in which 37 patients with ETwere followed for a mean of 6.5 years, VIM DBS offered long-term benefits and safety [Sydow et al. 2003].
VIM is the preferred stereotactic target in nearly all patients with ET. However, alternative targets may be needed in some situations. Parkinson tremor and ET in the same patient have responded to subthalamic DBS. Targets other than VIM should therefore be investigated in patients who are refractory to VIM DBS.
Several uncontrolled studies have reported favourable results with gamma knife thalamotomy. However, delayed complications have been observed and clinical improvement may take weeks to months [Young et al. 2000]. Controlled studies of gamma knife thalamotomy should be considered in advanced patients who are not candidates to surgery. DBS achieves excellent results in ET patients, and total suppression of antitremoric medication may be possible. There is a general consensus among experts that better results are obtained in postural ET tremor than in task-specific tremor.
Although it is the most frequent movement disorder, research in ET treatment is still scarce. The therapeutic arsenal and efficacy rates of antitremoric drugs are very limited. In the near future, ET research must be focused as follows:
It is well known that dystonic patients sometime have rhythmic movements, particularly in the arms and neck, manifested as tremor [Jankovic and Fahn, 1980]. In one survey, 68% of patients with cervical dystonia had head tremor [Pal et al. 2000]. Two basic types of tremors are seen in dystonic patients: an accompanying postural/action tremor that resembles ET, or an enhanced physiologic tremor and a tremor that is a rhythmic expression of rapid dystonic movements. The latter can usually be distinguished from the former by showing that the tremor appears only when the affected body part is placed in a position of opposition to the major direction of pulling by the abnormal dystonic contractions and disappears when the body part is positioned where the dystonia wants to place it.
The clinical criteria of dystonic tremor syndromes were reviewed by the Consensus Statement of the Movement Disorder Society on Tremor [Deuschl et al. 1998]. They propose three possible definitions:
Differentiation of psychogenic from dystonic tremor can be difficult [McAuley and Rothwell, 2004]. In fact, in dystonic tremor duration of tremor burst is widely variable reflecting its jerky nature and similar to some psychogenic tremors. Conversely, psychogenic tremor may have selective tremor absence and lack of disability, whereas dystonic tremor has selective disability and is usually steroeotypic.
Tremor is one of the clinical symptoms of dysto-nia. The treatment of dystonic tremor matches the treatment of dystonia. There are no specific therapeutic trials evaluating treatment efficacy on dystonic tremor. In cases of postural or intention tremor very similar, and difficult to discriminate from ET, therapeutic tremor strategies would be the same as in ET patients.
Alexandre Gironell, Movement Disorders Unit, Department of Neurology, Sant Pau Hospital, Autonomous University of Barcelona, Catalonia and Ciberned (Centro de Enfermedades Neurodegenerativas en Red), Spain.
Jaime Kulisevsky, Servei de Neurologia, Hospital de Sant Pau, Barcelona, Spain ; Email: tac.uaptnas@yksvesilukj.