Essential tremor (ET), also known as benign idiopathic tremor, familial tremor, or senile tremor, is a common motor disorder characterized by slowly progressive postural or motor tremor of both upper extremities [1]. Although the pathogenesis of ET has not been fully elucidated to date, studies have shown that its pathogenesis has an organic basis and that its progression to a certain level can significantly affect the motor function of patients, thus the designation “idiopathic” or “benign” is not exact [2].
Epidemiology
Because of the mild and unrecognizable symptoms of ET in its early stages, patients often fail to seek medical attention in time, and because the diagnosis of ET lacks a laboratory basis and the diagnostic criteria vary, the results of epidemiological investigations vary considerably. The prevalence of ET in the population has been reported in the literature to vary from 8/100,000 to 22,000/100,000, with a difference of 2,750 times; the general estimate is 300-5,600/100,000. the prevalence of ET increases with age, ranging from 1,300/100,000 to 5,050/100,000 above the age of 60 years and up to 10,000/100,000 above the age of 65 years [3]. Men and women have an equal chance of developing ET. Less information is available on the incidence of ET; a 45-year retrospective analysis in the United States showed an age- and sex-corrected ET incidence of 23.7 per 100,000? years. It is estimated that no more than 10% of patients with ET seek medical consultation.
Etiology
The etiology of ET is unknown and is likely to be a multi-causal syndrome in which genetic factors play an important role. According to statistics, 50% to 70% of ET patients have a positive family history of autosomal dominant inheritance with incomplete epistasis. The causative genes are located on chromosomes 3q13 (ETM1) and 2p22-25 (ETM2). Studies on dizygotic twins have shown that the co-prevalence of ET in monozygotic twins is 60-63%, while in dizygotic twins it is only 27-42%, further supporting the association of genetic factors with the development of ET [2].
Pathophysiology
To date, no specific structural damage has been found in ET, and the neurotransmitter changes and the exact pathophysiological processes of ET have not been fully elucidated. However, studies suggest that the pathogenesis of ET originates in the Guillain-Mollaret triangle, consisting of the red nucleus, the inferior olivary nucleus, and the cerebellum, which acts as a central oscillator and whose abnormal function can cause disorders in the cerebellar-brainstem-thalamo-cortical circuit, leading to ET. The injection of harmaline into animals induces a tremor similar to ET in humans; neurons in the inferior olivary nucleus of animals show firing at a frequency synchronized with the tremor; the firing is transmitted via crawling fibers to the Purkinje cells and nuclei of the cerebellum and then to the cerebellar-thalamo-cortical circuit. Positron emission scanning (PET) studies have shown that the metabolism of the inferior olivary nucleus is enhanced in ET animals; the metabolic rate of the inferior olivary nucleus and the activity of the cerebellum are also significantly enhanced in ET patients; when the cerebellum or the thalamus is damaged, the tremor disappears, and the above is a strong indication that the above structures are related to the pathogenesis of ET [1]. There is limited information on functional magnetic resonance (fMRI) studies, and the results of a study in patients with unilateral tremor ET showed that tremor is mainly associated with activation of the additional contralateral cerebellar pathway. The study suggests that in addition to central mechanisms, the pathogenesis of ET also involves peripheral mechanisms, with central oscillators transmitting oscillatory signals to the limb by affecting central and peripheral interconnected reflex circuits, causing limb tremor. β-adrenergic receptor blockers do not cross the blood-brain barrier but are effective in treating ET, also suggesting that the pathogenesis of ET is related to peripheral mechanisms [4].
Clinical presentation
There are two peaks in the age of onset of ET: young adulthood and old age, with a mean age of onset of 35 to 45 years and a few childhood onset. The prominent clinical manifestations are postural and/or motor tremors, first commonly in the forearm or hand (90% of cases) and later in the head (34%), lower limbs (13.7%), jaw (7.1%), face (2.9%), trunk (1.7%) and tongue (1%), usually symmetrical on both sides. The tremor is initially intermittent and gradually progresses to persistent. The frequency of the tremor is 6-12 Hz, and the frequency often decreases with age, but the amplitude increases; the symptoms increase with emotion and the amplitude tends to increase. 17% of cases have voice tremor, but it often coexists with other parts of the tremor. In long-standing cases, the amplitude of the tremor is often too large and affects the function of the motor and hinders normal life, and patients often do not seek medical attention until then. In a few cases, cerebellar dysfunction, such as postural instability and ataxic gait, is present. ET can also be associated with other rare symptoms, such as mild cognitive impairment (impaired near and working memory, verbal disfluency, etc.), suggesting frontal cortical or frontal cortico-cerebellar pathway involvement; emotional and personality changes, such as pessimism, fear, shyness, anxiety, and easy fatigue; and olfactory and hearing impairment [1,2].
ET is a risk factor for PD, and ET is also associated with dystonia in 3% to 12% of cases, with some reports as high as 47%, with cervical dystonia being the most common.
Diagnosis and differential diagnosis
To date, the diagnosis of ET is still based on clinical manifestations and lacks specific diagnostic indicators in serology, radiology or pathology. Age of onset, nature and location of tremor, rate of progression, and family history are of great value for diagnosis. In general, symmetrical and persistent postural and/or motor tremor of the hands and/or forearms and head bilaterally, a long duration (more than 3 years), a positive family history, and the ability of alcohol to temporarily relieve symptoms are helpful for the diagnosis. Conversely, sudden onset and rapid progression, resting tremor, unilateral tremor, isolated head, tongue, jaw or lower limb tremor with postural abnormalities, unsteady gait, limb tonicity and slow movements are not consistent with the diagnosis of ET [2]. In addition, care should be taken to exclude tremor due to psychological stimulation, coffee, smoking, drugs (amiodarone, atorvastatin, metoclopramide, tiquantin, β-adrenergic agonists, thyroxine, lithium salts, caffeine, prednisone, cyclosporine A, metronidazole, valproic acid, tricyclic antidepressants, selective 5-hydroxytryptamine reuptake inhibitors), etc. Tremor can also sometimes occur with vitamin B12 deficiency, hyperthyroidism or hyperparathyroidism, low calcium, low sodium, and abnormal liver and kidney function. Tremor due to hepatomegaly (Wilson’s disease) should also be excluded in young patients [1].
Tremor in PD is mainly seen at rest (resting tremor), whereas ET is postural or motor tremor; in addition to limb tremor, tremor in PD mainly involves the face, tongue and jaw, whereas ET mainly affects the head (head tremor in PD is due to intense resting tremor of the limbs) (PD with head tremor is due to severe resting tremor in the limbs that spreads to the trunk and thus affects the head). In addition, myotonicity and bradykinesia are absent in PD, while the positive family history is significantly higher in ET than in PD, and alcohol consumption temporarily reduces symptoms in ET but not in PD.
Physiological tremor is common in normal individuals, usually with high frequency and low amplitude, aggravated by coffee intake, hypoglycemia, anxiety, and without family history. Younger patients with ET are sometimes quite difficult to differentiate from physiological tremor due to the higher frequency of tremor.
Treatment
To date, there is no cure for ET, but most patients can have their symptoms reduced by medication or surgery. Before starting drug treatment, the relationship between drug efficacy and side effects must be weighed. At present, it is advocated that those with mild symptoms that do not affect motor function should not be treated urgently; drug treatment should be considered only when the symptoms are obvious and hinder the patient’s life and work. In severe patients with ineffective drug therapy, surgical treatment may be considered as appropriate [2].
Drug treatment
Although there are many drugs available for the treatment of ET, the pathophysiological mechanisms of ET are poorly understood, so drug therapy is only symptomatic. Some patients do not respond to all drugs, or they are initially effective and then fail. Generally, we start with first-line drugs, and if they are ineffective, we can switch to second-line drugs, and in severe cases, we can consider combining drugs.
The main first-line drugs are beta-adrenergic receptor blockers and primidone.
Beta-adrenergic receptor blockers are mainly propranolol. This drug has been used for 30 years for the treatment of ET and is effective in upper limb tremor, effectively reducing tremor amplitude by an average of 50% to 60; however, it has no effect on tremor frequency. The effectiveness rate is 50%-70%. The starting dose is 10-30mg per day, and the dose is increased week by week. In most cases, the daily dose of 40-160mg is effective, and the dose can be increased to 240-320mg per day if it is ineffective. elderly patients should reduce the dose appropriately (80-120mg per day). Propranolol extended release is similar or even better than regular propranolol. The mechanism of action of propranolol for ET is related to the blockade of peripheral β2 receptors, and its therapeutic effectiveness is corroborated by the involvement of peripheral mechanisms in the pathogenesis of ET because of its inability to cross the blood-brain barrier. Due to β2 receptor blockade, many side effects can be caused, including fatigue, slowed heart rate, weight gain, nausea, diarrhea, rash, impotence, memory loss, and mood changes such as depression. Severe bronchial asthma, sinus bradycardia, high atrioventricular block, cardiogenic shock, congestive heart failure, diabetes mellitus, and depression should be listed as contraindications [1,2]. Other β-adrenoceptor blockers such as metoprolol, nadolol, sotalol, and timolol are less effective than propranolol. Atenolol and pindolol are ineffective or weak for ET. Arotinolol (almarl) is a peripherally acting adrenergic receptor blocker with dual α and β effects, with a 1:8 ratio of antagonistic α to β. It provides relief of tremor and other clinical symptoms in ET patients by blocking β2 receptors, and studies have reported its efficacy to be similar to propranolol but with milder side effects [5].
Promethazine is an antiepileptic drug that is metabolized in vivo to phenethylbenzamide and phenobarbital, and its therapeutic mechanism is related to alteration of ion channels in neurons. The efficiency of treatment of ET is 40% to 50%. The starting dose is 25 mg daily at bedtime. In 30% of cases, drowsiness, nausea, vomiting, flu-like syndrome or ataxia occur after the first dose, thus interrupting the treatment. However, in contrast to propranolol, the side effects of paromidone are short-lived and well-tolerated on long-term use. Milanov et al. found that paromidone was more effective than propranolol for tremor outside the upper extremities [6].
Since the adverse effects of propranolol are heavier in older than younger people, and the sedative and cognitive impairment side effects of paromidone are heavier in younger than older people, propranolol is often preferred in younger patients, while older patients usually take paromidone first.
Second-line therapeutic agents include benzodiazepines, various antiepileptic drugs, and botulinum toxin.
Benzodiazepines may treat ET by binding to GABAA receptors and exerting GABA effects. alprazolam, clonazepam and lorazepam are more commonly used and are particularly suitable for patients whose tremor is exacerbated by concomitant anxiety. A double-blind trial showed that alprazolam (0.75-2.75 mg daily) was 75% effective in treating ET, but half of the cases showed sedative or drowsy side effects. The effect of clonazepam for ET is uncertain. The disadvantages of applying benzodiazepines are the tendency to sedation or impaired cognitive function, the risk of dependence or addiction with long-term high doses, and withdrawal symptoms with sudden discontinuation [1,2].
Antiepileptic drugs Several antiepileptic drugs have been used for ET treatment to date, including gabapentin, topiramate, and zonisamide, in addition to the above-mentioned paromidone. The structure of gabapentin is similar to that of the central inhibitory neurotransmitter GABA, and its efficacy may also be mediated by the modulation of synapses by GABA. Two clinical trials found that gabapentin (starting dose of 300 mg daily and effective dose of 1200-3600 mg daily) significantly reduced tremor with efficacy comparable to that of propranolol [7]. However, the results of another study by Pahwa et al. were negative. Side effects include fatigue, slurred speech, drowsiness, imbalance, and vomiting. Topiramate is a broad-spectrum antiepileptic agent with several mechanisms of action, including blockade of voltage-activated Na+ channels, potentiation of GABA, inhibition of the excitatory neurotransmitter glutamate, partial blockade of voltage-sensitive Ca2+ channels and inhibition of certain carbonic anhydrase isozymes, but exactly which mechanism is relevant to the treatment of ET is unknown. The improvement rate of topiramate in the treatment of ET has been reported to be 25% to 80%. The initial dose is 25 mg daily, increasing by 25 mg week by week to an effective dose (200-400 mg daily). Side effects are mainly weight loss and sensory abnormalities, and others include memory loss, glaucoma and nephrolithiasis [8].Morita et al. reported this year the results of zonisamide in the treatment of ET and found its efficacy to be similar to that of aurolol and more effective in tremor of the innervated muscles of the brain (e.g., voice, facial, tongue and head tremor) [9].
Ca2+ channel antagonists A crossover trial showed that flunarizine significantly reduced tremor in ET, but another trial had negative results. Nimodipine has also been shown to be effective in ET at a dosage of 120 mg daily, with postural hypotension as the main side effect [1].
Atypical antipsychotics Both open and double-blind controlled trials have shown that clozapine is effective in treating ET, with more than 50% reduction in tremor in most patients. Unfortunately, the use of clozapine is limited by the fact that it causes granulocyte deficiency in very few (1%) cases [1]. Other adverse effects are fever, hypotension, dizziness, headache, gastrointestinal symptoms, and weight gain.
Antidepressants Mirtazapine (mirtazapine) is a new antidepressant that enhances 5-hydroxytryptamine and norepinephrine function through presynaptic alpha 2 antagonism. There are only case reports of effective treatment for ET, so further trials are still needed.
Carbonic anhydrase inhibitors In 1991, methazolamide was found by chance to improve the symptoms of ET associated with the treatment of glaucoma. A subsequent open clinical trial showed that methazolamide was 43% effective in treating ET, but another double-blind controlled trial was negative. Adverse effects of this drug are frequent and include abnormal sensation, sedation, headache, and gastrointestinal symptoms. Acetazolamide has also been reported for the treatment of ET, but its efficacy is uncertain.
Clonidine Serrano-Duenas reported a double-blind randomized controlled trial of clonidine for mild to moderate ET with an efficiency similar to that of propranolol.
Botulinum toxin A If the above medications do not work, local injection of botulinum toxin A can be considered for treatment. Botulinum toxin is a neurotoxin produced by Clostridium botulinum, which is injected into the muscle to produce muscle weakness or block the impulse output of gamma motor neurons and muscle shuttle to reduce tremor. There are reports of significant symptom reduction in patients with head tremor after cervical injection of botulinum toxin A. However, there are also reports of ineffective results of bilateral cervical injections of botulinum toxin in 10 patients with head tremor without dystonia. Side effects included neck weakness and dysphagia. Open studies suggest that botulinum toxin may be useful for primary vocal tremor, with satisfactory improvement with unilateral injections, the most common side effects being transient volume loss and dysphonia after injection [2]. Two controlled trials treated hand tremor with botulinum toxin, both with poor efficacy. Botox treatment of rare sites of tremor (e.g., jaw and cheek) has been reported only sporadically.
Ethanol Most ET patients have improved tremor after alcohol consumption, but the mechanism of action is unknown. Studies of PET in alcohol-responsive ET patients have shown that alcohol decreases blood flow to the cerebellum but increases blood flow to the inferior olivary nucleus, suggesting that the effect of alcohol may be due to a decrease in impulses to the inferior olivary nucleus by inhibiting the overactivity of cerebellar synapses. The ineffectiveness of methylpentynol in the treatment of ET suggests that the basic body of alcohol does not counteract the tremor and that the anti-tremor effect of ethanol is not related to the sedative effect. Small amounts of intra-arterial ethanol input did not reduce tremor in this limb, suggesting that the effects of ethanol are centrally mediated. Observations have shown that the amount of alcohol consumed by ET patients to reduce symptoms gradually increases over time; moreover, chronic alcoholism itself can cause persistent tremor, and thus, the use of alcohol to reduce tremor in ET is not advisable [2].
Surgical treatment
Both thalamotomy and deep thalamic brain stimulation are included. Originally applied mainly to people with ET upper limb tremor, it was later found to be effective for head and voice tremor as well.
Thalamotomy According to the central oscillatory mechanism of ET pathogenesis, the tremor of the contralateral limb can be improved by stereotactic thalamotomy on one side [1,2]. Goldman reported that the treatment of ET was effective in all 8 cases. Adverse effects include limb weakness, dysarthria, and in a few cases, oculomotor spasm and ataxia.
Deep thalamic brain stimulation (DBS) The technique has been applied to treat ET since the mid-1980s, with the advantages of less damage to tissues, adjustable stimulation frequency, the ability to perform treatment on both sides, and the ability to terminate treatment at any time; the efficacy is better, with an efficiency of more than 70%. The disadvantages are the high cost, the possibility of infection or inflammatory reactions due to foreign body implantation, the need to adjust the stimulation parameters, and the need for regular battery replacement and other hardware [10]. A multicenter study of unilateral DBS for ET showed symptomatic improvement and significant improvement in quality of life in most cases (27/29) at 3 months after surgery [11].Sydow et al. followed 19 cases of DBS-treated ET for 6 years with stable tremor improvement; the efficacy was better for postural tremor than for motor tremor. Surgical complications include and intracerebral infection and bleeding, and side effects include sensory abnormalities, dysarthria, bradykinesia, gait instability, dystonia, and local pain, but are transient. In a few cases, the implanted device failed and required reoperation [12]. The side effects of thalamotomy such as ataxia, dysarthria, and gait stability (42%) were also significantly higher than those of DBS (26%), and 31% of the former side effects persisted, while DBS was able to eliminate them by adjusting the stimulation parameters. Thus, DBS is considered to be superior to thalamotomy for ET.
Conclusion
ET is clinically common and, despite its slow progression, can severely affect motor function in advanced stages. Since the pathogenesis of ET has not been fully elucidated, only symptomatic treatment is available, with propranolol and paromidone as the first choice. Surgical treatment may be considered for those who defy pharmacological treatment, as appropriate. Research on the etiology and pathophysiology of ET should be further deepened in order to cure the disease from its root cause.