Tremor is the most common movement disorder. In 1817, James Parkinson characterized the tremor in his essay on the shaking palsy as "involuntary tremulous motion in parts not in action." 1
Tremor is defined as a rhythmic, involuntary, oscillating movement of a body part occurring in isolation or as part of a clinical syndrome. In clinical practice, characterization of tremor is important for etiologic consideration and treatment. Common types include resting tremor, postural tremor, kinetic tremor, task-specific tremor, and intention tremor.
Resting tremor occurs when a body part is at complete rest against gravity. Tremor amplitude decreases with voluntary activity. Examples of resting tremor are provided in Box 1. Postural tremor occurs during maintenance of a position against gravity and increases with action. Action or kinetic tremor occurs during voluntary movement. Box 2 lists examples of postural and action tremors. Task-specific tremor emerges during a specific activity. An example of this type is primary writing tremor. Intention (or terminal) tremor manifests as a marked increase in tremor amplitude during a terminal portion of targeted movement. Examples of intention tremor include cerebellar tremor and multiple sclerosis tremor.
|Box 1: Examples of Rest Tremors|
|Drug-induced parkinsonism (neuroleptics, metaclopromide, and phenothiazines)|
|Long-standing essential tremor|
|Parkinson's plus syndromes (rest tremor is less common)|
© 2002 The Cleveland Clinic Foundation.
|Box 2: Examples of Postural and Action Tremors|
|Essential tremor (primarily postural)|
|Metabolic disorders (thyrotoxicosis, pheochromocytoma, hypoglycemia)|
|Drug-induced parkinsonism (lithium, amiodarone, β-adrenergic agonists)|
|Toxins (alcohol withdrawal, heavy metals)|
|Neuropathic tremor (neuropathy)|
© 2002 The Cleveland Clinic Foundation.
Prevalence rates vary, depending on the tremor type. Essential tremor is the most common form, with a prevalence rate ranging from 0.4% to 5.6%.2 Family history is positively identified in approximately 60% of patients, and the pattern of inheritance is autosomal dominant. Age at onset of essential tremor has two peaks, early in life and in older age groups.
Parkinson's disease tremor generally occurs during rest, but some patients have postural and action tremor components. According to Jankovic and colleagues,3 postural tremor in Parkinson's disease patients can be distinguished from essential tremor by observing the latency, which is the timed interval starting with assumption of outstretched posture and ending with tremor onset. He has designated this as emergent tremor and observes that the latency for the tremor to appear in Parkinson's disease (about 9 seconds) is significantly longer than the latency for essential tremor (about 1-2 seconds).
Population surveys for Parkinson's disease in different geographic regions of the world have shown a wide range of prevalence rates. For whites in Europe and North America, the age-adjusted prevalence ratio ranges from 56 to 234 per 100,000 compared with a range of 14 to 148 per 100,000 in Asia.
Four basic mechanisms are linked to the production of tremor.4-6 It is likely that combinations of these mechanisms produce tremor in different diseases. Mechanical oscillations of the limb can occur at a particular joint; this mechanism applies in cases of physiologic tremor. Reflex oscillation is elicited by afferent muscle spindle pathways and is responsible for stronger tremors by synchronization. This mechanism is a possible cause of tremor in hyperthyroidism or other toxic states. Central oscillators are groups of cells in the central nervous system present in the thalamus, basal ganglia, and inferior olive. These cells have the capacity to fire repetitively and produce tremor. Parkinsonian tremor might originate in the basal ganglia, and essential tremor might originate within the inferior olive and thalamus. Abnormal functioning of the cerebellum can produce tremor. Positron emission tomography studies have shown cerebellar activation in almost all forms of tremor.7
Signs and Symptoms
Tremor can be classified on a clinical and etiologic basis. Signs and symptoms depend on tremor type and cause.
Physiologic tremor is a very-low-amplitude fine tremor (6 Hz-12 Hz) that is barely visible to the naked eye. It is present in every normal person while maintaining a posture or movement. Neurologic examination results of patients with physiologic tremor are usually normal.
Enhanced Physiologic Tremor
Enhanced physiologic tremor is a high-frequency, low-amplitude, visible tremor that occurs primarily when a specific posture is maintained. Drugs and toxins induce this form of tremor. The suspected mechanism is mechanical activation at the muscular level. Signs and symptoms of drug toxicity or other side effects might or might not be present. Tremor symptoms can improve after the causative agents are discontinued.
Essential tremor is the most common form of all movement disorders. Classic essential tremor is predominantly a postural- or action-type tremor, and usually the patient has a positive family history of tremor. Drinking alcohol often temporarily reduces the tremor. Other associated symptoms can include mild gait difficulty and, as a group, patients with essential tremor have increased hearing disability compared with controls or patients with Parkinson's disease. The degree of hearing impairment seems to correlate with the tremor severity (Table 1).8
Table 1: Characteristics of Parkinson's Tremor versus Essential Tremor
|Characteristic||Parkinson's Tremor||Essential Tremor|
|Tremor type||Resting tremor||Postural and action tremors|
|Age||Older age (>60yr)||All age groups|
|Family history||Usually negative||Positive in >60% of patients|
|Muscle tone||Cogwheel rigidity||Normal|
|Gait||Decreased arm swing||Normal|
|Tremor latency||Longer: 8-9 sec||Shorter: 1-2 sec|
Parkinson's tremor is a low-frequency rest tremor typically defined as a pill-rolling tremor. Some patients also have postural and action tremors. Parkinson's tremor usually occurs in association with other symptoms, such as micrographia, slowness (bradykinesia), and rigidity. Usually, there is no family history of Parkinson's tremor, and alcohol consumption does not decrease movement (see Table 1).
Cerebellar tremor is a low-frequency (<4 Hz) intention tremor that usually occurs unilaterally. Common causes are multiple sclerosis, stroke, and cerebellar injury. Signs and symptoms of cerebellar dysfunction may be present, including ataxia, dysmetria, dysdiadochokinesia, and dysarthria.
Holmes' tremor or rubral tremor designates a combination of rest, postural, and action tremors due to midbrain lesions in the vicinity of the red nucleus.5 This type of tremor is irregular and low frequency (4.5 Hz). Signs of ataxia and weakness may be present. Common causes include cerebrovascular accident and multiple sclerosis, with a possible delay of 2 weeks to 2 years in tremor onset and occurrence of lesions.
Types of tremors induced by drugs include enhanced physiologic tremor, rest tremor, and action tremor. Signs and symptoms of drug-induced tremors depend on the drug used and on a patient's predisposition to its side effects. Some drugs cause extrapyramidal side effects manifesting as bradykinesia, rigidity, and tremor. Table 2 lists drugs that can induce tremor, along with the types of tremors and neurologic signs they produce. Tremor reappears in Alzheimer's disease patients treated with cholinesterase inhibitors, reinforcing the observation that anticholinergic agents are very effective in ameliorating the tremor of Parkinson's disease.9
Table 2: Drug-induced Tremors and Corresponding Neurologic Signs
|Drug or Drug Class||Tremor Type||Neurologic Signs|
|Lithium||Rest, postural, action||Extrapyramidal|
© 2002 The Cleveland Clinic Foundation.
Tremor Due to Systemic Disease
Tremor due to systemic disease usually occurs when the patient is moving or assumes a specific position. Associated symptoms include asterixis, mental status changes, and other signs of systemic illness. Diseases such as thyrotoxicosis and hepatic failure as well as delirium tremens and drug withdrawal are among the common causes.
Psychogenic tremor can involve any part of the body, but it most commonly affects the extremities. Usually, tremor onset is sudden and begins with an unusual combination of postural, action, and resting tremors. Psychogenic tremor decreases with distraction and is associated with multiple other psychosomatic complaints.9
Orthostatic tremor is considered to be a variant of essential tremor. This type of tremor occurs in the legs immediately on standing and is relieved by sitting down. Orthostatic tremor is usually high frequency (14 Hz-18 Hz), and no other clinical signs or symptoms are present.
Diagnostic evaluation of the tremor patient should include a thorough clinical history, clinical examination (including tremor rating), and differential diagnosis.
The Tremor Research Investigation Group has proposed a working definition of essential tremor for research studies. 10
Definite essential tremor is postural tremors in the arms that increase during action in the absence of any condition or drug known to cause enhanced physiologic tremor and in the absence of cerebellar symptoms and signs, and in the absence of Parkinson's disease and dystonia. Head tremor may or may not be present.
Probable essential tremor is postural tremor in the arms without increase during action in the absence of any condition or drug known to cause enhanced physiologic tremor and in the absence of cerebellar symptoms and signs, and in the absence of Parkinson's disease and dystonia. Vocal and head or neck tremor occur in the absence of any condition or drug known to cause enhanced physiologic tremor and in the absence of cerebellar symptoms and signs, and in the absence of Parkinson's disease and dystonia.
Possible essential tremor is postural tremor in the arms and action tremor in arms in the absence of any condition or drug known to cause enhanced physiologic tremor and in the absence of cerebellar symptoms and signs, but in the presence of Parkinson's disease and dystonia.
The clinical history must detail tremor onset, duration, severity, affected area, activating factors, relieving factors, effect of alcohol, family history, and associated symptoms.
The clinical examination should determine a tremor rating and tremor frequency. The patient also should be examined during rest, when assuming various positions, and when moving. An examination of gait, muscle tone, facial expressions, and dexterity is also important, particularly in differentiating essential tremor from Parkinson's disease. Tremor in each affected body part can be rated as resting, kinetic, or postural and with a scale developed by Findley and colleagues as follows: 11
- No tremor
- Slight tremor
- Moderate tremor (<2 cm excursion)
- Marked tremor (2 cm-4 cm excursion)
- Severe tremor (>4 cm excursion)
A laboratory workup is not necessary for most tremor patients. A thyroid function test is helpful to rule out hyperthyroidism in patients with signs of thyroid disease and tremor, particularly postural and action types. In young patients (younger than 40 years) with signs of parkinsonism and tremor, a serum copper, serum ceruloplasmin, 24-hour urinary copper, and slit-lamp examination are necessary to rule out Wilson's disease. To rule out systemic causes of tremor, such as hypoglycemia, liver disease, electrolyte imbalance, or drug abuse, appropriate tests should be ordered. A magnetic resonance imaging or computed tomography scan of the brain is needed in some patients if tremor onset is acute, progression is rapid, and cerebellar signs suggest stroke, demyelinating disease, or structural lesion. Tremor also can be analyzed and diagnosed with the help of accelerometers and surface electromyogram recordings.
Differential diagnosis of tremor includes myoclonus, clonus, asterixis, and epilepsia partialis continua. Myoclonus is irregular or rhythmic brief muscle jerks that can mimic tremor. Electrophysiologic analysis by electromyogram or electroencephalogram (EEG) as well as back-averaging help to make the diagnosis. Clonus is a rhythmic movement around joints that is stimulated through stretch reflex. Passive stretching increases the clonus but not tremor, helping to differentiate clonus from tremor. Asterixis is a type of myoclonus that can cause a flapping tremor of the extremities. Asterixis can be differentiated from tremor on the basis of irregular movements. In addition, electromyogram readings show pauses longer than 200 msec. Epilepsia partialis continua can cause rhythmic jerks in the extremities. A clinical history that is positive for epilepsy and EEG readings that show abnormal spikes help point to the correct diagnosis.
Treatment and outcomes
Essential and Parkinson's Tremors
Essential tremor is a slowly progressive disorder for which no preventive therapy is available. In some cases, no treatment is required, particularly when disability is minimal or the risks from taking medication outweigh its benefits. Treatment options for essential tremor include pharmacologic approaches and surgical management. Physical and psychological measures, such as biofeedback and relaxation techniques, may be helpful in managing mild tremor.
Parkinson's disease is a neurodegenerative disorder that manifests clinically with varying degrees of rest tremor of one or more limbs in association with rigidity and bradykinesia. No preventive or neuroprotective therapy is available. Mild rest tremor without disabling motor symptoms does not require treatment. A wide range of treatment options for Parkinson's disease tremor is available and includes oral medications, botulinum toxin injections, and deep brain stimulation surgery.
Treatment of essential tremor usually begins with primidone or propranolol monotherapy. The dosages are gradually increased to achieve optimal response. If tremor control remains inadequate with increased doses of monotherapy, combination therapy may be instituted. For appropriate candidates in whom pharmacologic therapy is inadequate, localized injections of botulinum toxin may be considered.
The β-adrenergic receptor antagonist propranolol (Inderal) is used in the treatment of essential tremor. Approximately 60% to 70% of patients notice reduction in tremor amplitude with therapy. Propranolol is most effective for upper limb tremor and less effective for head and voice tremors. Contraindications include heart failure, cardiac conduction disorders, asthma, and diabetes. Side effects include decreased exercise tolerance, fatigue, bradycardia, and peripheral vasoconstriction. Propranolol should not be stopped abruptly due to possible rebound hypertension.
Propranolol should be started at 40 mg twice daily for the treatment of essential tremor. The dosage may gradually be increased to 120 mg/day to 320 mg/day in once-daily or divided doses. Doses higher than 320 mg/day have not proved to be efficacious. Other beta blockers used in the treatment of essential tremor include atenolol, metoprolol, timolol, and nadolol; however, these are not as efficacious as propranolol.
Primidone (Mysoline) is a structural analogue of phenobarbital. The drug reduces tremor amplitude by 60% to 70%. Although primidone therapy reduces hand tremor, tremors of the head, voice, and other areas improve less. The starting dose of primidone should be low (12.5-25 mg), taken at bedtime, and gradually increased until tremor reduction is achieved. The maximum dosage is 750 mg/day in three divided doses. Primidone is slightly more effective than beta-blocker therapy. Side effects include nausea, vomiting, sedation, vertigo, ataxia, and headache. These side effects can be prevented if therapy is started at low doses.
If monotherapy with primidone or propranolol is not beneficial, the two agents may be used in combination. Primidone can gradually be increased to a range of 150 mg/day to 250 mg/day. Propranolol can gradually be increased over several weeks to 240 mg/day or as high as 320 mg/day.
The carbonic anhydrase inhibitors acetazolamide and methazolamide are effective in some patients with essential tremor, particularly those with head tremor. However, side effects are common, including headaches, sedation, confusion, depression, paresthesias, and gastrointestinal disturbances. Double-blind trials of these agents have demonstrated no proven efficacy when compared with placebo.
Benzodiazepines such as diazepam, alprazolam, and clonazepam improve tremor in some patients with essential tremor. However, benefits associated with benzodiazepine therapy in these patients may be due, in part, to its anxiolytic effects. Side effects include excessive sedation. A number of other agents have been tried but have shown inconsistent benefit in treating essential tremor. In double-blind controlled studies, gabapentin has proved to be no more efficacious than placebo. In small trials, the calcium channel blockers nimodipine and nicardipine have shown some promise; however, mirtazapine (Remeron) has shown no consistent benefits.
Botulinum toxin types A and B have been used for dystonia and spasticity and are now being used as a therapeutic option for select patients with tremor. Botulinum toxin acts through presynaptic inhibition of acetylcholine release at the neuromuscular junction. Open-label studies and double-blind studies have demonstrated the efficacy of botulinum toxin type A in treating limb, head, vocal, palatal, and other tremors.12,13 The role of antiepileptic drugs in the treatment of essential tremor continues to evolve; gabapentin (Neurontin) is the most widely studied.
Parkinson's disease tremor usually improves with dopaminergic and anticholinergic medications. Anticholinergics include trihexyphenidyl, benztropine, and procyclidine. The combination of dopaminergic agents and anticholinergics is effective in tremor-predominant Parkinson's disease. However, the side effects of anticholinergic therapy, such as dry mouth, blurry vision, urinary difficulty, and confusion, can limit the use of these agents. These drugs should be avoided in older patients, and medication should be stopped gradually to avoid severe rebound effect on tremor.
Dopaminergic drugs are the mainstay of treatment for Parkinson's disease tremor. Box 3 lists dopaminergic agents used to treat the disorder and the major side effects they can cause.
|Box 3: Dopaminergic Drugs Used to Treat Parkinson's Disease Tremor and Their Side Effects|
© 2002 The Cleveland Clinic Foundation.
For patients with severe, disabling, medication-refractory essential tremor, surgery is a reasonable treatment option. Surgical management includes ablative therapy through stereotactic thalamotomy or chronic thalamic deep brain stimulation. The ventral intermediate nucleus of the thalamus is the best target for both ablative and deep brain stimulation surgeries. Contraindications for surgical management of essential tremor include unstable medical illnesses, swallowing difficulty, and marked cognitive problems.
Similarly in Parkinson's disease, tremor improves significantly after subthalamic nucleus deep brain stimulation surgery. Although these surgical techniques are widely available, they should be used with caution and only after exhausting all possible pharmacologic treatment options.
|Box 4: Treatment of Less Common Forms of Tremor|
|Enhanced Physiologic Tremor|
© 2002 The Cleveland Clinic Foundation.
Pharmacologic therapy should be considered initially for less common forms of tremor such as enhanced physiologic tremor, dystonic tremor, orthostatic tremor, and cerebellar tremor. If pharmacologic treatment fails, deep brain stimulation surgery should be considered in certain tremor types.
- Tremor is the most common movement disorder.
- It is characterized by rhythmic, involuntary, oscillating movement of a body part.
- Abnormal functioning of the cerebellum can produce tremor. Positron emission tomography studies have shown cerebellar activation in almost all forms of tremors.
- Tremor can be classified on a clinical and etiologic basis. It can occur at rest (Parkinson's disease) or with posture and action (essential tremor).
- Differential diagnosis of tremor includes myoclonus, clonus, asterixis, and epilepsia partialis continua.
- Treatment includes pharmacologic therapy and deep brain stimulation.
- Parkinson J. An Essay of the Shaking Palsy. London: Whittingham and Rowland; 1817.
- Findley LJ, Koller WC. Essential tremor: a review. Neurology 1987; 37:1194â€“1197.
- Jankovic J, Schwartz KS, Ondo W. Re-emergent tremor of Parkinson's disease. J Neurol Neurosurg Psychiatry 1999; 67:646â€“650.
- Elble RJ. The pathophysiology of tremor. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York, NY: McGraw-Hill; 1997:405â€“417.
- Deuschl G, Krack P, Lauk M, Timmer J. Clinical neurophysiology of tremor. J Clin Neurophysiol 1996; 13:110â€“121.
- Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol 1996; 13:133â€“144.
- Wills AJ, Jenkins IH, Thompson PD, Findley LJ, Brooks DJ. Red nuclear and cerebellar but no olivary activation associated with essential tremor: a positron emission tomographic study. Ann Neurol 1994; 36:636â€“642.
- Ondo WG, Sutton L, Dat Vuong K, Lai D, Jankovic J. Hearing impairment in essential tremor. Neurology 2003; 61:1093â€“1097.
- Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004; 351:2509â€“2518.
- Koller W, Lang A, Vetere-Overfield B, et al. Psychogenic tremors. Neurology 1989; 39:1094â€“1099.
- Findley LJ, Koller WC, De Witt P, et al. Classification and definition of tremor. In: Lord Walton of Detchant, ed. Indications For and Clinical Implications of Botulinum Toxin Therapy. London: Royal Society of Medicine Press; 1993:22â€“23.
- Bain PG, Findley LJ, Atchison P, et al. Assessing tremor severity. J Neurol Neurosurg Psychiatry 1993; 56:868â€“873.
- Jankovic J, Schwartz K, Clemence W, Aswad A, Mordaunt J. A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor. Mov Disord 1996; 11:250â€“256.
- Wissel J, Masuhr F, Schelosky L, Ebersback G, Poewe W. Quantitative assessment of botulinum toxin treatment in 43 patients with head tremor. Mov Disord 1997; 12:722â€“726.
- Findley LJ. Classification of tremors. J Clin Neurophysiol 1996; 13:122â€“132.
- van den Noort S. Essential tremor. N Engl J Med 2002; 346:709â€“710.