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Table of Contents

Revised March 28, 2005

Patrick J.
Sweeney, MD

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Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy
and Outcomes

References

Tremor is the most common movement disorder. It is also probably the oldest sign in medicince as the quote from the Book of Psalms testifies to: "the Lord reignth, let the people tremble." In 1817, James Parkinson characterized the tremor in his essay on The Shaking Palsy. "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 of tremor include:

• Rest or Resting 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 Table 1.
  
• Postural Tremor
  Postural tremor occurs during maintenance of a position against gravity and increases with action.
• Action or Kinetic Tremor
  This form of tremor occurs during voluntary movement. Table 2 lists examples of postural and action tremors.
• Task-specific Tremor
  This tremor emerges during specific activity. An example of this type is primary writing tremor.
• Intention or Terminal Tremor
  Intention 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.

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 of onset of ET has two peaks, early in life and in older age group.

Parkinson's disease tremor generally occurs during rest, but some patients have postural and action tremor components. Jankovic³ has emphasized that in those Parkinson patients who present with postural tremor distinction from Essential Tremor is possible by observing the latency (that is the timed interval starting with assumption of outstretched posture and ending with tremor onset) before the tremor emerges. 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 within Europe and North America age adjusted prevalence ratio range from 56 to 234/100,000 compared to a range of 14 to 148/100,000 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 production of 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 may possibly originate in basal ganglia, and essential tremor within the inferior olive and thalamus.
• Abnormal functioning of the cerebellum may produce tremor. Positron emission tomography studies have shown cerebellar activation in almost all forms of tremor.⁷

Physiological Tremor
This is a very-low-amplitude fine tremor (between 6 Hz and 12 Hz) that is barely visible to the naked eye. It is present in every normal individual during maintaining a posture or movement. Neurologic examination results of patients with physiologic tremor are usually normal.

Enhanced Physiologic Tremor
This 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 may or may not be present. Tremor symptoms may improve after discontinuation of the causative agent.

Essential Tremor
Essential tremor is the most common form of all movement disorders. Classical essential tremor is predominantly a postural- or action-type tremor and usually patient has positive family history of tremor. Drinking alcohol often temporarily reduces the tremor. Other associated symptoms may include mild gait difficulty and, as a group, patients with essential tremor have increase hearing disability compared to controls or patients with Parkinson's Disease. The degree of hearing impairment seems to correlate with the tremor severity.⁸

Parkinson's Tremor
This is a low-frequency rest tremor typically defined as a pill-rolling tremor. In some patients, postural and action tremor may also occur. 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 (Table 3).

Cerebellar Tremor
Cerebellar tremor is a low-frequency (less than 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, dysdiadokinesia and dysarthria.

Holmes' Tremor
The term 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 slow 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.

Drug-induced Tremor
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 4 is a list of drugs that may induce tremor, along with the types of tremors and neurologic signs they produce. It has recently been observed that tremor reappears in Parkinson's patients treated with cholinesterase inhibitors reinforcing the observation that anticholingergic agents are very effective in amelurating the tremor of Parkinson's Disease.⁹

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
Psychogenic tremor may 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
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 to 18 Hz), and no other clinical signs and 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 (TRIG) proposed a working definition of essential tremor for research studies:¹⁰

Definite essential tremor: Postural tremor in the arms which increases during action in the absence of any condition or drug known to cause enhanced physiological tremor and in the absence of cerebellar symptoms and signs, and in the absence of PD and dystonia. Head tremor may or may not be present.

Probable essential tremor: Postural tremor in the arms without increase during action in the absence of any condition or drug known to cause enhanced physiological tremor and in the absence of cerebellar symptoms and signs, and in the absence of PD and dystonia. Vocal and head or neck tremor in the absence of any condition or drug known to cause enhanced physiological tremor and in the absence of cerebellar symptoms and signs, and in the absence of PD and dystonia.

Possible essential tremor: Postural tremor in the arms and action tremor in arms in the absence of any condition or drug known to cause enhanced physiological tremor and in the absence of cerebellar symptoms and signs, but in the presence of PD and dystonia.

Clinical History
The clinical history must detail tremor onset, duration, severity, affected area, activating factors, relieving factors, effect of alcohol, family history, and associated symptoms.

Clinical Examination
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 with a scale developed by Kahn et al as follows:¹¹

0 - No tremor
1 - Slight tremor
2 - Moderate tremor (less than 2 cm excursion)
3 - Marked tremor (2 cm to 4 cm excursion)
4 - Severe tremor (more than 4 cm excursion)

Laboratory Work-up
A laboratory work-up 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 of age) with signs of parkinsonism and tremor, a serum copper, serum ceruloplasmin, 24-h urinary copper, and slit-lamp examination is 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 (EMG) recordings.

Differential Diagnosis
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 EMG or electroencephalogram (EEG) as well as back-averaging help to make the diagnosis. Clonus is a rhythmical movement around joints that is stimulated through stretch reflex. Passive stretching increases the clonus but not of 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, EMG 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.

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 risk of taking medication is higher than its benefit. Treatment options for essential tremor includes pharmacologic approaches and surgical management. Additionally, 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 variable degree 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.

Pharmacologic Management
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 monotherapy dosages, combination therapy may be instituted. For appropriate candidates in whom pharmacologic therapy is inadequate, localized injections of botulinum toxin may be considered.The beta-adrenergic receptor antagonist propranolol (Inderal) is used in the treatment of essential tremor. Approximately 60% to 70% of patients may notice reduction in tremor amplitude with therapy. Propranolol is most effective for upper limb tremor and less effective for head and voice tremors. Contraindications to its use 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 analog of phenobarbital. The drug reduces tremor amplitude by up to 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 mg to 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 may 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 and propranolol is not beneficial, the two agents can 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 may 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 previously had been tried but showed inconsistent benefit in the treatment of 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 is now being used as a therapeutic option for selected patients with tremor. Botulinum toxin acts through presynaptic inhibition of acetylcholine release at the neuromuscular junction. Open-label studies as well as 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 ant-epileptic drugs in the treatment of essential tremor continues to evolve with gabapentin (Neurontin) being 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, may 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. Table 5 is a brief list of dopaminergic agents used to treat the disorder as well as the major side effects they may cause.

Surgical Management
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.

Less common forms of tremor may be treated as indicated in Table 6.¹⁴

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.

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1. Parkinson J: An Essay on the Shaking Palsy. London: Whittingham and Rowland, 1817.
   
   
2. Findley LJ, Koller WC. Essential tremor: a review. Neurology. 1987;37:1194-1197.
   
   
3. Jankovic J, Schwartz KS, Ondo W. Re-emergent tremor of Parkinson's disease. J Neurol Neurosurg Psychiatry. 1999;67:646-650.
   
   
4. Elble RJ. The pathophysiology of tremor. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York:McGraw-Hill Inc, 1997;405-417.
   
   
5. Deuschl G, Krack P, Lauk M, Timmer J. Clinical neurophysiology of tremor. J Clin Neurophysiol. 1996;13:110-121.
   
   
6. Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol. 1996;13:133-144.
   
   
7. 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;36:636-642.
   
   
8. Ondo WG, Sutton L, Dat Vuong K, Lai D, Jankovic J. Hearing impairment in essential tremor. Neurology. 2003;61:1093-1097.
   
   
9. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for Dementia Associated with Parkinson's Disease. N Engl J Med. 2004;351:2509-18.
   
   
10. Koller W, Lang A, Vetere-Overfield B, et al. Psychogenic tremors. Neurology. 1989;39:1094-1099.
    
    
11. Findley LJ, Koller WC, De Witt P, et al: Classification and definition of tremor. Cited by Findley LJ, in Lord Walton of Detchant(ed): indications for and clinicam implications of botulinum toxin therapy. London: Royal society of medicine, 1993, PP 22-23.
    
    
12. Bain PG, Findley LJ, Atchison P, Behari M, Vidailhet M, Gresty M, Rothwell JC, Thompson PD, Marsden CD. Assessing tremor severity Journal of Neurology, Neurosurgery & Psychiatry.1993;56:868-73.
    
    
13. 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;11:250-256.
    
    
14. Wissel J, Masuhr F, Schelosky L, Ebersbach G, Poewe W. Quantitative assessment of botulinum toxin treatment in 43 patients with head tremor. Mov Disord. 1997;12:722-726.
    

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