A comprehensive review of tremor

An organized approach to the patient assessment is crucial to reaching an accurate diagnosis. Consider the constellation of signs and symptoms, and know the characteristics of each form of tremor.

Kevin T. Wyne, MPAS, MSc

The author is a PA at the Rockford Spine Center in Rockford, Ill. He has indicated no relationships to disclose relating to the content of this article.

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A 65-year-old man presents to his primary care provider with bilateral tremor in his upper extremities that has worsened gradually over the past several months. The tremor is slightly worse on the left side and more pronounced near his hand. The tremor embarrasses the patient, and he feels that his coworkers have begun to question his ability to perform required tasks. These situations make him nervous, which makes his tremor worse. His father had Parkinson’s disease (PD), and the patient is worried that he is also developing the condition.

Many practitioners feel unprepared to deal with a patient like this one, which means that patients who present with tremor often are inadequately treated or referred quickly to a neurologist. Knowing a few basic concepts, however, can help clinicians to assess tremor symptoms quickly and maximize therapy, as well as to recognize when additional interventions are needed. 

Differentiating pathologic forms of tremor

Although pathologic tremors can be readily observed, the challenge is determining the etiology and the most effective treatment. More than 10 distinct types of tremor, with varying patterns of onset and degrees of progression, have been identified.¹ Although their characteristics have been documented, the underlying disease mechanisms are not well understood, leading to disagreement about how particular tremors are categorized and treated. Another complicating factor can be multiple kinds of tremor in the same patient.

All patients have physiologic tremor, or rhythmic oscillatory movements of a body part with a relatively constant frequency and variable amplitude.¹ Most people are unaware of these tremors, which are not usually visible to the naked eye. However, several factors can exacerbate inherent tremors to the point of dysfunction. Most of these factors increase sympathetic activity; they include medications, toxins, and physiologic or emotional states (see Table 1).^2,3 While enhancement of normal physiologic tremor is most common, several pathologic forms can also occur and can be helpfully characterized as either resting or action tremors.

Resting tremor occurs when the affected body part is relaxed, stationary, and completely supported by gravity; it lessens or disappears with active motion. Since resting tremor does not affect voluntary activity, it does not usually limit a patient’s ability to function, although it can lead to embarrassment by complicating motor activities that involve pauses, such as using utensils or handwriting.^4,5 PD is the most common cause of resting tremor (see “Differentiating types of tremor”).

Action tremor, by contrast, occurs with muscle contraction and is further divided into postural, isometric, and kinetic forms. Postural tremor occurs when the affected body part maintains its position against gravity. Isometric tremor occurs with muscle contraction against stationary objects. Kinetic tremor is associated with movement and can be subdivided into simple tremor, which occurs with any movement, and intention tremor, which occurs with goal-directed movements. With the latter, the tremor typically increases as the hand moves closer to its goal; this contrasts with postural and isometric tremors, which either are constant throughout the range of motion or increase after the affected extremity reaches its goal.

Although these classifications are helpful, several types of tremor do not easily fit into these categories. For example, some postural tremors can continue when the limb is supported, thus making the distinction between postural and resting tremor difficult.⁵  

History and physical examination

A careful history and a review of systems are crucial for accurate diagnosis and subsequent treatment. This approach should include a detailed characterization of the tremor itself and a thorough family and social history, including all medications and drug or alcohol use. The practitioner must also consider any underlying medical conditions that can influence tremor manifestation.

Along with the history, the practitioner uses clinical judgment and observation of the tremor to make a diagnosis. The key variables include the degree of symmetry, rhythmicity (regular or irregular oscillations), location (distal or proximal), amplitude (degree of limb displacement with involuntary muscle contraction), and frequency (number of oscillations per second).⁶ Though precise determinations of these variables can be determined only electrophysiologically, rough estimates can greatly facilitate tremor diagnosis. For example, frequency can be characterized as slow (2-5 Hz), intermediate (5-10 Hz), or fast (10-18 Hz). Amplitude can similarly be described as fine, medium, or coarse, depending on the degree of displacement produced by the tremor.⁷

Observation of resting tremor should occur when the patient is relaxed, with the hands resting comfortably in the lap. If no tremor is observed, the practitioner can ask the patient to perform mental calculations or complex movements with the opposite limb (eg, rapidly touching each finger to the adjacent thumb).⁸ The resting tremor may be elicited by activating a neural system that is not involved with the tremulous limb. In addition, these tasks may evoke bradykinesia, leading toward a diagnosis of PD, or eliminate the tremor completely, indicating that it may be psychogenic.^4,6 Patients should also passively flex and extend their limbs to elicit any rigidity. Affected limbs will usually evidence a decrease in tremor amplitude when weighted, while psychogenic tremors often become exacerbated.⁹

If no tremor is elicited at rest, several maneuvers may provide clues to the origin of the probable action tremor. Postural tremor can often be observed by having the patient extend the hands perpendicular to the body. The semipronated position (palms partially downward) can increase essential tremor (ET), while the supinated position (palms upward) can inhibit it.⁶ Isometric tremor can be elicited by having the patient make a fist or squeeze the examiner’s fingers. Intention tremor often indicates an underlying cerebellar disease and can be elicited by finger-to-finger, finger-to-nose, or heel-to-shin testing (see Figure 1). Alternatively, the wing position—bilateral shoulder abduction and elbow flexion with palms facing downward and index fingers pointed toward one another in front of the chest—often reveals proximal tremors associated with multiple sclerosis (MS) or other cerebellar diseases.^6,9

These maneuvers, in conjunction with a detailed patient history, should allow the practitioner to determine the nature of the patient’s tremor. However, this task is more difficult if the presentation is atypical or if the patient has multiple tremor syndromes. In these cases, the practitioner should determine the predominant tremor syndrome, noting that a tremor that diminishes with movement is likely to be a resting tremor and one that worsens with movement is an action tremor, even if it is present at rest.⁹ Signs or symptoms that may indicate an underlying disorder should also be noted. For example, bradykinesia or rigidity points toward PD, while nystagmus or ataxia may indicate cerebellar dysfunction. While formulating the differential diagnosis, the practitioner should bear in mind the characteristics of common tremor syndromes, which are discussed in the next section and summarized in Table 2.  

Common forms of tremor

Essential tremor is the most prevalent movement disorder, affecting 0.4% to 6% of the US population.¹⁰ Its cause is unknown, though the patient often has a family history of tremor. ET is usually an asymmetric postural or kinetic tremor that typically affects the hands when they are in active use. It can also affect the head (as either an up-and-down or a back-and-forth movement), voice, trunk, and legs. Typically, the tremor is the only neurologic sign present. ET is a slowly progressing disorder whose onset peaks both in the teenage years and in the sixth decade.¹¹ The tremor has a frequency of 4 to 12 Hz, and its amplitude increases with anxiety or fatigue and at the very end of goal-directed movements.²

Advanced forms of ET can have clinical characteristics similar to those of cerebellar tremor, thus complicating diagnosis.¹² ET can occasionally occur at rest, which may cause some practitioners to mistake it for parkinsonian tremor.¹³ Evidence suggests that there are clinical subtypes and even ethnic differences in the characteristics of ET, possibly reflecting differences in genotypes or in environmental exposures.^14,15 However, these phenomena have not been well studied.

Parkinson’s disease is 20 times less common than ET, but the disorder affects approximately 1 million Americans, including around 1% of those at least 65 years old and 2% of those aged 85 years or older.¹⁶ PD is thought to result from a combination of environmental and genetic factors leading to the loss of dopamine-secreting nerve cells in the substantia nigra and to subsequent continuous excitation of the corticospinal motor control system.^17,18 Diagnosis can be challenging since symptoms of PD often develop insidiously and can be mistaken for ET, arteriosclerotic pseudoparkinsonism, drug-induced parkinsonism, and multiple system atrophy, among other conditions.¹⁹ Mistakenly treating other conditions as PD can cause dyskinesias, hallucinations, and accelerated dopamine degeneration, with serious social and psychological consequences.¹⁶

The characteristic symptoms of PD are asymmetric bradykinesia, tremor, rigidity, and postural instability. Bradykinesia, either slowing of active movement or slowness in initiating movement, is a necessary component for diagnosis.¹² However, the most common complaint of patients with PD is an asymmetric resting tremor in an upper extremity with 4 to 6 visible oscillations per second. This tremor, classically described as pill rolling because of its pronation-supination quality, occurs in as many as 75% of patients with PD.¹⁶ The tremor most commonly affects an upper extremity, although it can also involve the legs, lips, jaw, chin, and tongue. It does not affect the head, however, which can help to distinguish it from ET.⁹ Rigidity can either be cogwheel (interrupted or jerky movement as force is applied across the joint) or lead pipe (smooth, but with increased muscle tone throughout passive flexion and extension). Other nonspecific symptoms may accompany the tremor, including difficulty turning in bed, shuffling walk, micrographia, difficulty rising from a chair, loss of balance, and trouble opening jars.^16,20

Cerebellar tremor is commonly caused by MS, stroke, traumatic brain injury and brain-stem tumor, alcoholic cerebellar degeneration, or vitamin E deficiency. These events are thought to damage the thalamus, brain stem, or cerebellum, structures involved in the control of targeted voluntary movements.⁶ Patients present with a slow (4-6 Hz) unilateral or bilateral intention tremor, which worsens as an extremity approaches a target. Patients may complain of tremor during meals, especially when trying to bring food into their mouths or when drinking from a cup. They may also manifest other signs of cerebellar dysfunction, including unsteady gait, slurred speech, or abnormal eye movements.^9,10 Titubation, or to-and-fro movements of the head and neck, can also be associated with cerebellar tremors. Holmes’ tremor (rubral or midbrain tremor) is a severe form of cerebellar tremor that tends to affect the proximal muscles (head, shoulders, neck) more than the distal muscles, oscillating with lower frequency (2-4 Hz) and greater amplitude.

Psychogenic tremor is diagnosed when all possible organic causes have been excluded. It can develop at any age as a resting, postural, or kinetic tremor or as some combination of these.⁶ The tremor is usually obvious, manifests with variable frequency and amplitude, and occurs in more than one limb position.^9,12 It may decrease when the patient is not aware of being observed and with placebo administration. The tremor often has a sudden onset and a variable course, with spontaneous periods of remission.²⁰ A history of somatization may also be present. Clinical tests such as entrainment, where the patient is asked to maintain a tapping rhythm in an uninvolved body part at a different frequency than the presenting tremor, are useful for diagnosis.²¹ The psychogenic tremor will often change to the frequency of the imposed movement because maintaining two separate rhythms at the same time is difficult. Diagnosis is entirely clinical, though electromyography and accelerometry are potential quantitative measures.^22,23

Tremors in children are not uncommon. As in adults, ET is the most frequent form, but tremor can also occur as the result of underlying metabolic, endocrine, or degenerative disorders and from medications or illicit drug use.²¹ Of special note is tremor due to Wilson’s disease. This is a rare autosomal-recessive disorder, usually occurring between the ages of 10 and 40 years, that causes errors in copper metabolism and leads to excessive accumulation of copper in the brain, liver, and corneas.²⁴ Tremor is the predominant sign of the disease and may be resting, postural, or kinetic in nature. It is commonly asymmetric and often accompanied by a wing-beating movement when the arm is abducted at the shoulder.²¹ Behavioral and personality changes, evidence of liver dysfunction, and Kayser-Fleischer rings (copper pigmentation in the cornea) may also be present. The condition can be fatal if untreated.  

Rare forms of tremor

Orthostatic tremor manifests as unsteadiness when the patient is standing still but generally disappears with walking. This symptom can be observed by simply having the patient stand still. A fine, rippling movement can usually be observed in the legs, and this unsteadiness usually increases to the point that the patient has to take a step to maintain balance.²⁵ The patient rarely falls, however. During auscultation of the leg muscles, the examiner may hear a thudding that sounds like a distant helicopter.²⁶

Neuropathic tremor results from demyelinating neuropathies that have hereditary (eg, IgM paraproteinemia neuropathy), acquired (eg, diabetes, uremia, alcoholism, etc.), or idiopathic (eg, Guillain-Barré syndrome) causes.^6,11 These diagnoses must be considered when signs of peripheral neuropathy accompany the tremor.

Task-specific or position-specific tremor may be a variant of ET, dystonic tremor, or its own distinct syndrome.²⁷ Primary writing tremor is the most common type. It is limited to the hand and is characterized by supination-pronation movements at 5 to 6 Hz.² Similar tremors can affect typists and musicians.²⁸

Palatal tremor is a chronic tremor that manifests as rhythmic involuntary movements of the soft palate. It has two forms: symptomatic palatal tremor (SPT), which is often associated with cerebellar disease, and essential palatal tremor (EPT), where palatal tremor is the only symptom.¹¹ Ear clicks, as well as cerebellar signs, can help differentiate SPT from EPT.  

Treatment

If the patient’s symptoms are not improved by eliminating unnecessary medications or stimulants, or by making behavioral changes, then drug therapy is usually the next step. General guidelines can help the provider to select efficacious agents. The goal of treatment is an increase in functionality,¹⁰ so the patient and family members may want to keep a detailed log of responsiveness to medication regimens in order to maximize therapy. Common first-line and second-line treatments, along with appropriate dosages and side effects, are shown in Table 3.

Injections or surgical intervention may help patients whose tremor does not respond to oral medications. Deep brain stimulation (DBS) and surgical lesioning of various thalamic nuclei have proven to be effective long-term treatments for reducing some types of tremor.²⁹ Injection of botulinum toxin A can also reduce some forms of tremor, though weakness is often a limiting side effect.^30,31 Anecdotal evidence suggests that relaxation techniques, including meditation, yoga, hypnosis, and biofeedback, may also be helpful.

The decision to refer a patient often depends on the practitioner’s level of comfort with second-line pharmacologic agents.² Consultation is advised if the presenting tremor is not clearly diagnosable, if the tremor is unresponsive to first-line pharmacotherapy, or if symptoms recur on standard treatment regimens. Any patient with intention tremor or with signs of cerebellar dysfunction should see a neurologist.

Treating essential tremor ET may decrease with rest, beta-blockers, or certain anticonvulsant medications. The first-line pharmacologic treatment is propranolol or primidone. If the patient is affected only occasionally, intermittent use of medication is acceptable, though regular use is advised if the tremor is interfering with activities of daily living. If propranolol or primidone is ineffective, a combination of the two may be more successful. Beta-blockers such as metoprolol, atenolol, or nadolol may also be used, though their efficacy is unproven. The anticonvulsants gabapentin and topiramate, as well as the benzodiazepine aprazolam, have also demonstrated a statistically significant reduction in tremors in placebo-controlled trials and are useful second-line drugs.¹⁰ Agents such as carbonic anhydrase inhibitors, calcium channel blockers, clonidine, and clozapine are either unproven in randomized, double-blind assessments or contraindicated because of side effects.³⁰ Ethanol ingestion before meals or social events can decrease tremor, though an increased rebound in the tremor occurs once the alcohol effect wears off.³ The use of alcohol to manage tremor is not recommended.

Parkinson’s disease Because PD is a degenerative condition, treatment of patients who present with resting tremor is largely symptomatic. As a rule, the lowest dosage that elicits a response should be used. The most effective treatment is a combination of the dopamine precursor levodopa and carbidopa, which prevents the breakdown of levodopa before it reaches the brain. However, long-term administration of this combination has serious side effects, ranging from lightheadedness and nausea to more severe psychiatric side effects and dyskinesias. For this reason, the age of the patient should be considered when initiating treatment.

Patients younger than 70 years who present with parkinsonian features should generally not take levodopa/carbidopa. Instead, these patients can initially use a dopamine agonist such as bromocriptine, pergolide, ropinirole, or pramipexole.^9,32,33 These agents are equally efficacious and have similar side-effect profiles.³⁴ Although they have historically been used as adjuncts to levodopa, they can be useful as alternatives to it in early PD. The side effects associated with long-term levodopa administration can be effectively delayed if a dopamine agonist is administered first. If the patient is older than 70, a levodopa/carbidopa combination should be the first-line treatment. Dosages should be increased as needed as the disease progresses. Patients whose symptoms do not respond to high dosages of levodopa (1,000 mg daily) are more likely to have parkinsonism caused by something other than PD.³²

Anticholinergic medications such as trihexyphenidyl and benztropine can also be used as monotherapy when tremor is the predominant sign or as an adjunct to the current regimen. Their benefit is often limited by intolerable side effects, however.³⁴ Both dopamine agonists and anticholinergic medications can be added to a stable antiparkinsonian regimen to further reduce symptoms. Other second-line agents include amantadine, propranolol, nadolol, and gabapentin, but their efficacy has been debated. PD changes nearly every aspect of a patient’s life and therefore demands a holistic approach, including rehabilitation services and psychosocial support.

Cerebellar tremor These tremors are notoriously difficult to manage pharmacologically. One approach is to try agents that are helpful for ET and then proceed to isoniazid or DBS if the tremor is unresponsive.³⁵

Sometimes the tremor will improve when the underlying cause is addressed.

Psychogenic tremor Since psychogenic tremor is not generally responsive to pharmacologic management, psychotherapy is the most efficacious treatment.

Wilson’s disease Penicillamine, which binds to copper and facilitates its removal from the body, is usually the treatment of choice. Drugs such as trientine or zinc acetate are also used, but they have serious side effects. Patients should see a specialist since rapid treatment and close monitoring are often required.³⁶   

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