Diagnosis and Treatment of Essential Tremor

Abstract

PURPOSE OF REVIEW:

Essential tremor is a chronic, progressive syndrome that primarily presents with an action tremor involving the arms and hands. This article reviews the history and physical examination features pertinent for diagnosis, differential diagnoses, and treatments and approaches for optimal control of symptoms.

RECENT FINDINGS:

Essential tremor is a syndrome with symptoms extending beyond tremor to involve disturbances in gait, speech, cognition, and mood. Although the new guidelines on the definition and biaxial classification scheme have provided clarity, some tremor experts have critiqued the recently coined term essential tremor plus. For treatment, new orthotic devices and peripheral stimulation devices are now available in addition to pharmacologic and surgical options.

SUMMARY:

Essential tremor has a rich clinical phenomenology with many subtleties and nuances. A detailed history with open-ended questions and focused questions encompassing medical history, social history, and family history is key for establishing the diagnosis. The presence of bilateral action tremor for 3 years and absence of isolated head and voice tremor and absence of task- and position-dependent tremor are necessary for diagnosis. Dystonic tremor, Parkinson disease tremor, physiologic tremor, and drug-induced tremor are common differential diagnoses. Differentiating these tremor disorders from essential tremor based on phenomenology and physical examination alone could be challenging; thus, clinicians should seek additional clues from a detailed history. Treatment could begin with noninvasive and nonpharmacologic therapies, especially in mild cases. As the severity increases, they can advance stepwise to include pharmacotherapies and surgical interventions. With the growing recognition that essential tremor is not a monosymptomatic disorder, management should involve a multidisciplinary team. Furthermore, treatment selection should be based on shared decision making between patients and providers that gives due consideration to severity of symptoms, level of functional disability, impact on social interactions, patient preferences, and patient expectations.

INTRODUCTION

Tremor is an involuntary, rhythmic, oscillatory movement of a body part.¹ Essential tremor is a chronic, progressive syndrome that primarily presents with an action tremor involving the arms and hands. Essential tremor is among the most prevalent movement disorders with a pooled prevalence estimate of about 1% across all ages in population studies.² The prevalence increases to 5% in people who are older than 60 years and to 20% in people who are older than 95 years.³ Diagnosis of essential tremor is clinical; however, the process is not straightforward because the syndrome is highly nuanced. Many debates and discussions surround the terminology, nosology, and phenomenology. The term essential implies a disorder lacking a known proximate cause (ie, idiopathic) or, similar to essential hypertension and essential thrombocythemia, a disorder that is unitary and intrinsic to an individual.⁴ However, the pitfall of the continued use of the term became increasingly apparent as the etiology and pathophysiologic understanding of the disorder advanced. Despite serious concerns, a task force commissioned by the International Parkinson and Movement Disorder Society decided to retain the term because clinicians and researchers widely used it and patients and their families requested its continued use. The task force proposed a new biaxial scheme for classifying the tremor syndrome. The first axis emphasizes detailed consensual clinical phenotyping based on the age of onset, sex, body distribution, and temporal evolution of symptoms, and the second axis focuses on etiologic considerations.¹ Alongside the recent developments in clinical definitions and classifications, many treatments have emerged that can effectively control the symptoms. The purpose of this article is to discuss and recognize the clinical subtleties when approaching a patient with essential tremor for an accurate diagnosis and selection of appropriate treatments.

MEDICAL HISTORY

A thorough history is an invaluable tool for the establishment of the diagnosis. The first part of the interview should include open-ended questions to obtain pertinent clinical information. The characteristic history of essential tremor is the presence of a hand tremor that frequently interferes with activities of daily living such as eating, drinking, pouring, handling utensils, dressing, and using keys or other household tools. Some patients report using a smartphone, computer keyboard, and mouse as quite problematic. The second part of the interview should include focused questions with the following items for further improvement of diagnostic certainty.

SEX, AGE AT ONSET, AND TEMPORAL EVOLUTION

The prevalence estimates for men and women are about the same,^5,6 and symptoms present insidiously for most individuals. The age of onset in multiple clinical studies has revealed a bimodal distribution pattern with peaks occurring around the third and seventh decades of life. However, community-based studies have found a steady age-associated increase in the prevalence.^7–9 Overall, an estimated 2% worsening of symptoms has been reported to occur on a year-to-year basis.¹⁰ Some investigators have found phenotypic differences between early-onset and late-onset essential tremor.¹¹ Early-onset essential tremor is frequently associated with a positive family history and a presence of a mild, stable tremor that progresses over many years whereas late-onset essential tremor is observed to progress at a faster pace.¹²

DURATION OF SYMPTOMS, BODY DISTRIBUTION, AND ACTIVATION CONDITIONS

The new definition for essential tremor requires the presence of an isolated tremor of the arms and hands for at least 3 years that may or may not be accompanied by a tremor in the head, voice, or lower limbs. Tremor less than 3 years is an indeterminate syndrome. A 3-year guardrail is meant to reduce the odds of diagnosing concurrent neurologic signs (eg, dystonia, parkinsonism, or ataxia).¹ If other neurologic signs begin to codominate, regardless of whether they occur early in the course or later after 3 years, symptoms should be labeled as a combined tremor syndrome. Essential tremor is primarily an action tremor syndrome affecting the arms that interferes with day-to-day motor tasks (postural and kinetic components) (CASE 5-1). Sometimes essential tremor worsens with precision goal-directed tasks (intention component), thus lending difficulties in performing fine motor tasks such as working with a screwdriver, inserting keys in a lock, applying makeup, or wearing jewelry. Essential tremor in 20% of patients manifests during the resting state (resting component), especially in long-standing cases; however, the tremor usually affects only the arms. Essential tremor is not a task- and position-specific tremor. Head and voice tremors usually evolve in 30% to 40% of patients after the onset of arm tremor.¹ Isolated focal tremor affecting the head or voice is inconsistent with the diagnosis. Head tremor occurs when sitting, standing, and walking but tends to disappear when lying down. Voice tremor is seen to manifest and affect daily conversations.¹³ Indeed, arm tremor is functionally disabling, but pronounced head and voice tremors can lead to social embarrassment in day-to-day functioning.

CASE 5–1.

A 72-year-old man presented for a neurologic consultation with a bilateral hand tremor first noticed in high school. However, the tremor was intially mild, intermittent, and did not affect day-to-day functioning. He had several family members with similar tremors, including his mother, grandmother, maternal uncle, and a cousin. He worked as an accountant, and the tremor did not become bothersome until he reached his fifties when it began to interfere with writing, typing, and using the computer mouse and keyboard. At home, he had trouble using garage and gardening tools and pouring himself coffee. He avoided going to restaurants with friends because he had difficulty eating spaghetti with a fork and soup with a spoon. He observed that a glass of wine helped his tremor. He had been treated with propranolol 160 mg/d, which helped him some. He later started receiving primidone as an additional medication for further control of tremors. He tolerated both drugs without dizziness, nausea, and gait imbalance. However, as the symptoms continued despite adequate doses of medications, he decided to seek early retirement.

The arm tremor was moderately severe on examination, involving the metacarpophalangeal and wrist joints when he was asked to stretch his arms forward. The tremor was also noted when asked to write, draw spirals, and perform the finger-nose-finger maneuver. The tremor was absent when his arm was resting. He decided to consider deep brain stimulation surgery for control of his symptoms.

COMMENT

This case illustrates the age of onset and familial nature of essential tremor, gradual worsening of symptoms over decades, kinetic tremor interfering with day-to-day fine motor activities, long-term social and professional consequences, and consideration of surgical treatments when pharmacologic agents do not alleviate symptoms.

DIET AND SOCIAL HISTORY

Dietary history including consumption of alcohol¹⁴ or environmental history that contributes to essential tremor pathogenesis could provide clues for etiologic origins. Some interest has been shown in assessing the relationship between high amounts of meat in the diet and linkage with essential tremor because harmane, which has tremorgenic properties, is abundantly present in meat.¹⁵ Eating meat cooked at high temperatures for a long time is a particular risk,¹⁶ but a high adherence to the Mediterranean composite diet, known for its high antioxidant content, has been suggested to lower the odds of essential tremor.¹⁷ Besides toxicity effects related to chronic consumption of alcohol,¹⁸ essential tremor has been found to exacerbate with caffeine and improve with alcoholic drinks in the acute clinical setting.^19,20

FAMILY HISTORY

Ascertainment of family history is critical because essential tremor has shown high rates (30% to 70%) of heritability.^14,21 The family history is often consistent with a Mendelian pattern of inheritance.¹⁴ The vast majority (more than 80%) of patients with early-onset essential tremor report at least one affected first-degree family member.⁹ Although several studies including genome-wide association studies, linkage analysis, and whole-exome sequencing have attempted to advance the genetic understanding, only a few reliable and replicable findings are available so far. One such example is the single nucleotide polymorphism identified in the region of LINGO1.²² Whether a single rare high-penetrant variant or many common low-penetrant variants contribute to familial aggregation remains unclear.²³

NEUROLOGIC EXAMINATION

The patient should be relaxed and seated comfortably. Bilateral arm tremor elicited during postural and kinetic motor tasks is a hallmark finding. The postural component is examined by having the patient outstretch both arms extended directly forward, parallel to the ground, with the wrists straight and the fingers extended and slightly abducted. The rhythmic oscillatory movements comparable to a pendulum swinging from a fixed point (the shoulder joint in this case) are usually distal, involving the metacarpophalangeal and wrist joints. The oscillatory movements are flexion-extension rather than pronation-supination. Another task for examining the postural component is an assumption of a wing-beating position. The patient extends the arm outward and flexes the elbow parallel to the ground to position the wrist under the chin. In this position, the oscillatory movement increases in amplitude and tends to involve the proximal wrist or elbow joints (these joints become the distal pendulum). In the wing-beating posture, tremors in both arms sometimes oscillate out of phase, which could be leveraged for functional benefits. For example, a patient holding a cup with both hands can counterbalance the dropping movement of one hand with the other (VIDEO 5-1). The kinetic component is examined by asking patients to perform standard tasks such as pouring water from a cup, writing a sentence, or drawing spirals on a paper following standardized instructions. In the spiral-drawing task, tremor waveforms are drawn perpendicular to the pen movement, and they characteristically align along an axis. A spiral drawn using the right hand reveals an axis pointing toward the upper right quadrant, whereas a spiral drawn with the left-hand points toward the upper left quadrant. This alignment is not usually seen in other tremor disorders such as dystonic tremor and Parkinson disease tremor. The intentional component can be elicited by patients touching their nose precisely with their fingers and touching the examiners’ fingers, going back and forth. This elicits a worsening of tremor amplitude because the task requires a high level of visuomotor coordination. Another task is the dot approximation task which requires the patient to point a pen close to a marking made on the paper. The intentional component of head tremor can be evident when the patient attempts to reach a spoon or cup during meals. For the resting component, it is imperative that the patient is examined in a proper resting position. Patients should be sitting on a chair with the arms fully relaxed and resting on the armrest or the arms supported on their lap. If possible, patients could also be examined in a lying-down position to achieve a proper resting condition.

VIDEO 5-1. Clinical characteristics of essential tremor.

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The first segment shows a 65-year-old woman with mild bilateral slightly asymmetric postural tremor affecting the arms, most significantly in amplitude at the wrist joint, rather than more proximal or distal joints. Generally, the tremor involves wrist flexion-extension rather than rotation-supination. The kinetic component is observed during a dot approximation task. The next segment shows a 60-year-old man with a similar asymmetric postural arm tremor. The final segment reveals the out-of-phase character seen in some patients (seesaw effect seen when arms are held in the wing-beating position). When a bimanual task is performed (not shown in the video), the movement direction of one side could potentially cancel the out-of-phase direction of the other side; this can be leveraged by the patients during a functional task.

GAIT AND COGNITION

It is increasingly recognized that essential tremor is not a monosymptomatic disorder but is frequently associated with gait and cognitive changes.^24,25 These nonmotor abnormalities arguably justify the label “essential tremor is a tremor syndrome,” as proposed by the Movement Disorders Society.¹ Some have advocated that essential tremor should be regarded as a disease or a family of diseases. The disease entity encompasses a good amount of knowledge on etiology, clinical presentation, course, and prognosis. As the knowledge of genes, environmental factors, pathophysiology, and the natural disease course have considerably advanced, it is reasonable to consider essential tremor as a disease.

Gait changes, which can be revealed during a simple bedside tandem walking task, are frequently seen in essential tremor.^26–28 Most studies have found that about 30% to 50% of patients with essential tremor have two or more missteps during walking.^27–29 Gait impairment, albeit mild in most patients, can become moderately severe and bothersome in some patients. These abnormalities, which increase the susceptibility to falls, are more commonly associated with the head tremor than the arm tremor.²⁷ Neurologic examination should encompass cognitive assessment to capture deficits in attention, concentration, working memory, executive function, language, and global cognitive function; these have been reported to be present in essential tremor.³⁰

ESTABLISHMENT OF DIAGNOSIS

According to a recent consensus statement released by the Movement Disorder Society, essential tremor is defined as an isolated tremor syndrome of bilateral upper limb action tremor of at least a 3-year duration, with or without a tremor in other locations (eg, head, voice, or lower limbs), and absence of other neurologic signs, such as dystonia, ataxia, or parkinsonism.¹ The consensus panel also introduced a new term, essential tremor plus, defined as a tremor with the characteristics of essential tremor with additional soft neurologic signs of uncertain clinical significance, such as impaired tandem gait, questionable dystonic posturing, memory impairment, or other mild neurologic signs of unknown clinical significance. Essential tremor with a resting component is also included within the spectrum of essential tremor plus.¹ Many groups of investigators have raised concerns over the term because the descriptors are relatively subjective and it is not known whether essential tremor plus is biologically distinct from essential tremor.³¹ Until further research sheds insights into this newly coined entity, it is prudent that the clinician continues to document the co-occurring neurologic features noted during the neurologic examination.

DIFFERENTIAL DIAGNOSIS

The overdiagnosis of essential tremor is common because many tremor disorders can have overlapping phenomenology (FIGURE 5-1). Indeed, studies show that 30% to 50% of “essential tremor” cases have diagnoses other than essential tremor, with many of these patients having dystonia or Parkinson disease.³²

FIGURE 5-1. Differential diagnoses of essential tremor with key characteristics for individual tremor disorders.

TREMOR IN DYSTONIA

The 2013 criteria laid out by the Movement Disorders Society propose that dystonic tremor is a tremor in a body part affected by dystonia, and tremor associated with dystonia is a label to be considered when dystonia and tremor are found to affect different body parts.³³ Although this criterion is debatable, in clinical experience, patients with focal and/or segmental dystonia frequently exhibit tremors affecting the head, arm, or voice.³⁴ The prototypical history consists of a 45- to 50-year-old woman presenting to the clinic with a long history of isolated head tremor. Unlike essential tremor, the head tremor noticeable when patients are seated comfortably upright in the chair may not resolve when they assume a supine position. The patient may additionally report accompanying symptoms of pulling, tightness, and spasms (described as “knots”) in the neck and shoulder muscle groups. Restriction in head movements will result in pain, fatigue, and difficulties with reading a book, watching television, driving a car, or working for long strenuous hours on a computer. Patients sometimes have bioccipital headaches. The head and neck symptoms could improve partially in response to alcohol consumption, further complicating the distinction from essential tremor. Symptoms could also be mitigated when the head is held in certain positions (CASE 5-2). Sometimes the patient may endorse a “sensory trick,” resulting in a “magical” disappearance of abnormal movements or posture.

CASE 5–2.

A 48-year-old woman presented with a chief complaint of head tremor, occipital headaches, head pulling, and neck muscle tightness for 3 years. She had spasms and knots in her shoulder muscles. It was easier for her to look to the right than the left. Her head tremor worsened when she looked to the left. She worked as a schoolteacher, and her symptoms worsened toward the end of the day. She found herself holding her chin when talking to coworkers and children in the school. She could watch television or read a book only if she had a pillow to support her head. She denied symptoms in her eyes, jaws, and arms.

On examination, her head appeared to be preferentially turned to the right and tilted toward her right shoulder. She had a mild to moderate head tremor that worsened when asked to close her eyes and turn her head to the extreme left. The head tremor was jerky and irregular and persisted even when she laid down on her back on the examining bed. An arm tremor was not observable. Her left sternocleidomastoid muscle was slightly hypertrophic.

She was treated with IM onabotulinumtoxinA injections administered every 12 weeks. OnabotulinumtoxinA was targeted mainly to the left sternocleidomastoid, right splenius capitis, and right longissimus capitis muscles, which helped control her headaches, neck pain, spasms, and tremor. However, she reported the benefits lasted for only 9 of 12 weeks.

COMMENT

This case illustrates the characteristic history and examination features of a patient with cervical dystonia presenting with dystonic head tremor. The age of onset; female sex; abnormal posturing; irregular, jerky tremor; presence of sensory trick; hypertrophy of muscles; presence of null point; and persistence of tremor during recumbent positioning all support a diagnosis of dystonic tremor.

A careful neurologic examination will provide further clues for diagnosis. Besides the twisting movement and posture and apparent neck muscle hypertrophy related to dystonia, the coarse and jerky or fine and rhythmic character of the head tremor that is generally slow is elicitable during the maintenance of posture or kinetic tasks (VIDEO 5-2). The examiner may observe the head tremor as directional with a “null point,” which is a point during performance of voluntary head movements that leads to the complete disappearance of tremor. For example, in a patient with right torticollis (head turned to the right) with head tremor, if the patient is instructed to turn to the extreme left (against the will of dystonia), the tremor may worsen, but a nullification may occur when the head turns in the same direction as dystonia (following the will of dystonia). Sometimes, patients may not exhibit rhythmic or oscillatory qualities during a clinical examination.¹ Thus, whether the “tremor” in the strictest sense of the word is a tremor is debatable. FIGURE 5-2 represents a simple illustration of rhythmicity, oscillations, sinusoidal waves, or sawtooth waves that can be assessed with kinematic analysis.³⁵

VIDEO 5-2. Head tremor in patients with cervical dystonia.

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The video shows a 68-year-old woman with cervical dystonia and slow head-bobbing, a 78-year-old woman with right arm dystonic tremor, and a 71-year-old man with cervical dystonia and a jerky head tremor that remains persistent when he is lying supine with his head at rest.

FIGURE 5-2. Conceptual understanding of tremor. The horizontal arrows indicate the time interval between two successive peaks of periodic waves. Rhythmic tremor that is regularly recurrent has a constant interval. Irregular tremors with changing time intervals will clinically appear as jerky. Oscillation indicates rotation around a central plane. Vertical arrows of different lengths mean that the tremor is nonoscillatory. Such tremors clinically appear as directional. If the periodic waves lose their sinusoidal characteristics and assume sawtooth waves, such tremors will also clinically appear jerky.

Arm tremors may occur with or without dystonic posture and movements. Dystonic arm tremor is jerky, is usually a little proximal, and frequently manifests in a resting position. However, if the arm tremor is fine and rhythmic, it may be difficult to distinguish from essential tremor. In these circumstances, features evident in the history could provide clues. Arm tremor in dystonia usually manifests several years after the onset of head tremor. Head tremor reveals clear underlying cervical dystonia, unlike a head tremor of essential tremor. Besides fine motor difficulties involving distal hand fingers, patients may report trouble holding a glass or cup or throwing a softball (proximal muscles). Tremor is mild in many cases and is remarkably asymmetric or unilateral. The posturing of the arm is appreciable during the physical examination as splaying and spooning of fingers, thumb hyperextension, and/or shoulder elevation.³⁶ The spiral drawing typically does not reveal an axis.³⁷ If dystonia involves other body parts, that can provide further clues. When the dystonic tremor affects the voice, patients report voice breaks or strangulated speech, which is not the case for essential tremor.

Distinguishing dystonic tremor from essential tremor is not always that straightforward because these clues are not necessarily seen in all patients. Sometimes, the history can be confusing; for example, one family member reports classic essential tremor, but another member has clear history and examination features consistent with a diagnosis of dystonia. Sometimes, patients with essential tremor begin to exhibit dystonic characteristics with the progression of time. These quandaries have resulted in considerable debates that will likely be resolved as high-resolution imaging and physiology-based markers for reliable differentiation of the two tremor disorders become available in clinical practice.^38,39

PARKINSON DISEASE TREMOR

Although postural and kinetic components are the main elements of essential tremor, the presence of a resting tremor seen in a small proportion of patients with advanced essential tremor can potentially lead to an erroneous diagnosis of Parkinson disease. The arms and hands should be fully supported by the patient’s lap or the armrests of the examination chair to elicit a true resting component (VIDEO 5-3).⁴⁰ The resting component of essential tremor could be differentiated from tremor in Parkinson disease by noting observations during coactivation motor tasks such as walking or counting backward. These tasks do not increase amplitude in essential tremor, but a worsening of tremor in Parkinson disease will be seen.⁴¹ The resting tremor component in essential tremor is seen to mainly involve the arms, but the resting tremor of Parkinson disease can affect both arms and legs. Although a certain degree of asymmetry is commonly seen, essential tremor is a symmetric disease. However, tremor in Parkinson disease is remarkably unilateral or asymmetric.⁴¹ With the patient’s arms stretched in a postural position, the arm tremor in Parkinson disease reveals a reemergent quality (a tremor that occurs after a finite latency period from the time the patient assumes a horizontal posture of the arm to the onset of the wrist and/or finger tremor), which is not seen in essential tremor. Other clues supporting a diagnosis of Parkinson disease tremor include a history of rapid eye movement (REM) sleep behavior disorder or anosmia, pronounced bradykinesia, rigidity, and gait and speech disturbances. Jaw tremor in Parkinson disease is seen when the patient’s mouth is closed, whereas essential tremor appears during speaking. These clinical features may not always be evident; thus, additional testing such as dopamine transporter imaging for demonstration of presynaptic nigrostriatal dopaminergic innervation in Parkinson disease is used.⁴² In recent times, measuring phosphorylated α-synuclein in CSF or peripheral tissue, such as a skin biopsy, has been described in patients with Parkinson disease and might be useful in distinguishing patients with Parkinson disease tremor from those with essential tremor.⁴³ However, the accuracy, sensitivity, specificity, and the optimal tissue analysis technique will require more studies before a broader implementation in clinical practice.

VIDEO 5-3. Resting tremor assessment in Parkinson disease.

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The video shows a 78-year-old man diagnosed with Parkinson disease exhibiting a resting tremor in his left hand when his arm is resting on the armrest. A resting tremor is seen in both legs, more in his left than in his right. Resting tremor in his hand is also elicited with his arm resting in his lap (both positions are commonly used during the neurologic examination). Tremor in Parkinson disease involves the distal joints (fingers and wrist), is characterized by wrist pronation-supination, and has a slight pill-rolling quality.

PHYSIOLOGIC AND DRUG-INDUCED TREMOR

In theory, when exposed to certain physiologic conditions, all healthy people are vulnerable to developing a tremor. Enhanced physiologic tremor occurs when physiologic conditions such as hypoglycemia, hypothermia, hyperthyroidism, or anxiety are heightened.⁴⁴ Tremor is usually bilateral, affects the arm symmetrically, and may affect the voice but tends to skip the head. Usually, no intentional component is present during the finger-nose-finger maneuver.

Sometimes exposure to drugs leads to tremors as a side effect. Drug-induced tremor is fast (high frequency), fine (low amplitude), and rhythmic in most patients. Although psychotropic drugs, such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, neuroleptics, and lithium (CASE 5–3), are commonly implicated as a cause of drug-induced tremor; many nonpsychotropic drugs such as β-agonists, immunosuppressants, and hormonal therapies can also cause or exacerbate tremor.⁴⁴ Most tremor-inducing drugs cause postural tremor, but tremors induced by psychotropics and neuroleptics can have resting and intentional components.^45,46 Physiologic tremor is usually fast (high frequency), fine (low amplitude), and rhythmic in most patients, but sometimes, in patients receiving medications such as valproic acid, the tremor can exhibit a coarse character (VIDEO 5-4). A simple bedside assessment may not reliably distinguish enhanced physiologic tremor from essential tremor.⁴⁷ Clinical electrophysiology testing may provide additional helpful information. During EMG recordings, enhanced physiologic tremor generally exhibits a higher frequency and lower amplitude. Given a predominant peripheral (mechanical) origin, the response pattern to inertial loading, which applies weights to the wrist, may reveal distinct findings. With inertial loading, the mechanical component may sometimes separate from the central component, leading to a display of two frequency peaks, which is not the case for essential tremor.⁴⁸

CASE 5–3.

A 55-year-old man presented for evaluation of a 1-year history of bilateral symmetric hand tremor alongside progressive slowness of movements, decreased facial expression, and a slight shuffling gait. Further questioning revealed that the tremor appeared when he would sit on a sofa with his arms resting as well as when his arms were engaged in eating, drinking, dressing, and writing. His medical history revealed treatments for long-standing bipolar disorder. He had been prescribed lithium for the past year with doses titrated to 1800 mg/d.

On examination, he had a hypomimic facial expression, bradykinesia, rigidity, a parkinsonian gait, and a bilateral fine distal hand tremor. He underwent a trial with carbidopa/levodopa; doses were escalated to a total daily dose of 1000 mg/d of levodopa with no improvement of symptoms. He underwent dopamine transporter imaging, which was unremarkable.

COMMENT

This case exemplifies the importance of obtaining medication history, which can provide important clues for a diagnosis of drug-induced tremor. The patient had been receiving lithium for treatment of bipolar disorder; his lithium levels were found to be 1.5 mEq/L instead of the recommended therapeutic range of 0.6 mEq/L to 1.2 mEq/L. The history of symmetric bilateral hand tremors was temporally related to the initiation of lithium therapy. The case illustrates that lithium-induced tremors can be potentially confused with essential tremor in clinical practice.

VIDEO 5-4. Bilateral physiologic arm tremor.

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The video reveals a spectrum of physiologic tremors. The first patient is a 75-year-old woman presenting with a tremor that manifested within a few months of using valproic acid for a mood disorder. The tremor was coarse with resting, postural, and kinetic components. The second patient is a 50-year-old woman with generalized anxiety disorder; she had fine rhythmic distal tremors involving her hands.

TREMORS SECONDARY TO A STRUCTURAL AND GENETIC ETIOLOGIES

Holmes tremor occurs in the setting of stroke, head trauma, and demyelination involving brain regions in tremorgenic circuitry connecting the cerebellum, red nucleus, and thalamus. The Holmes tremor is usually slow and unilateral, affects the proximal arm, and reveals a kinetic > postural > resting component (VIDEO 5-5).⁴⁹ Another example of secondary tremor is fragile X-associated tremor/ataxia syndrome. This syndrome is an X-linked recessive disorder presenting with bilateral arm tremor in older men. The postural and kinetic components are pronounced, but sometimes, notable resting and intentional components are present.⁵⁰ As the name of the syndrome implies, these may have features of progressive ataxia and sometimes parkinsonism and cognitive impairment. Wilson Disease is an autosomal recessive disease that leads to abnormal copper metabolism resulting in excessive deposition of copper in various tissues, including the brain. A tremor well appreciated during the wing-beating position is a prototypical tremor, but a wide-ranging phenomenology can be seen. These tremors can be distinguished from essential tremor based on other elements in the history and examination features such as cognitive changes, ataxia, and parkinsonism.⁵¹

VIDEO 5-5. Head and arm tremor in a patient with cerebellar lesions.

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The video shows a 48-year-old woman diagnosed with multiple sclerosis with lesions involving the cerebellum and the brainstem; she presented with tremors of bilateral arms and head. The tremor in her left arm is seen during resting, postural elevation, and kinetic tasks. The tremor is more pronounced proximally and has a significant intentional component.

NEUROPATHIC AND FUNCTIONAL TREMOR

Patients with acquired and familial neuropathies may also exhibit mild to moderate action tremor of the arms. In these patients, important clues can be obtained from the history because the tremor often begins after the onset of neuropathy. Although the severity of neuropathy correlates with the occurrence of tremor, it does not necessarily correlate with the severity of the tremor.⁵² Functional tremor, a tremor without known organic etiology, should be on the list of differential diagnoses. Functional tremor often has an abrupt-onset tremor that fluctuates remarkably in amplitude and frequency and is distractible, suggestible, and entrainable. Sometimes, a patient has a history of spontaneous remission. Examination features that are highly supportive of an underlying functional basis include entrainment, distractibility, and suggestibility.

MANAGEMENT

Essential tremor is a syndrome with symptoms extending beyond tremor in many patients to involve disturbances in gait, speech, mood, and cognition. A multidisciplinary team involving neurology, neurosurgery, occupational therapy, physical therapy, neuropsychology, and psychiatry is warranted for a comprehensive assessment and high-quality holistic care (FIGURE 5-3).

FIGURE 5-3. Multidisciplinary team for management of essential tremor, which should be centered on the patient and not the disease.

Many options are available for treating the motor symptoms, and treatment selections mainly depend on the severity of symptoms, level of functional disability, impact on social interactions, patient preferences, and patient expectations.^53–57 It is critical to treat the individual patient and not the disease. A stepladder approach for treating essential tremor symptoms is proposed (FIGURE 5-4), and shared decision making between the patients and their clinical providers at each step is encouraged. When the symptoms are mild, nonpharmacologic therapies could be the first consideration. Occupational therapists can help develop a practical, individualized approach. An occupational therapy evaluation will focus on modification of the functional task and encourages the use of compensatory strategies such as proper body mechanics and core stability for hand control. Several adaptive devices, such as weighted spoons, forks, utensils, or rocker knives; weighted pencils and pens; and modified computer mouses and keyboards, are available for a more efficient task performance. In recent times, many wearable orthotic devices have become available. Although some devices follow the principles of increasing weights around the wrist to stabilize the arm mechanically, some use tuned mass damper technology to dampen vibrations and a gyroscope to reduce the angular momentum. Peripheral limb cooling with icepacks around the forearm is another technique that modulates the feedback from the peripheral muscles to the brain that can temporarily control the tremor.⁵⁸ In 2022, a peripheral wearable device that stimulates the median and radial nerve at the wrist to modulate the peripheral feedback⁵⁹ was cleared by the US Food and Drug Administration (FDA) to treat essential tremor symptoms.⁶⁰ Thus, it is increasingly recognized that nonpharmacologic therapies can potentially improve patients’ quality of life without presenting many risks.

FIGURE 5-4. Stepwise approach for management of arm symptoms in essential tremor. Treatments assigned to step 2 or 3 can be combined with treatments in step 1. Surgical treatments, even though powerful, are considered only when the tremor is refractory to pharmacologic therapies.

DBS = deep brain stimulation; MRI = magnetic resonance imaging.

When the symptoms interfere significantly with activities of daily living, pharmacologic therapies are initiated.⁶¹ Beta-blockers are FDA-approved first-line agents for the treatment of essential tremor. Short- and long-acting propranolol reduces tremor by 50% to 70% in 50% of patients at daily doses varying from 60 mg/d to 200 mg/d.⁵⁵ Dizziness, fatigue, erectile dysfunction, and sedation are common side effects. Propranolol, a nonselective beta-blocker, is contraindicated for patients with bronchial asthma. However, cardioselective atenolol and metoprolol, which do not affect the bronchial muscles, could be used in these circumstances.^62,63 Primidone is an alternative first-line therapy and is effective at a total daily dose of 250 mg/d. Besides direct benefits related to actions against sodium channels in the neuronal membrane, the efficacy of primidone is related to the metabolites such as phenobarbital and phenylethylmalonamide.⁵³ Confusion, ataxia, and nausea are side effects more commonly seen in older patients using high doses. These side effects could be minimized with the initiation of therapy at low doses and slow titration.⁶⁴ In one study, pretreatment with phenobarbital initiated 3 days before primidone was found to mitigate the psychotropic side effects.⁶⁵ Combined therapy with propranolol and primidone has been observed to yield better clinical outcomes.

Although the medications improve arm tremor, efficacy in controlling the head tremor is limited. When the arm and/or head tremor persists or the medications cannot be tolerated, the next step in the treatment ladder is to use topiramate,⁶⁶ gabapentin,⁶⁷ benzodiazepines,⁶⁸ and botulinum toxin type A injections.^69,70 The medications investigated in clinical trials have shown these agents to be relatively less efficacious compared with the first-line agents or have revealed insufficient evidence for controlling symptoms.⁷¹ Thus, prescribing these drugs is more justified in the presence of comorbidities. For example, benzodiazepines could be chosen if psychiatric comorbidities are present.

Surgical intervention is recommended for symptoms that are refractory to all available medications yet are functionally disabling and socially embarrassing. Multiple surgical modalities are available, each with risks and benefits that need due consideration. Deep brain stimulation is the most frequently used surgical procedure; it electrically modulates the behavior of the tremor circuitry. Deep brain stimulation has gained widespread acceptance and popularity because of its efficacy in controlling arm and head tremors, and, more importantly, unlike thalamotomy, which involves creating a lesion, the surgery is nondestructive and reversible in nature. It can be used to treat bilateral tremor symptoms without the high risk of severe complications, such as dysarthria, dysphagia, and ataxia reported in studies with bilateral thalamotomy procedures.⁷² The main disadvantages are high expenses and potential risks related to infection, seizure, stroke, and hardware complications. The implantation of a battery in the chest with replacement at appropriate time intervals requires general anesthesia, although rechargeable batteries are becoming commonly available. In 2016, the FDA approved transcranial MRI-guided focused ultrasound (MRgFUS) treatment, which is noninvasive or minimally invasive and involves creating permanent lesions with ultrasound energy.⁷³ Although direct comparison has not been performed, MRgFUS has efficacy similar to deep brain stimulation. The MRgFUS procedure does not require drilling of a burr hole and implantation of hardware. It is essential to discuss that complete hair removal is needed, and the patients will need to lie in an MRI scanner for 3 to 4 hours during the MRgFUS procedure.⁷⁴ No data are available on long-term follow-up or whether unilateral MRgFUS can effectively control axial symptoms such as head tremor. Nevertheless, because the procedure is noninvasive and has immediate benefits, more and more centers are offering this procedure. Another noninvasive procedure is stereotactic radiosurgery, which does not require a burr hole or hair removal; however, the procedure is used less often because the clinical benefits are delayed and unpredictable.⁷²

CONCLUSION

Essential tremor is among the most prevalent movement disorders. A thorough history and detailed neurologic examination are required to identify the patterns and nuances for an accurate diagnosis. Treatments for tremor control involve the use of adaptive and orthotic devices, pharmacotherapies, and surgical interventions in medication-refractory cases. Because essential tremor is not a monosymptomatic disorder, ideal management involves a multidisciplinary team of a neurologist; neuropsychologist; occupational, speech, and physical therapists; and in some cases a neurosurgeon.

KEY POINTS.

• The involuntary movements of essential tremor are both rhythmic and oscillatory.

• Tremor syndrome classification is biaxial, first based on clinical phenotyping and second based on underlying etiologies.

• Essential tremor is among the most prevalent movement disorders.

• Isolated tremor syndrome of bilateral upper limb action tremor present for at least 3 years is a requirement for the diagnosis of essential tremor.

• Patients with early-onset essential tremor commonly report at least one affected first-degree family member.

• Essential tremor is a syndrome with symptoms in many patients extending beyond tremor to involve disturbances in gait, speech, mood, and cognition.

• Essential tremor with a resting component or accompanied by soft signs of dystonic posturing or parkinsonism is labeled as essential tremor plus; currently, no evidence has been found that essential tremor plus is biologically distinct from essential tremor.

• Dystonic head tremor commonly affects women in their fifth decade and includes headaches, neck pain, posturing, and isolated head tremor.

• Isolated head tremor, voice tremor, and task- or position-specific tremor should not be diagnosed as essential tremor.

• Unlike essential tremor, dystonic head tremor often persists when the patient is examined while lying down.

• The tremor in dystonia may be neither rhythmic nor oscillatory.

• Arm tremor in dystonia is frequently unilateral and asymmetric.

• Unlike essential tremor, dystonic arm tremor may not reveal a clear axis during the spiral-drawing task.

• Based on physical examination alone, dystonic tremor may not be distinguishable from essential tremor; history must be given consideration.

• Unlike essential tremor, resting tremor in Parkinson disease increases in amplitude with walking and mental calculation and is generally asymmetric.

• Unlike essential tremor, arm tremor in Parkinson disease reveals a reemergent quality (a tremor that occurs after a finite latency period from the time the patient assumes a horizontal posture of the arm to the onset of the wrist and/or finger tremor).

• In contrast to essential tremor, the jaw tremor of Parkinson disease is more often noted when the patient’s mouth is closed and relaxed rather than while the patient is speaking.

• Head tremor is not a feature of enhanced physiologic tremor or drug-induced action tremor.

• Holmes tremor has resting, postural, and kinetic components.

• Fragile X-associated tremor/ataxia syndrome has a prominent intentional component.

• Wilson disease has prominent wing-beating postural tremor.

• Functional tremor is abrupt in onset and distractible, suggestible, and entrainable.

• Management of essential tremor requires a multidisciplinary team, and treatment selection requires shared decision making between patients and providers.

• Adaptive tools, orthotic devices, limb cooling, and peripheral stimulation devices are useful nonpharmacologic therapies for essential tremor.

• If the tremor severity does not reduce despite multiple medication trials, surgical intervention may be warranted.