Tremor
Lesley D. Wilkinson
Carol Stewart
Nancy Tyre
CLINICAL PEARLS
Tremor is not part of normal aging.
Tremor is common in the geriatric population. It can cause substantial disability and can severely diminish quality of life.
Most geriatric patients with tremor will have one of three syndromes: Essential tremor (ET), toxic/metabolic tremor, or Parkinson disease (PD).
Tremor at rest suggests PD; tremor with activity suggests essential or toxic/metabolic tremor.
All patients with geriatric tremor should have medications and underlying disorders considered as etiologies for their tremor.
Treatment for ET is initially β-blockers; second line is primidone.
Physical therapy, weights for the arms, and surgery may be useful when pharmacologic treatment does not suffice.
Tremors are oscillating involuntary movements. Most older patients with tremor will ultimately prove to have one of the three major tremor syndromes—essential tremor (ET), Parkinson disease (PD), or toxic/metabolic tremor. However, there are many potential causes of tremor. Tremor in the older population is not unusual. It is the most common movement disorder. Up to 9% of people older than 80 have tremor, and >5 million people in the United States have tremors.
Normal aging does not include developing a tremor, but tremor is more likely to manifest with greater age. Although tremor may be associated with a variety of syndromes, many patients with tremor are otherwise healthy. Still, tremor itself can be a significant source of disability and diminished quality of life. Evaluation and treatment of tremor can significantly ameliorate chronic disabling symptoms and
contribute to management of contributing diseases as well. This chapter will provide the practitioner with information to help confidently address this common and potentially disabling symptom.
contribute to management of contributing diseases as well. This chapter will provide the practitioner with information to help confidently address this common and potentially disabling symptom.
DIFFERENTIAL DIAGNOSIS
Tremor is best differentiated by clinical examination.1 There is a large differential, although most patients have one of three common entities: (i) ET, (ii) toxic/metabolic tremor, or (iii) PD. Table 29.1 provides an extensive list of causes for tremor, with an associated table, Table 29.2, listing drug-related causes.2
Description and Definition of Tremor
Tremor is an involuntary movement disorder with a regular and consistent movement. Other hyperkinetic movement disorders (such as choreas, tics, dystonias, and myoclonus, including asterixis, and spasms) involve irregular and/or variable movements. Tremor involves a rhythmic, oscillatory movement of part of the body. It is usually fairly consistent in frequency, but varies in amplitude. Movement is caused by contractions of reciprocally innervated antagonistic muscle groups firing either asynchronously or synchronously. Although there are some clear pathophysiologic pathways, overall tremor is poorly understood. Most tremors show positive positron emission tomography (PET) scan findings in the cerebellum but do not necessarily originate there. Much remains to be understood in all but a few unusual syndromes.
TABLE 29.1 DIFFERENTIAL DIAGNOSIS OF TREMOR | |||||||||||||
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Incidence and Prevalence of Tremor
The incidence and prevalence of tremor in the general population is largely a factor of the prevalence and incidence of ET, which is the dominant tremor disorder. The next most common tremor is from PD. Other tremors are much less common. At least 7% to 8% of the entire geriatric population older than 60 suffers from tremor, and
it has been asserted that 9% of the population older than 80 suffers from a tremor.3
it has been asserted that 9% of the population older than 80 suffers from a tremor.3
TABLE 29.2 DRUGS THAT CAN CAUSE TREMOR | ||||||||||||||||||||||||||||||||||||||
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Signs and Symptoms of Tremor
The signs and symptoms of tremor (see Table 29.3) are the key to classifying, diagnosing, and treating these disorders.1 This is an area of medicine where astute clinical diagnosis is still by far the most important factor in successful management.
TABLE 29.3 SUMMARY OF THREE COMMON TREMOR DISORDERS | ||||||||||||||||||||||||||||||||||||||||
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There are three major tremor syndromes in the geriatric population, and multiple less common causes of tremors. While it can be impossible in some patients to precisely determine the classification of the tremor, even partial characterization is critical to adequately differentiate tremors and select management.
The most crucial tremor distinction is between “resting” tremors and “action” tremors. Resting tremors occur when the patient is not using the affected body part and its muscles are entirely at rest. Action tremors arise when the patient is using the affected body part. Of course this includes situations when the patient is performing an activity with the limb/part, but it also includes when the patient is not moving the limb/part but is holding it against gravity. It is then referred to as a “postural” tremor. It is therefore particularly important to make sure a limb is truly at rest, and not being partially activated or held against gravity, when determining whether a tremor is an active or a resting tremor.
TREMOR SYNDROMES
Parkinsonian Rest Tremors
Tremors at (genuine) rest are virtually all parkinsonian. There is only a small subset of rest tremors that are not parkinsonian. Some patients with advanced/severe forms of action tremors, including ET, can show some rest component. When this occurs it usually represents a concordance of two common disorders: PD and ET. A minority may have a parkinsonian action tremor.4,5 Wilson disease and rubral tremors can also have rest components. The site of the core pathology for PD and all Parkinson-type tremors is impairment of the substantia nigra pars compacta.
Incidence and Prevalence
Parkinson resting tremor is the second most common type of tremor. The prevalence of PD is in approximately 2% of the population older than 65.6 Of patients with PD, 70% to 75% have the typical resting tremor, while 25% to 30% never develop tremor. The older the age of onset of PD, the less likely tremor will be the initial complaint and the more likely rigidity and paucity of motion will be the major expressions.
Signs and Symptoms of Parkinsonian Tremors
Classically, 50% to 80% of PD will begin insidiously with a tremor in one arm with a finger/hand “pill-rolling” motion, supination/pronation of the forearm, or flexion/extension at the elbow. The tremor worsens with stress and with the use of another limb or limbs, including walking, and improves with the use of the involved limb. There may be a concomitant action component, but the resting component is the key to determining the classification and diagnosis.
Typically as PD progresses, the tremor spreads to the other ipsilateral limb in 1 to 3 years, and to the contralateral limbs in 3 to 8 years.6 Parkinsonian tremor can involve all four limbs plus the chin, lips, tongue, and neck. It essentially never involves the voice and does not cause head or neck tremor (yes/yes or no/no movements). PD can affect phonation (causing the voice to be too soft) but it does not cause a quavery voice. Tremors of the legs and feet, when present, are much more likely with PD than with ET.
Appropriately diagnosing a parkinsonian tremor is aided considerably by noting other PD features such as bradykinesia, stiffness or rigidity, micrographia, and reduced facial animation.
Etiologies of Parkinsonian Tremors
In addition to idiopathic PD, parkinsonian tremors can also be caused—far less commonly—by medications (Table 29.2),2 and by vascular lesions, tumors, or infections that damage the substantia nigra. Manganese poisoning, carbon monoxide, cyanide, and carbon disulfide can also cause a parkinsonian syndrome. These causes are rare in actual practice but these exceptional situations must be kept in mind, as they may be reversible.7,8
Action and Postural Tremors
There are two common causes of action and postural tremors: (i) Toxic/metabolic tremor (or “enhanced physiologic tremor”) and (ii) ET. It is difficult to differentiate these two types of tremor through symptoms or examination. Occasionally, symptoms from an underlying etiology may help to differentiate a toxic/metabolic tremor. There is generally no additional symptomatology in ET besides tremor. These tremors are primarily noted when holding the arms out against gravity or making goal-directed movements with the arms. The arms are generally involved in both of these etiologies.
Toxic/Metabolic Tremor (Also Known as “Enhanced Physiologic Tremor”)
CASE ONE
B.D. was a 65-year-old man who presented as a new patient due to an insurance change. He requested referral to oncology for treatment already under way for a recent diagnosis of lung cancer. At the time of presentation, he had no tremor. We discussed smoking cessation for this heavy smoker now diagnosed with lung cancer. He reported that he had virtually quit while taking bupropion. However, he had a significant tremor when he used bupropion, which had made it difficult for him to function and was intolerable. The tremor had resolved quickly upon cessation of bupropion. This is an example of a toxic/metabolic tremor. Since bupropion is not a direct enhancer of endogenous epinephrine, this particular medication’s mechanism of action is unknown.
CASE TWO
M.G. was a 62-year-old woman without medical insurance who presented complaining of malaise, exercise intolerance, and anxiety. She reported that she had been anxious for years due to a kidnapping in the past that had left her with posttraumatic stress disorder. She felt that
her tremor was due to this anxiety and had not changed recently. On examination she had a very noticeable postural tremor when holding out her hands. Her vital signs were unremarkable with normal pulse, temperature, and blood pressure. She had a loud heart murmur heard diffusely over the precordium. Laboratory tests were normal, with the exception of a thyroid-stimulating hormone (TSH) below the level of detection. She was treated with methimazole and had resolution of virtually all of her signs and symptoms, including 90% to 95% of her tremor. This illustrates an example of toxic/metabolic tremor successfully resolved by treating the underlying disorder.
her tremor was due to this anxiety and had not changed recently. On examination she had a very noticeable postural tremor when holding out her hands. Her vital signs were unremarkable with normal pulse, temperature, and blood pressure. She had a loud heart murmur heard diffusely over the precordium. Laboratory tests were normal, with the exception of a thyroid-stimulating hormone (TSH) below the level of detection. She was treated with methimazole and had resolution of virtually all of her signs and symptoms, including 90% to 95% of her tremor. This illustrates an example of toxic/metabolic tremor successfully resolved by treating the underlying disorder.
Incidence and Prevalence
Toxic/metabolic tremor, also known as an enhanced physiologic tremor, does not have a well-defined incidence and prevalence because it is generally tied to an underlying disorder or medication, and it can resolve or improve when the condition ends. Toxic/metabolic tremor happens to most people at some point in their lives.
This type of tremor is so common in the geriatric population, particularly in the setting of polypharmacy or anxiety, that it should be considered in every patient with tremor.
Pathophysiology
The term enhanced physiologic tremor is based on the fact that all people have a normal, minimal physiologic tremor of about 4 to 12 Hz, which is virtually undetectable unless its amplitude is enhanced. It may be possible to appreciate a normal physiologic tremor when extending a hand holding a piece of paper or pointing a light.9 Multiple etiologies can cause an increase in the amplitude of this tremor, making it clinically significant. Tremor is probably due to reflex oscillations produced by afferent muscle spindle pathways. Underlying causes are usually due to medication side effects or metabolic derangements; hence the term toxic or metabolic tremor.
Signs and Symptoms of Toxic/Metabolic Tremor
This is often difficult to differentiate from ET because it can present in a similar manner. Generally, patients show a tremor with the use of their hands. Tremor is not noticeable at rest. The tremor begins with either holding the arms up against gravity or using them for directed movements.
Etiologies of Toxic/Metabolic Tremor
Many of the disorders and/or medications that cause toxic/metabolic tremor are due to excess epinephrine, but there are a number of other medications which cause tremor without directly raising epinephrine. All patients with action/postural tremors should have these etiologies considered. Even in patients who also have ET, their tremor can be significantly worsened by contributions from an enhanced physiologic tremor.
Please see Table 29.1 for the large differential of toxic/metabolic tremor,7,8,10 and Table 29.22 for medications known to contribute to tremor. Of note, bupropion is not even on the standard lists, so it is clear that additional medications can idiosyncratically cause tremor as well.
Essential Tremor
CASE THREE
A.T. was a 64-year-old woman. She reported a long-standing tremor, which had been getting worse recently to the point that she was having trouble eating soup or drinking water without making a mess and embarrassing herself. She had a history of hypertension and gastroesophageal reflux disease (GERD), and was on hydrochlorothiazide and ranitidine. She had no family history of tremor. On examination, her vital signs were stable and she was in no acute distress. Her tremor was not noticeable at rest. It became evident when she held her hands out, and worsened when she tried to pick up her pen and complete her new patient questionnaire. Her labs included a normal complete blood count (CBC), TSH, and chemistry panel. Her presentation was consistent with ET, so she was prescribed long-acting propranolol. This worked well for her hypertension, and minimized the tremor so that it no longer limited her activities.
Over the next 9 years, a head tremor and shaky voice became noticeable, although well tolerated. Her upper extremity tremor was somewhat more noticeable than it had been when she used her hands to get on the examination table. Even her gait seemed a little shaky by age 73.
A.T.’s case is illustrative of a fairly standard course for ET, though she was fortunate to respond so well to propranolol. She did not have a known family history, so it would not be labeled familial. At this point one might consider the addition of another pharmacologic agent, and perhaps physical therapy. The underlying mechanism of ET is not well understood despite multiple studies. There may be central oscillators in the thalamus and/or the inferior olive.
Incidence and Prevalence
The prevalence of ET in the geriatric population (age >60) is approximately 6%.11 There are at least five million individuals in the United States living with it, and probably more. ET is the most common cause of chronic tremor in all ages. The greatest number of patients with ET is in the geriatric age-group, but there is an early demographic group as well, so quite a few older patients will have had their tremor for many years by the time they are encountered as geriatric patients. Little concrete information is available about the incidence of ET but it may be about 0.5% per year in those older than 65.12
ET is distributed equally between genders, but may be more likely in whites than in other ethnicities. The most important risk factor for developing ET is having a family history of ET.
Genetics
ET is frequently inherited as an autosomal dominant trait. At least half of ET patients have a family history of ET.13,14 There are two loci that have been found to link with the manifestation of familial ET: 3q13 and 2p24.1. A rare variant has been found in a gene of indefinite function that maps in the 2p24.1 area and may be related to some familial ET.15 There have also been families with hereditary ET in which they clearly do not link to any of the known chromosomal loci, or they do link to the 2p24.1 chromosomal locus but do not manifest the gene variant. There is apparently considerable genetic heterogeneity corresponding to its variable clinical presentations, time of onset, affected body part, and severity.
Signs and Symptoms of Essential Tremor
ET usually begins in the upper extremities and affects the hands in 90% to 95% of cases. The frequency of the tremor is 4 to 12 Hz, usually closer to 4 to 6 Hz in the older population. It is a classic action and/or postural tremor. The patient is fine at rest, and then the tremor starts to show as they begin a motor movement with the affected part. It can begin unilaterally, but is usually bilateral. If it is persistently unilateral over years, it calls the diagnosis into question.5
ET is usually slowly progressive over time in a given patient. It commonly becomes more severe and spreads to other body parts, ultimately affecting the head (34% to 50%) with either yes-yes or no-no action, face (5%), voice (12% to 30%), trunk (5%) and lower limbs (15% to 20%).18,19 It is unusual to affect only the head (1% to 10% of patients)20 or voice in isolation. In fact, if the voice is solely affected, dystonia needs to be considered. ET is associated with a quavering voice with normal phonation; dysphonia, even if subtle, suggests dystonia.
The tremor in ET either remains consistent as the patient holds out the arms against gravity and/or approaches a goal of movement, or there is a brief terminal increase as the goal is reached. When ET is more severe, this can cause significant disability due to interference with eating, drinking, writing, and other skilled motor activities. Many patients do ultimately have some disability, and patients with severe cases can be totally disabled. From 15% to 60% must alter their careers due to their tremor.12
In contrast, cerebellar tremors—which can also lead to severe disability—cause an increasing tremor amplitude as the patient performs the movement, not just as the goal is reached. So the amplitude grows to be quite large by the time the goal is reached. This variation may be hard to differentiate at times.
One feature of ET, which is not present in any other type of tremor, is that it is generally very sensitive to alcohol. Many patients will discover that a drink temporarily resolves, or at least significantly decreases, their tremor.
Until recently, ET has been believed to be an isolated problem, without associated symptoms. There is growing evidence that there can be associated findings, but they should not be those of PD (unless the patient suffers dual disease). Generally, patients are neurologically well. However, in keeping with the heterogeneity of ET, some patients can have subclinical cognitive abnormalities uncovered with careful testing. They can show postural instability and ataxic gait. They are more likely to have poor hearing, and they may show olfactory deficits.12 Patients with severe ET may even have a resting tremor, though it is difficult to test for this carefully enough, because the limb must be at complete rest. ET-associated rest tremors will not be “pill-rolling” in nature. Some forms of ET may actually be a mild degenerative disease with associated symptoms and signs, but definitive characterization and delineation are not yet available. Formal inclusion/exclusion instruments for ET have been developed but are only useful as research tools. Ultimately the clinician must rely on symptoms and signs for diagnosis.
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