Tremors

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35 Tremors

E. Prather Palmer, H. Royden Jones, Jr.

Clinical Vignette

A 31-year-old woman had the spontaneous onset of a relatively mild horizontal (“no-no”) head tremor. She had no family history of neurologic disorders. This tremor was initially inconsequential but it gradually increased in severity. Turning her head to the right seemed to increase the tremor, whereas turning her head to the left decreased the tremor. Mild finger pressure on her left chin dampened the tremor and the involuntary movements of her head. Beta blockers, primidone, and alcohol had little effect. Eighteen months later, driving had become difficult because her head tended to turn involuntarily. Attempts to hold her head in the neutral position as well as stress markedly increased the tremor, leading to neck discomfort. Over time, the involuntary movements were continuously present. Neurologic examination demonstrated right sternocleidomastoid muscle hypertrophy. A trial of anticholinergic medication increased the tremor and precipitated a psychotic reaction. Eventually, the patient was treated with botulinum toxin in the right sternocleidomastoid muscle and some of the left paracervical muscles. This treatment controlled the involuntary movements and dampened the involuntary tremor.

Tremors are involuntary, rhythmic, and stereotyped oscillatory movements of a body part. These are the most prevalent movement disorders and are usually distinguishable from other abnormal involuntary movements by their rhythmic quality, with concomitant involvement of agonist and antagonist muscle groups. They result from alternating or irregularly synchronous contractions of reciprocally innervated skeletal muscles.

The precise pathogenesis for a tremor is unclear. With neurophysiologic testing, reciprocal bursts of electromyographic (EMG) activity occurring in agonist and antagonist muscles are separated by relative silence. Simultaneous EMG bursts in agonist–antagonist muscle pairs are not characteristic of tremors; the recorded pattern of any tremor can vary over a short period (i.e., co-contraction of the muscles, alternation of contraction, or contraction of the antigravity muscles alone). More complex relations between the agonist and antagonist muscles also occur. Hence, no universal method exists for definitively rating, measuring, or classifying tremors. Clinical examination is still the most important step in tremor evaluation.

Physiologic Tremor

This is normally present in healthy individuals and is related to a number of factors. Physiologic tremor typically has an 8- to 12-Hz frequency in young adults and decreases to 6–7 Hz in the senior population (Table 35-1).

Table 35-1 Approximate Frequencies of Tremors

Frequency Range, Hz	Tremor Type
1–5	Holmes cerebellar tremor
2–10	Multiple sclerosis
2–12	Drug-induced tremor
2–12	Neuropathic tremor
3–10	Parkinsonian tremor
3–10	Task- and position-specific tremor
3–12	Dystonic tremor
4–10	Psychogenic tremor
4–8	Essential tremor
7–12	Physiologic and enhanced physiologic tremor
16–25	Orthostatic tremor

Adapted from Bain PG. The management of tremor. J Neurol Neurosurg Psychiatry. 2002;72(Suppl. 1):i3-i16.

Peripheral components include muscle mass and stiffness, long and short loop reflexes, grouped motor neuron firing rates, and the inertia of muscles and other structures. The primary component of a physiologic tremor, the central generator, contributes weak 8- to 12-Hz low-amplitude movement not affected by inertial loading or physical manipulation. Other components, including the heartbeat (cardioballistics), may also contribute. This normal tremor is best seen by holding an arm straight in front of the body and placing a sheet of paper across the outstretched fingers.

The most common tremor is referred to as an enhanced physiologic tremor (EPT). It may result when motor units become discharged in groups. Typically this type of tremor becomes enhanced during muscular fatigue, fear, excitement, or emotional distress. It may occur in various medical conditions, for example, thyrotoxicosis, pheochromocytoma, catecholamine intake, methylxanthine use, drug withdrawal, and alcohol intoxication. Beta receptor agonists enhance physiologic tremor, and β-receptor blockade or β₂ receptor antagonists effectively decrease it. Early on, essential tremors (ETs) are difficult to separate from exaggerated physiologic tremors.

Pathophysiology

The etiology of many tremors is unknown. Although Parkinson disease (PD) lesions predominate in the substantia nigra, experimental animal lesions within the substantia nigra do not cause tremor, and not all patients with lesions at this level have a tremor. Moreover, a tremor develops in only half of patients poisoned with the analog of meperidine (MPTP) that preferentially destroys part of the substantia nigra and classically leads to a mimic of PD. However, even with MPTP, the tremors are not the typical resting pill rolling ones of PD tremor; these have more of an action or postural component. In contrast, ventromedial tegmentum lesions made in a monkey midbrain do produce a resting-type tremor. Pathologic tremors such as ET, dystonic tremor, and the PD tremors are thought to have multiple central generators, resulting in variable frequencies of approximately 1–26 Hz (see Table 35-1).

Pathologic Tremor

The most useful classification of pathologic tremors is based on their clinical features, especially anatomic distribution (proximal or distal, body part involved), symmetry, and the conditions that best activate them (Table 35-2). Rest tremors occur when a body part is completely supported against gravity (Fig. 35-1). Action tremors occurring during voluntary muscular contraction are further classified as (1) postural (occur in a body part maintained in position against gravity), (2) kinetic (occur during voluntary movement), or (3) isometric (occur within a muscle contracting against a stationary object).

Table 35-2 Classification of Tremors

Type of Tremor	Clinical Features	Common Examples
Postural	A posture is maintained against gravity	Physiologic tremor Essential tremor Drug-induced tremor

Kinetic With voluntary movements

Parkinson disease

Cerebellar lesions (intention tremor)

Writing tremor

Holmes tremor

Isometric With voluntary muscle contraction against a rigid, stationary object Orthostatic tremor Orthostatic tremor Tremor of lower limbs on standing and remits on walking or sitting

Orthostatic tremor

Head trauma

Neuropathic tremor

Dystonic tremor Tremor in body part affected by dystonia Spasmodic torticollis Resting tremor Limb fully supported against gravity; improves with voluntary movement Parkinson disease Psychogenic tremor Acute onset, inconsistent, fatigues, decreases amplitude with distraction

Somatoform disorders

Malingering

Depression

Asterixis Arrhythmic lapses of sustained postures Toxic and metabolic encephalopathies

Figure 35-1 Tremor.

Essential Tremor

This tremor is neither “essential” (an inherent characteristic of the individual) nor “benign.” It is an acquired tremor that usually worsens with age and may eventually significantly interfere with normal activities. This type of action tremor has a lower frequency (4–8 Hz) than do physiologic tremors (7–12 Hz). It often occurs in isolation unrelated to any other neurologic disability. Approximately 50% of these patients have a positive family history, usually involving an autosomal dominant trait with virtually complete penetrance. These are referred to as familial or hereditary tremor. If the ET occurs late in life, it may be called a senile tremor. Although the familial forms tend to begin earlier, they rarely occur during infancy or after the sixth decade.

ET is 20 times more frequent (prevalence, 0.2–33%) than PD. Many adult patients with ET tremors initially fear they have PD, and although classically it has not been thought that ET is an indication that PD will develop, more recent evidence demonstrates a small link between ET and PD. Similarly a postural tremor may appear years before the onset of other extrapyramidal symptoms of PD. Common genes or similar pathologic findings may underlie the development of both ET and PT and later PD. Functional neuroimaging studies demonstrate a dopaminergic deficit in some ET patients. Additionally, autopsy studies support such a relationship as some ET individuals have classic Lewy’s body pathology in their brains similar to that present in PD.

Typically ETs are mild, symmetric postural tremors of the upper limbs, accentuated by voluntary movements. They commonly consist of pronation–supination and extension–flexion movements, and in severe or advanced cases, they may have a resting or kinetic component. They may spread to the head, face, lips, voice, jaw, tongue, chin, or occasionally the legs.

Head tremors may be horizontal (“no-no”) or vertical (“yes-yes”). Although ET is a monosymptomatic illness, abnormalities in tandem gait are seen in nearly 50% of patients. Mild parkinsonian features (i.e., rest tremor, cogwheeling, and breakdown in rapid alternating movements) may also be present. As with classic ET, patients with the head tremor variation also have a somewhat greater incidence of PD. Additionally some instances of “no-no” head tremor may be a forme fruste later leading to spasmodic torticollis (dystonia) as per the vignette.

Treatment is not indicated for mild tremors that do not interfere with patients’ quality of life. However, when the ET begins to interfere with the patient’s daily activities, various therapeutic options are available. Although most patients experience a reasonable response to beta adrenergic antagonists, such as propranolol, its side effects of bronchospasm, impotence, and sleep alterations are sometimes limiting. Other beta blockers may have a lower incidence of such side effects. The majority of ET patients experience a dramatic reduction in tremor after alcohol intake. Sometimes this response is helpful in making a differential diagnosis between ET and some variants of PD. Alcohol reduces the cerebellar overactivity that is demonstrated on PET scans of ET patients. However, over time, increasing amounts of alcohol are needed to produce this effect. Alcoholism is a potential outcome. Occasionally, treatment of ET can be very frustrating (Table 35-3). In the rare instance when the patient is very significantly incapacitated, surgical intervention (thalamotomy and deep brain stimulation) is effective.

Table 35-3 Pharmacologic Options for Essential Tremor

Clinical Vignette

A 13-year-old boy was evaluated for a long-standing hand tremor that was accentuated by stress and physical activity, particularly having an essential quality. He had a grandmother with a head tremor and a grandfather with PD. Neurologic examination demonstrated intermittent bilateral action tremor of his hands most pronounced by finger-to-nose testing. His muscle stretch reflexes were hypoactive and he evidenced bilateral pes cavus. He refused an EMG. A trial of propranolol was considered. He returned 2 years later while attending vocational high school where he was studying welding. His tremor had increased and now involved his lower extremities and his head. He now had minimal distal weakness and sensory loss.

DNA testing was negative for Charcot–Marie–Tooth (CMT) polyneuropathy. Nerve conduction studies demonstrated multifocal demyelinating motor and sensory conduction slowing typical for an acquired chronic inflammatory demyelinating polyneuropathy (CIDP). Cerebrospinal fluid protein was 107 mg/dL. Treatment with intravenous immunoglobulin led to clinical improvement. Serendipitously, his Mom had an EMG that had some findings similar to his. Further DNA testing was carried out and demonstrated X-linked CMT polyneuropathy associated with 13-basepair deletion in the coding region of connexin-32.

Comment: Although this is a very uncommon clinical scenario, this patient’s clinical presentation emphasizes the need to take a broad perspective when evaluating a patient with an ET as it can be mimicked by either acquired or hereditary demyelinating polyneuropathies.

Resting Tremor

PD and sometimes its variant are typified by a resting tremor (Chapters 33 and 34). The classic “pill-rolling” PD tremor has both a flexion–extension, abduction–adduction, of the fingers or hand and a pronation–supination component of the hand and forearm. This is typically unilateral at its first appearance and may remain asymmetric for a significant time. It is slowly progressive. Although this primarily affects the hand, it sometimes can include the feet, mandible, and lips. This PD tremor is somewhat suppressed by anticholinergic drugs and, less consistently but occasionally impressively so, by levodopa and other dopamine agonist drugs. On occasion, one sees patients with monosymptomatic resting tremors unassociated with other parkinsonian features. In contrast to PD per se, these isolated tremors are often refractory to treatment; however, sometimes other features of PD do respond to treatment eventually a number of years later.

With the increased understanding of the pathogenesis and treatment of PD, many patients mistakenly assume that most tremors are related to it. The physician must be able to differentiate the more common, postural ET from the serious resting tremor of PD (Table 35-4).

Table 35-4 Essential Tremor Versus Parkinson Tremor

Characteristic	Essential Tremor	Parkinson Tremor
Type	Action/postural	Resting, “pill rolling”
Frequency	4–10 Hz	3–5 Hz
Age at onset	All ages	Middle age or elderly
Family history	First-degree relative often	None affected
Body part	Hands, head, voice	Hands, legs
Symmetry	Usually symmetric onset	Asymmetric onset, slowly
Course	Stable or slowly progressive	Progressive proximal as it generalizes to both sides
Other symptoms	Usually monosymptomatic	Rigidity, bradykinesia, flexed posture, balance problems
Origin	Olivocerebellar and other midbrain circuitry	Multiple generators within corticobasal ganglia and corticocerebellar circuitry
Other	Often transmitted as autosomal dominant, classically diminished by alcohol	May exhibit many types of tremors, including a postural one at the wrist at 5–8 Hz that may be difficult to distinguish from an essential tremor

Orthostatic and Action Tremor

Clinical Vignette

A 72-year-old man had experienced difficulty playing golf during the past 6 months. When he would step to the tee standing still to get ready to hit the ball, his legs became increasingly tremulous. Although he could walk all 18 holes without difficulty, he was eventually unable to maintain his balance when he tried to stand still to make his shots. To compensate, he assumed an ever-widening posture, but this gradually became less helpful. Similarly, he had routinely begun to sit down when he urinated. Neurologic examination demonstrated an alert, pleasant man with normal facial expression. He arose from his chair without difficulty, walking with a normal gait, including a good arm swing. However, when he stopped and tried to stand still, he stood with an abnormally wide base and would soon develop an 18- to 20-Hz tremor involving both legs. It became necessary for him to hold on to someone to keep from falling. While seated, he had no rest tremor. He had no cogwheeling or rigidity, and his neurologic examination was otherwise normal.

Various medications were tried, including primidone, but no effective remedies were found.

Orthostatic tremor (OT) is a rare and often misdiagnosed problem of late middle age affecting the legs. It is typically precipitated by weight bearing and is characterized by a 16- to 25-Hz tremor. Isometric limb muscle contraction, the critical generation factor, induces the tremor. No other tremors have a frequency greater than 16 Hz. Often, if patients cannot sit down or resume walking, they become distressed and sometimes fall. The tremor classically abates in the non–weight-bearing setting when the patient sits or begins to walk. Thirty percent of OT individuals also have an ET of the leg. In contrast to OT, this does not attenuate with walking.

The differential diagnosis of OT is a very limited one; the possibilities include aqueduct stenosis, pontine lesions, head trauma, and chronic inflammatory demyelinating neuropathy (CIDP). Brain MRI is important to exclude most of these. If this is normal, an EMG is indicated to exclude CIDP. Treatment is frequently problematic. Gabapentin may be helpful for OT. Treatment with topiramate, benzodiazepines, or valproic acid is sometimes of limited help. The nature of OT is commonly poorly understood by family and friends. They may need reassurance as to the nonpsychiatric nature of the patient’s symptoms especially when he or she appears so normal in all other aspects. Patient anxiety is often a result; it may also require treatment (Table 35-5).

Table 35-5 Other Action-Type Tremors

Type	Description
Isolated chin tremors	Familial syndrome with onset in infancy or childhood; often intermittent and stress-induced
Dystonic tremor	A postural or kinetic tremor in an extremity or body part by dystonia; may at times be more obvious than the dystonic movement it accompanies.
Isolated voice tremor	May be a variant of essential tremor or dystonic tremor accompanying focal dystonia of the vocal cords (spasmodic dystonia)
Alcohol withdrawal tremor	An action/postural tremor is a prominent feature of the alcohol withdrawal syndrome; after recovery from the withdrawal state, some individuals have a persistent essential-type tremor; withdrawal of other sedative-type drugs (barbiturates, benzodiazepines) after prolonged use may also produce the same type of tremor
Task-specific tremors	May occur primarily during the performance of specific tasks or postures; primary writing tremor is the most common, but similar task-specific tremors have been described in typists, musicians, and sportsmen
Neuropathic tremor	Irregular, asymmetric, usually distal tremor, with frequencies of 3–12 Hz; may occur at rest, with posture with movement, and is associated with peripheral nerve disease; usually subsides with successful treatment of the underlying neuropathy or with beta blockers

Ataxic Intention Tremor (AIT)

These are classified as either action or kinetic tremor. Their clinical characteristics have similarities to the tremor of cerebellar disorders and thus make this a separate clinical entity. The tremor is not intentional but occurs primarily during the demanding phase of active volitional movement. AIT is not apparent when the limbs are at rest and during the beginning of a voluntary movement. As an action is initiated and continues, fine motor adjustments are demanded (e.g., finger-to-nose task). In the instance of AIT, 2- to 4-Hz side-to-side oscillations eventually interrupt the movement and may continue for several beats after the target has been reached. Ataxic intention tremor always occurs in combination with cerebellar ataxia and may seriously interfere with performance of many skilled acts.

Another more violent form of an intention tremor, Holmes tremor, is associated with cerebellar ataxia, wherein slight lifting of the arms or maintenance of a static posture (e.g., arms abducted at the shoulders) results in a wide-range, rhythmic, 2- to 5-Hz “wing-beating” movement, often sufficiently forceful to throw patients off balance. The lesion is usually in the midbrain near the red nucleus (the tremor was formally called a rubral tremor). There is no treatment for these tremors. In severe cases, surgery (usually a thalamotomy) may help.

Palatal Tremor (Palatal Myoclonus)

These rare tremors are rapid, rhythmic, and involuntary movements of the soft palate. Previously considered to be a form of myoclonus (hence the term palatal myoclonus or palatal nystagmus), palatal tremor has two forms: essential and symptomatic. Essential palatal tremor has no pathologic basis. It is associated with rhythmic activation of the tensor veli palatini, often recognized by the patient noting an audible click that ceases with sleep. MRI demonstrates no specific abnormalities in essential palatal tremor.

Symptomatic palatal tremor is often associated with a pendular vertical nystagmus, oscillopsia, and cerebellar signs. It is not inhibited by sleep. Unlike essential palatal tremor, this involves the levator veli palatini muscles. Symptomatic palatal tremor is associated with vascular disorders, multiple sclerosis, encephalitis, trauma, and neurodegenerative diseases. MRI demonstrates tegmental lesions as well as unilateral or bilateral inferior olivary nucleus enlargement.

Asterixis

This is typified by a series of arrhythmic interruptions in a sustained posture (i.e., sustained muscular contractions) with an intermittent lapse in postural muscle tone. The latter is associated with EMG silence for a period of 35–300 milliseconds. During this silence, gravity or the inherent elasticity of muscles produces the movement. Asterixis, therefore, differs physiologically from tremors and myoclonus. It is easily demonstrated by asking patients to hold their arms outstretched with hands dorsiflexed and fingers extended. Flexion hand movements may occur several times each minute. Asterixis can be produced by persistent contraction of any muscle group. Classically, this is precipitated by a sustained dorsiflexion of the wrists or less commonly protrusion of the tongue. It can occur in normal persons in the neck and arms with drowsiness.

Asterixis typifies the clinical picture of hepatic or uremic encephalopathy. Sometimes it is found in other metabolic and toxic states, including those iatrogenically induced by various medications such as phenytoin and other anticonvulsants. Unilateral asterixis is rarely found with contralateral thalamic or brainstem lesions. Treatment with clonazepam, sodium valproate, tetrabenazine, and haloperidol is sometimes helpful.

Drug-Induced (Iatrogenic) Tremor

Many pharmacologic agents can induce tremors, depending on the individual and the underlying illness. Some drugs, such as lithium, can cause several types of tremor, depending on the dose or treatment duration. The most common drug-induced tremor is an enhanced physiologic tremor related to sympathomimetics or antidepressants (especially the tricyclics and serotonin reuptake inhibitors). Although specific predisposing risk factors are not well defined, patients with an ET, older patients, and women are thought to have a higher risk for drug-induced tremors.

A parkinsonian-like resting tremor may occur after ingestion of neuroleptic, antidopaminergic drugs (including dopamine-depleting drugs). Unlike the tremor of PD, the resting, pharmacologically induced tremor is initially bilateral and symmetric. An intention tremor may occur with lithium intoxication or chronic alcoholism. A tardive tremor is associated with long-term neuroleptic use. The anticonvulsants phenytoin and sodium valproate can cause various action tremors. An action tremor resembling an enhanced physiologic tremor is also produced by medications such as calcium channel blockers, amiodarone, theophylline, adrenaline, amphetamine, lithium, caffeine, cocaine, marijuana, and drug or alcohol withdrawal (Table 35-6).

Table 35-6 Drug-Induced Tremors

Drug	Type of Tremor
Alcohol withdrawal	Postural, intention
Drug withdrawal	Postural
Insulin (by inducing hypoglycemia)	Postural
CNS acting
Neuroleptics Reserpine Metoclopramide Antidepressants Lithium Cocaine Alcohol