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Introduction
Tremor is a rhythmic, oscillatory movement produced by alternating or synchronous contractions of antagonist muscles. It is the most common form of involuntary movement, but only a small fraction of those who shake seek medical attention. Indeed, in one epidemiologic study of normal controls, 96% were found to have clinically detectable postural tremor and 28% had a postural tremor of “moderate amplitude” ( ).
Tremors can be classified according to their phenomenology, distribution, frequency, or cause ( ; ; ; ; ; ; ; ; ; ). Phenomenologically, tremors are divided into two major categories: rest tremors and action tremors ( Table 10.1 ). Rest tremor is present when the affected body part is fully supported against gravity and not actively contracting; rest tremor is diminished or absent during voluntary muscle contraction and during movement. Action tremors occur with voluntary contraction of muscles, and they can be subdivided into postural, kinetic, task-specific or position-specific, and isometric tremors. Postural tremor is evident during maintenance of an antigravity posture, such as holding the arms in an outstretched horizontal position in front of the body. Some parkinsonian patients exhibit postural tremor that emerges after a latency of a few seconds. This tremor, referred to here as reemergent tremor, probably represents a rest tremor that has been “reset” during posture holding ( ) ( Fig. 10.1 ). The relationship of this reemergent tremor to the typical rest tremor is supported by the observation that this reemergent repose tremor shares many characteristics with the typical rest tremor; it has the same 3- to 6-Hz frequency, and it also responds to dopaminergic therapy ( ). Rarely, postural tremor occurring after a brief (2- to 4-second) latency can be seen even without observable rest tremor ( ). Kinetic tremor can be seen when the voluntary movement starts (initial tremor), during the course of the movement (dynamic tremor), and as the affected body part approaches the target, such as while performing the finger-to-nose or the toe-to-finger maneuver (terminal tremor, also called intention tremor). Task-specific tremors occur only during, or are markedly exacerbated by, a certain task, such as while writing (primary handwriting tremor) ( ), while speaking or singing (voice tremor) ( ; ), or while smiling ( ). Besides writing, task-specific tremors may be triggered during other activities, such as while playing golf, particularly when putting ( ). Position-specific tremors occur while holding a certain posture (e.g., the “wing-beating” position or holding a spoon or a cup close to the mouth). One example of a task- or position-specific tremor is the tremor that occurs in performing the dot test (“dot approximation test”), during which the subject, seated at the desk with elbow elevated to a 90-degree shoulder abduction, is asked to hold the tip of the pen as close to a dot on a horizontal paper as possible without touching the dot. Patients with essential tremor (ET) or other action tremors usually exhibit exacerbation of the tremor during this specific task. A variant of this tremor occurs in performing the modified finger-nose-finger test, during which the subject stands in front of a paper mounted on a wall and is asked to mark the center of the drawn target and to make a mark with a felt-tipped pen five times ( ). Isometric tremor occurs during a voluntary contraction of muscles that is not accompanied by a change in position of the body part, such as maintaining of a tightly squeezed fist or while standing (e.g., orthostatic tremor; see later). 
Table 10.1
Categorization of tremors
| Rest | Action | ||
|---|---|---|---|
| Postural | Kinetic | Miscellaneous | |
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Video 10.1 Reemergent tremor.
Video 10.2 Task-specific tremor.
Video 10.3 Task-specific tremor.
Tremors also can be classified according to their anatomic distribution—for example, head, tongue, voice, and trunk. Some patients describe “internal tremor,” found in 32.6% of patients with Parkinson’s disease (PD) and 54.5% of those with ET ( ). Orolingual tremors include physiologic, essential, task- and position-specific, dystonic, orthostatic, parkinsonian, palatal (also termed palatal myoclonus), drug-induced, hereditary, and psychogenic ( ; ; ). Because of the complexity of limb tremors, it is best to describe them according to the joint about which the oscillation is most evident—for example, metacarpal-phalangeal joints, wrist, elbow, and ankle tremor. In most tremors, the frequency ranges between 4 and 10 Hz, but the cerebellar tremors may be slower, with a frequency of 2 to 3 Hz. The “slow” tremors (frequency: 1–3 Hz) are sometimes referred to as myorhythmia and are usually associated with brainstem pathologic processes ( ; ; ; ). The “fast” tremors (frequency: 11–20 Hz) may be distinct tremor disorders, such as orthostatic tremor, or may represent harmonics of other tremors. The clinical characteristics of tremors provide the most important clues to their cause ( Table 10.2 ).
Table 10.2
Classification and differential diagnosis of tremors
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MPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Assessment of tremors
There have been many attempts to quantitate tremor, but it is not apparent whether electromyographic (EMG), accelerometric, or other methods of measuring tremor correlate with the clinical rating scales ( ; ). Indeed, one study suggested that assessments of spirography and handwriting correlated better with overall functional tremor-related disability than did the electrophysiologic methods ( ). However, because the physiologic measurements and the clinical ratings were not performed simultaneously and because of other technical problems, interpretation of the study was challenging. described the use of a digitizing tablet in quantification of tremor during writing and drawing. Although relatively good intertrial correlations were obtained with this method, the tablet failed to capture the speed of writing or the amount of effort exerted by the patient who during the task was trying to control the tremor while simultaneously writing. One study found high interobserver reliability using a diagnostic protocol for ET ( ). The investigators also found high specificity and sensitivity of a screening questionnaire compared with the physician’s examination in patients with definite and probable ET, but actual examination of the subjects was necessary to detect mild ET ( ). In another study, the authors concluded that when a limited number of tests was available in large epidemiologic surveys, a test such as the finger-nose maneuver may be used to screen populations for ET, whereas to exclude normal subjects, the spiral drawing test, water pouring test, or arm extension test may be preferable ( ). In a study in which 54 Archimedes spirals were drawn using a digitizing tablet by nine ethanol-responsive patients with ET before and after the administration of ethanol, computerized scores correlated with visual ratings ( P < 0.0001) and quantitative ratings provided better sensitivity than visual rating when recording the overall effects of an ethanol challenge ( P < 0.05) ( ). A performance-based test for ET has been validated and compared with other measures of tremor ( ). Although this performance-based test was thought to objectively assess functional capacity in patients with ET, the test was cumbersome to perform because it required a variety of props, such as a milk carton, a glass, a soup spoon, a bowl, a saucer, a wallet, coins, an electrical socket, a thread and needle, a strip of buttons, and a telephone. Using another instrument, the modified Klove-Matthews Motor Steadiness Battery and the Nine-Hole Steadiness Tester, showed that these portable instruments provided a reliable and valid means of collecting objective quantitative data on tremor severity. A Tremor Disability Questionnaire was developed and found to reliably correlate with multiple measures of tremor severity ( ). Another screening instrument for ET, consisting of 7 items and a spiral drawing, has been found to have 70.5% sensitivity, 68.2% specificity, and 64.9% positive predictive value ( ). A simple, user-friendly clinical tool, with a higher sensitivity, specificity, and predictive value is needed to assess tremors in the clinic and in the field. A teaching videotape for assessment of ET was developed to improve the uniform application of the Washington Heights–Inwood Genetic Study of Essential Tremor ( ). Using a clinical evaluation (interview and videotaped examination) and an electrophysiologic evaluation (quantitative computerized tremor analysis using accelerometry and EMG), found a very high concordance rate between the two methods in 51 of 54 (94%) subjects, suggesting that using either technique would result in a similar diagnosis. Although not yet validated, the Unified Tremor Rating Assessment developed by the Tremor Research Group has been used in a number of clinical therapeutic trials ( ; ). The other scale that has been used in several tremor studies is the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) ( ). Although the inter-rater reliability of this scale has been shown to be relatively poor, there has been good consistency, with an average Spearman correlation of 0.87, when the same rater repeatedly assesses the tremor ( ). Using the TRS, Putzke and associates ( ) showed that the total score increased by about 2 points during prospective follow-up of patients with ET over a mean of 3.6 years and that older age, longer duration of disease, and asymmetrical onset of tremor was associated with increased tremor severity.
Another tremor rating scale, The Essential Tremor Rating Scale (TETRAS), developed by the Tremor Research Group (TRG), has been validated against the TRS ( , ). TETRAS comprises two subscales, the Activities of Daily Living (ADL) subscale and the Performance subscale. The TETRAS Performance has been shown to be a valid scale with excellent inter-rater and intrarater reliabilities ( ). One study on temporal fluctuations in ET over 6 hours has demonstrated a good correlation of a quantitative motor assessment system with TETRAS for upper limb tremor, a subset of the TETRAS Performance scale ( ). Using accelerometry as a measure of tremor in 15 ET patients after a single oral ethanol dose calculated to reach 0.05 g/dL breath alcohol content, significant correlation was found between the accelerometry data TETRAS results with the calculated minimum detectable change of TETRAS of 8.9%. This demonstrated sensitivity to change of the scale for assessing effects of a therapeutic intervention ( ). In general, the minimum detectable change for an individual is about 50% of baseline, but when comparing groups, a 30% change is considered by most experts as significant.
The existing five tremor severity scales (the Fahn-Tolosa-Marin Tremor Rating Scale, the Bain and Findley Clinical Tremor Rating Scale, the Bain and Findley Spirography Scale, the Washington Heights–Inwood Genetic Study of Essential Tremor Rating Scale, and the Tremor Research Group Essential Tremor Rating Assessment Scale), one ADL/disability scale (the Bain and Findley Tremor ADL Scale), one quality-of-life scale (the Quality of Life in Essential Tremor Questionnaire), and one screening instrument (the Washington Heights–Inwood Genetic Study of Essential Tremor Rating Scale, version 1) have been evaluated, and all have been found useful in assessing tremor. However, “a more comprehensive analysis of sensitivity to change in order to judge their utility in clinical trials and individual patient assessments” has been recommended ( ).
The TETRAS has been found to correlate with quantitative assessments using the Kinesia (CleveMed) system ( ; ; ). Any assessment of tremor must take into account minute-to-minute and hour-to-hour amplitude variability ( ; ), and potential provocations, such as voluntary isometric contraction in the case of action tremors and walking and counting backward in the case of rest tremor ( ). In one study, a maximal 23% absolute variation in tremor amplitude was found in patients with ET, TETRAS, quantitative motor assessment system (QMAS), and videos were used to record tremor amplitude every 2 hours for 6 hours ( ). There also has been an emerging wearable technology that uses accelerometers and other sensors coupled with computers to quantitate tremors and other movement disorders ( ),
Rest tremors
Diagnosis
Rest tremor is most typically present in patients with PD, although 19% of ET patients have rest tremor ( ). In one study, all 34 patients with pathologically proven cases of idiopathic (Lewy body) parkinsonism demonstrated typical rest tremor sometime during the course of their illness ( ). Although this study suggests that parkinsonian patients who do not exhibit rest tremor probably do not have idiopathic parkinsonism (PD), another study, involving 100 pathologically proven cases of PD, found that 32% of all patients apparently never manifested tremor during the course of their disease ( ). Although rest tremor in PD typically involves the hands or legs, it may also involve the face and jaw. In one study 28 of 559 (5%) patients with PD had facial tremors and these tremors responded to levodopa in 46% of patients ( ). Facial tremors, such as lip, chin and jaw tremor can be the initial early sign of PD ( ).
Several studies have suggested that the natural course of PD is in part related to the presence or absence of tremor ( ; ; , ). Tremor-dominant PD may be associated with earlier age at onset, less cognitive decline, and slower progression than the type of PD that is dominated by postural instability and gait difficulty (PIGD) ( ). Clinicopathologic correlations are needed to answer the question as to whether the tremor-dominant form and the PIGD-dominant form represent different diseases or merely variants of one disease, namely, PD. In support of the former is the finding that 27% of patients with the PIGD form of idiopathic parkinsonism had Lewy bodies at autopsy ( ). In another clinicopathologic study, demonstrated that patients with PD and prominent tremor have degeneration of a subgroup of midbrain (A8) neurons, whereas this area was spared in PD patients without tremor. This observation supports the hypothesis that differential damage of subpopulations of neuronal systems is responsible for the diversity of phenotypes seen in PD and other parkinsonian disorders. It is unclear whether the occasional patients with long-standing unilateral tremor and minimal or no other parkinsonian findings have a benign form of PD, as is suggested by positron emission tomography (PET) scans that have revealed low fluorodopa uptake in the contralateral putamen ( ), or whether this condition represents a separate disease entity. In contrast to patients with the PIGD form of PD, patients with tremor-dominant PD have increased metabolic activity in the pons, thalamus, and motor-association cortices ( ). When rest tremors involve the fingers, hands, lips, jaw, and tongue in the same individual, they share a common frequency, suggesting that they may be of central origin ( ). This pattern, however, changes during sleep in that non–rapid eye movement (REM) sleep transforms the alternating tremor that is typically seen in the awake patient into subclinical repetitive muscle contractions of variable frequency and duration during sleep stages I to IV, and the tremor disappears during REM sleep ( ).
Rest tremor has other causes in addition to PD and related parkinsonian disorders ( Table 10.3 ). Patients with severe ET may have tremor at rest and prominent kinetic tremor. It is not known whether the ET patients with rest tremor have associated PD, whether they later develop other features of PD, or whether the rest tremor is a feature of ET ( ; ).
Table 10.3
NIH Essential Tremor Consortium diagnostic criteria for essential tremor
Participants in the July 1996 NIH meeting: J. Beach, S. B. Bressman, M. F. Brin, D. De Leon, L. Goldfarb, M. Hallett, J. Jankovic, W. Koller, D. Mirel, K. Wilhemsen.From Brin MF, Koller W. Epidemiology and genetics of essential tremor. Mov Disord. 1998;13(Suppl. 3):55–63.
| Definite |
| 1. Bilateral arm tremor with 2+ amplitude rating in at least one arm and 1+ in the other arm or 2. Predominant cranial-cervical tremor with 2+ amplitude rating and 1+ rating in at least one arm. The head tremor is rhythmical, without directional preponderance, and without asymmetry of cervical muscles 3. Exclude obvious secondary causes of tremor: For example, physiologic, drug-induced, Charcot–Marie–Tooth (CMT), chronic inflammatory demyelinating polyradiculoneuropathy (CIPD), Parkinson disease (PD) (coexistent dystonia is allowed, but coexistent PD is not) |
| Probable |
| 1. 1+ arm tremor bilaterally or 2. Isolated cranial-cervical tremor with 2+ amplitude rating or 3. Convincing history of ET 4. Exclude obvious secondary causes of tremor: For example, physiologic, drug-induced, CMT (coexistent dystonia is allowed; coexistent PD is allowed if there is a convincing history of preexisting ET) |
| Possible |
| 1. Isolated 1+ cranial-cervical tremor 2. Task/position specific hand/arm tremor 3. Unilateral arm tremor 4. Orthostatic tremor |
Tremor rating: 0, none perceived; 1, slight (barely noticeable); 2, moderate, noticeable, probably not disabling (<2-cm excursions); 3, marked, probably partially disabling (2–4 cm excursions); 4, severe, coarse, disabling (>4 cm excursions).
Some patients with lesions in the cerebellar outflow pathways, particularly in the superior cerebellar peduncle near the red nucleus, in addition to postural and kinetic tremor, also have tremor at rest, probably because of an interruption of the nigrostriatal pathway ( ; ). In 1904, Gordon Holmes described a syndrome characterized by a low-frequency rest tremor (less than 4.5 Hz), which was accentuated by posture and intentional movements. Because isolated lesions in the red nucleus are not tremorogenic and animal and clinicopathologic studies have shown that this tremor typically resulted from lesions of adjacent structures (involving cerebellothalamic and nigrostriatal tracts) the term “Holmes tremor” is preferred rather than “rubral” tremor. Holmes tremor is characterized by a large and irregular (2–5Hz) amplitude tremor often affecting predominantly proximal upper extremities ( ). The exact pathophysiology remains unknown, but this tremor has been described in patients with lesions involving the cerebello-thalamo-cortical and dentato-rubro-olivary pathways and is often associated with dysfunction in the nigrostriatal pathway. This predominantly unilateral tremor may be associated with other neurologic signs, such as ataxia, bradykinesia, and ophthalmoplegia. It is often associated with midbrain pathologic conditions, such as multiple sclerosis, stroke, tumor, or arteriovenous malformation ( ). In one series of 29 patients, the most common causes were vascular (48.3%) and the median latency from lesion to tremor onset was 2 months ( ). The affected arm or leg may possibly be ataxic and may be associated with third nerve palsy (Benedikt syndrome) ( ). Holmes tremor is most often caused by trauma, stroke, multiple sclerosis, and Wilson disease ( ; ; ; ). Strokes involving the posterior circulation may involve the thalamus, producing slow (1- to 3-Hz) rest and postural tremors, sometimes referred to as myorhythmia ( ; ; ; ). Holmes tremor rarely responds to any medical therapy; however, wrist weights, levodopa, dopamine agonists, amantadine, propranolol, clonazepam, isoniazid, and levetiracetam ( ) may be effective in reducing the amplitude of this often disabling tremor. Several case reports and small series of patients with positive benefits have been treated with deep brain stimulation (DBS), although the results on proximal tremor are often not robust ( ).
Video 10.4 Cerebellar outflow tremor.
Myorhythmia is a slow (1- to 3-Hz) frequency, continuous or intermittent, relatively rhythmic movement that is present at rest but may persist during activity ( ; ). It may be associated with palatal myoclonus, and it disappears with sleep. Except for the slower frequency, the presence of flexion–extension rather than the typical supination–pronation pattern, and the absence of associated parkinsonian findings, myorhythmia resembles a parkinsonian tremor. In the cases that were examined at autopsy, the sites of maximum pathologic findings involved chiefly the brainstem (particularly the substantia nigra [SN] and the inferior olive) and the cerebellum. The causes of myorhythmia include brainstem stroke, cerebellar degeneration, Wilson disease, and Whipple disease ( ; ; ).
Palatal myoclonus, sometimes referred to as palatal tremor, has some features of tremor, but in contrast to tremor, which is produced by alternating or synchronous contractions of antagonist muscles, the palatal movement is produced by rhythmical contractions of agonist muscles; thus, the term myoclonus has been preferred by many experts despite the arguments raised against this nosology ( ). Because of its rhythmicity many experts also refer to it as a tremor and thus we will include it in this chapter. Palatal myoclonus, a form of segmental myoclonus, manifests as rhythmical contractions of the soft palate resulting from acute or chronic lesions involving the Guillain-Mollaret triangle, which includes the circuit of the dentate nucleus and red nucleus via the central tegmental tract with connections to the inferior olivary nucleus. Symptomatic palatal myoclonus (SPM) usually persists during sleep, whereas essential palatal myoclonus (EPM) is frequently associated with an earclicking sound and disappears with sleep. In EPM the muscle agonist is the tensor veli palatini, which opens the Eustachian tube and is innervated by the trigeminal nerve. In the SPM, the palatal movement is due to contractions of the levator veli palatine, innervated by the facial nucleus and nucleus ambiguous. When the tensor muscle contracts, as in EPM, the entire soft palate moves, whereas only the edges of the soft palate move when the levator muscle contracts in the SPM. Symptomatic, but not essential, palatal myoclonus is often associated with hypertrophy of the inferior olive ( ). SPM has been associated with a variety of lesions involving the brainstem and some neurodegenerative disorders such as Alexander disease ( ).
Treatment with neuroleptics can also result in persistent tremor, referred to as tardive tremor ( ). This rest, postural, and kinetic tremor, with a frequency of 3 to 5 Hz, is aggravated by, and persists after, neuroleptic withdrawal and improves after treatment with the dopamine-depleting drug tetrabenazine. The tremor may be accompanied by other tardive movement disorders, including akathisia, chorea, dystonia, myoclonus, and stereotypy. There is usually no family history or other explanation for the tremor.
Spasmus nutans is characterized by the triad of nystagmus; abnormal head position; and irregular, multidirectional head nodding that disappears during sleep. This condition is self-limited, and often a familial condition is first noted between the ages of 4 and 12 months, and it usually disappears within a year or two. Another oculomotor cause of head tremor is “head-shaking nystagmus” seen in patients with lateral medullary infarction ( ). The 2- to 3-Hz horizontal head shaking has been postulated to result from unilateral impairment of nodulouvular inhibition of the multisensory rotation estimator (velocity storage).
Pathophysiology
The pathophysiology of rest tremor is not well understood, but emerging data suggest primary involvement of the cerebello-thalamo-cortical circuit in the generation of this tremor. This circuit rather than pallidal or other basal ganglia or thalamic neurons fires in synchrony with ongoing resting tremor in PD ( ; , ). Although the rest tremor appears to be generated in the cerebello-thalamo-cortical loop, it is likely that the rest tremor is triggered by a pacemaker autorhythmic activity in the thalamus or basal ganglia ( , ). According to the proposed “dimmer-switch model” of parkinsonian tremor “depletion of pallidal dopamine (and possibly serotonin) causes pathologic activity in the striato-pallidal circuit that triggers—through the motor cortex—tremor-related activity in the cerebello-thalamo-cortical circuit” ( , ). This striato-pallidal activity can emerge only under rest conditions when the basal ganglia are not involved in voluntary movement; therefore, the classic PD tremor can be observed both at rest and during fixed postural holding (reemergent tremor) ( ). By simultaneous recording of local field potentials from the subthalamic nucleus (STN) in 11 patients with PD, showed increased local field potential power at individual tremor frequency and decreased cortical power in the beta band (13–30 Hz). These findings demonstrate a direct relationship between the synchronization of cerebral oscillations and tremor frequency.
Treatment
The treatment of rest tremors is similar to that of parkinsonism ( ; also see Chapter 6 ). Secondary and potentially curable causes should be excluded, particularly when there are associated features to suggest disorders other than PD (see Table 10.3 ). Anticholinergic and dopaminergic drugs provide the most effective relief of rest tremors; however, because of side effects anticholinergics are rarely used. Clozapine, an atypical neuroleptic that does not significantly exacerbate parkinsonism but can in rare cases lead to potentially serious side effects such as agranulocytosis, has been shown to be effective in the treatment of parkinsonian tremor (and ET) ( ; Friedman et al., 1997; ). Ethosuximide, an anticonvulsant that blocks low-threshold Ca ++ conductance in the thalamus, has been shown to reduce tremor in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys and potentiate the effects of a D2 agonist ( ). However, ethosuximide was found ineffective in a pilot study of six PD patients with drug-resistant tremor ( ). Mirtazapine (Remeron), a novel antidepressant that enhances noradrenergic and serotonergic transmission and acts as a presynaptic alpha2, 5HT 2 , and 5HT 3 receptor antagonist, has been reported to improve rest tremor ( ). Other drugs reported to have a possible beneficial effect in patients with ET include mirtazapine, clozapine, sodium oxybate, dimethoxymethyl-diphenyl-barbituric acid (T-2000), and carisbamate ( ). High-amplitude parkinsonian tremors and rest tremors caused by disorders other than PD usually do not improve with pharmacologic therapy.
In some cases, botulinum toxin (BTX) injections in the involved muscles produce a satisfactory reduction in the tremor amplitude ( ; ; ). A multicenter, randomized, double-blind, controlled trial confirmed the results of an earlier study ( ) that BTX injections produce significant reduction in the postural hand tremor of ET and modest functional improvement ( ). By avoiding injections of the forearm extensor muscles there can in many cases be a prevention of finger extensor weakness, which is a relatively frequently reported complication ( ).
Ventral lateral thalamotomy, particularly involving the ventral intermediate nucleus of the thalamus (VIM) was considered the neurosurgical treatment of choice for disabling, drug-resistant tremors until the later 1980s, when the ablative procedure fell out of favor compared with high-frequency thalamic DBS ( ; ; ; ). Although effective in a majority of cases, tremor and/or ataxia worsen in about 20% of patients, and there can be considerable risk for contralateral hemiparesis, hemianesthesia, ataxia, speech disturbance, and other potential complications. Unilateral thalamic lesions are, however, still excellent therapy especially when carefully placed into the target. The risks of lesions are compounded when the procedure is performed bilaterally. Thalamic DBS has become the surgical treatment of choice for patients with disabling tremors ( ; ; ; ; ) (see Chapter 7 ). DBS targeting the STN has been reported to be effective not only in the treatment of PD tremor but also in ET ( ; ). Bilateral caudal zona incerta nucleus has been suggested as a better target for DBS treatment of ET because it appears to cause less disequilibrium or tolerance ( ). The long-term benefits of DBS of the caudal zona incerta in ET are increasingly being recognized ( ). Some patients who have failed to respond to VIM DBS have had a modest improvement when they were reoperated and the stimulating electrode was placed in the caudal zona incerta ( ). There have been several small studies with zona incerta DBS showing improvements similar to those with VIM DBS (Martinez, 2018). The U.S. Food and Drug Administration (FDA) has achieved approval for focused ultrasound therapy for ET ( ), and the outcomes have been correlated to lesion location ( ).
Recently 76 patients were treated with magnetic resonance imaging (MRI)-guided focused ultrasound therapy for ET. Subjects were assigned 3:1 to ultrasound thalamotomy or to a sham group. The primary outcome for the study was the between-group difference in the change from baseline to 3 months in hand tremor. Hand-tremor scores improved more in the ultrasound group (18.1 points versus 9.6). The between-group difference was 8.3 points. The improvements were reported as maintained at a 1-year and later at a 2-year second follow-up study. Gait issues were reported in 36% and sensory changes in 38%. Limitations of the ultrasound procedure include skull thickness that may prevent treatment predictability of lesion size and lesion location. Additionally, this procedure should be applied only unilaterally to prevent the occurrence of pseudobulbar speech and swallowing issues ( ; ; ).
DBS has been proposed for chronic treatment of parkinsonian, essential, and other tremors. Using high-frequency (100 Hz or greater) stimulation, with the tip of a monopolar electrode implanted stereotactically in the VIM contralateral to the disabling tremor, noted “complete relief” of contralateral tremor in 27 of 43 (63%) thalami that were stimulated and “major improvement” in 11 (23%). The series included 26 patients with PD and 6 with ET, 7 of whom had been previously treated with thalamotomy. The benefit of thalamic stimulation was maintained for up to 29 months (mean follow-up, 13 months). The results were similar in their subsequent report of long-term effects of chronic VIM stimulation in 117 patients, 74 of whom had bilateral implantation ( ). The most robust tremor suppression was noted in patients with PD (n = 80), but patients with ET (n = 20) also benefited, although 18.5% deteriorated with time. Dysarthria and ataxia still occurred, but the patients were able to adjust the intensity of stimulation to ameliorate these side effects, though at the expense of increased tremor. Nevertheless, the investigators thought that the reversible nature of the side effects was the chief advantage of DBS over the permanent lesion produced by thalamotomy. To compare thalamic DBS with thalamotomy, conducted a prospective, randomized study of 68 patients with PD, 13 with ET, and 10 with multiple sclerosis. They found that the functional status improved more in the DBS group than in the thalamotomy group, and tremor was suppressed completely or almost completely in 30 of 33 (90.9%) patients in the DBS group and in 27 of 34 (79.4%) patients in the thalamotomy group. Although one patient in the DBS group died after an intracerebral hemorrhage, DBS was associated with significantly fewer complications than was thalamotomy. This procedure may also be advantageous in elderly patients and when bilateral effects are desirable ( ). We found that bilateral thalamic DBS was more effective than unilateral DBS in controlling bilateral appendicular and midline tremors of ET and PD, and thalamic DBS did not seem to improve meaningfully any parkinsonian symptoms other than tremor ( ). In addition, we found that VIM DBS produces modest improvement, rather than tremor augmentation as previously suggested, in ipsilateral tremor in patients with ET ( ). A review of long-term efficacy of VIM DBS in 39 patients (20 with PD and 19 with ET) showed that the benefits may be maintained for at least 6 months ( ). DBS has been found to be safe and effective in patients followed for up to 10 years with hardware complications rate of 23% of patients over that period of observation ( ). In one of our patients, minimal foreign body reaction and gliosis around the electrodes was found 12 years after implantation, the longest reported follow-up with autopsy examination after DBS, supporting the long-term safety of DBS ( ). One emergent issue in the field has been worsening of tremor suppression over time. evaluated this issue and concluded that disease progression (tremor and ataxia) were the main factors influencing worsening over time. The importance of this study is that much of the literature may overstate tolerance, which is a relatively rare effect.
In addition to improving distal tremor associated with PD and ET, VIM DBS can effectively control ET head tremor, which usually does not respond to conventional therapy ( ). Other midline tremors, such as voice, tongue, and face tremor, also may improve with unilateral VIM DBS, although additional benefit can be achieved with contralateral surgery ( ). The risk for local gliosis with chronic stimulation of the thalamus is minimal ( ; ; ). Unfortunately, thalamic stimulation does not appear to be as effective in patients with predominantly kinetic and axial tremors, and it does not improve other parkinsonian features such as bradykinesia, rigidity, and levodopa-related motor complications. Furthermore, although VIM DBS is very effective in improving PD tremor, when performed bilaterally it is often associated with dysarthria and postural and gait abnormality ( ), as a result of which STN has been suggested as a more appropriate target in PD patients with severe tremor ( ; ; ; ) and even in patients with severe ET ( ). The mechanism of action of DBS is unknown, but “jamming” of low-frequency oscillatory inputs has been suggested as a possible mechanism for the antitremor effects of DBS. Regional cerebral blood flow, measured by PET scan, demonstrated that tremor suppression was associated with decreased cerebellar blood flow and, presumably, decreased synaptic activity in the cerebellum ( ). The biology of DBS effects has been clarified, though there are still many uncertainties. DBS has neurophysiologic, neurochemical, neurovascular, neurogenic, and neuro-oscillatory effects ( , 2015). Which effects are most important to tremor suppression is debated; however, a 2008 paper in Nature Medicine showed adenosine as important to tremor suppression ( ).
In 1992, Laitinen of Stockholm, Sweden, reported the results of 90 pallidotomies in 86 patients with severe PD ( ). The external, posteroventral portion of the medial globus pallidus internus (GPi) was the intended target for the stereotactically placed lesion. Nearly all patients had “marked improvement in tremor and akinesia.” In addition, some patients apparently also noted improvement in their gait, speech, and pain. Only two patients suffered permanent visual field defect, and one had “minor stroke with hemiparesis.” Several pallidotomy series have since confirmed the beneficial effects of pallidotomy on various parkinsonian symptoms, including tremor ( ). These results provide support for the notion that surgical or chemical lesions of these structures may have a therapeutic value not only in controlling tremor but also in improving bradykinesia (Bergman et al., 1990; ). Although some investigators ( ) have suggested that posteroventral pallidotomy is as effective as thalamotomy in controlling parkinsonian tremor, others ( ) think that pallidotomy provides only partial relief of tremor.
Postural tremors
Diagnosis and clinical features
Physiologic tremor
Normal and enhanced physiologic tremors are the most common forms of postural tremor, but they rarely require medical attention. Postural tremors are clinically similar despite different causes. In contrast to ET, the frequency of physiologic tremor can be slowed by mass loading ( ). Indeed, there appear to be two components to physiologic tremor: variable frequency (peak 8 Hz), which is dependent on loading, and consistent frequency (peak 10 Hz), which is independent of peripheral influence. The latter suggests central origin of the tremor, as is presumed the case in ET. Thus, the amplitude of ET is less dependent on the position of the tested limb than is the amplitude of other postural tremors, including physiologic tremors ( ).
Essential tremor
Although the term essential implies necessary or desirable, it actually means that there is no known cause and the term is synonymous with idiopathic . The term essential tremor did not gain regular and widespread use until a century or so after its initial use in 1874 by Pietro Burresi, a professor of medicine at the University of Siena, Italy ( ). He coined the term tremore semplice essenziale or “simple essential tremor” when he described the case of an 18-year-old man suffering from severe tremor of the arms when engaged in voluntary movement. He also described head tremor. In the past, the modifier “benign” was used (“benign ET”) to indicate favorable prognosis of ET, even though it is now well accepted that ET can produce marked physical and psychosocial disability ( ; ; ; ; ; ; ; ). Although the amplitude of ET tends to increase with age, the tremor frequency decreases with age ( ; ). The International Classification of Disease–10th Revision–Clinical Modification (ICD-10-CM) assigned a specific diagnostic code for ET: G250, essential tremor).
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