9 Essential Tremor Application Abstract Tremor is the most common movement disorder and essential tremor (ET) affects a significant portion of the population that increases with age. Although ET can be identified with a handful of clinical tests, the Movement Disorder Society has recently published The Essential Tremor Rating Assessment Scale (TETRAS) to provide a consistent and more accurate measure of ET severity and disability. The medical treatment of ET has a 50 to 60% response rate with beta blockers (propranolol) and primidone having level A recommendations as initial therapy. In addition to the initial failure rate, 10 to 15% of responders will develop tolerance within 1 year of treatment, and the failure rate increases over time. Surgical treatment of patients with ET has been proven to be safe and highly efficacious. Deep brain stimulation (DBS) to the ventral intermediate (Vim) or ventrolateral (VL) thalamus is the gold standard for surgical treatment of ET with a reported average of 80 to 85% improvement in tremor. Unilateral or bilateral DBS to the Vim nucleus of the thalamus is the most commonly utilized target. The Vim is not well visualized on magnetic resonance imaging for direct image-guided targeting, and therefore, traditional awake surgery remains the most common technique utilized in cases of ET. Well-established potential surgical and stimulation side effects, including dysphagia, dysarthria, and disequilibrium, are more likely to occur with bilateral Vim DBS. Patients who are unable or unwilling to undergo undergo DBS surgery may have clinically significant improvement in tremor with less invasive thalamotomy techniques such as gamma knife thalamotomy and high-frequency focused ultrasound. Keywords: deep brain stimulation, essential tremor, ventrolateral thalamus/Vim, thalamotomy, surgical technique Essential tremor (ET) is one of the most common neurological movement disorders, estimated to affect 0.4 to 1% of the world’s population with an increasing prevalence (4–7%) in people over 65 years of age.1 The diagnostic hallmark of ET on physical examination is a regular 8 to 12-Hz recurrent and progressive kinetic tremor usually affecting both upper extremities. The tremor may also be postural in nature or increased in severity with certain postures. ET may also affect the head, face, voice, and/or lower extremities. ET is usually bilateral and symmetric, in contrast to the resting tremor of Parkinson’s disease (PD) that is often unilateral or asymmetric. Unilateral tremor or progression is less common in ET and may predict worse prognosis.2 Recent studies have also suggested nonmotor symptoms of ET may also affect or exacerbate cognitive, psychiatric, and sensory disabilities.3 A careful clinical exam is critical as it is reported that 37% of ET patients are misdiagnosed.4 The differential diagnosis of an observed tremor on exam includes PD, hyperthyroidism, dystonic tremor, Wilson’s disease, drug effects, and physiological tremor. ET may be distinguished from other entities on the basis of history and physical exam. Lab tests and nuclear imaging are less commonly needed or utilized. ET may be distinguished from a Parkinsonian tremor, which classically presents as a predominant resting tremor in the setting of associated bradykinesia. Dystonic tremor is often associated with limb posturing. Physiological tremor is heightened by emotional states and does not include head tremor. Recent neurophysiological studies propose a Tremor Stability Index to help determine the kinematic characteristics of tremor in order to distinguish the most likely pathologic classification of the tremor with 92% accuracy.5 A consensus for tremor classification was proposed by the Movement Disorder Society in 1998 that provided a useful syndromic and clinical classification to identify the ET syndrome.5 The International Parkinson and Movement Disorder Society Task Force on tremor classification is undergoing reclassification by updates in genetic, pathophysiologic, and pathologic evidence of ET pathogenesis.6 The utility of classification in ET is to attempt to uncover pathophysiologically homogenous groups in order to help assess prognosis and customize the treatment options. The ET syndrome can be subclassified by genetic predisposition (hereditary and sporadic subgroups), age of onset (early and late onset; cutoff at 65 years of age), and anatomic distribution of tremor (isolated arm, arm and head, other focal tremors). Hereditary ET is clinically significant and fully penetrant by 60 years of age.1 An older age of onset of ET is less likely hereditary and has been associated with more rapid progression of the disease.1 Faster rate of progression has also been reported in patients with involvement of head tremor as opposed to an isolated arm tremor.7 Earlier age of onset of ET is associated with a familial form.1 The severity of ET may be described by the severity of the observed tremor, impairment of activities of daily living (Bain and Findley Tremor activities of daily living [ADL] questionnaire), and impact on quality of life (Quality of Life in Essential Tremor [QUEST] questionnaire).5 The impairment related to ET may be visualized with simple writing (writing name and sentence), or drawing (Archimedes spiral) tasks. The Fahn–Tolosa–Marin (FTM) tremor rating scale is widely used to quantify ET severity based on tremor location (Part A: arms, head, face, etc., rated from 1–4, at rest, with posture, and with action), specific motor tasks (Part B: handwriting, spiral drawing, pouring), and functional disabilities (Part C: speaking, eating, drinking, etc.).6 The widespread use of the FTM tremor rating scale often lead it to be referred to as the Clinical Tremor Rating Scale (CRST). Due to limitations of the FTM scale in severe ET, the Tremor Research Group has published a comprehensive ET rating scale known as The Essential Tremor Rating Assessment Scale (TETRAS) that has high reliability especially for head and upper extremity tremor.7 Tremor rating scales in ET are further discussed later in this chapter. More than 50% of patients with ET have a positive family history, suggesting the importance of genetic influence.8 ET is thought to be conferred in an autosomal-dominant fashion.9 Analysis in mono- and dizygotic twins have shown that mono-zygotic twins have a significantly higher concordance rate.10 However, problems in genetic studies including phenotypically heterogeneous samples, small sample sizes, and difficulties in reproducibility limit these studies’ impacts.11 A number of genes have been linked to ET through genome-wide association studies (GWAS), mapping studies, linkage analysis, and exome sequencing. Linkage studies found three loci of interest ETM1–3 related to ET: ETM1, a polymorphism in the DRD3 gene (chromosome 13q13.31) that encodes a dopamine-receptor subtypes found in numerous areas of the brain including regions of the cerebellum12; ETM2 locus mapped to HS1BP3 gene (hematopoetic lineage cell-specific protein binding protein 3, Ch 2p25-p22)13; ETM3 locus (6p23) with unclear related gene expression.14 A recent linkage analysis showed relation of Ch 5q35 to ET.15 Whole exome sequencing in a French-Canadian ET family discovered a nonsense-mediated mRNA decay of the FUS gene product (fused in sarcoma, Ch 16p11).16 Polymorphisms indicated by GWAS studies have suggested other genes of interest including LINGO1 (Leucine rich repeat and Ig domain containing 1, involved in intracellular signaling in response of myelin-associated inhibitors) (chromosome 15q24)17; SLC1A2 (Ch 11p13) whose gene product EAAT2 glutamate reuptake transporter is highly expressed in the inferior olive18; STK32B (a serine/threonine kinase), PPARGC1A (a transcriptional activator), and CTNNA3 (a cell adhesion molecule) were linked with ET.19 The genetic landscape of ET is complex, and although numerous candidate genes of interest have been found, no clear causative genes have been studied, in part due to the phenotypic and diagnostic variability inherent in the populations.20 Interestingly, a number of these genes may be localized to cerebellar and olivary circuitry, implicating their role in the cerebellum and inferior olive in effecting the network oscillation thought to underlie ET.21 The olivocerebellar hypothesis of tremor pathophysiology is the predominant theory of disturbance underlying the rhythmic network oscillation of ET.22 Initial data from harmaline-induced tremor animal models and human neurophysiological studies in ET patients pointed toward electrophysiologic dysfunction of the inferior olivary nucleus (ION) as the origin of ET dysfunction. The bursting oscillatory nature of pathologic ION cells was spread to the extremities via the reticulo- and vestibulospinal pathways.23,24 However, more recent data questioned the involvement of ION as the postmortem neuropathological examination of ET patients showed no structural difference in the ION and neuroimaging studies showed no ION activation.25,26 Latest data are suggestive of a cerebellar hypothesis.27 Neuroimaging data from resting state functional magnetic resonance imaging (fMRI) in ET patients (matched with controls) showed intrinsic variations in network properties compared to control patients specifically in the cerebellum, pre- and postcentral gyri, supplementary motor area (SMA), and paracentral lobule.28 Postmortem pathophysiological evidence from ET patients show changes that include structural (Purkinje cell morphology) and functional (Purkinje-basket cell and Purkinjeclimbing fiber interface dysfunction) components29 as well as pathological findings (‘torpedoes’ and Bergmann glia).30 At the cellular level, this process may be driven by Purkinje neuron loss, as evidenced by studies of decreased cell counts and increased intercell distance in ET patients compared to controls.31 In this sense, ET shares the feature of specific cell loss as seen in cases of other neurodegenerative diseases. Neuroimaging, pathological, and electrophysiological studies suggest that the tremor circuitry involves olivo-cerebello-thalamo-cortical connections. The ION is the primary input of climbing fibers to the cerebellar Purkinje inhibitory cells; the output of the cerebellar Purkinje cells is to the deep cerebellar nuclei, which then target the VL thalamus. The output of VL thalamus include motor and premotor cortices. Interestingly, the pathological and electrophysiological characteristics of the tremor may be determined by the specific nature of dysfunction within the circuit; tremors may be generated by mechanical oscillations, reflex-driven oscillations, centrally driven oscillations, or oscillations driven by feedforward or feedback loops.22 ET is thought to be a centrally driven tremor; the structural and functional changes in the olivocerebellar network generate rhythmic disinhibition of the thalamus. The tremor oscillation is effected by gamma-aminobutyric acid (GABA)ergic dysfunction of the cerebellar dentate nuclei as they project to the thalamus. Neurochemical studies have supported this GABAergic dysfunction in the cerebellum.32 Noninvasive transient manipulation of the cerebellar circuit with transcranial alternating current stimulation allowed for entraining the neural oscillation in ET patients.33 There are no tests to diagnose ET; the diagnosis is made typically on clinical evaluation with the presence of the typical kinetic/postural tremor. Standard neuroimaging with computed tomography (CT) and MRI scans of the head is usually normal and demonstrate no specific findings for ET.34 However, specialized imaging with single-photon emission CT (SPECT) and ioflupain 123 I (DaTSCAN) may be used to rule out other causes of tremor such as PD.35,36,37 The exact mechanism of ET has not been completely understood, but diffusion tensor imaging (DTI) performed on patients with ET demonstrated increased apparent diffusion coefficient in the red nucleus suggestive of cell loss as a result of a neurodegenerative disorder.38 Several structural and functional imaging studies have identified pathology involving the cerebellum (dentate nucleus, vermis, and superior and inferior cerebellar peduncles), the ION, the red nucleus, the thalamus, the cortex, and the interconnecting pathways.34 The clinical significance and the application of such findings is still not clear. The simple bedside tests for essential tremor include: • Arm extension test. • Finger-to-nose test. • Heel shin test. • Drawing a spiral. • Drawing a straight line. • Archimedes spiral. • Signing of name. • Pouring water from one cup to the next back and forth. • Having the patient utter a single sound such as “aaahhh” or “eeehhh” and hold it for as long as possible. The presence of a tremor and its characteristics in terms of its frequency and amplitude are noted while certain functions are tested. The finger-to-nose test is the most useful screening test in a general population and is usually abnormal in approximately 50% of patients with ET.29 To exclude normal subjects, tests such as a sustained arm extension, drawing a spiral, and pouring of water have been very effective.29,39 There are several grading scales and screening instruments for ET. Tremor grading scales that were recommended by the task force of the Movement Disorder Society include40: • The Essential Tremor Rating Assessment Scale (TETRAS). • The Fahn–Tolosa–Marin Tremor Rating Scale (FTM). • Quality of Life in Essential Tremor Questionnaire. • Bain and Findley Clinical Tremor Rating Scale. • Bain and Findley Spirography Scale. • Bain and Findley Tremor activities of daily living scale. • Washington Heights-Inwood Genetic Study of Essential Tremor (WHIGET) Tremor Rating Scale, Version 2. The Movement Disorder Society task force further recommended the WHIGET Tremor Rating Scale, version 1 as a screening tool for ET.40 In this system, patients were categorized as having possible, probable, or definite ET. The tremor (postural and kinetic) was rated as 0 to 3 grade based on motor task performance. The presence of grade 2 or more makes the diagnosis of ET definite.40 TETRAS is a short, valid, and easy-to-use scale that was designed for clinical assessment of severity of ET.7 It rates the presence of tremors in a range of 0 to 4 for 10 test items ( This scale is divided into three main parts A, B, and C, where part A (items 1–9) looks at the amplitude of rest, postural, and kinetic tremors in specific anatomic sites (face, tongue, voice, head, bilateral upper and lower extremities, and the trunk; part B (items 10–14) evaluates the degree of tremor in handwriting, drawing, and pouring; and part C (items 15–21) assesses activities of daily living (speaking, eating, drinking, hygiene, dressing, writing, and working).6,40 This scale utilizes a 5-point grading scheme with a maximum total of 144 points ( Table 9.3 Global assessment percentage score by the examiner
9.1 Presentation
9.1.1 Classification of Essential Tremor
9.1.2 Tremor Severity
9.2 Genetics
9.3 Pathophysiology and Tremor Circuitry
9.4 Diagnostic Testing
9.4.1 Testing and Grading Scales for Essential Tremor
Table 9.1).
The Fahn–Tolosa–Marin Tremor Rating Scale
Table 9.2). The total score is calculated as a percentage of 144. In addition, a global assessment percentage score for the examiner (
Table 9.3) and for the patient (
Table 9.4) can be obtained based on their subjective assessment of the patient’s ability to perform the activities of daily living.6
Score | Impairment (%) |
0 | No functional disability |
1 | Mild disability (1–24% impaired) |
2 | Moderate disability (25–49% impaired) |
3 | Marked disability (50–74% impaired) |
4 | Severe disability (75–100% impaired) |
Table 9.4 Follow-up assesment table
Score | Improvement/decline (%) |
+ 3 | Marked improvement (50–100% improved) |
+ 2 | Moderate improvement (25–49% improved) |
+ 1 | Mild improvement (10–24% improved) |
0 | Unchanged |
−1 | Mild worsening (10–24% worse) |
−2 | Moderate to marked worsening (25–49%) |
−3 | Marked worsening (50–100%) |
The scoring below (
Table 9.4) can be used to subjectively follow the patient during visits.
The TETRAS and FTM, used in the context of kinetic tremors, have been shown to correlate very closely; however, the TETRAS scale has an advantage due to its simplicity and its lack of the ceiling effect seen with the FTM when assessing severe tremor.41
9.5 The Medical Management of Essential Tremor
The medical management of ET is largely dependent on the use of beta-adrenergic antagonists (propranolol), anticonvulsants (primidone), second-generation antipsychotics (clozapine), antidepressants (mirtazapine), and alcohol and botulinum toxin A (Botox injections).42,43
Both propranolol and primidone are first line in the pharmacological management of ET.42,43 Propranolol causes blockade of the peripheral beta-2 adrenoceptor and results in a 50 to 70% response in individuals with ET, particularly causing a reduction in the tremor amplitude affecting the upper and lower extremities.42 However, it should be avoided in patients with asthma and diabetes mellitus. The starting dose of propranolol is 40 mg every 12 hours and it is usually titrated to a daily maintenance dose of 120 to 320 mg given every 8 to 12 hours.42 Like propranolol, primidone offers a 50 to 70% response, by reducing the tremor frequency.42 Due to its sedative effects, this anticonvulsant medication is less tolerable in the young patients. Other drugs, such as topiramate, are usually considered in cases of failure of the first-line therapy. Clozapine has been shown to demonstrate good effect on tremors of the upper extremity. Botulinum toxin is a good option for head and neck tremors. However, its effectiveness is limited to 3-month intervals and for head and neck tremors only as it causes undesirable weakness in the extremities.43 Botulinum toxin can be effective in upper extremity tremors, but the patient must be willing to deal with the resulting weakness.
9.6 Surgical Management of Essential Tremor
9.6.1 Surgical Patient Selection
One of the most challenging obstacles in deep brain stimulation (DBS) surgery is picking the right candidate. Many centers, such as ours, utilize a collaborative, multidisciplinary preoperative assessment of patients consisting of movement disorder neurologists, a functional neurosurgeon, neuropsychologists, a patient coordinator, and physical, speech and occupational therapists. Each potential candidate for surgery is systematically evaluated and then presented, reviewed and discussed, typically in a movement disorders or DBS conference. The group reviews the risks and benefits of surgery and a consensus is reached by the team. This individualized, committee evaluation process helps to ensure that the surgical management of a patient’s disease achieves successful results.44,45 The evaluation assesses each patient’s tremor characteristics, its impact on that patient’s quality of life, the number of failed medications and duration of therapy, patient’s medical and psychological comorbidities, and the strength of patient’s support system for the postoperative management of the implanted devices. In addition, the ability of the patient to cope with known potential side effects such as imbalance or dysarthria is also analyzed.
9.6.2 Tremor Evaluation
For ET patients, tremor in the arms and hands are most common, but head tremor (40% of patients), voice tremor (20% of patients), and leg or trunk tremors (20% of patients) are also seen.46,47 The surgery is most benifical for the patients with ET who typically have an intention tremor located in the distal upper extremities, rather than proximally, such as the shoulder or the head. Voice tremor has also been more difficult to manage with DBS, but bilateral procedures have shown significant responses.45,48
Characteristically, most patients referred for surgery have a medication-refractory ET.46,49 While there has not been a standardized guideline, the American Academy of Neurology recommends level A evidence that primidone and propranolol should be offered to patients who desire treatment for limb tremor.47 As mentioned in the section above, most patients would have been treated with a medical therapy but have less than optimal symptomatic control. Careful evaluation by a movement disorder specialist helps categorize the features of the tremor and also helps determine the etiology, distinguishing how likely surgery will be beneficial for each patient.50
9.6.3 Quality of Life
Tremors seen in ET patients can be very debilitating and disruptive to a patient’s ability to perform activities of daily living as well as to their function in society through employment and social interactions. In severe cases, performing activities of daily living, such as feeding, drinking, writing, or communicating can be quite challenging.47 Patients should have realistic expectations about the improvement that should be expected with DBS or thalamotomy. The ability to change stimulation with DBS can be quite an advantage since one can modulate the effects to improve efficacy of tremor control and to control side effects. In addition, modern DBS generators are capable of holding multiple stimulation programs and patients can select between stimulation programs depending on whether they require precise tremor control or they can tolerate some tremor for a reduction in side effects such, as those effecting speech. Reports have shown that both head tremor and voice tremor responses to DBS can be variable and uncertain.45 Therefore, patients with severe head, neck, or voice tremors must be counseled on the lower likelihood of optimal treatment for these types of tremors relative to tremors of the upper extremities.
9.6.4 Comorbidities
As with any elective surgery, the patient’s risks for safely undergoing the surgery must be evaluated. Preoperative medical evaluation and clearance is commonly obtained with attention to the relevant specifics of the patient’s medical or anesthesia history (i.e., hypertension, diabetes, anesthesia complications). Particular attention should be payed to the patients with pulmonary or cardiovascular issues that may increase the risk of airway compromise during a frame-based surgery that utilizes conscious sedation. It is typical for patients to undergo laboratory evaluation, including coagulation panel, and patients over the age of 65 years often undergo screening with electrocardiography (EKG) and chest X-ray. Further preoperative evaluation is done as per the patient’s medical history. In addition, the neuropsychiatric evaluation provides important information regarding the patient’s cognitive function and psychiatric or mood disorders. Recent longitudinal studies have shown an association between ET and cognitive impairment or dementia. Careful consideration should be given to patients with significant cognitive impairment or psychiatric condition. Cognitive, psychotic, and mood disorders, severe brain atrophy, and alcoholism preclude an individual from getting DBS.46,48 Furthermore, patient participation is needed for optimal intraoperative testing during microelectrode recording (MER), and stimulation mapping and testing.50 Age of the patient and life expectancy must also be taken into account. Specific to DBS for ET, patients with preexisting dysarthria and dysphagia are cautioned as thalamic stimulation can possibly worsen these issues.47,51
9.6.5 Strength of Support System
Patients, who undergo DBS implantation, and their families must understand that the therapy is a lifelong commitment with numerous postoperative visits for reprogramming, and end-of-life generator replacements.45 Recent introduction of rechargeable batteries within the pulse generators can reduce the repeated surgeries for end-of-life generator replacements, but would require recharging of the device at home. Having a strong support system helps unburden patients with logistical issues, such as remembering the different appointments, traveling to the different facilities, emotional support during recovery or in the event of complications, side effects or unexpected outcomes, and vigilance for recharging, hardware failures or infections.
9.7 Surgical Interventions
9.7.1 Deep Brain Stimulation—Stereotactic Frame
The operative day begins with placing the stereotactic frame on the patient. The patient is instructed not take his/her tremor medications that morning in order to facilitate intraoperative testing. The time-out procedure is performed, and the patient receives intravenous lines for the administration of sedatives, antibiotics, and antihypertensives if necessary. A mild and/or short-acting sedative can be utilized to assist with placement of the stereotactic frame. It is important to understand the potential impact of any medications on the MERs. The scalp is cleansed and prepared. The stereotactic frame is then applied after local anesthesia. We prefer a mixture of short-acting and long-lasting local anesthetics (e.g., Lidocaine and bupivicaine) mixed in the ratio 9:1 with sodium bicarbonate injected into the pin sites for the stereotactic frame placement. The frame is carefully aligned to be parallel to the anterior commissure (AC)-posterior commissure (PC) and as symmetric as possible. Ear bars are used to minimize lateral movement or rotation during placement. Once the frame is satisfactorily secured, high-fidelity, high-resolution imaging is obtained with the fiducial box applied to the frame for localization. Both CT and MRI may be utilized for frame imaging. We prefer the use of CT imaging with the stereotactic frame in place. MRI with the stereotactic frame may also be used, but is limited to 1.5 T MRI with head only send-receive coil. There are small but known distortions in MRI from the titanium frame and trials with the Leksell frame in 3 T MRI have suggested distortions that are too large for stereotactic procedures. If the patient traveled for the in-frame imaging, they are returned to the operating room and transferred to the operative table in the supine position. If they are utilized, the arterial line and foley are placed at this time during stereotactic planning. Close monitoring of the blood pressure is essential and although this may be done with repeat blood pressure cuff measures, we prefer intensive monitoring and control with an arterial line for continuous monitoring, especially in patients with preoperative hypertension. It is recommended that systolic blood pressure should be maintained below 140 mm Hg throughout the operation and especially during placement of electrodes.
9.7.2 Target and Trajectory Planning (
Fig. 9.1)
During this time, the stereotactic planning is performed on a computer planning station. At our institution, after localization of the stereotactic frame on CT imaging, this CT scan is fused with a high-quality preop MRI. There are a variety of sequences that can be utilized for stereotactic planning. We utilize a high-resolution anatomical T1 sequence magnetization-prepared rapid gradient echo (MPRAGE) with contrast and volumetric fluid-attenuated inversion recovery (FLAIR) or inversion recovery sequences for every case. MPRAGE sequences are utilized for accurate fusion, localization of the AC and PC, and trajectory planning. The second sequence is utilized for direct imaging-based confirmation of the target when feasible. Many institutions use the short tau inversion recovery (STIR) sequence for the grey-white differentiation for direct target verification. At our institution, this is best accomplished with a volumetric FLAIR sequence. We recommend collaborating with neuroradiology to develop a high-quality sequence for grey-white differentiation as this can vary depending on the particular MRI scanner(s) utilized. The ventral intermediate (Vim) target of the ventrolateral (VL) thalamus, however, is not well visualized on MRI and is, therefore, targeted via standard indirect coordinates. After the AC-PC line is established, the coordinates for the Vim target are mapped using typical stereotactic coordinates based on the PC point.
X: 11.5 mm lateral + ½ width of third ventricle
Y: Anterior to PC by 20% of AC-PC line length
Z: In the plane of the AC-PC line
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