Deep brain stimulation for essential tremor

Handbook of Clinical Neurology, Vol. 116 (3rd series) Brain Stimulation A.M. Lozano and M. Hallett, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 13

Deep brain stimulation for essential tremor JULES M. NAZZARO1,2,3, KELLY E. LYONS2*, AND RAJESH PAHWA2 Department of Neurosurgery, University of Kansas Medical Center, Kansas City, KS, USA

1

2

Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA

3

Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA

INTRODUCTION Essential tremor (ET) is the most common cause of tremor and one of the most common movement disorders (Louis and Ferreira, 2010; Zesiewicz et al., 2011). It is characterized most commonly by a postural and kinetic tremor during voluntary movement and may rarely be present at rest (Deuschl et al., 2011). A recent meta-analysis reported a worldwide prevalence of ET of 0.4–0.9%, with a significant increase to 4.6% in persons 65 years of age and older (Louis and Ferreira, 2010). The tremor, which has a frequency of 4–12 Hz with variable amplitude, is increased with anxiety or stress and is commonly relieved for short periods with small amounts of alcohol (Critchley, 1949; Koller and Biary, 1984). ET is commonly inherited in an autosomal dominant fashion and thus is often seen in several members of the same family, although the gene or genes responsible remain to be defined (Deng et al., 2007). Involvement of body parts varies with approximately 95% of patients with ET having tremor in the upper extremities. Approximately 30% of patients with ET have head tremor, whereas lower-extremity tremor is present in 20%, voice tremor in 12%, and 5% have tremor affecting the face or trunk (Lyons et al., 2003). Although the disease may be expressed in childhood, it is seen most commonly in adults, with males and females equally affected. Over time, tremor may increase in severity and in the distribution of affected body parts. The primary disability is in completing activities of daily living such as eating, drinking, writing, dressing, personal hygiene, social activities, and employment. Several studies have reported that quality of life is significantly reduced in patients with ET (Troster et al., 2005; Lorenz et al., 2006; Nguyen et al., 2007; Lorenz et al., 2011; Chandran et al., 2012).

The medical management of ET is limited. The b-adrenoceptor antagonist propranolol and the antiepileptic drug (AED) primidone are the medications most commonly used, either as monotherapy or in combination to treat ET, and only propranolol is approved by the US Food and Drug Administration (FDA) for this indication (Pahwa and Lyons, 2003). However, 30–50% of patients with ET do not respond to these medications, and of the remaining patients response to medications is variable with many gaining only partial tremor relief (Lyons and Pahwa, 2008). In addition, medication-related side-effects often affect compliance. In a recent survey of 223 patients with ET, 71% had taken propranolol or primidone although one or both of the medications were subsequently stopped by 56% (Diaz and Louis, 2010). Several other medications, such as other b-adrenoceptor antagonists, other AEDs such as gabapentin and topiramate, and benzodiazepines, as well as other drugs, have been employed for tremor in ET (Zesiewicz et al., 2011). However, taken together, only 50% of patients with ET have a satisfactory response to medications (Lyons and Pahwa, 2008). In patients with disabling medication-resistant upper-extremity tremor who have tried at least a b-adrenoceptor antagonist and primidone without satisfactory resolution of tremor, neurosurgical intervention should be considered if the patient does not suffer from dementia or significant comorbidities such as severe cardiac or pulmonary issues.

DEEP BRAIN STIMULATION History There is an extensive neurosurgical history dating to the 1950s regarding stereotactic operations directed to the ventral lateral tier of thalamic nuclei for tremor

*Correspondence to: Kelly E. Lyons, Ph.D., Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Blvd, MS 2012, Kansas City, KS 66160, USA. Tel: 913-588-7159, Fax: 913-588-6920, E-mail: [email protected]

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(Burchiel, 1995). In the past, lesions were created most commonly with radiofrequency heating techniques. In the course of such work, the locations of tremor cells within the thalamus were mapped and numerous investigators reported tremor relief upon intraoperative stimulation above 100 Hz of specific thalamic sites. While long-term tremor relief was accomplished in many patients secondary to ablative surgery, a major drawback of such surgery was the risk of permanent neurological deficit. Those experiences gave rise to a concerted effort to develop implantable hardware with which adjustable and reversible electrical stimulation could be delivered long-term for the treatment of tremor. With these developments, in the 1980s investigators began implanting stimulating electrodes, directed to the ventral intermediate thalamic nucleus (VIM), a site within which the majority of ablative operations for the treatment of tremor (thalamotomy) were directed. In 1997, the FDA approved unilateral VIM deep brain stimulation (DBS) in the treatment of medication-resistant upper-extremity tremor in patients with ET and Parkinson’s disease. DBS had been approved in Europe, Canada, and other countries outside the USA by 1993. Presently, VIM DBS is the operation of choice in patients with ET and disabling medicationresistant tremor. How DBS accomplishes tremor control is unclear. While the ultimate effect on tremor control in patients with ET is the same as that with successful ablative surgery, authors have suggested inhibition, excitation, as well as resetting of neural pathways by the stimulation (McIntyre et al., 2004; Perlmutter and Mink, 2006; Montgomery and Gale, 2008). With regard to the morphological effects of long-term stimulation, autopsy studies have demonstrated minimal gliosis immediately adjacent to the DBS lead (Boockvar et al., 2000; DiLorenzo et al., 2010).

VIM DBS surgery Surgery for tremor control in patients with ET is directed to the VIM. The VIM is part of the ventral lateral tier of thalamic nuclei. Several nomenclature methods that have been utilized for classifying thalamic anatomy and over 120 thalamic nuclei have been identified (Hassler, 1959, 1982; Jones, 1997; Macchi and Jones, 1997; Morel et al., 1997; Krack et al., 2002; Percheron, 2004; Hamani et al., 2006; Lemaire et al., 2010). The Schaltenbrand and Wahren atlas is the stereotactic brain atlas used most commonly for planning DBS surgery in patients with ET, and employs the terminology of Hassler for thalamic anatomy (Schaltenbrand and Wahren, 1977, 1997). Hassler’s VIM corresponds to the ventral part of the ventral lateral posterior (VLp) nucleus according to the human thalamic nomenclature system used in the Hirai and Jones (1989) and Morel et al.

(1997) atlases, and the overlapping ventral intermediate and ventral posterior lateralis (VPL) in the Talairach stereotactic human atlas (Talairach, 1957; Hirai and Jones, 1989; Lemaire et al., 2010). The nucleus is viewed as receiving primarily cerebellar afferents with projections to the motor cortex and adjoining cortical areas involved in movement initiation and control (Hamani et al., 2006). Kinesthetic, tremor, and voluntary cells are found within the VIM. Kinesthetic cells have increased activity upon passive movement of contralateral joints, whereas voluntary cells have increased activity just before or during active movements. Tremor cells fire in rhythm with increased rate and intensity upon contralateral kinetic and postural tremor. Within the VIM there is a clear homunculus representation with kinesthetic leg cells situated laterally, adjacent to the more laterally situated internal capsule. Kinesthetic arm cells are located medial to those representing leg, and facial cells are situated medial-most, adjacent to the central thalamic nucleus which borders the third ventricle (El-Tahawy et al., 2004; Hamani et al., 2006). Immediately posterior to the VIM is the ventralis caudalis nucleus (Vc), which receives sensory afferents from the medial lemniscus. Tactile cells responsive to light touch of a well defined body part are situated within the Vc, with homunculus representation as in the VIM. The Vc extends further laterally than VIM, which should be accounted for when interpreting electrophysiological and stimulation data during surgery. Tremor cells may also be localized within Vc, most usually near the Vc–VIM border. Located within the ventral–anterior aspect of the Vc are cells responsive to contralateral deep pressure. The VIM is bordered anteriorly by the ventralis oralis posterior nucleus (Vop), within which tremor and voluntary cells are located. Tremor cells within the Vop are most commonly situated near the Vop–VIM border. Background cellular activity increases during electrophysiology recordings, passing from Vop to VIM, and there is further increased activity as the Vc is encountered (El-Tahawy et al., 2004; Hamani et al., 2006). There are many aspects of VIM DBS surgery that are left largely to the surgeon’s preference, and there are few, if any, data to suggest that one method is superior to another. The surgery may be performed with use of a stereotactic frame or via frameless (“miniframe”) techniques. Some surgeons utilize microelectrodes or semimicroelectrodes for localization via electrophysiological recordings, and these may also be utilized to teststimulate for localization purposes (Gross et al., 2006). Microelectrodes may be passed one at a time or in arrays of up to five electrodes at a time. Others conduct the surgery and localization solely via DBS lead test stimulation, looking for efficacy in the absence of side-effects. Most surgeons now utilize magnetic

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR resonance imaging (MRI) in surgical planning, although, despite advances, the VIM is not clearly visualized by present MRI scanners. Landmarks including the anterior commissure (AC), posterior commissure (PC), third ventricle, internal capsule, lateral border of the thalamus, sulci, and vessels are better seen on MRI than computed tomography (CT). Planning based on ventriculography is largely no longer performed. Although various targeting methods have been described (Papavassiliou et al., 2004), there are few differences between these and the general location of the arm representation within the VIM is approximately 11.0–11.5 mm lateral to the lateral wall of the third ventricle, and anteriorly–posteriorly approximately midway between the midcommissural point and the PC along the plane of intercommissural line (ICL). Depending on method, some initially target an area more posterior than this, approximately 2 mm anterior to the PC, in order clearly to define laterality by way of making use of the homunculus representation of cutaneous sensory responsive cells within the Vc. Others may target initially more anteriorly and test-stimulate for tremor control in an area further away from Vc. Stimulation of Vc gives rise to contralateral paresthesias, which may also be obtained if the underlying medial lemniscus is stimulated. Constitutional symptoms such as dizziness and nausea upon test stimulation also suggest that the DBS lead is too deep. Test stimulation without sideeffects but with suboptimal efficacy in the patient with ET suggests that the lead may be situated too anteriorly or too medially. Stimulation of the internal capsule gives rise to dystonic and tetanic-like movements. When the thalamic–internal capsule border is visualized on planning imaging, the target should be at least 3 mm medial to internal capsule. Data have suggested that optimal VIM DBS lead placement for tremor control in patients with ET may be at (Papavassiliou et al., 2004) or slightly anterior–dorsal (Tasker and Kiss, 1995; Kiss et al., 2003) to the location of optimal lesion placement for VIM thalamotomy. Other variables that are surgeon-dependent include the degree of patient head elevation during the surgery (supine to semi-sitting), method of opening the dura (wide versus minimal), and whether the pulse generator should be implanted at the time of lead placement or separately at a later date. Upon planning the surgery, trajectories of approach are important variables. Some may utilize a transventricular approach, but others avoid the ventricles, if possible, given concerns of DBS lead deflection by the ventricular walls, bleeding given paraventricular vessels, as well as potential complications related to cerebrospinal fluid (CSF) issues including leakage of CSF along the DBS lead track during and after surgery (Elias et al., 2009; Zrinzo et al., 2009; Bilger et al., 2011). Important considerations when planning the surgical approach

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include how the approach angles along the sagittal and also the coronal planes affect the degree of involvement of the internal capsule along the trajectory. In addition, the electrophysiological and possibly intraoperative test stimulation data obtained when directed to a given target point would be anticipated to differ, for example, when a 55 sagittal angle of approach in reference to the AC/PC line is compared with that obtained upon a 75 sagittal angle of approach (Fig. 13.1). Theoretically, it would be expected that a more posterior trajectory to the VIM plans an approach along the sagittal (dorsal–ventral) axis of that nucleus which measures approximately 10 mm in height (Schaltenbrand and Wahren, 1997). Thus, upon microelectrode recording (MER), it may be anticipated that a comparatively long localization of kinesthetic cells will be obtained from an approach more perpendicular to the ICL than one that approaches the area from a more frontal entry point. Similarly, upon test stimulation, a lead along the dorsal–ventral axis of the VIM may elicit paresthesias from several, if not all, of the stimulation contacts if the lead is too close to the posteriorly situated Vc, whereas a lead placed via a considerably more frontal entry point may elicit paresthesias only from the ventral-most (deepest) contact. If the target point is adjusted during surgery, trajectory considerations are taken into account and the anticipated electrophysiological data may differ between methods using parallel approaches and those in which the entry point is fixed. However, there is little agreement among the available data to suggest that one trajectory to the VIM is better than another, and this variable awaits further study (Yamamoto et al., 2004; Pilitsis et al., 2008; Kobayashi et al., 2010). If MER are utilized, following satisfactory electrophysiological location, the microelectrode is withdrawn together with associated reducing tube, and the guide cannula is advanced to the MER-defined target point. The guide tube is advanced to the target point to help ensure that the DBS lead follows the intended course. Which DBS lead to utilize depends upon electrophysiological data obtained, including the length of tremor and kinesthetic cells localized as well as the distance of the internal capsule along the trajectory of the electrode from the target point. The DBS lead is advanced within the guide cannula with microdrive to the target point, the guide is then withdrawn to expose the stimulating lead electrodes following which test stimulation is accomplished upon connecting the DBS lead to the physician programmer. Test stimulation is accomplished using bipolar parameters in progressive fashion to 6 V. Often there is partial and on occasion total tremor relief upon MER and, more likely should it occur, upon guide cannula and lead advancement. Upon test stimulation, there should be nearly complete resolution of contralateral

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Fig. 13.1. Illustration of the thalamic nuclei encountered upon different sagittal trajectories (red lines) to target points commonly used in stereotactically directed ventral intermediate thalamic nucleus (VIM) surgery. Sagittal representations are from the atlas of Schaltenbrand and Wharen (1997), with permission from Thieme Medical Publishers, taken at 10.5, 12.0, 14.5, and 16.0 mm from midline. The horizontal scale is along the anterior commissure (AC)/posterior commissure (PC) line in 2-mm increments. The vertical scale is along the midcommissural line in 2-mm increments. (A) This panel demonstrates a 55 angle of approach in relation to the AC/PC line, directed to target points situated 4, 6, and 8 mm posterior to the midcommissural point (MCP). (B) This panel demonstrates a 75 angle of approach in relation to the AC/PC line, directed to target points situated 4, 6, and 8 mm posterior to the MCP. Note differences in the thalamic nuclei areas encountered depending upon the sagittal angle of approach and distance from midline to a given target point.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR upper-extremity within 3 V, preferably at 1–2 V, and no unwanted side-effects through 6 V. Often there are brief paresthesias upon test stimulation that resolve rapidly. If unwanted side-effects such as persistent paresthesias or tonic movements are obtained at or within 2 V of the clinically desirable stimulation range, a decision must be made whether or not to reposition the lead and repeat the test stimulation. Once the lead is placed and test stimulation accomplished, the utility of further microelectrode runs needs to be weighed, given the consideration that the already passed DBS lead and guide tube have outer diameters of 1.27 and 1.5 mm respectively. Recently available DBS hardware and software now make it possible also to test the impedances of the lead-electrodes (Nazzaro et al., 2011). The lead is secured utilizing a skull fixation cap following satisfactory test stimulation. Generally, a fine-cut CT study is obtained upon discharge from the recovery room and fused to preoperative imaging to verify lead position. Methods utilizing intraoperative fluoroscopy (Eller and Burchiel, 2008; Sierens et al., 2008), CT (Shahlaie et al., 2011; Smith and Bakay, 2011), and MRI (Lee et al., 2005) to corroborate intracranial DBS hardware positioning have been described. The pulse generator and lead extension are then implanted either during the same setting or at a later date as a separate operation. Programming is typically initiated approximately 4–5 weeks after electrode implantation to allow time for healing and resolution of any changes such as localized edema in the area to be stimulated.

CLINICAL STUDIES The efficacy of VIM DBS in the treatment of patients with ET has been demonstrated repeatedly in shortand long-term studies (Benabid et al., 1996; Koller

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et al., 1997, 2001; Limousin et al., 1999; Rehncrona et al., 2003; Sydow et al., 2003; Putzke et al., 2004; Pahwa et al., 2006; Blomstedt et al., 2007; Zhang et al., 2010). Improvements in targeted hand tremor ranging from 50% to 91% have been demonstrated in several long-term studies (Table 13.1). These studies, with 1–7 years of follow-up, have also shown improvements in head and voice tremor ranging from 15% to 100%, although marked head and voice tremor control usually requires bilateral stimulation (Table 13.2). The majority of ET studies assess tremor with the Fahn– Tolosa–Marin Tremor Rating Scale (TRS) (Fahn et al., 1988). The TRS is a well established standardized 21-item tremor clinical rating scale in which tremor severity by body part is assessed. The TRS incorporates examiner tremor ratings (items 1–14) and patient activities of daily living (ADL) ratings (items 15–21), with the scoring of each item ranging from 0 (normal) to 4 (severe). Subsequently, small modifications have been made to the rating scale (Fahn et al., 1993). Data from representative larger long-term studies are discussed in detail below. Pahwa et al. (2006) reported 60-month follow-up data for 22 patients with ET; 15 received unilateral VIM DBS and 7 had bilateral stimulation. Targeted contralateral upper-extremity tremor improved in 75% in the unilateral group, which also demonstrated a 44% improvement in pouring, a 57% improvement in drawing, and a 51% improvement in ADLs as measured by the TRS. In patients who had bilateral VIM DBS, targeted upperextremity tremor improved by 65% on the left side and by 86% on the right. These patients also demonstrated up to a 57% improvement in functional abilities and a 36% improvement in ADLs at long-term follow-up. Stimulation parameters were similar overall at 1 and 5 years after surgery, and on average were 3.6 V, frequency

Table 13.1 Selected long-term studies of thalamic deep brain stimulation for essential tremor (percentage improvement compared with baseline)

Reference

No. of patients*

Age (years)

Follow-up (months)

Koller et al. (2001) Sydow et al. (2003) Putzke et al. (2004) Pahwa et al. (2006)

25/0 12/7 29/23 15/7

72 62 72 71

40 80 36 60

Blomstedt et al. (2007) Zhang et al. (2010)

18/1 23/11

68 58

86 57

* Unilateral (u)/bilateral (b); {Writing, drawing, pouring. ADLs, activities of daily living.

Overall tremor (%)

Hand tremor (%)

Functional ability (%){

ADLs (%)

50 41 – 46 (u) 78 (b) 32 80

78 50–70 87 75 (u) 65–86 (b) 60 –

– 37 – 44–57 (u) 35–57 (b) 35 70

– 39 70 51 (u) 36 (b) 5 –

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Table 13.2 Selected studies of thalamic deep brain stimulation for the treatment of essential tremor: head and voice tremor (percentages improvement compared with baseline) Reference

No. of patients*

Koller et al. (1999) Limousin et al. (1999)

20/0 28/9

Obwegeser et al. (2000)

Follow-up (months)

Head tremor (%)

Voice tremor (%)

67 63

12 12

11/11

73

Ondo et al. (2001)

11/11

72

11 (u) 12 (b) 3

– 33 (u) 40 (b) 28 (u) 83 (b) –

Sydow et al. (2003)

12/7

62

80

Putzke et al. (2005) Pahwa et al. (2006)

0/13 15/7

– 71

24 60

Blomstedt et al. (2007)

18/1

68

86

50 15 (u) 85 (b) 38 (u) 95 (b) 30 (u) 65 (b) 45 (u) 85 (b) 90 46 (u) 78 (b) 60

*

Age (years)

25 (u) 60 (b) 65 75 (u) 65–86 (b) 0

Unilateral (u)/bilateral (b).

158 Hz, and pulse width 111 ms in the unilateral group; in the bilateral group, stimulation parameters were on average 3.6 V, 155 Hz, 111 ms and 3.2 V, 153 Hz, 129 ms for first- and second-side DBS leads respectively. It should be noted that, more recently, pulse widths generally do not exceed 90 ms. Several stimulation-related adverse events such as paresthesia were often viewed as mild and usually corrected with adjustments of the stimulation. However, other stimulation-related side-effects were seen in a markedly higher percentage of bilateral patients, including dysarthria (17% unilateral, 63% bilateral), abnormal gait (0% unilateral, 25% bilateral), hypophonia (6% unilateral, 25% bilateral), and dysphagia (6% unilateral, 13% bilateral), and the authors noted that adverse events such as dysarthria and balance difficulties may persist despite stimulation adjustments. Sydow et al. (2003) reported on 19 patients who had VIM DBS (12 unilateral, 7 bilateral) with an average follow-up of 80 months. For the entire group, targeted upper-extremity tremor as assessed using the TRS demonstrated a 53% improvement at 1 year and 41% at 6 years after surgery, whereas functional status improved by 37% at long-term follow-up. There was an 82% improvement in functional status 1 year after surgery, which decreased to 39% at 6 years, although ADL scores on long-term follow-up were significantly greater than those at baseline, suggesting that the decline in ADL scores upon stimulation may be related to disease progression. Stimulation parameters at 1 year were, on average, 2.3 V, frequency 163 Hz, and pulse width 86 ms, and were similar to those upon long-term followup (2.6 V, 173 Hz, 89 ms). There was one case of hemiparesis secondary to thalamic hemorrhage and two infections

requiring replacement of each of the DBS systems. The most common stimulation-related side-effects were paresthesias, gait disorders, and dysarthria, the latter being more common with bilateral stimulation. Other complications included skin erosion associated with the hardware in two patients, one subcutaneous hematoma, and one lead requiring repositioning owing to an unsatisfactory effect. Blomstedt et al. (2007) reported on 19 patients with ET who underwent VIM DBS with an average follow-up of 7 years (range 66–102 months). Among these, 2 had a history of ipsilateral thalamotomy, 1 had contralateral thalamotomy, and 3 had previous or subsequent contralateral VIM DBS. One year after surgery, with stimulation and in comparison to baseline, tremor of the contralateral upper extremity as measured utilizing the TRS was reduced by 82%, and on long-term follow-up contralateral hand tremor was reduced by 60%, indicating continued benefit although with decreased effect over time. Hand function was also assessed; at 1 year after surgery this had improved by 68%, decreasing in the long term to 35%. ADL scores showed a marked improvement 1 year following surgery, although they returned to near preoperative baseline values on long-term follow-up. However, it was noted that ADL scores off-stimulation upon long-term follow-up declined significantly compared with preoperative baseline ADL values, suggesting that other morbidities associated with advancing age contributed to the overall decline in ADL scores. Data specific to the patients who had contralateral VIM DBS or ablative surgeries were not presented separately. Stimulation parameters at 1 year were on average 1.8 V, frequency 164 Hz, and pulse width 68 ms, increasing to 2.6 V, 171 Hz, and 68 ms at 7 years. No adverse events were

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR reported other than lead breakage, which occurred in 6 of the 19 patients (32%) and were attributable to lead– extension wire connections located in the neck. Zhang et al. (2010) reported the results of 34 consecutive patients after unilateral (23 patients) or bilateral (11) VIM DBS. Average follow-up was 56.9 months (range 3–128 months), and in a subset of 12 patients the average follow-up was 90.7 months, although the number of patients having unilateral and bilateral VIM DBS in the follow-up groups was not specified. For the entire group there was an overall 80% improvement in tremor and 70% improvement in handwriting. In the 12 patients followed long-term, there was no significant change in TRS tremor or handwriting scores when results at an average follow-up of 57.3 and 90.7 months were compared. Adverse events included paresthesias, weakness, gait disturbance, and slurring of speech; they usually resolved with changes in stimulation parameters, although two patients stopped using their DBS systems because of stimulation-associated side-effects. Required stimulation parameters gradually increased over primarily the first 5 years of stimulation; initial averaged parameters for the 37 stimulators available for analysis were 2.44 V, frequency 161 Hz, and pulse width 82 ms, whereas for the 9 stimulators for which data were available for analysis at more than 7 years averaged stimulation parameters were 3.2 V, frequency 168 Hz, and pulse width 90 ms. Adverse events encountered in unilateral versus bilaterally implanted patients were not specified. Hardware-related complications occurred in 8 patients, giving an overall reported hardware-related complication rate of 23.5%, including infection requiring removal of the entire DBS system in 3 patients. Improvement in head and voice tremor has been reported following VIM DBS in patients with ET (see Table 13.2) (Koller et al., 1999; Limousin et al., 1999; Taha et al., 1999; Ondo et al., 2001; Sydow et al., 2003; Putzke et al., 2004, 2005). Limousin and colleagues (1999) reported 12-month follow-up data on 35 patients who had VIM DBS (26 unilateral, 9 bilateral). In patients receiving unilateral stimulation, there was a 15% improvement in head tremor and a 33% improvement in voice tremor compared with baseline TRS scores. Among patients receiving bilateral stimulation, head tremor improved by 85% and voice tremor by 40%. In the series of 19 patients with ET who had VIM DBS (12 unilateral, 7 bilateral) reported by Sydow et al. (2003), head and voice tremor improved following unilateral stimulation by 45% and 25% respectively, whereas among bilaterally implanted patients head and voice tremor improved by 85% and 60% respectively. Other investigators have reported improvement of 15–51% in head and voice tremor upon unilateral VIM DBS, and 39–100% with bilateral stimulation

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(Koller et al., 1999; Putzke et al., 2004, 2005). Investigators have reported higher incidences of adverse events, particularly with regard to speech, swallowing, and gait in bilaterally implanted patients (Benabid et al., 1996; Pahwa et al., 1999, 2006; Taha et al., 1999; Ondo et al., 2001; Putzke et al., 2004, 2005), and also in patients receiving VIM DBS contralateral to prior thalamotomy (Benabid et al., 1996; Taha et al., 1999). Unilateral VIM DBS has been reported to improve quality of life (QoL) significantly in patients with ET (Fields et al., 2003; Hariz et al., 2008). Fields and colleagues (2003) reported on a series of 40 patients with ET and examined the impact of unilateral VIM DBS on QoL. To measure QoL, they modified the 39-item Parkinson Disease Questionnaire (PDQ-39) (Peto et al., 1995) in which the words “Parkinson’s disease” were replaced with the words “essential tremor.” The PDQ39 is a validated and widely used QoL measure in Parkinson’s disease, consisting of 39 questions addressing eight (mobility, ADLs, emotional wellbeing, stigma, social support, cognition, communication, and bodily discomfort) QoL dimensions. The authors reported significant improvements in the PDQ-39 dimensions of ADL, emotional wellbeing, and stigma at 1 year after unilateral VIM DBS. Hariz et al. (2008) also reported on the QoL of 19 patients with ET at an average of 1 and 7 years after unilateral VIM DBS. The authors utilized the Nottingham Health Profile (NHP), which provides a general measure of health-related QoL (Hunt et al., 1985; Wiklund, 1990). Part 1 of the NHP covers the dimensions of emotional reactions, sleep, energy level, pain, physical mobility, and social isolation, and Part 2 measures aspects of daily life that can be affected by the disease (Hariz et al., 2008). Overall there were no changes in Part 1 domains 1 year after surgery, although on long-term follow-up deterioration had occurred. In contrast, improvements in Part 2 domains of “social life,” “interests and hobbies,” and “looking after home” were present in the short term and sustained on long-term follow-up, although only in males. For the entire group, “social life,” as measured using a visual analog scale, was significantly improved in both the short and long term. The study demonstrated a worsening in mobility-related aspects of QoL, suggesting the importance of aging and medical comorbidities other than ET on long-term patient wellbeing.

DBS OF NON-VIM AREAS FOR TREMOR CONTROL IN PATIENTS WITH ESSENTIAL TREMOR Areas other than the VIM have been investigated regarding the safety and efficacy of DBS for ET. Areas that

162 J.M. NAZZARO ET AL. have received attention include the subthalamic nucleus from contacts situated above the ICL in 4 leads, and (STN) as well as the area adjacent to, although outside, there were intolerable side-effects in 5 others upon the STN, the posterior subthalamic area (PSA) stimulation below the ICL, including contralateral (Kitagawa et al., 2000; Hamel et al., 2007; Blomstedt paresthesias and stimulation-induced dysarthria. et al., 2009a, 2010, 2011; Barbe et al., 2011; Plaha et al., Plaha and colleagues (2011) reported on 15 consecu2011; Sandvik et al., 2011). tive patients with ET who underwent DBS directed to the bilateral caudal ZI (cZI), defined as the area posterior–medial to the posterior–dorsal STN. Tremor Posterior subthalamic area DBS was assessed on- and off-stimulation for a mean  SD of 31.7  28.6 (range 12–84) months. The TRS total Tremor control in patients with tremor secondary to ET tremor score improved by 73.8% and benefit was mainand other etiologies has been reported with stereotactic tained in the 4 patients with more than 4 years of followablative and stimulation studies of the PSA. The PSA is up. Stereotactic coordinates of optimal lead-contacts generally viewed to be comprised of the zona incerta (ZI) were not provided. In this series, 3 of the 15 patients and the radiatio prelemniscalis (Raprl), although assocideveloped bilateral stimulation-related dysarthria and ated areas may be included (Hamel et al., 2007; Blomstedt et al., 2009b, 2011). Approaches to the area hypophonic speech, described as mild and reversible often reflect standard approaches to the ventral lateral upon decreased stimulation. Sandvik et al. (2011) reported on 44 DBS electrodes in tier of thalamic nuclei, although they ultimately extend 36 patients with ET (17 VIM, 19 PSA). Leads targeted to further ventrally, beyond the base of the thalamus the PSA were directed to the area posterior–medial to (Hamel et al., 2007; Barbe et al., 2011; Deuschl et al., STN. Stimulation on/off tremor scores assessed at each 2011). Alternatively, others have utilized axial MRI to lead-contact in progressive fashion were assessed at target an area between the widest portion of the red 1 year and on average 66  38 months following DBS nucleus and the midposterior (Blomstedt et al., 2009a) or posterior-most (Blomstedt et al., 2011) STN. surgery. TRS total tremor score was reduced by 48% Blomstedt and coworkers (2010) reported on 21 conin the VIM group and by 58% in the PSA group, whereas the improvement in hand tremor/hand function was 57% secutive patients with ET operated on with PSA DBS. in the VIM group and 88% in the PSA group. The authors Among this group, 31 DBS leads were implanted; 2 of reported that lead-contacts yielding the best tremor the patients had bilateral leads and 4 had an additional reduction were in the PSA in 43% and in the VIM in ipsilateral lead implanted (3 STN, 1 VIM). Tremor was 18%, with coordinates on average in relation to the assessed before and 1 year after DBS, on- and offMCP (12.1  1.8 mm lateral, 5.5  1.9 mm posterior, stimulation. The authors reported that the TRS total tremor score was reduced by 60%, contralateral and 1.2  2.9 mm inferior). However, optimal results upper-extremity tremor was improved by 95%, and within the PSA group included lead-contacts in unexpected areas, including the substantia nigra (SN), contralateral hand function improved by 87%. Transient ventro-oralis posterior thalamic nucleus, pedunculoponmild dysphagia lasting from 1 day to 5 weeks occurred in tine nucleus (PPN), medial lemniscus, STN, reticular 8 patients. Active lead-electrodes were localized at nucleus of the thalamus, as well as other sites. a mean  SD of 11.6  1.8 mm lateral to midline, Interpretation of PSA DBS in patients with ET is lim6.3  1.6 mm posterior to the midcommissural point, ited due to several factors including the limited numbers and 3  2.3 mm below the intercommissural line. Barbe et al. (2011) studied 40 DBS leads in 21 patients of patients studied, varying locations of stimulation with ET who had VIM DBS (19 bilateral, 2 unilateral). In electrodes labeled as within the PSA, together with the distinct and multiple areas and pathways included within all patients the 40 leads were implanted within the VIM, the PSA designation. The trajectory of leads directed to and among these 26 leads extended below the VIM as the PSA may well often travel through the VIM, and the estimated by the ICL and thus with lead-electrodes optimal stimulating DBS lead-contact has been reported viewed as within the PSA. Data were collected for at least in some studies to be situated minimally (within 1.5 mm) 3 months after DBS surgery and tremor severity was ventral to the intercommissural line, a landmark generassessed using a three-dimensional ultrasound kinematic analysis tool. The authors reported comparable postural ally taken to be the most ventral aspect of the VIM. Howhand tremor control from lead-electrodes (contacts) sitever, the base of the thalamus is difficult to discern with certainty and depends on multiple variables including uated within the VIM and those situated in the PSA, individual patient anatomical differences together with although the stimulation parameters required for tremor the inability clearly to demarcate the ventral extent control upon PSA stimulation were overall lower than of the ventral thalamic tier with present MRI. Further, those required within the VIM. However, for the 26 electhe z-coordinate is most commonly the coordinate with trodes within the PSA, optimal stimulation was obtained

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR the greatest variability in DBS surgery. Indeed, DBS leads targeted to the PSA, though ultimately situated as far ventrally as PPN and SN, gave tremor relief in one study (Sandvik et al., 2011). The most pressing questions, and for which thus far there are few supportive data, include whether PSA DBS is more efficacious than VIM DBS in patients who develop tolerance to the effects of DBS in the setting of a well positioned DBS lead, and whether bilateral PSA DBS is safer and better tolerated than bilateral VIM DBS. These questions, together with the optimal location and orientation of DBS leads directed to the PSA, await further carefully controlled studies.

Subthalamic nucleus DBS Limited studies have addressed DBS within the STN for patients with ET (Stover et al., 2005; Lind et al., 2008; Blomstedt et al., 2011). Stover and colleagues (2005) reported on a patient with Parkinson’s disease and ET, with a prior history of left pallidotomy and right STN DBS for parkinsonian signs and symptoms, and in whom right upper-extremity action and postural tremor were viewed as secondary to ET, who was treated successfully with left STN DBS. The authors reported that the benefit was maintained up to 3 years. Lind et al. (2008) described 12 patients with ET who had stimulating electrodes situated in the STN. The patients were among 18 patients with ET in whom a DBS lead was implanted within either the VIM or the STN, depending on the results of intraoperative test stimulation, with the target that gave the best test-stimulation results being implanted. Of those receiving STN implantations, follow-up was 8–9 years in 3 patients and 1– 3 years in the remaining 9. All 3 patients with long-term STN DBS had excellent tremor control, whereas, of the 9 patients assessed 1–3 years after surgery, 2 had excellent tremor control, 6 had some reappearance of tremor, and in 1 patient STN DBS was replaced with a VIM lead owing to dystonic foot posturing upon stimulation. Speech and/ or balance problems were reported in 4 of the patients with STN DBS who were aged 73 years or more. Blomstedt and coworkers (2011) reported on 4 patients with ET, each with two ipsilateral DBS leads, with one lead situated within the STN and the other within the cZI. Patients were evaluated by means of TRS scores on- and off-stimulation before surgery and at 4, 7, and 12 months after surgery, followed by yearly evaluations thereafter. The authors found that contralateral upperextremity tremor was well controlled in all patients on long-term follow-up of up to 6 years with either STN or cZI leads. In 3 patients, cZI stimulation was employed as lower stimulation parameters were required, whereas the remaining patient preferred STN stimulation.

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SUMMARY ET is a common movement disorder and frequently is not satisfactorily treated with medication. VIM DBS is to be considered when medical measures fail to control the tremor. The clinical results of VIM DBS and VIM thalamotomy are comparable overall, but thalamotomy is now rarely utilized given the incidence of permanent neurological deficits associated with the ablative surgery. Unilateral VIM DBS for contralateral upperextremity tremor is FDA-approved, and short- and long-term benefit for targeted tremor has been demonstrated repeatedly. Bilateral VIM DBS is associated with a higher incidence of neurological deficits, particularly dysphagia and balance problems. Head and voice tremor may improve with unilateral VIM DBS, although greater improvement is seen upon bilateral stimulation. Surgery within other brain areas, such as the PSA and the STN, for ET remain investigational.

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