R Mehanna MD 1 ; AG Machado MD, PhD 2 ; S Oravivattanakul MD 2 ; G Genc MD 2 ; SE Cooper MD, PhD 2

1. Tremor refractory to Vim DBS: are 2 leads better than one, and where should we implant? Cleveland Clinic R Mehanna MD1; AG Machado MD, PhD2; S Oravivattanakul MD2; G Genc MD2; SE Cooper MD, PhD2 1 University of Texas Health Science Center, Houston, Texas 2 Cleveland Clinic Foundation, Cleveland, Ohio. Abstract Background: A sizable proportion of medication refractory tremor patients may not respond satisfactorily to deep brain stimulation (DBS) to the ventralis intermedialis nucleus of the thalamus (Vim). Implanting a second DBS lead ipsilateraly to the first one is thought to be beneficial, based on scarce and un-blinded data, and the best target is unknown. Objective: To report a double-blind assessment of 5 patients with a second DBS lead for refractory tremor. Method: Tremor was assessed by 2 blinded movement disorders specialists using a videotaped tremor rating scale (TRS) evaluation of each patient in 4 conditions: both leads OFF, Vim ON/2nd lead OFF, Vim OFF/2nd lead ON and both leads ON. Results: Tremor was secondary to multiple sclerosis in 2 patients and to essential tremor in 3. The second lead was in the ventralis oralis anterior nucleus of the thalamus (Voa) in 3 patients, and in the posterior subthalamic white matter (PSWM) in 2 patients. There was 17 to 60% tremor improvement after the implant of the 2nd lead, on double blinded evaluation in 4 of our 5 patients. The improvement was marked in all 3 patients with the second lead in the Voa, and moderate in 1 of 2 patients with the second lead in the PSWM. These results were constant whether the tremor was rated on the whole body, the contralateral limb only or the contralateral hemibody only. Conclusion: We report objective improvement after addition of a 2nd DBS lead in patients with tremor refractory to Vim DBS. Targeting the Voa rather than PSWM seems to yield better tremor control. Larger studies are needed to confirm these results. • Thus, some of our patients were judged clinically (and judged themselves) to have marked improvement with the addition of a second lead, while others did not. However, this was based on un-blinded assessment by the patients and their physicians.  We undertook a systematic, quantitative double blind assessment of these patients to determine if the benefits, in the "successful" group were due to a real stimulation effect, or to placebo and/or observer bias. • After data were un-blinded, the improvement for each patient in each of the 3 stages of stimulation (Vim ON, 2nd lead ON and double ON) was calculated by subtracting the double OFF score from each of these values. Improvement of the tremor was given a positive sign, while worsening was given a negative sign. This was done for the total TRS scores , the isolated contralateral upper limb score as well as the contralateral hemibody score. • With each of the measure used, the Spearman rho test showed good inter-rater reproducibility. • However, when taken as a group, there was no statistical significance in the absolute improvement of tremor score between double ON and Vim ON alone, double ON and 2nd lead ON alone or Vim ON alone and 2nd lead ON alone • Accelerometry reported that, in all 5 patients, tremor power was less in the Both On condition than in the Vim On/2nd lead OFF condition.  This was significant for total power in the 3-9 Hz band (p=0.045), but not (p=0.087) for peak power. In addition, it was not significant when the frequency band was changed from 3-9 Hz to 2-8 Hz (p=0.0958 for band power, p= 0.1019 for peak power).  Repeating the analysis with water-pouring included did not affect these results. • Methods • Stimulator OFF since previous evening • Tremor medications held for 24 hours prior to visit. • All patients were evaluated clinically with • video recording of the examination • accelerometric measurements to detect infraclinical variations. • Patients examined in 4 conditions, in random order, different for each patient: • double OFF, • Vim ON/2nd lead OFF, • Vim OFF/2nd lead ON, • double ON . • 30 min between changing stimulation and assessing using tremor rating scale (TRS) • Patient blinded to the condition by use of soft start (no jolt). • Videotaped clinical examination = first 15 items TRS + wing position of each UE. • Videos blindly rated in random order by 2 movement disorders specialists who had never seen the patients. • Specific training was done to insure adequate training of the video raters and minimize inter-rater variability. • Accelerometric measurements were done using a Silicon Designs model 2422-010 triaxial accelerometer taped to the back of the patient's hand contralateral to the tested leads.  • For each patient, we subtracted the double OFF TRS from the TRS of each state, in order to measure the improvement of tremor in each scenario. The 2 series of blinded scores thus obtained from the 2 raters were then compared for reproducibility, using a Spearman rho test, and the average value for each scenario was used for subsequent analysis. • This was also done with the tremor rate of the isolated upper limb contralateral to the dual implant (= the sum of the scores of the rest tremor, postural tremor, action tremor, drawing, pouring and, when it was the dominant hand, writing ) and the tremor rate of the hemibody contralateral to the dual implant (=the sum as upper limb tremor as calculated above and the lower limb tremor of that side). • 2 hypotheses were tested, using a paired t test: • A) is double stimulation different than stimulation of Vim alone? • B) is double stimulation different than stimulation of the 2nd lead alone? • The threshold for statistical significant was fixed at <0.05 with correction for multiple analyses. • We also compared Vim-alone to 2nd lead-alone stimulation, as an exploratory analysis without formal significance testing. • Tremor power was compared using a linear mixed model with patient as the random factor and stimulation condition (Vim only vs. double stimulation) as the fixed factor. • Results • Table 2: Chronic deep brain stimulation parameters: Figure 1: Total body tremor score improved in patients 1 to 4 after the addition of the 2nd lead Discussion • Rationale behind implanting an additonal electrode in VOA: to include the pallidal receiving area (Voa/Vop) in addition to the cerebellar receiving area (Vim) (9,17) and to involve a broader thalamic somatotopy. • Rationale behind implanting an additonal electrode in in the posterior subthalamic white matter (PSWM), which includes RaPRL and ZI (5): to activate the cerebellothalamic afferents (6). • Double-blind tremor rating scores confirmed that open labeled improvement was not a placebo effect. • Relative improvement with double ON stimulation was notable, exceeding 60% in patient 3, 40% in patient 1, and 20% in patient 2 when using the hemibody tremor score. • Improvement was reproducible with the different ratings used. • Unblindedreports of improvement after dual electrode stimulation in earlier studies do reflect real non-placebo improvement, so could tentatively accept those results as evidence of efficacy. • In the sample as a whole, difference was not statistically significant, and accelerometry showed borderline statistical significance at best. This could be because of 1- double blind ratings: by eliminating the placebo effect, overall effect smaller. 2- small sample size: lacking in statistical power. 3 -heterogeneous sample: variety of tremor etiologies and two different locations for the second electrode. • Introduction • Tremor can be refractory to medical treatment and require deep brain stimulation (DBS). • The most frequent target is the Ventralisintermedius (Vim) nucleus of the thalamus, controlateral to the tremor. The efficacy of Vim DBS for the control of ET has been well documented (1-4). • Alternative targets have been proposed in the prelemniscal radiations (RaPrL) (5,6), posterior zonaincerta (ZI)(7,8) and the nucleus ventralisoralis anterior of the thalamus (Voa) (9). • 25% of ET patients either may not get satisfactory relief from Vim DBS initially, or worsen after an initial good response (10,11). • Symptomatic tremor responds less to Vim DBS (12) although recent studies have showed some short term improvement in tremor secondary to multiple sclerosis (MS)(13,14). • When tremor is refractory to Vim DBS, it has been proposed to add a second electrode (9,15,16). This could improve tremor by stimulating different neurons than Vim DBS such as cerebellothalamic afferents in the RaPrL (6) or pallidal-receiving neurons in the case of Voa (9). Alternatively, it might improve tremor simply by expanding the volume of tissue affected by stimulation (16). • To date, only a small number of such patients have been published, with outcomes assessed in an un-blinded fashion. In the movement disorders clinic of the Center for Neurological Restoration at the Cleveland Clinic Foundation, we identified 6 patients with tremor refractory to Vim DBS in whom a second electrode had been implanted, 5 of whom consented to submit to measuring, in double-blind fashion, the amount of benefit from the additional electrode. • Case series • Table 1: Patient population: Figure 2:Contralateral upper limb score improved in patients 1 to 4 after the addition of the 2nd lead Conclusions Implanting a second electrode in another target might be beneficial in Vim DBS refractory ET or MS tremor. Targeting the Voa might yield better results than the PSWM. Confirmation with a larger sample is needed. References 1. 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Benabid AL, Pollak P, Gao D, Hoffmann D, Limousin P, Gay E, et al. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203-14. 11. Papavassiliou E, Rau G, Heath S, Abosch A, Barbaro NM, Larson PS, et al. Thalamic deep brain stimulation for essential tremor: relation of lead location to outcome. Neurosurgery 2004;54:1120-9. 12. Yamamoto T, Katayama Y, Kano T, Kobayashi K, Oshima H, Fukaya C. Deep brain stimulation for the treatment of parkinsonian, essential, and poststroke tremor: a suitable stimulation method and changes in effective stimulation intensity. J Neurosurg. 2004;101:201-9. 13. Zakaria R, Vajramani G, Westmoreland L, Fletcher N, Eldridge P, Alusi S, et al. Tremor reduction and quality of life after deep brain stimulation for multiple sclerosis-associated tremor. Acta Neurochir (Wien). 2013:155:2359-64. 14. Hosseini H, Mandat T, Waubant E, Agid Y, Lubetzki C, Lyon-Caen O, et al. Unilateral thalamic deep brain stimulation for disabling kinetic tremor in multiple sclerosis. Neurosurgery. 2012;70:66-9. 15. Yamamoto T, Katayama Y, Fukaya C, Oshima H, Kasai M, Kobayashi K. New method of deep brain stimulation therapy with two leads implanted in parallel and side by side. J Neurosurg. 2001;95:1075-8. 16. Yu H, Hedera P, Fang J, Davis TL, Konrad PE. Confined stimulation using dual thalamic deep brain stimulation leads rescues refractory essential tremor: report of three cases. Stereotact Funct Neurosurg. 2009;87:309-13. 17. Lehéricy S, Grand S, Pollak P, Poupon F, Le Bas JF, Limousin P, et al. Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions. Neurology 2001;57:1055-66. Figure 3: Contralateral hemibody score improved in patients 1 to 4 after the addition of the 2nd lead Legend: L: left, R: right, Vim: ventralis intermedius, Voa: ventralis oralis anterior. Legend: ET: essential tremor, MS: multiple sclerosis; Vim: ventralis intermedius, Voa: ventralis oralis anterior, PSWM: posterior subthalamic white matter. .