Auditory-Perceptual Evaluation of Deep Brain Stimulation on Voice and Speech in Patients With Dystonia

ARTICLE IN PRESS

Auditory-Perceptual Evaluation of Deep Brain Stimulation on Voice and Speech in Patients With Dystonia *,†Mary E. Finger, *Mustafa S. Siddiqui, †Amy K. Morris, †Kathryn W. Ruckart, †S. Carter Wright, *Ihtsham U. Haq, and †Lyndsay L. Madden, *yWinston-Salem, North Carolina ABSTRACT: Objective. To determine the effects of globus pallidus interna (GPi) deep brain stimulation (DBS) on speech and voice quality of patients with primary, medically refractory dystonia. Methods. Voices of 14 patients aged ≥18 years (males = 7 and females = 7) with primary dystonia (DYT1 gene mutation dystonia = 4, cervical dystonia = 6, and generalized dystonia = 4) with bilateral GPi DBS were assessed. Five blinded raters (two fellowship-trained laryngologists and three speech/language pathologists) evaluated audio recordings of each patient pre- and post-DBS. Perceptual voice quality was rated using the Grade, Roughness, Breathiness, Asthenia, and Strain scale and changes in speech intelligibility were assessed with the Clinical Global Impression scale of Severity instrument. Inter-rater and intrarater reliability rates for perceptual voice ratings were assessed using the kappa coefficient. Results. Voice quality parameters showed mean improvements in Grade (P < 0.0001), Roughness (P = 0.0043), and Strain (P < 0.0001) 12 months post-DBS. Asthenia increased from baseline to 6 months (P = 0.0022) and declined significantly from 6 to 12 months (P = 0.0170). Breathiness did not change significantly over time. Speech intelligibility also improved from 6 to 12 months (P = 0.0202) and from pre-DBS to 12 months post-DBS (P = 0.0022). Grade and Strain ratings had nearly perfect and substantial inter-rater agreement (0.84 and 0.71, respectively). Conclusions. Voice and speech intelligibility improved after bilateral GPi DBS for dystonia. GPi DBS may emerge as a potential treatment option for patients with medically refractory laryngeal dystonia. Key Words: Primary dystonia−Voice−Deep Brain Stimulation−Speech−Globus Pallidus Interna. Abbreviations: DBS, Deep Brain Stimulation−GPi, Globus Pallidus Interna−STN, Subthalamic Nucleus−VIM, Ventral Intermediate nucleus−BFMDRS, Burke−Fahn−Marsden Dystonia Rating Scale−CGI-s, Clinical Global Index of Severity.

INTRODUCTION Movement disorders such as essential tremor (ET), Parkinson's disease (PD), and primary dystonia are frequently accompanied by dysarthria and dysphonia. Proposed mechanisms for these complications include interference with speech and voice−−either directly affecting muscles involved in these processes, or indirectly by causing dysfunction due to the overlap between movement regulation and speech and voice modulation.1,2 Deep brain stimulation (DBS) is approved by the U.S. Food and Drug Administration for treatment of medically refractory motor symptoms of ET and PD. DBS of globus pallidus interna (GPi) has a Humanitarian Device Exemption from the Food and Drug Administration and has emerged as the surgical treatment Accepted for publication February 19, 2019. Presented at the American 139th Annual Meeting of the American Laryngological Association at the Combined Otolaryngology Spring Meetings, National Harbor, Maryland, United States of America, April 18−22, 2018. Funding: L.L.M. received statistical support through a grant from National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR001420 (McClain, PI). This funding organization did not contribute to the design or conduct this study. Conflicts of Interest: The authors have no other funding, financial relationships, or conflicts of interest to disclose. From the *Departments of Neurology, Wake Forest School of Medicine, WinstonSalem, North Carolina; and the yDepartments of Otolaryngology-Head and Neck Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina. Address correspondence and reprint requests to Lyndsay L. Madden, 1 Medical Center Blvd, Winston-Salem, NC 27157. E-mail: [email protected] Journal of Voice, Vol. &&, No. &&, pp. &&−&& 0892-1997 © 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jvoice.2019.02.010

of choice for adults and children with medically refractory, disabling motor symptoms of primary (idiopathic) dystonia. While DBS of subthalamic nucleus, ventral intermedius (VIM) nucleus, and GPi improve motor symptoms of PD, ET, and primary dystonia, it may also have a negative effect on voice and speech. The majority of studies examine the effects of DBS on speech quality in patients with PD, with many studies showing that DBS can have deleterious effects on speech leading to dysarthria.3−5 However, the effects of DBS on speech and voice in patients with primary dystonia are still unclear. The gold standard of treatment for focal dystonias like spasmodic dysphonia,6 laryngeal dystonia,7 oromandibular dystonia,8 writer's cramp,9 and blepharospam10 has been botulinum toxin injection. Only recently have unilateral and bilateral DBS been explored as a treatment option for focal dystonias.11,12 Past research on DBS as a treatment for patients with dystonia has largely been found in neurology literature.13,35 Unfortunately, these studies do not use specific voice and speech outcome measures to adequately characterize perturbations with respect to voice and speech. Most studies have focused on the effect of bilateral DBS for dystonia on speech intelligibility and whether dysarthria improved or worsened after DBS, or the effect of stimulation parameters on speech and voice.4,14 Follow-up has largely been limited to reported 6 months after surgery, with only a few studies extending later.15,16 Risch et al conducted a study with 15 patients diagnosed with cervical dystonia who received

ARTICLE IN PRESS 2

Journal of Voice, Vol. &&, No. &&, 2019

bilateral GPi DBS; they examined its effects on parameters of voice and speech such as articulation rate and speech intelligibility.17 Similarly, Rusz et al examined the effects of DBS stimulation on speech fluency, speech intelligibility, and dysarthria in 19 patients with various types of dystonia who received bilateral GPi DBS.18 However, both studies examined patients off and on stimulation during the same day (in 45-minute or 2-hour periods between off and on settings). Furthermore, they reported only on the effects of DBS stimulation on patient voice and speech. The progression and change in the voice and speech of patients implanted with bilateral DBS for primary and vocal dystonia has not been investigated previously, to the best of our knowledge. Review of the few long-term followup studies supports that patients with dystonia can experience delayed improvements in speech intelligibility for several years following surgery.19,20 The purpose of this study was to more thoroughly characterize changes in voice and speech 6 and 12 months post-DBS bilateral implantation, using auditory perceptual analyses. METHODS Participants Recordings of 14 patients with dystonia (7 male and 7 female) were obtained from two fellowship-trained movement disorder specialists in the Department of Neurology at Wake Forest Baptist Health. A retrospective chart review was completed. Inclusion criteria were: (1) patients with a diagnosis of primary dystonia made by a fellowship-trained movement disorder neurologist; (2) patients who received bilateral DBS for medically refractory primary dystonia; (3) patients who were 18−85 years of age; and (4) patients who had a pre-DBS video recording and at least one post-DBS video recording. Exclusion criteria were: (1) patients with a diagnosis of secondary dystonia; (2) patients who were younger than 18 or older than 85 years of age. Study design This study was approved by the Institution Review Board (IRB00039291) at Wake Forest Baptist Medical Center.

Clinical assessments and patient audio recordings were obtained pre-DBS, 6 months post-DBS, and/or 12 months post-DBS. These recordings were measured in an off-medication state for pre-DBS recordings and in an off-medication, on-stimulation state for post-DBS recordings. Four patients with DYT1-mutation positive disease, six patients with cervical dystonia, and four patients with generalized dystonia were included in the study. Prior to receiving DBS, two patients had dysarthria, two patients had laryngeal dystonia, five patients had both laryngeal dystonia and dysarthria, four patients had no perceptible neurological voice condition, and one patient lacked a pre-DBS voice/speech assessment (this patient was excluded from analyses). Patients underwent DBS programming using our standard of care protocol to optimize motor symptoms (not voice quality); these programming data were recorded (Table 1). Following a standardized protocol, participants read from the standardized Rainbow Passage,21 sustained vowel phonation (i:), and/or spoke several connected sentences according to the level of their comfortable modal pitch and volume. Video recordings were obtained. The audio from the videos was then extracted to ensure only patient audio remained; all patient identifying information, including diagnosis, was then removed. Preoperative recordings were defined as recordings from the patient pre-DBS implantation; postoperative recordings were defined as recordings of the patient obtained 6 and 12 months post-DBS implantation. Ten of the 14 patients were analyzed at 6-month postDBS; four patients were not included due to either insufficient audio for analysis or loss to follow-up. Six of these 10 patients as well as one additional patient were analyzed at 12-month post-DBS. Three of the 10 patients that were analyzed at 6-month post-DBS were lost to follow-up and therefore could not be assessed at 12-month post-DBS.

Surgery In Phase 1 of DBS surgery, all patients were bilaterally implanted with appropriate leads (Medtronic, Minneapolis, MN, Medtronic electrode 3389) in the GPi. One patient with severe cervical dystonia received bilateral implantation

TABLE 1. Last recorded stimulation parameters at 12-month post-DBS for the 10 patients with dystonia included in GRBAS and CGI-s analyses. A positive value for the mean change from 6 months to 12 months indicates an increase in stimulation parameter at the 12-month appointment.

Bilateral GPi Stimulation Parameters Right Left Average change from 6 months postDBS programming

Median Frequency (Range of Frequency) (Hz)

Median Amplitude (Range of Amplitude) (V)

Median Pulse Width (Range of Pulse Width) (msec)

135 (60−185) 135 (60−185) 9.375

3.55 (2.1−4.2) 3.5 (2.2−4.7) 0.425

140 (90−270) 150 (60−270) 2.5

ARTICLE IN PRESS Mary E. Finger, et al

Effect of Deep Brain Stimulation on Dystonia Voice & Speech

of the VIM and unilateral implantation of the right GPi. In Phase 2 (11−14 days after Phase 1), all patients were implanted and connected to a neurostimulator in the subclavicular area (unilateral Activa PC 37601 = 4, unilateral Activa SC 37603 = 1, unilateral Activa RC 37612 = 2, unilateral Kinetra = 2, bilateral Activa PC 37601 = 1, bilateral Activa SC 37603 = 4). Before DBS programming, patients underwent postoperative computerized axial tomography to confirm lead locations. All leads were in the intended targets. Clinical evaluation Burke−Fahn−Marsden Dystonia Rating Scale As part of routine clinical care, patients were evaluated for the severity of motor symptoms using the Movement (M) and Disability (D) subsections of the Burke−Fahn−Marsden Dystonia Rating Scale (BFMDRS-M/D).22 Patients were rated preoperatively, immediately postoperatively, and 6 months post-DBS implantation. Perceptual ratings of voice and speech intelligibility GRBAS Raters were blinded to patient diagnosis as well as the timing of the recording in terms of whether it was before or after surgery. Blinded raters rated the audio recordings separately from each other. Two laryngologists and one speech language pathologist were blinded raters for the Grade, Roughness, Breathiness, Asthenia, and Strain (GRBAS) assessment. Raters were not aware if the audio was pre-DBS or post-DBS. All recordings were randomly presented to the raters, with four recordings randomly repeated to assess intra-rater reliability. The raters listened to each consecutive recording and assessed each voice using the GRBAS23 scale. This scale was selected to subjectively assess changes in voices of the patients at each time point. Each rater graded each audio recording from 0 to 3 (0 indicating normalcy, 3 indicating most affected) for each GRBAS scale category. CGI-s Blinded raters again rated the audio recordings separately from each other. Two laryngologists and three speech language pathologists served as blinded raters for the Clinical Global Impression Scale of Severity (CGI-s) assessment. The same raters for the GRBAS portion of the study served as blinded raters for the CGI-s24; in addition, two other speech language pathologists were introduced as raters. The CGI-s is a numerical scale from 0 to 7 (with zero indicating normalcy) designed for clinicians to rate the severity of a specified symptom, which in this case was dysarthria. This scale and the GRBAS scale were used to subjectively assess changes in severity of speech intelligibility at each time point. Inter-rater and intrarater reliability We tested inter-rater reliability by comparing scores of all three blinded raters for each audio recording. Additionally,

3

to test the ability of the blinded raters to reproduce the same score for a given recording, four audio recordings were randomly selected to be repeated within the group of the audio recordings for the blinded raters to score. Lastly, to verify reproducibility of the CGI-s scale scores between raters, we compared scores assigned by the blinded raters for each audio recording.

Statistical analysis The statistical software used for all statistical analysis was SAS version 9.4. To test whether the BFMDRS-M/D scores changed significantly over time, a mixed model was fitted separately for the BFMDRS-M data and then again for the BFMDRS-D data. A repeated measures analysis of variance model, including the terms MONTH and RATER, was used to explore changes in CGI-s scores over time and to evaluate changes over time among the GRBAS categories. Kappa statistics and the intraclass correlation coefficient were calculated using Cohen's kappa coefficient test to assess inter-rater reliability. Intrarater reliability was assessed using the intraclass correlation coefficient and descriptive statistics. RESULTS Patients age ranged from 19 to 82 years old (mean age 62.6 § 16.3). Bilateral GPi DBS significantly improved BFMDRS-M/D scores from baseline to directly following surgery (Table 2). Motor and disability portions of the BFMDRS showed significant differences in scores from pre-DBS to directly post-DBS and from pre-DBS to 6month post-DBS, but not from directly post-DBS to 6month post-DBS.

GRBAS perceptual rating of voice Grade, Roughness, and Strain declined significantly from pre-DBS to 12-month post-DBS (P < 0.0001, P = 0.0043, P < 0.0001, respectively). Asthenia increased from pre-DBS to 6-month post-DBS (P = 0.0022) and then declined significantly from 6-month post-DBS to 12-month post-DBS (P = 0.0170), but did not significantly differ between preDBS and 12-month post-DBS time points (P = 0.6271). Breathiness did not significantly change over time (P = 0.1765). Among the 10 patients with dystonia, preDBS scores did not significantly improve in any GRBAS category compared to 6-month post-DBS (Table S1−S5), and two−four patients worsened compared to their preDBS GRBAS score in each category (Figure 1). Between five and seven patients had the same GRBAS scores in each category pre-DBS and 6-month post-DBS. However, of the seven patients with pre-DBS and 12-month post-DBS data, no patient worsened in any category and most improved compared to their pre-DBS score in each category (Figure 2). Progressive changes in individual patients’ scores for each GRBAS category are shown in Figure 3.

ARTICLE IN PRESS 4

Journal of Voice, Vol. &&, No. &&, 2019

TABLE 2. Clinical profile of patients with dystonia. Patients one−11 were the total number of patients included in GRBAS and CGI-s analyses; Patients one−10 comprise data for the 6 months post-DBS time point and patients one−six and 11 comprise data for the 12 months post-DBS time point. Patients 12−14 either did not have sufficient audio for analysis or were lost to follow-up.

Patient Age

Sex

Disease Type

Disease Duration (years)

BFMDRSMotor/Disability Score Pre-DBS

1

71

Female Cervical dystonia

30

28/12

2

40

Male

DYT1 positive dystonia

35

56/15

3

61

Male

DYT1 positive dystonia

20

39/13

4 5

80 61

Female Cervical dystonia Male DYT1 positive dystonia

37 40

31/15

6

82

Female Generalized dystonia

15

43.5/18

7

73

Female Cervical dystonia

12

22/5

8

71

Male

28

43.5/18

9

53

Female DYT1 positive Dystonia

20

40/25

10

19

Male

DYT1 positive dystonia

10

60/22

11

63

Male

Generalized dystonia

40

46/22

12

70

Female Cervical dystonia

25

28/13

13

35

Male

8

34.5/16

14

46

Female Cervical dystonia

5

7/1

Measure BFMDRS-M BFMDRS-D Measure BFMDRS-M BFMDRS-D

Cervical dystonia

Generalized dystonia

BFMDRS-Motor/ Disability Score directly post-DBS and 6 months post-DBS

% Improvement in BFMDRSMotor/Disability Score

Post-op: 10/5 6 months: 5/2 Post-op: 10/8 6 months: 6/2 Post-op: 8/4 6 months: 5/3

82/83

Post-op: 7/6 6 months: 4/2 Post-op: 8/5 6 months: 6/3 Post-op: 12/3 6 months: 10/2 Post-op: 8/5 6 months: 6/3 Post-op: 35/20 6 months: 33/20 Post-op: 11/9 6 months: 9/9 Post-op: 36/18 6 months: 34/18 Post-op: 6/3 6 months: 5/2 Post-op: 8/5 6 months: 6/3 Post-op: 4/1 6 months: 19/1

87/87

89/87 87/77

83/86 55/60 83/86

85/59 26/18 83/81 83/81 ¡43/0

Mean (stdev)

Mean (stdev)

Mean(stdev)

Pre-DBS 36.7 (3.7) 13.9 (1.8) Pre-DBS vs post-DBS P value <0.0001 0.0003

6-month post-DBS 11.4 (3.7) 6.4 (1.8) Pre-DBS vs 6-mo post-DBS P value

12-month post-DBS 10.4 (3.7) 5.3 (1.8) Post-DBS vs 12-mo postDBS P value 0.8300 0.5176

CGI-s rating of speech intelligibility Ten patients with dystonia were included in the pre-DBS compared to 6-month post-DBS CGI-s study, and seven patients with dystonia were included in the pre-DBS compared to 12-month post-DBS CGI-s study (Figure 4). CGI-s scores significantly decreased over time (P = 0.0081), from 6-month to 12-month post-DBS (P = 0.0202), and pre-DBS to 12-month post-DBS (P = 0.0022) (Table S6). Speech intelligibility improved when pre-DBS and 6-month postDBS CGI-s scores were compared, but it was not statistically significant (P = 2312). Statistically significant

<0.0001 <0.0001

reductions in CGI-s scores are not necessarily clinically significant; however, no patient experienced an increase in CGI-s score or, by extension, in dysarthria over time postDBS. The progressive change in CGI-s score for each patient is shown in Figure 3.

Inter-rater and intra-rater reliability Kappa statistics were used to find the degree of agreement between raters for GRBAS. It was found that Grade and Strain had the highest inter-rater agreement ratings

ARTICLE IN PRESS Mary E. Finger, et al

Effect of Deep Brain Stimulation on Dystonia Voice & Speech

10 9 worse

Number of Subjects

8 7

same

7 6

better

6 5

5

5

5

raters). This shows that variability in values was due mostly to differences between subjects, not rater differences. For intra-rater reliability, each participant was rated twice by the same rater on five characteristics (“pre” and “post”). From these repeated ratings pre-DBS to six and twelve months post-DBS. No single characteristic was more likely to be associated with disagreement.

4 4 3

3

3

3

3 2

2

2 1

1

1 0 Grade

Roughness Breathiness Asthenia

Strain

GRBAS Category

FIGURE 1. GRBAS scores for each of 10 patients with dystonia 6 months post-DBS. Change in Asthenia score significantly improved (P = 0.0022). Change in Grade (P = 0.6694), Roughness (P = 0.1653), and Strain (P = 0.1638) scores did not significantly improve. Breathiness was not tested because it did not significantly change over time. Worsening in score was defined as 0.5+ unit increase in GRBAS score pre-DBS compared to 6 months postDBS. Improvement in score was defined as 0.5+ unit decrease in GRBAS score pre-DBS compared to 12 months post-DBS.

(k = 0.84 and k = 0.71 respectively), while Asthenia had the lowest (k = 0.30). Mixed model analyses to determine effects of time and rater on CGI-s yielded an intraclass correlation coefficient of 0.78 (1 indicates perfect agreement between 10 9

worse

8 Number of Subjects

5

same

7

5 4

better

6

6

5

5

5

4

3

3

2

2

2

2

1

1 0 Grade

Roughness Breathiness Asthenia

Strain

GRBAS Category

FIGURE 2. GRBAS scores for each of seven patients with dystonia 12 months post-DBS. Change in GRBAS scores for seven patients with dystonia at 12 months post-DBS. Grade (P = 0.0211), Roughness (P = 0.0011) and Strain (P = 0.0035) were significantly improved. Asthenia (P = 0.6271) did not significantly improve and Breathiness was not tested because it did not significantly change over time. Worsening in score was defined as 0.5+ unit increase in GRBAS score pre-DBS compared to 6 months post-DBS. Improvement in score was defined as 0.5+ unit decrease in GRBAS score pre-DBS compared to 12 months post-DBS.

Patient speech and voice outcomes Voice and speech outcomes for the seven patients with preDBS and 12-month post-DBS data are shown in Table 3. While the voice and speech outcomes for patients at 6month post-DBS did not show significant improvement in any GRBAS category or CGI-s analysis, all patients with dystonia included in the 12-month post-DBS analysis experienced improvement in at least one GRBAS category and CGI-s speech score. However, only the Grade, Roughness, and Strain categories showed statistically significant improvements. No single type of primary dystonia was associated with greater voice and speech improvement. DISCUSSION To our knowledge, no other reports have studied effects of bilateral GPi DBS on voice quality and speech intelligibility in patients with dystonia at multiple time points post-DBS using perceptual analysis of voice. We found that bilateral GPi DBS resulted in significantly improved speech and voice quality of patients with primary dystonia 12 months post-DBS, based on perceptual analysis of patient voice and speech using blinded raters. This significant improvement was not observed 6 months post-DBS, indicating that there is a potentially delayed beneficial effect for patients with dystonia, particularly in the neural pathways associated with speech and voice production and control. The quality and magnitude of voice and speech using perceptual analysis of voice improvement postbilateral GPi DBS implantation has not been studied in patients with primary dystonia. Although studies in the field of otolaryngology have examined effects of stimulation parameters on voice and speech in patients with dystonia, to our knowledge none have compared multiple post-DBS time points using the methods in this study. It is thought that patients with dystonia have abnormal plasticity in their motor learning, which leads to abnormal sensorimotor assimilation.25,26 Attempted eradication of this abnormal plasticity, as with DBS implantation, may have a greater effect on motor dysfunction at later time points evaluated18,27 secondary to corrupt motor memories already established and thus difficult to eradicate. These deeply embedded motor memories may explain why DBS implantation sometimes results in delayed improvement in patient motor symptoms.28 Most previous studies largely focused on patients with PD or ET and showed no effect, or even worsening, of speech intelligibility after DBS; some report reduced benefit for speech.29 The few previous reports that examined

ARTICLE IN PRESS 6

Journal of Voice, Vol. &&, No. &&, 2019

Change in Grade Score for Each Subject

Change in Roughness Score for Each Subject

4

9

5

10 11

e

e

ra d -D BS G

10

po 12

12

6

m

o

m o

P

po s

re

po st -D BS

st -D B po m o 6

9

0

G

ra d SG

Pr eDB SG

Change in Asthenia Score for Each Subject

4

4

3

2

1

6

2

7

3

8

4

9

5

1

10 11

Asthenia Score from GRBAS

3

2

1

6

2

7

3

8

4

9

5

1

10 11

0 Pr eDB SG ra de

12

6

m

m

o

o

po st -D B SG ra de

de po st -D BS G ra m

6

12

m

o

o

po

Pr e

-D BS

Gr

st -D BS G ra

ad e

de

0

po st -D BS G ra de

Breathiness Score from GRBAS

8

4

11

Change in Breathiness Score for Each Subject

Change in CGI-s Score for Each Subject

Change in Strain Score for Each Subject 4

8

3

2

1

1

6

2

7

3

8

4

9

5

10

6 CGI-s Score

Strain Score from GRBAS

7

3

5

1

ra d

e

ra de

0

2

6

2

ra de

8

1

SG

3

3

st -D B

7

ra de

1

6

2

m o

2

1

4

t- D BS G

3

Roughness Score from GRBAS

Grade Score from GRBAS

4

4

2

11 0

1

6

2

7

3

8

4

9

5

10 11

ra de o m

12

6

m o

P

po

re

st -D B

po st -D B SG

SG

-D B SG

ra

ra de

de

de po m o

12

6

m o

Pr

po st -D

eDB SG

B SG ra

st -D BS G ra

de

ra de

0

FIGURE 3. Changes in GRBAS and CGI-s scores for each patient following DBS. For 6 months post-DBS data, n = 10; for 12 months post-DBS data, n = 7. Patients with overlapping scores are shown as one line. For detailed individual GRBAS and CGI-s scores, please refer to the Supplemental Material.

patients with dystonia either focused on dysarthria, did not use perceptual analysis of voice to compare longitudinal effects of DBS on voice and speech, or secondarily reported on voice improvement in the context of focal dystonias. Vidailhet et al followed 22 patients with primary generalized dystonia over 3 years and used the two subsections of

the BFMDRS scale where the clinician rates patients’ mouth movements, speech, and swallowing abilities. They reported that speech and swallowing of patients with dystonia did not significantly improve following GPi DBS.30 In a recent study, Rusz et al examined the effect of stimulation in 19 patients with dystonia at a single time point after

ARTICLE IN PRESS Mary E. Finger, et al 3.5

Mean CGI-s score

3 2.5 2 1.5

1 0.5 0 Pre-DBS (n=11)

7

Effect of Deep Brain Stimulation on Dystonia Voice & Speech

6 mo post-DBS 12 mo post-DBS (n=10) (n=7)

FIGURE 4. Long-term improvement in CGI-s scores post-DBS in patients with dystonia. Pre-DBS scores were significantly improved compared to 12 months post-surgery (P = 0.0022) and when comparing 6 months post-surgery to 12 months post-surgery (P = 0.0202). Pre-DBS scores also improved compared to 6 months post-DBS, although it was not a significant improvement (P = 2312). Error bars indicate standard errors of the least squares mean.

bilateral GPi DBS with the average time post-DBS being 3.2 (SD 1.9) years. Specific speech and voice concerns, such as an increase in dysfluent words, were reported when stimulation was on; however, they did not note if any patients had speech or voice conditions, such as laryngeal dystonia, prior to the study.18 Another report examined long-term outcomes of patients implanted with bilateral VIM for ET and adductor spasmodic dysphonia as a secondary

complaint. Of 10 patients with concurrent laryngeal dystonia, two showed no benefit and two worsened (six were not reported on).31 A few case reports have described voice improvement after bilateral GPi DBS. Risch et al examined the effects of on/off DBS stimulation in 15 patients with cervical dystonia; they describe one patient with laryngeal dystonia who benefited after bilateral DBS implantation to the GPi for primary cervical dystonia.17 Similarly, Mure et al reported voice improvement following bilateral GPi DBS in a patient with DYT6 dystonia and concurrent laryngeal dystonia.32 The present study has several limitations. Dystonia is a rare disorder, and only a small percentage of this population undergoes DBS implantation. This makes prospective studies on dystonia challenging. As a result, our study had the limitations of a retrospective design. Regardless, our study is among the larger studies of DBS in dystonia which have looked at speech and voice as outcome measures at multiple time points post-bilateral DBS in a blinded fashion. In the original cohort of 14 patients, 10 patients were analyzed at 6-month post-DBS. Six out of these 10 patients plus one additional patient were analyzed at 12-month post-DBS. The number of patients lost to follow-up is a study limitation and could introduce bias into our results. However, we minimized this potential bias by ensuring that all patients received the same evaluation and assessment, and by using inter-rater and intrarater analyses. Another limitation is the fact that audio recordings were obtained during patient visits in the neurology clinic. However, the quality of these audios was satisfactory and allowed us to gather data that support our prospective study of how voice and speech are affected post-DBS in patients with dystonia. In our patients

TABLE 3. 12-month post-DBS voice and speech outcomes, pre-DBS voice/speech diagnoses, and type of dystonia for the 7 patients with dystonia with pre-DBS and 12-month post-DBS analyses. Note: Patient numeric identifiers are consistent between Tables 1 and 2 (i.e., Patient 6 in Table 1 corresponds to Patient 6 in Table 2).

Patient

Diagnosis

1

Cervical dystonia

2

Generalized dystonia DYT1-positive dystonia Cervical dystonia

3 4 5 6 11

DYT1-positive dystonia Generalized dystonia Generalized dystonia

Pre-DBS voice and/or Speech Diagnosis

Voice Improvement in Specific GRBAS Categories*

No perceptible neurological voice condition Laryngeal dystonia and dysarthria Laryngeal dystonia and dysarthria Laryngeal dystonia and dysarthria Laryngeal dystonia Dysarthria

Roughness, strain

Laryngeal dystonia and dysarthria

Grade

Speech Improvement in CGI-s Rating#

Grade, roughness, asthenia, strain Roughness, strain

No change 56.5% improvement

Roughness

84.8% improvement

Breathiness, asthenia, strain Grade, roughness, strain

57.1% improvement 57.1% improvement Increase in dysarthria observed 70% improvement

* Improvement in each GRBAS category score was defined as 0.5+ unit decrease in GRBAS score pre-DBS compared to 12-month post-DBS. # Improvement in CGI-s score was calculated as average 12-month post-DBS CGI-s speech rating divided by pre-DBS CGI-s speech rating multiplied by one hundred.

ARTICLE IN PRESS 8 with dystonia, we are now prospectively collecting Cepstral Spectral Index of Dysphonia33 data and patient-reported voice quality of life measures pre-DBS and post-DBS implantation with the standardized, validated Voice Handicap Index − 10.34 CONCLUSIONS Our study demonstrates that GPi DBS can improve voice and speech in patients with primary dystonia up to one year following implantation. The fact that the improvement in speech/voice was not significant 6 months post-DBS suggests a delayed treatment effect, a phenomenon commonly seen in motor symptoms of dystonia following GPi DBS. However, the improvement in speech/voice was not universal; therefore, we need further studies to identify prognostic factors for speech/voice outcomes in patients who undergo GPi DBS, specifically in the placement of DBS electrodes and identification of voice and speech pathways in focal laryngeal dystonia. With further studies and fine-tuning of the techniques involved with electrode placement, DBS can potentially be expanded as a treatment option for focal laryngeal dystonia.

ACKNOWLEDGMENTS We acknowledge statistical assistance from Julia Rushing and editorial assistance from Karen Klein, both of the Wake Forest Clinical and Translational Science Institute. We also acknowledge help from Omar Saeed, MD who assisted with collecting the BFMDRS scores for the subjects included in our study, and Kevin Cunningham, CCC-SLP who assisted with the blinded ratings of the audio obtained from our subjects. SUPPLEMENTARY MATERIALS Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. jvoice.2019.02.010. REFERENCES 1. Hickok G, Poeppel D. The cortical organization of speech processing. Nature Rev Neurosci. 2007;8:393–402. 2. Purves D, Augustine G, Fitzpatrick D, et al. Neuroscience. 5th ed. Sunderland, MA: Sinauer Associates Inc.; 2012. 3. Sapir S, Ramig L, Fox C. Speech and swallowing disorders in Parkinson disease. Curr Opin Otolaryngo. 2008;16:205–210. 4. Alomar S, King NKK, Tam J, et al. Speech and language adverse effects after thalamotomy and deep brain stimulation in patients with movement disorders: a meta-analysis. Mov Disord. 2017;32:53–63. 5. Tsuboi T, Watanabe H, Tanaka Y, et al. Distinct phenotypes of speech and voice disorders in Parkinson's disease after subthalamic nucleus deep brain stimulation. J. Neurol Neurosurg Psychiatry. 2015;86:856– 864. 6. Blitzer A, Brin MF, Stewart CF. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope. 2015;125:1751–1757.

Journal of Voice, Vol. &&, No. &&, 2019 7. Olthoff A, Grosheva M, Reichel G, et al. Treatment of laryngeal dystonia with botulinum toxin. Fortschritte Der Neurologie-Psychiatrie. 2017;85:450–462. 8. Nastasi L, Mostile G, Nicoletti A, et al. Effect of botulinum toxin treatment on quality of life in patients with isolated lingual dystonia and oromandibular dystonia affecting the tongue. J Neurol. 2016;263:1702–1708. 9. Jackman M, Delrobaei M, Rahimi F, et al. Predicting improvement in writer's cramp symptoms following botulinum neurotoxin injection therapy. Tremor Other Hyperkinet Mov. 2016;6:410. 10. Ababneh OH, Cetinkaya A, Kulwin DR. Long-term efficacy and safety of botulinum toxin A injections to treat blepharospasm and hemifacial spasm. Clin Exp Ophthalmol. 2014;42:254–261. 11. Poologaindran A, Ivanishvili Z, Morrison MD, et al. The effect of unilateral thalamic deep brain stimulation on the vocal dysfunction in a patient with spasmodic dysphonia: interrogating cerebellar and pallidal neural circuits. J Neurosurg. 2018;128: 575–582. 12. Hawkshaw MJ, Sataloff RT. Deep brain stimulation for treatment of voice disorders. J Voice. 2012;26:769–771. 13. Albanese A. Deep brain stimulation for cervical dystonia. Lancet Neurol. 2014;13:856–857. 14. Pauls KAM, Br€ ockelmann PJ, Hammesfahr S, et al. Dysarthria in pallidal deep brain stimulation in dystonia depends on the posterior location of active electrode contacts: a pilot study. Parkinsonism Relat Disord. 2018;47:71–75. 15. Volkmann J, Wolters A, Kupsch A, et al. Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol. 2012;11: 1029–1038. 16. Yianni J, Bain P, Giladi N, et al. Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit. Mov Disord. 2003;18:436–442. 17. Risch V, Staiger A, Ziegler W, et al. How does GPi-DBS affect speech in primary dystonia. Brain Stim. 2015;8:875–880. 18. Rusz J, Tykalova T, Fecíkova A, et al. Dualistic effect of pallidal deep brain stimulation on motor speech disorders in dystonia. Brain Stim. 2018;11:896–903. 19. Loher TJ, Capelle H-H, Kaelin-Lang A, et al. Deep brain stimulation for dystonia: outcome at long-term follow-up. J Neurol. 2008;255:881–884. 20. Vidailhet M, Vercueil L, Houeto J-L, et al. Deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol. 2007;6:223–229. 21. Fairbanks G. Voice and Articulation Drill Book. New York: Harper & Row; 1960. 22. Burke RE, Fahn S, Marsden CD, et al. Validity and reliability of a rating scale for the primary torsion dystonias. J Neurol. 1985;35: 73–77. 23. Hirano M. Psycho-acoustic evaluation of voice. In: Arnold, Winckel, Wyke, eds. Disorders of Human Communication, 5, Clinical Examination of Voice. New YorkWien: Springer-Verlag; 1981:81–84. 24. Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration; 1976. 25. Quartarone A, Morgante F, Santangelo A, et al. Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia. J Neurol Neurosurg Psychiatry. 2008;79:985–990. 26. Weise D, Schramm A, Beck M, et al. Topographic specificity of LTDlike plasticity in non-dystonic body parts in focal dystonia. Brain Stim. 2008;1:261. 27. Volkmann J, Wolters A, Kupsch A, et al. Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol. 2012;11: 1029–1038. 28. Quartarone A, Hallett M. Emerging concepts in the physiological basis of dystonia. Mov Disord. 2013;28:958–967.

ARTICLE IN PRESS Mary E. Finger, et al

Effect of Deep Brain Stimulation on Dystonia Voice & Speech

29. Deuschl G, Herzog J, Kleiner-Fisman G, et al. Deep brain stimulation: postoperative issues. Mov Disord. 2006;21:S219– S237. 30. Vidailhet M, Vercueil L, Houeto J-L, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med. 2005;352:459–467. 31. Lyons MK, Boucher OK, Evidente VGH. Spasmodic dysphonia and thalamic deep brain stimulation: long-term observations, possible neurophysiologic mechanism and comparison of unilateral versus bilateral stimulation. J Neurosurg Neurophysiol. 2009;1: 1000106.

9

32. Mure H, Morigaki R, Koizumi H, et al. Deep brain stimulation of the thalamic ventral lateral anterior nucleus for DYT6 dystonia. Stereotact Funct Neurosurg. 2014;92:393–396. 33. Roy N, Mazin A, Awan SN. Automated acoustic analysis of task dependency in adductor spasmodic dysphonia versus muscle tension dysphonia. Laryngoscope. 2014;124:718–724. 34. Rosen CA, Lee AS, Osborne J, et al. Development and validation of the voice handicap index-10. Laryngoscope. 2004;114:1549–1556. 35. Coubes P, Roubertie A, Vayssiere N, et al. Treatment of DYT1-generalised dystonia by stimulation of the internal globus pallidus. Lancet Neurol. 2000;355:2220–2221.