Unilateral Pallidotomy As a Potential Rescue Therapy for Cervical Dystonia After Unsatisfactory Selective Peripheral Denervation

CLINICAL ARTICLE J Neurosurg Spine 33:658–666, 2020

Unilateral pallidotomy as a potential rescue therapy for cervical dystonia after unsatisfactory selective peripheral denervation

*Yijie Lai, MD,1 Peng Huang, MD,1 Chencheng Zhang, MD, PhD,1 Liangyun Hu, ME,1 Zhengdao Deng, MD,1,2 Dianyou Li, MD, PhD,1 Bomin Sun, MD, PhD,1 Wei Liu, MD, PhD,1 and Shikun Zhan, MD, PhD1

1Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and 2Research Group of Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven, Belgium

OBJECTIVE Selective peripheral denervation (SPD) is a widely accepted surgery for medically refractory cervical dystonia (CD), but when SPD has failed, the available approaches are limited. The authors investigated the results from a cohort of CD patients treated with unilateral pallidotomy after unsatisfactory SPD. METHODS The authors retrospectively analyzed patients with primary CD who underwent unilateral pallidotomy after SPD between April 2007 and August 2019. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was used to evaluate symptom severity before surgery, 7 days postsurgery, 3 months postsurgery, and at the last follow-up. TWSTRS subscores for disability and pain and the 24-item Craniocervical Dystonia Questionnaire (CDQ-24) were used to assess quality of life. RESULTS At a mean final follow-up of 5 years, TWSTRS severity subscores and total scores were significantly improved (n = 12, mean improvement 57.3% and 62.3%, respectively, p = 0.0022 and p = 0.0022), and 8 of 12 patients (66.7%) were characterized as responders (improvement ≥ 25%). Patients with rotation symptoms before pallidotomy showed greater improvement in TWSTRS severity subscores than those who did not (p = 0.049). The most common adverse event was mild upper-limb weakness (n = 3). Patients’ quality of life was also improved. CONCLUSIONS Unilateral pallidotomy seems to offer an effective and safe option for patients with CD who have other- wise experienced limited benefits from SPD. https://thejns.org/doi/abs/10.3171/2020.4.SPINE191523 KEYWORDS pallidotomy; selective peripheral denervation; cervical dystonia; functional neurosurgery

ervical dystonia (CD), also known as spasmodic Botulinum toxin (BT) is the first-line therapy for CD.4 torticollis, is the most common form of dystonia.1 However, BT therapy sometimes loses its initial efficacy It has been estimated to affect 28–183 cases per due to immunoresistance, and its prolonged use carries in- millionC people worldwide, with the incidence ranging cremental risks of side effects, such as dysphagia.4 In an from 8 to 12 cases/million person-years.2 CD is charac- international survey of 1071 patients with CD in 38 coun- terized by involuntary contraction of the neck muscles, tries, only 56% of those treated with BT were satisfied which leads to jerky head movements (turning, tilting, or with their clinical outcome.5 Selective peripheral dener- shifting) or awkward head positions. Patients experience vation (SPD) is an alternative treatment for patients who decreased quality of life and impaired socio-occupational have not responded adequately to BT therapy. The thera- functioning due not only to motor impairment, but also to peutic improvement in patients who underwent SPD has pain and social stigma.3 been reported to range from 22% to 59%, as measured by

ABBREVIATIONS AC-PC = anterior commissure–posterior commissure; BT = botulinum toxin; CD = cervical dystonia; CDQ-24 = 24-item Craniocervical Dystonia Ques- tionnaire; DBS = deep brain stimulation; GPi = globus pallidum internus; SPD = selective peripheral denervation; TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale. SUBMITTED December 19, 2019. ACCEPTED April 8, 2020. INCLUDE WHEN CITING Published online June 26, 2020; DOI: 10.3171/2020.4.SPINE191523. * Y.L. and P.H. contributed equally to this work and share first authorship.

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Unauthenticated | Downloaded 09/29/21 02:21 AM UTC Lai et al. the Toronto Western Spasmodic Torticollis Rating Scale brain atrophy (detected by MRI or CT); and relevant or- (TWSTRS).6 However, despite careful intraoperative ganic brain diseases, e.g., tumor, cerebrovascular disease, searching for small nerve branches and variations of in- or other neurological or psychiatric comorbidities (Fig. 1). nervation, clinically relevant symptoms of major concern occurred after about 29% of SPD procedures, due to either Surgical Procedure reinnervation of the denervated muscles or disease pro- The main criterion for choosing pallidotomy rather gression to muscles in the neck that were not previously 6,7 than a repeat SPD or muscle resection was electromyo- denervated. Moreover, complications may occur after gram results showing widespread activity involving neck SPD, including dysesthesia, dysphagia, and weakness of 6–9 muscles available for denervation. Stereotactic pallidoto- the corresponding muscles. my was performed contralateral to the contracting spleni- The globus pallidus is a known brain target for vari- 17 10,11 us-complexus group using the Leksell G frame under lo- ous kinds of dystonia, including CD. For patients who cal anesthesia. CT scans and 1.5-T MRI were performed, have not benefited from BT and SPD treatment, globus and the scans were fused using the Leksell SurgiPlan sys- pallidum internus (GPi) deep brain stimulation (DBS) or 12,13 tem (Electra). GPi was located 2–4 mm anterior to the ablation (pallidotomy) may serve as a rescue therapy. anterior commissure–posterior commissure (AC-PC) line While GPi DBS is a preferential treatment for refractory midpoint, 18–22 mm lateral to the AC-PC line, and 2–4 dystonia, it is more expensive than pallidotomy, and the mm below the AC-PC line. A radiofrequency electrode hardware implantations make it unacceptable for many 10,13,14 (Radionics) with a 2-mm-diameter radiofrequency probe patients. Choosing an appropriate pallidal approach and a 2-mm exposed tip was used for impedance mea- for patients in whom medical or surgical peripheral de- surement, followed by a stimulation test and creation of a nervation has failed is a crucial clinical question. How- lesion. Test stimulation was conducted through the elec- ever, evidence for the efficacy of pallidotomy for CD after 13 trode, with administration of 2 Hz and 100 Hz, respec- SPD failure is limited to 1 case report published in 2016. tively, for motor and sensory responses while the patient Moreover, although neuroablation, including pallidotomy, was awake. Corticospinal tract activation was evaluated has been used as an approach for dystonia, its effective- 11 by the patient’s subjective symptoms and objective signs ness has seldom been assessed with validated scales. of muscle contractions. A contraction response from the Also, most reports of the effectiveness of pallidotomy in corticospinal tract to > 1 V or patient symptoms of par- CD have included either too few cases or only cases with 11,15 esthesia were considered to indicate a safe level of activa- relatively short follow-ups. tion. A coagulation test was then carried out through the In this article, we report the results of a series of patients electrode at 50°C for 60 seconds to check symptoms and with CD who were treated with unilateral pallidotomy and signs. The tip of the electrode was then heated to 70°C– whose therapeutic improvement was assessed with stan- 80°C for 60 seconds. The length of the lesion was about dardized TWSTRS scoring. Also, we propose factors that 5 mm. MRI or CT was performed within 48 hours after may be predictive for the effectiveness of this method for surgery to visualize the localization of the lesion and to treating CD. identify possible complications (Fig. 2). The volumes of the lesions were calculated as the hyperintense ring seen Methods on early T1-weighted scans using the Leksell GammaPlan Patients system (Electra).18 Distances from the center of the lesion This retrospective observational study was approved by lateral to the midline, inferior to the AC-PC line, and an- the ethics committee of the Ruijin Hospital Shanghai Jiao terior to the midcommissural point were also measured. Tong University School of Medicine. Written informed The patient’s preoperative medication regimen remained consent was obtained from each patient. Between April unchanged after the surgery and until the patient achieved 2007 and August 2019, 15 patients who had complaints a satisfactory response. about unsatisfactory outcomes of SPD were treated with unilateral pallidotomy at our center. Of these patients, 2 Assessment of CD Severity and Quality of Life (13%) were lost during follow-up and 1 patient (7%) lacked Evaluations were performed regularly before surgery data records of TWSTRS severity scores before pallidot- and at 7 days and 3 months following surgery. All in- omy. The inclusion criteria for participation in this study cluded patients were contacted for long-term follow-up. were as follows: diagnosed with idiopathic CD by an ex- CD severity was assessed with the TWSTRS, which is a perienced neurologist; < 25% improvement in TWSTRS reliable and validated instrument that is widely used in severity score after SPD; data recorded by an experi- CD clinical trials.12,19,20 The TWSTRS includes both pa- enced neurologist for TWSTRS assessment total scores tient- and clinician-rated scores, with a minimum score and subscores for severity, disability, and pain at baseline of 0 and a maximum of 75. TWSTRS scores were divided (before SPD and before pallidotomy), 7 days postsurgery, into subscores for severity (range 0–35), disability (range and short-term (3 months postsurgery) and long-term (≥ 0–20), and pain (range 0–20).46,47 Patients were classified 1 year postsurgery) follow-ups; unsatisfactory response to as responders if they showed ≥ 25% improvement in the 3 sessions of BT treatment and to oral medications be- TWSTRS severity score.16 The 24-item Craniocervical fore SPD;16 normal neurological functioning other than Dystonia Questionnaire (CDQ-24) was administered be- the dystonia; and normal MRI of the brain. The exclusion fore surgery and at the 3-month and last follow-up assess- criteria were as follows: previous brain surgery; marked ments. The CDQ-24 is a tool to evaluate the severity of

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FIG. 1. Flowchart of patient screening and inclusion.

impairments in social, occupational, and psychological pare baseline and follow-up TWSTRS total scores and functioning using a global score ranging from 0 to 96.21 subscores and CDQ-24 scores. The Wilcoxon rank-sum The TWSTRS disability scale and CDQ-24 questionnaire test was used to compare percentages of improvements were not administered at 7 days postsurgery. in TWSTRS severity and total scores at the last follow-up between categorical groups, which included the following: sex (men vs women), side of pallidotomy (left vs right), Statistical Analysis baseline rotation (presence vs absence), baseline latero- Descriptive results are reported as mean ± SD. A Wil- collis (presence vs absence), baseline antero-/retrocollis coxon matched-pairs signed-rank test was used to com- (presence vs absence), and baseline head tremor (presence

FIG. 2. Postoperative MRI. Sagittal (A), coronal (B), and axial (C) T1 MR images showing the localization of a unilateral lesion in the left GPi at 3 days postsurgery.

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TABLE 1. Patient characteristics

Patient Age at Pdt CD Duration Time After Pdt LFU TWSTRS Severity Score Imp at No. (yrs)/Sex (mos) SPD (mos) Initial Oral Medication Side (yrs) Pre-SPD Baseline (Pre-Pdt) LFU (%) 1 69/F 251 230 Trihexyphenidyl LtH 4 19 22 100.0 2 63/M 23 6 Trihexyphenidyl LtH 6 21 24 20.8 3 55/M 33 8 Trihexyphenidyl, diazepam LtH 6 20 20 80.0 4 20/M 25 3 Trihexyphenidyl, clonazepam LtH 4 23 25 100.0 5 41/F 71 24 Trihexyphenidyl RtH 6 21 22 4.5 6 34/F 167 18 Trihexyphenidyl RtH 4 18 14 7.1 7 25/F 29 5 Trihexyphenidyl, clonazepam RtH 6 21 21 23.8 8 47/F 143 120 Baclofen RtH 3 27 29 65.5 9 39/F 23 8 Trihexyphenidyl, clonazepam RtH 7 28 25 100.0 10 63/M 131 22 Trihexyphenidyl, diazepam RtH 4 22 24 41.7 11 40/M 23 5 Trihexyphenidyl RtH 4 25 25 44.0 12 61/M 27 7 Baclofen RtH 4 21 21 100.0 Imp = improvement; LFU = last follow-up; LtH = left hemisphere; Pdt = pallidotomy; RtH = right hemisphere.

vs absence). Percent improvements in TWSTRS severity my treatment to the last follow-up visit was 5.0 ± 1.3 (3–7) and total scores were also correlated with continuous vari- years. Four patients received left-hemisphere pallidoto- ables via Spearman correlation analysis, including age at mies and 8 received right-hemisphere pallidotomies. The pallidotomy, age at CD onset, duration of disease, length of TWSTRS severity scores before SPD surgery ranged from follow-up, interval between SPD and pallidotomy, baseline 18 to 27, and the improvements after SPD surgery ranged TWSTRS severity subscore and total score, lesion volume, from −14% to 22% (Table 1). Before pallidotomy, the aver- and distance of lesion centers lateral to the midline, infe- age TWSTRS severity, disability, and pain subscores and rior to the AC-PC line, and anterior to the midcommis- total scores were 22.7 ± 3.7 (range 14.0–19.0), 17.2 ± 4.3 sural point. Significance was considered for a two-tailed p (range 11.0–25.0), 6.7 ± 3.9 (range 3.0–14.3), and 46.5 ± < 0.05. The Stata 14.0 software package was used. 9.4 (range 30.3–67.0), respectively. The baseline CDQ-24 score was 48.1 ± 6.9 (range 35–58), indicating serious to major impairments in social and occupational functioning. Results Ten patients (83.3%) received oral trihexyphenidyl treat- Twelve patients (6 men and 6 women) were included in ment, and all patients had previously received BT treatment the analysis (Tables 1 and 2). The average age at pallidot- before SPD. The interval between SPD and pallidotomy omy was 46.4 ± 15.9 (range 20–69) years, the age at CD was 39.0 ± 72.0 (range 3.0–243.5) months. There were no onset was 39.8 ± 14.8 (18–61) years, the duration of disease significant differences in baseline TWSTRS severity and was 6.6 ± 6.3 (2–21) years, and the length from pallidoto- total scores between men and women. The mean volume

TABLE 2. Surgical details of SPD Patient No. CD Type (TWSTRS severity score) Previous SPD (rhizotomies and ramisectomies) 1 Rt rotation (4) Rt C1–2 + rt posterior C3–6 + denervation of lt SCM 2 Rt laterocollis (3) Rt C1–2 + rt posterior C3–6 + denervation of levator scapulae and rt SCM 3 Rt rotation (3) Rt C1–2 + rt posterior C3–6 + denervation of lt SCM 4 Rt rotation (3) Rt C1–2 + rt posterior C3–6 + denervation of lt SCM 5 Lt laterocollis (1) + retrocollis (2) Lt C1–2 + partial rt C1–2 + lt posterior C3–6 + denervation of lt SCM and levator scapulae 6 Lt rotation (4) Lt C1–2 + lt posterior C3–6 + denervation of rt SCM 7 Lt rotation (3) + retrocollis (1) Lt C1–2 + partial rt C1–2 + lt posterior C3–6 + denervation of rt SCM 8 Lt rotation (4) + laterocollis (1) + retrocollis (4) Lt C1–2 + partial rt C1–2 + lt posterior C3–6 + denervation of rt SCM and levator scapulae 9 Lt rotation (4) + laterocollis (3) + retrocollis (2) Lt C1–2 + partial rt C1–2 + lt posterior C3–6 + denervation of rt SCM and levator scapulae 10 Lt rotation (4) Lt C1–2 + lt posterior C3–6 + denervation of rt SCM 11 Lt rotation (4) + retrocollis (1) Lt C1–2 + partial rt C1–2 + lt posterior C3–6 + denervation of rt SCM 12 Lt rotation (4) Lt C1–2 + lt posterior C3–6 + denervation of rt SCM SCM = sternocleidomastoid muscle.

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TABLE 3. Lesion volume and localization Patient Lesion Center* Age Vol Lateral Anterior Inferior No. Sex (yrs) Side (mm3) (mm) (mm) (mm) 1 F 69 Lt 147.7 19.2 2.5 0.8 2 M 63 Lt 93.6 19.5 0.8 0.0 3 M 55 Lt 81.6 19.7 3.6 1.0 4 M 20 Lt 98.9 18.8 3.0 0.6 5 F 41 Rt 94.1 19.3 1.7 0.0 6 F 34 Rt 82.4 18.5 3.0 0.7 7 F 25 Rt 125.9 18.1 2.5 1.0 8 F 47 Rt 85.8 18.0 2.5 0.5 9 F 39 Rt 114.4 18.5 2.7 0.7 10 M 63 Rt 102.4 19.2 2.9 0.7 11 M 40 Rt 97.4 21.0 2.0 1.2 12 M 61 Rt 90.7 19.0 1.7 1.2 * Lesion location was described as the distance from the center of the lesion lateral to the midline, inferior to the AC-PC line, and anterior to the midcommissural point.

of pallidotomy lesions was 101.8 ± 19.3 mm3. The center of the lesion was 19.1 ± 0.8 mm lateral to the midline, 0.7 ± 0.4 inferior to the AC-PC line, and 2.4 ± 0.8 anterior to the midcommissural point (Table 3). Compared to baseline scores, the mean improvements in the TWSTRS severity scores were 44.1% ± 29.8% (range 4.2%–95.0%; p = 0.0022) at 7 days postsurgery, 46.5% ± 29.6% (range 4.2%–85.0%; p = 0.0022) at 3 months postsurgery, and 57.3% ± 38.2% (range 4.5%– 100%; p = 0.0022) at the last follow-up (Table 1 and Fig. 3A). Similar improvements were seen in the TWSTRS FIG. 3. Improvements in measurement scores for disease severity and quality of life after surgery. A: Changes (bars indicate SD) in TWSTRS total scores, with 53.2% ± 25.1% (range 12.5%–85.8%; p severity scores over the follow-up period. B: Responders, nonre- = 0.0022) at 3 months and 62.3% ± 35.4% (range 10%– sponders, and patients who had relapsed (nonresponders who were 100.0%; p = 0.0022) at the last follow-up. The presurgical responders at previous follow-ups) at the time of follow-ups. C: Changes mean TWSTRS severity score of 22.7 decreased to 12.3 at in TWSTRS disability scores and CDQ-24 scores. LFU = last follow-up. 7 days postsurgery, and this improvement was sustained **p < 0.01. Figure is available in color online only across the population as a whole at all patient follow-up assessments. According to the criterion of a 25% de- crease in the TWSTRS severity score to indicate a full response, 8 of the 12 patients (66.7%) were characterized (Fig. 3C). The TWSTRS disability score improved from as responders at their last follow-up (Fig. 3B). One of the 17.2 ± 4.3 (range 11–25) at baseline to 7.7 ± 3.9 (range 4 nonresponders (25%) was an initial responder, and all 4–15) at the 3-month follow-up (p = 0.0031) and to 8.2 responders were initial responders at 7 days postsurgery. ± 4.0 (range 4–15) at the last follow-up (p = 0.0031). The We also observed significant improvements postopera- CDQ-24 total scores improved from 48.1 ± 6.9 (range 35– tively compared to baseline in the TWSTRS pain scores 58) at baseline to 28.3 ± 14.2 (range 8–50) at the 3-month (7 days postsurgery: 94.6% ± 13.3%, range 57.9%–100.0%, follow-up (p = 0.0022) and to 22.6 ± 18.5 (range 2–51) at p = 0.0022; 3 months postsurgery: 95.2% ± 11.6%, range the last follow-up (p = 0.0022). 64.9%–100.0%, p = 0.0022; last follow-up: 87.8% ± The patients tolerated the unilateral pallidotomy well. 35.5%, range –23.1% to 100.0%, p = 0.0028). One patient Three patients (patients 1, 4, and 7) developed mild up- (patient 7) experienced worsening of pain (improvements per-limb weakness (Medical Research Council muscle of –23.1%) at the last follow-up, and she was an initial re- strength ranked grade 4 on day 1 postsurgery) at the con- sponder who relapsed. Disability and quality of life were tralateral side of the lesion immediately after surgery. assessed using the TWSTRS disability scale and CDQ- At follow-up visits, muscle strength had become normal 24 questionnaire at 3 months and the last follow-up; most (grade 5) in all 3 patients. No infection, visual defect, or patients reported a significant and sustained improvement death was noted after the surgery.

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TABLE 4. Comparison of outcomes between categorical variables at the last follow-up No. of TWSTRS Severity Score TWSTRS Total Score Categorical Variable Patients Improvement (%) p Value Improvement (%) p Value Sex 0.5144 0.4151 Female 6 50.2 ± 44.4 53.6 ± 41.9 Male 6 64.4 ± 33.5 71.0 ± 28.7 Pallidotomy side 0.2996 0.2262 Lt 4 75.2 ± 37.5 82.6 ± 28.5 Rt 8 48.3 ± 37.6 52.2 ± 35.7 Rotation at baseline 0.0490* 0.0802 Yes 10 66.2 ± 35.2 69.8 ± 33.4 No 2 12.7 ± 11.5 25.2 ± 21.5 Laterocollis at baseline 0.4366 0.5451 Yes 4 47.7 ± 21.7 55.5 ± 38.9 No 8 62.1 ± 37.5 65.8 ± 35.9 Antero-/retrocollis at baseline 0.5084 0.3212 Yes 5 47.6 ± 37.1 51.1 ± 37.1 No 7 4.2 ± 40.3 70.3 ± 34.7 Head tremor at baseline 0.6836 0.5683 Yes 6 53.0 ± 35.2 57.2 ± 35.0 No 6 61.6 ± 43.9 67.5 ± 38.4 Mean values are expressed ± SD. * p < 0.05.

The presence of rotation symptoms before pallidot- verity score from 12 to 1 after pallidotomy.13 This patient omy was associated with greater improvements in the declined hardware implantation and was therefore offered TWSTRS severity score at last follow-up (p = 0.049; Table an ablative procedure. The only postoperative complica- 4). Age at pallidotomy, age at onset, duration of disease, tion was transient aggressive behavior, and no recurrence length of follow-up, interval between SPD and pallidoto- of this symptom was observed within a year postsurgery. my, baseline TWSTRS severity and total scores, and vol- The effectiveness of pallidotomy for CD has been reported ume and location of lesion were not correlated with the in several studies, while few investigators have reported the improvement of TWSTRS severity and total scores (all p > use of a standardized quantitative assessment tool, such as 0.05). Though this finding was not statistically significant, the TWSTRS scale.11 In 2004, a comprehensive review of larger lesion volumes (124.2 ± 24.4 vs 93.4 ± 10.7 mm3, p the literature on the effectiveness and safety of ablative sur- = 0.0522) were found in the 3 patients who complained of geries for CD was conducted by Loher et al.11 Amelioration mild weakness compared to lesion volumes in the patients of CD was achieved in about 50%–70% of patients in most who did not. studies. Compared to thalamotomies, pallidotomies were associated with a lower rate of postoperative side effects, Discussion such as dysarthria, dysphagia, and ataxia. However, some studies did not clearly differentiate between focal and seg- To our knowledge, this is the largest reported series to mental dystonia, while others included patients with both date of patients with primary CD treated with unilateral CD and generalized dystonia. Through a systematic search pallidotomy after unsatisfactory SPD. The results provide in PubMed and Embase, we identified 15 studies that in- evidence for the efficacy of unilateral pallidotomy and add 1 vestigated the efficacy of pallidotomy for primary dysto- value to the current guidelines for the management of CD. nia. These studies included 66 patients with primary dys- The overall improvements in TWSTRS severity and total tonia who underwent pallidotomy. At a follow-up of 3–180 scores at the last follow-up were 57.3% and 62.3%, which months, the median improvement in dystonic symptoms are comparable with results reported in previous stud- 12,13 was 63.8% (range –20.4% to 91.7%; Table S1). Complica- ies. Patients also experienced significant improvements tions were reported in about 17% of patients, which includ- in quality of life and social functioning. ed hypertonicity, pain, jaw-opening dystonia, anarthria, seizure, hemiparesis, lethargy, and weakness. Though gen- Effectiveness eral effectiveness was seen in pallidotomy, as all but 2 of The effectiveness of pallidotomy for CD after unsatis- the studies demonstrated significant improvement, poten- factory SPD was first demonstrated in a case reported by tial publication bias should be taken into consideration as Horisawa et al. of a patient who underwent an unsatisfac- most of the reports are sample-size limited. tory SPD and obtained a reduction in the TWSTRS se- An immediate effect was seen in most of our patients

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Unauthenticated | Downloaded 09/29/21 02:21 AM UTC Lai et al. after surgery, with a mean improvement of 44.1% in the of concerns regarding expense and hardware implantation, TWSTRS severity score 7 days postsurgery. Similarly, in none of the 4 nonresponders in our study accepted further 1998, Lozano et al. described a patient with generalized surgical interventions. dystonia who showed a delayed and progressive response after bilateral pallidotomy.22 At 5 days, the dystonia score Complications dropped from 75 to 52 (31% improvement), and this score In this study, the most common adverse event was mild had further improved to 16 by 3 months. However, because upper-limb weakness, which occurred in 25% of patients. incision pain may have restricted the motion of the head Compared to other studies using shorter durations of le- and neck, and brain edema may have affected the outcome, sioning, e.g., 30 seconds, our method with 60 seconds of whether this immediate effect would have been sustained 25 23,24 ablation created larger lesion volumes. Though the ef- over the long term has been argued by researchers. Re- fectiveness of the 2 lesioning durations seems comparable, cently, Horisawa et al. reported an improvement of 54.9% the rate of adverse events was higher in our study, which 1 week postoperatively in CD patients who underwent uni- may be attributed to the impact of edema on the posterior lateral pallidotomy, and this therapeutic effect was main- 25,34 25 limb of the internal capsule. Taken together with our tained at the 6-month follow-up. In our study, 1 (8.3%) finding of a nonsignificant trend indicating larger lesion initial responder had relapsed and experienced worsening volumes in patients with postoperative weakness, shorten- of pain at the last follow-up. These results suggest that the ing of the duration of lesioning may be an effective way therapeutic effects of pallidotomy, at least in some specific to reduce this adverse effect. The efficacy of unilateral forms of dystonia, could be sustained in the long run. pallidotomy is an advantage, as bilateral pallidotomy has Selection of candidates was of great importance in 8,26 a higher rate of adverse effects that can include drooling, improving the effectiveness of surgery for CD. In our worsening of speech, and cognitive impairment.35 In a study, the presence of rotation symptoms before pallidoto- survey of patients undergoing pallidotomy for Parkinson’s my was found to be correlated with greater improvements disease, the incidences of fatigue, speech disorders, drool- in the TWSTRS severity scores after pallidotomy. In a pre- ing, dysphagia, and hypersomnia were consistently higher vious study of GPi-DBS for CD, the authors found that the in the unilateral than in the bilateral pallidotomy group.36 presence of a lateral shift was negatively correlated with 27 Nevertheless, the unilateral technique also involves ther- postsurgical TWSTRS severity subscores. Also, in previ- mal coagulation of GPi, and the involvement of nearby vious studies, particularly striking benefits in patients with tal structures can result in various complications, e.g., the DYT1+ generalized dystonia were noted after either palli- 22,28 edema generated from coagulation could encroach on the dal lesions or stimulation. Unfortunately, because none optic tract and cause visual defects.37 Thus, the size of the of the patients in our study presented with lateral shift or final lesion should be carefully evaluated to minimize the had validated genotypes, we were unable to investigate the risk of complications. impact of these conditions. According to previous studies, the manifestations of antero- or retrocollis CD basically Study Limitations indicate symmetrical hemispheric abnormalities, which makes it difficult to recommend an optimal surgical side Our study has some limitations. First, this was a retro- in unilateral pallidotomy.25,29 However, some researchers spective observational study and the sample size is rather found that patients with retrocollis could also benefit from small. Large-scale prospective studies are needed to fur- a unilateral procedure.30 In our study, 5 patients (patients ther validate the results. Second, the duration of disease 5, 7, 8, 9, and 11) presented with retrocollis, and 3 of these was relatively short compared to that in previous studies. patients (patients 8, 9, and 11) became responders after Though not found in our study, in some cases initial CD evolves into generalized dystonia, which makes diagnosis pallidotomy. Though the results reported here for these 24 3 patients suggest that pallidotomy may also be useful in and assessment of treatment efficacy more difficult. Pre- treating patients with retrocollis, it should be noted that the vious reports have indicated that patients with generalized rates of overall response and improvements were lower in dystonia (especially inherited types) benefit more from GPi approaches, while patients with focal, segmental, or patients with retrocollis than in the whole patient popula- 28 tion. Furthermore, considering that the dominant dystonic secondary dystonia benefit less from these interventions. symptom in these 3 responders was rotation, the possibil- Third, in some of the patients, the interval between these ity could not be ruled out that the abnormal contraction 2 surgeries was relatively short, and the possibility could of contralateral muscles was a consequence of ipsilateral not be ruled out that the SPD surgery exerted a delayed abnormalities. In the future, prospective studies are war- treatment effect. However, the long-term outcomes of SPD ranted to determine the effectiveness of pallidotomy in were inconsistent with regard to its delayed benefits, for which some studies38,39 reported the presence of delayed subtypes of CD. 40,41 When pallidotomy has failed or lost its initial efficacy, benefits and others did not. It should be noted that, due further approaches may include repeated pallidotomy, to the debilitating nature of the disease, caution should be globus pallidus internus stimulation, subthalamic nucleus urged when making decisions in clinical practice so that stimulation, or pallidothalamic tractotomy.31–33 Interest- the patient’s health and quality of life are not compro- ingly, Waln and Jankovic found that even after previous mised by withholding appropriate treatment. GPi lesioning, DBS electrodes could be implanted into the GPi region and provide benefit to a patient with dystonia Future Directions who had prior bilateral pallidotomy.31 However, because Pallidotomy is now considered a rescue procedure when

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DBS fails or is not available.10 However, this rescue role ripheral denervation for cervical dystonia: long-term follow- of pallidotomy was likely to have been limited to histori- up. J Neurol Neurosurg Psychiatry. 2015;86(12):1307–1313. cal problems during an earlier period of DBS use, as no 7. Chung M, Han I, Chung SS, et al. Effectiveness of selective peripheral denervation in combination with pallidal deep clear evidence has shown inferiority of effectiveness in brain stimulation for the treatment of cervical dystonia. Acta pallidotomy compared to pallidal DBS. In 2008, Gross Neurochir (Wien). 2015;157(3):435–442. reported that the outcomes after bilateral GPi DBS were 8. Wang J, Li J, Han L, et al. Selective peripheral denerva- in the same range as those seen after bilateral pallidoto- tion for the treatment of spasmodic torticollis: long-term mies.14 More recently, in a case series of 14 patients, Levi follow-up results from 648 patients. Acta Neurochir (Wien). et al. compared the effects of pallidotomy and GPi DBS 2015;157(3):427–433. in patients with status dystonicus and suggested that DBS 9. Taira T, Kobayashi T, Hori T. Selective peripheral denerva- and pallidotomy are equally safe and effective therapies tion of the levator scapulae muscle for laterocollic cervical 42 dystonia. J Clin Neurosci. 2003;10(4):449–452. for drug-resistant status dystonicus. The use of pallidot- 10. Cif L, Hariz M. Seventy years with the globus pallidus: pal- omy also has obvious advantages in younger patients, as lidal surgery for movement disorders between 1947 and 2017. it means they do not need to change or charge batteries Mov Disord. 2017;32(7):972–982. Published correction in repeatedly during their lifetime.43 Also, neuroablation is Mov Disord. 2017;32(10):1498. free from hardware complications like erosion and breaks 11. Loher TJ, Pohle T, Krauss JK. Functional stereotactic sur- in leads or wires, which are common in DBS surgeries. gery for treatment of cervical dystonia: review of the expe- However, the benefits of pallidotomy have not been well rience from the lesional era. Stereotact Funct Neurosurg. understood by younger generations of neurosurgeons, who 2004;82(1):1–13. 10 12. Volkmann J, Mueller J, Deuschl G, et al. Pallidal neurostimu- may have limited experience with ablative procedures. lation in patients with medication-refractory cervical dys- With the advent of novel noninvasive techniques, includ- tonia: a randomised, sham-controlled trial. Lancet Neurol. ing MRI-guided focused ultrasound and MRI-guided laser 2014;13(9):875–884. interstitial thermal therapy, the popularity of pallidotomy 13. Horisawa S, Goto S, Takeda N, et al. Bilateral pallidotomy in treating motor symptoms in Parkinson’s disease and for cervical dystonia after failed selective peripheral denerva- other movement disorders may once again increase.44,45 tion. World Neurosurg. 2016;89:728.e1–728.e4. The results of our study provide evidence for further ap- 14. Gross RE. What happened to posteroventral pallidotomy for Parkinson’s disease and dystonia? Neurotherapeutics. plications of these novel noninvasive techniques to treat 2008;5(2):281–293. patients with medically refractory CD. 15. Cersosimo MG, Raina GB, Piedimonte F, et al. Pallidal surgery for the treatment of primary generalized dystonia: long- Conclusions term follow-up. Clin Neurol Neurosurg. 2008;110(2):145–150. 16. Misra VP, Ehler E, Zakine B, et al. Factors influencing re- This study provides evidence that unilateral pallidotomy sponse to Botulinum toxin type A in patients with idiopathic improves medically refractory primary CD after failure or cervical dystonia: results from an international observational relapse of SPD. An immediate treatment effect was found study. BMJ Open. 2012;2(3):e000881. after surgery. The complications of unilateral pallidotomy 17. Bertrand C, Molina-Negro P, Martinez SN. Combined stereo- were tolerable and had little impact on patients’ quality tactic and peripheral surgical approach for spasmodic torticollis. Appl Neurophysiol. 1978;41(1–4):122–133. of life. Patients with rotation symptoms seemed to obtain 18. Gross RE, Lombardi WJ, Lang AE, et al. Relationship of better relief of symptoms than those without. Large-scale lesion location to clinical outcome following microelec- prospective studies are needed to validate the reliable pre- trode-guided pallidotomy for Parkinson’s disease. Brain. dictors of treatment response and to optimize the selection 1999;122(Pt 3):405–416. of patients and increase the benefits of treatment. 19. Cano SJ, Hobart JC, Fitzpatrick R, et al. Patient-based outcomes of cervical dystonia: a review of rating scales. Mov Disord. 2004;19(9):1054–1059. Acknowledgments 20. Comella CL, Stebbins GT, Goetz CG, et al. Teaching tape for We thank Dr. Hongxia Li for her constructive comments and the motor section of the Toronto Western Spasmodic Torti- linguistic assistance on this manuscript. No specific funding was collis Scale. Mov Disord. 1997;12(4):570–575. provided for this study. 21. Müller J, Wissel J, Kemmler G, et al. Craniocervical dystonia questionnaire (CDQ-24): development and validation of a disease-specific quality of life instrument. J Neurol Neuro- References surg Psychiatry. 2004;75(5):749–753. 1. Balint B, Mencacci NE, Valente EM, et al. Dystonia. Nat Rev 22. Lozano AM, Kumar R, Gross RE, et al. Globus pallidus Dis Primers. 2018;4(1):25. internus pallidotomy for generalized dystonia. Mov Disord. 2. Defazio G, Jankovic J, Giel JL, Papapetropoulos S. Descrip- 1997;12(6):865–870. tive epidemiology of cervical dystonia. Tremor Other Hyper- 23. Fonoff ET, Campos WK, Mandel M, et al. Bilateral subtha- kinet Mov (N Y). 2013;3:tre-03-193-4374-2. lamic nucleus stimulation for generalized dystonia after bilat- 3. Ben-Shlomo Y, Camfield L, Warner T. What are the deter- eral pallidotomy. Mov Disord. 2012;27(12):1559–1563. minants of quality of life in people with cervical dystonia? J 24. Anca MH, Zaccai TF, Badarna S, et al. Natural history of Neurol Neurosurg Psychiatry. 2002;72(5):608–614. Oppenheim’s dystonia (DYT1) in Israel. J Child Neurol. 4. Castelão M, Marques RE, Duarte GS, et al. Botulinum toxin 2003;18(5):325–330. type A therapy for cervical dystonia. Cochrane Database 25. Horisawa S, Fukui A, Kohara K, et al. Unilateral pallidotomy Syst Rev. 2017;12:CD003633. in the treatment of cervical dystonia: a retrospective obser- 5. Comella C, Bhatia K. An international survey of patients vational study. J Neurosurg. Published online December 20, with cervical dystonia. J Neurol. 2015;262(4):837–848. 2019. doi:10.3171/2019.9.JNS191202 6. Bergenheim AT, Nordh E, Larsson E, Hariz MI. Selective pe- 26. Bertrand CM. Selective peripheral denervation for spasmodic

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torticollis: surgical technique, results, and observations in 42. Levi V, Zorzi G, Messina G, et al. Deep brain stimulation 260 cases. Surg Neurol. 1993;40(2):96–103. versus pallidotomy for status dystonicus: a single-center case 27. Witt JL, Moro E, Ash RS, et al. Predictive factors of outcome series. J Neurosurg. Published online December 20, 2019. in primary cervical dystonia following pallidal deep brain doi:10.3171/2019.10.JNS191691 stimulation. Mov Disord. 2013;28(10):1451–1455. 43. Alkhani A, Bohlega S. Unilateral pallidotomy for hemidysto- 28. Eltahawy HA, Saint-Cyr J, Giladi N, et al. Primary dystonia nia. Mov Disord. 2006;21(6):852–855. is more responsive than secondary dystonia to pallidal inter- 44. Gross RE, Stern MA. Magnetic resonance-guided stereotac- ventions: outcome after pallidotomy or pallidal deep brain tic laser pallidotomy for dystonia. Mov Disord. 2018;33(9): stimulation. Neurosurgery. 2004;54(3):613–621. 1502–1503. 29. Lee JR, Kiss ZH. Interhemispheric difference of pallidal lo- 45. Jung NY, Park CK, Kim M, et al. The efficacy and limits of cal field potential activity in cervical dystonia. J Neurol Neu- magnetic resonance-guided focused ultrasound pallidotomy rosurg Psychiatry. 2014;85(3):306–310. for Parkinson’s disease: a Phase I clinical trial. J Neurosurg. 30. Escamilla-Sevilla F, Mínguez-Castellanos A, Arjona- 2019;130(6):1853–1861. Morón V, et al. Unilateral pallidal stimulation for segmental 46. Comella CL, Stebbins GT, Goetz CG, et al. Teaching tape for cervical and truncal dystonia: which side? Mov Disord. the motor section of the Toronto Western Spasmodic Torti- 2002;17(6):1383–1385. collis Scale. Mov Disord. 1997;12(4):570–575. 31. Waln O, Jankovic J. Bilateral globus pallidus internus deep 47. Boyce MJ, Canning CG, Mahant N, et al. The Toronto West- brain stimulation after bilateral pallidotomy in a patient ern Spasmodic Torticollis Rating Scale: reliability in neurolo- with generalized early-onset primary dystonia. Mov Disord. gists and physiotherapists. Parkinsonism Relat Disord. 2013;28(8):1162–1163. 2012;18(5):635–637. 32. Novak KE, Nenonene EK, Bernstein LP, et al. Successful bilateral subthalamic nucleus stimulation for segmental dystonia after unilateral pallidotomy. Stereotact Funct Neurosurg. Disclosures 2008;86(2):80–86. The authors report no conflict of interest concerning the materi- 33. Horisawa S, Fukui A, Tanaka Y, et al. Pallidothalamic trac- als or methods used in this study or the findings specified in this totomy (Forel’s field H1-tomy) for dystonia: preliminary re- paper. sults. World Neurosurg. 2019;129:e851–e856. 34. Cohn MC, Hudgins PA, Sheppard SK, et al. Pre- and postop- Author Contributions erative MR evaluation of stereotactic pallidotomy. AJNR Am J Neuroradiol. 1998;19(6):1075–1080. Conception and design: Zhan, Lai, Li, Sun. Acquisition of data: 35. Intemann PM, Masterman D, Subramanian I, et al. Staged Lai, Huang, Hu, Deng, Liu. Analysis and interpretation of data: bilateral pallidotomy for treatment of Parkinson disease. J Zhan, Lai, Huang, Hu, Deng, Liu. Drafting the article: Lai. Neurosurg. 2001;94(3):437–444. Critically revising the article: all authors. Reviewed submitted 36. Hua Z, Guodong G, Qinchuan L, et al. Analysis of com- version of manuscript: all authors. Approved the final version of plications of radiofrequency pallidotomy. Neurosurgery. the manuscript on behalf of all authors: Zhan. Statistical analysis: 2003;52(1):89–101. Zhan, Lai, Hu. Administrative/technical/material support: Zhan, 37. Khandelwal A, Pandia MP, Lamsal R. Delayed emergence Huang, Zhang, Hu, Li, Sun, Liu. Study supervision: Zhan, Huang, from anaesthesia and bilateral mydriasis following bilateral Zhang, Li, Sun, Liu. pallidotomy. Indian J Anaesth. 2018;62(6):466–469. 38. Krauss JK, Toups EG, Jankovic J, Grossman RG. Symptom- Supplemental Information atic and functional outcome of surgical treatment of cervical Online-Only Content dystonia. J Neurol Neurosurg Psychiatry. 1997;63(5):642– Supplemental material is available with the online version of the 648. article. 39. Meyer CHA. Outcome of selective peripheral denervation for Table S1. https://thejns.org/doi/suppl/10.3171/2020.4. cervical dystonia. Stereotact Funct Neurosurg. 2001;77(1– SPINE191523. 4):44 – 47. 40. Ford B, Louis ED, Greene P, Fahn S. Outcome of selective Correspondence ramisectomy for botulinum toxin resistant torticollis. J Neu- rol Neurosurg Psychiatry. 1998;65(4):472–478. Shikun Zhan: Ruijin Hospital, Shanghai Jiao Tong University 41. Münchau A, Palmer JD, Dressler D, et al. Prospective study School of Medicine, Shanghai, China. [email protected]. of selective peripheral denervation for botulinum-toxin resistant patients with cervical dystonia. Brain. 2001;124(Pt 4):769–783.

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