Downloaded from https://academic.oup.com/neurosurgery/advance-article-abstract/doi/10.1093/neuros/nyz039/5366465 by Departm of Anaesth. Cantonal Hospital St. Gallen Switz. user on 27 March 2019 RESEARCH-HUMAN-CLINICAL TRIALS

Stereotactic Lesion in the Forel’s Field H: A Two-Years Prospective Open-Label Study on Motor and Nonmotor Symptoms, Neuropsychological Functions and Quality of Life in Parkinson Disease Fabio Godinho, MD, PhD ∗ ‡§ Michel Magnin, PhD¶ BACKGROUND: Stereotactic lesion in the Forel’s field H (campotomy) was proposed in ∗ 1963 to treat Parkinson disease (PD) symptoms. Despite its rationale, very few data on Paulo Terzian Filho, MD ‡ this approach have emerged. Additionally, no study has assessed its effects on nonmotor Paul Reis, MD symptoms, neuropsychological functions and quality of life. || Osmar Moraes, MD OBJECTIVE: To provide a prospective 2-yr assessment of motor, nonmotor, neuropsycho- Marivaldo Nascimento, MD# logical and quality of life variables after unilateral campotomy. Carlos Costa, MD∗∗ METHODS: Twelve PD patients were prospectively evaluated using the Unified Parkinson’s Maira Okada de Oliveira, Disease Rating Scale (UPDRS), the Rating Scale and the Parkinson’s disease ∗∗ quality of life questionnaire (PDQ39) before campotomy, and after 6 and 24 mo. Nonmotor, PhD ‡‡ neuropsychiatric, neuropsychological and quality of life variables were assessed. The Maria Sheila Rocha, MD, impact of PD on global health was also rated. ∗∗ PhD RESULTS: A significant reduction in contralateral rest tremor (65.7%, P < .001), rigidity (87.8%, P < .001), bradykinesia (68%, P < .001) and axial symptoms (24.2%, P < .05) in ∗Department of Functional Neurosurgery, Hospital Santa Marcelina, São Paulo, offmedication condition led to a 43.9% reduction in UPSDRS III scores 2 yr after campotomy Brazil; ‡Division of Functional Neurosur- (P < .001). Gait improved by 31.9% (P < .05) and walking time to cover 7 m was reduced by gery, Institute of Psychiatry of Hospital 43.2% (P < .05). Pain decreased by 33.4% (P < .01), while neuropsychiatric and neuropsycho- das Clínicas, University of São Paulo, < Medicine School, São Paulo, Brazil; logical functions did not change. Quality of life improved by 37.8% (P .05), in line with a §Faculdade Santa Marcelina – Medicine 46.7% reduction of disease impact on global health (P < .001). ¶ School, São Paulo, Brazil; Centre de CONCLUSION: A significant 2-yr improvement of motor symptoms, gait performance and Recherche en Neurosciences de Lyon, NeuroPain lab, INSERM U 1028, UMR pain was obtained after unilateral campotomy without significant changes to cognition. 5292 – Lyon, Rhône-Alpes, France; QualityoflifemarkedlyimprovedinparallelwithasignificantreductionofPDburdenon || Department of Neurosurgery, Hospital global health. Santa Marcelina, São Paulo, Brazil; #De- partment of Anesthesiology, Hospital KEY WORDS: neuropsychological tests, pain, Parkinson disease, quality of life, subthalamus, stereotaxic ∗∗ Santa Marcelina, São Paulo, Brazil; De- techniques, Forel’s field H partment of Neurology, Hospital Santa Marcelina, São Paulo, Brazil; ‡‡Global Neurosurgery 0:1–10, 2019 DOI:10.1093/neuros/nyz039 www.neurosurgery-online.com Brain Health Institute, University of California-San Francisco, San Francisco, California ibers connecting struc- Many recent approaches confirmed that lesions Correspondence: tures to the , extending into fiber tracts coursing in the Fabio Godinho, MD, PhD, and cerebellum have been very early vicinity of the subthalamic nucleus (STN) 592, Maestro Cardim, F Conj 1101, Bela Vista, targeted by different neurosurgical approaches and the pallidum gave better clinical results 1-3 4,5 São Paulo, Brazil – 01323-001. to control Parkinson disease (PD) symptoms. than lesions confined within these nuclei. E-mail: [email protected]

Received, May 20, 2018. ABBREVIATIONS: AC, anterior commissure; ADL, activities of daily living; DBS, ; D.im.e, Accepted, January 29, 2019. Dorsointermedius externus; FF, Forel’s Field H; L.po, Lateropolaris; PC, posterior commissure; PD, Parkinson disease; PPN, pedunculopontine tegmental nucleus; QoL, quality of life; SD, standard deviation; SEM, standard Copyright C 2019 by the errorofthemean;STN, subthalamic nucleus; V.im, Ventrointermedius; V.o.a, Ventro-oralis anterior thalamic Congress of Neurological Surgeons nucleus; V.o.p, Ventro-oralis posterior thalamic nucleus; VAS, visual analogue pain intensity scale; UDysRS, Unified Dyskinesia Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale

Supplemental digital content is available for this article at www.neurosurgery-online.com.

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In addition, when high-frequency stimulation of the STN was Clinical, Neuropsychological and Neuropsychiatric used, the most effective contacts of quadripolar electrodes were Assessments located in the rostrodorsal part of the STN, close to the zona Primary outcomes were motor symptoms and QoL at 6 mo and incerta and the Forel’s Field H (FF).6 These data emphasize 2 yr after surgery (means ± SEM). Secondary outcomes were neuropsy- that functional modulation of subthalamic fibers is an important chological, neuropsychiatric and nonmotor symptoms. Evaluations were factor to achieve a satisfactory motor improvement in PD, using performed preoperatively, 6 and 24 mo after surgery using UPDRS either lesion or electrical stimulation. and Hoehn and Yahr (H&Y) scales, the CAPSIT-PD recommended Among the subthalamic fiber tracts, the FF and its vicinity by the core assessment program for intracerebral transplantation and comprise a complex bundle of pallidofugal, cerebellothalamic the Unified Dyskinesia Rating Scale (UDysRS). We assessed pain intensity through visual analogue pain intensity scale – VAS, the and pallidomesencephalic axons.7-9 Pallidothalamic fibers project overall nonmotor symptoms (nonmotor symptoms scale), fatigue severity predominantly onto Lateropolaris (L.po), Ventro-oralis anterior (fatigue severity scale) and sleep quality (SCOPA-sleep). Neuropsy- (V.o.a) and Ventro-oralis posterior (V.o.p) thalamic nuclei, while chiatric evaluation excluded dementia and other major psychiatric cerebellar fibers terminate preferentially into the Ventrointer- disorders using the Neuropsychiatric Inventory, Scales for Outcomes medius (V.im) and Dorsointermedius externus (D.im.e.) thalamic in PD – Psychiatric Complications (SCOPA-PC) and Beck Depression nuclei (Hassler nomenclature). These thalamic nuclei project to Inventory. The neuropsychological evaluation comprised tests recom- motor, premotor and supplementary motor cortical areas.10,11 As mended by the movement disorders society. QoL was estimated through to the pallidomesencephalic fibers, they project to mesencephalic the Brazilian version of PD QoL questionnaire – PDQ-39.16 The locomotor area and are likely involved in axial motor functions.12 subjective impact of PD on global health was rated preoperatively Despite these anatomical considerations, only one surgical team and at 2 years according to a 5-point Likert scale as follows: 1 – has reported results based on the direct approach of the FF in notatall,2–slightly,3–moderately,4–very,5–extremely.All 13-15 motor scales were performed in off and onmedication conditions, while PD patients during the last 5 decades. Using stereotactic nonmotor functions were evaluated only in onmedication condition. lesions centered at the FF (campotomy), significant reductions Adverse events were collected and reported according to the Medical 14 of tremor, rigidity and bradykinesia were reported. However, Dictionary for Regulatory Activities, version 17 (MedDRA 17.0 – 2014). no study so far analyzed the possible effects of campotomy on If no spontaneous complaints have occurred, an active inquiry was nonmotor symptoms, cognitive functions and quality of life performed. (QoL) in PD patients. In this study, we performed a compre- hensive and prospective evaluation of motor and nonmotor variables in 12 PD patients after unilateral campotomy followed- Surgical Procedure up for 2 yr. We hypothesized that reduction in motor symptoms Anatomical targeting was performed by fusing a stereotactic tomog- would result in significant improvement in QoL after surgery, raphy with a nonstereotactic volumetric 1.5T Magnetic Resonance = while neuropsychological and neuropsychiatric effects would be Imaging (MRI). The FF localization was estimated as following: X 7.5 limited or absent. mm from the lateral border of the third ventricle at the anterior commissure – posterior commissure level (AC–PC); Y = 1 mm posterior to the midcommissural point; Z = 1 mm inferior to the AC–PC METHODS level.17 Microelectrode recordings were performed using a set of 2 or 3 parallel tungsten microelectrodes (microTargetingR electrodes, FHC, Patients Greenville, Massachusetts). Recordings were started at 5 mm above the We enrolled 12 out of 19 right-handed patients with advanced PD anatomical target and performed every millimeter until recording spikes in this prospective open-label clinical trial. Data from 7 patients were from STN neurons. STN cell firings were used as an internal marker, excluded as they lived far away from our center and were followed-up not only to estimate the FF position (anterior, medial and superior by local Neurologists. All patients were recruited and operated on at a to STN) but also to avoid as much as possible STN lesions. Macros- single hospital from January to July 2014. Clinical and imaging data timulation (130 Hz, 100 μs, 1 to 3 V) and neurological assessment from each subject was identified by 2 digits to assure confidentiality. began 5 mm above the target and were performed every millimeter on Exclusion criteria were major psychiatric illness, PD dementia, previous a trajectory lacking STN spikes. Therefore, campotomies were always intracranial surgery, major clinical disorders and poor clinical response performed medially to the electrophysiologically defined STN. In the to levodopa challenge (motor scores reduction in the Unified Parkinson’s superoinferior axis, the electrodes were placed 1 mm superior to the Disease Rating Scale – UPDRS III – below 30%). This clinical trial beginning of STN recordings and contralateral to the worst clinical adheres to the Standard Protocol Items: Recommendations for Interven- side. One single radiofrequency lesion was made by means of a 1.1 mm tional Trials – 2013 (SPIRIT) guidelines and was approved by the insti- diameter and 5.0 mm length exposed tip electrode. Special attention was tutional review board. All written informed consents were obtained by drawn to avoid the mammillothalamic tract, which is located slightly the first author. medial and anterior to FF. A test at 50◦C during 60 s was followed by a This study is registered in the Brazilian Clinical Trials Registry definitive lesion (75◦C, 60 s) over the trajectory yielding the best clinical (http://www.ensaiosclinicos.gov.br/rg/RBR-9rh8vr/5 Register Number: responses after macrostimulation (Cosman RFG 4 AR , Burlington, RBR-9rh8vr). Massachusetts).

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Postoperative Management axis by means of atlas. Given this consideration and in order to Patients were discharged 3 d after surgery on average. We repeated a ensure a complete covering of the FF, an eventual encroaching nonstereotactic MRI 6 mo after surgery and fused it with the surgical of the extreme ventral border of overlying thalamic nuclei V.o.a stereotactic tomography to determine the mean volume ± 1 standard and posterior (V.o.p) may have occurred, as shown in Figure 1B deviation (SD) and the corresponding mass center of the lesion. and 1C. Statistical Analysis Data were expressed as means and standard errors of the mean (SEM), except for the anatomical characteristics of the lesions (means Motor Variables, Activities of Daily Living (ADL) and and Standard Deviation – SD). They were tested for normality using Drug-Induced Complications D’Agostino & Pearson test. One-way repeated-measures Analyses of ANOVA showed a main campotomy effect on UPDRS III Variance (ANOVA) were applied on normal distributed variables, while scores both in off [F(11,2) = 46.70, P < .001] and on the Friedman test was applied on skewed distributions. Degrees of = < freedom were corrected using the G–G (Greenhouse–Geisser) ε for corre- [F(11,2) 9.53, P .01] medication states (Figure 2Aand lated measures. Tukey’s range test was used to assess significant differ- Table 2). Posthoc offstate analyses showed a 56.3% reduction at < ences between periods of analysis (preoperative, 6 mo and 24 mo). 6mo(P .0001) and a 43.9% reduction at 2 yr after surgery Subjective global impression scores about health status were compared (P < .001). In onstate, a significant improvement between preop- between preoperative and 24-mo postoperative periods using a Wilcoxon erative and 6 mo after surgery (40.7%, P < .01) was only observed matched-pairs test. Analyses were performed using the Graphpad Prism (Figure 2A). Rest tremor, rigidity and bradykinesia contralateral 6.0d software with a two-tailed P < .05 considered as significant. to campotomy had a sustained and significant improvement in offmedication condition (Figure 2Band2C; Table 2). Ipsilateral RESULTS bradykinesia, tremor and rigidity were also significantly amelio- rated after 6 mo, but returned close to preoperative levels after 2 yr Patient Characteristics (Table 2). Motor fluctuation (items 36 to 39 of the UPDRS) also The distribution of PD phenotypes, as defined by Jankovic et improved significantly in all 10 patients presenting this compli- al,18 is shown in Table 1. Ten patients had severe motor fluctua- cation [Friedman statistics = 24, P < .001], showing a 71% tions, while 7 had levodopa-induced . reduction in the first 6 mo (P < .001) which remained stable until the final assessment (Figure 2C and Table 2). Furthermore, a Mean Volume and Anatomical Localization of the significant reduction of dyskinesia (82.5%, P = .04) was obtained Campotomy at the final follow-up in the 7 patients presenting this symptom The average height (6.0 ± 2.3 mm) and diameter (3.0 ± 1.8 (Figure 2D and Table 2). mm) of the lesion corresponded to a mean volume of 30 The preoperative levodopa equivalent dosage (581.8 ± 66.76 mm3 ± 12 mm3 after 6 mo. A typical lesion is illustrated in mg/d) showed no significant reduction after surgery Figure 1A. Since the lesions were placed 1 mm above the electro- [F(11,2) = 3.20, P = .08]. Postoperatively, UPDRS-IV scores physiologically defined dorsal STN and this later varies signifi- for drug-induced complications improved significantly cantly among patients, the relationship between lesions and the [F(11,2) = 13.01, P < .01] both at 6 mo (57.9%, P < .01) and surrounding structures is difficult to show in the superoinferior at 2 yr (60.6%, P < .01; Table 2).

TABLE 1. Clinical Baseline Demographics of the Patients Treated With Unilateral Campotomy

Variables N Mean ± SEM Range

Male/Female 7/5 Age at disease onset (years) 50.6 ± 2.3 38 to 61 Age at surgery (years) 59.9 ± 2.0 51 to 71 Disease duration (years) 9.3 ± 1.5 5 to 21 Hoehn & Yahr stage 2.9 ± 0.2 2.0 to 4 Schwab and England scores 68.6 ± 5.0 49 to 86 Baseline UPDRS – total score 88.1 ± 7.0 49 to 131 Levodopa challenge test improvement (%) 56.48 ± 4.1 35 to 79 Motor fluctuations/Dyskinesias 10/7 Campotomy: right/left 5/7 PD subtype: Tremor dominant/PGID 8/4

N = number of patients; PGID = postural and gait instability disorder

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FIGURE 1. Anatomical localization of campotomies. A, typical example of a lesion (arrow) as observed in one patient after 6 mo on a Flair-MRI axial slice at the AC- PC plane. B and C, localization of the mean center mass of 12 lesions is shown on axial T2-weighted slices displaying anatomical structures from Schaltenbrand’s atlas. Its mean coordinates + /− SD are: X = 7.98 ± 1.80 mm (from the lateral border of the third ventricle), Y =−1.08 ± 1.07 mm (posterior to the midcommissural point), Z =−0.35 ± 1.90 mm (inferior to the AC–PC level). Slice B is 0.5 mm superior, while slice C is 1 mm inferior to the AC–PC plane. Most of the mean lesion volume (blue) fits tightly with the FF location (shown in C) and extended dorsally upon the Ventro-oralis anterior and Ventro-oralis posterior thalamic nuclei (V.o.a and V.o.p in B). White solid lines correspond to AC and PC positions and dashed lines to the midcommissural level. A color version is provided online.

Axial and Gait Symptoms 2yr(P < .05 – Figure 3D). Finally, the number of steps in 7 m As illustrated in Figure 3A, ANOVA showed a main showed a transient decrease after 6 mo (P < .05), although this effect of campotomy on axial symptoms in offmedication significance did not survive after 2 yr (P = .08; Table 2). condition [F(11,2) = 11.75, P = .005], while in onmedication condition, a nonsignificant trend toward a reduction was observed Nonmotor, Psychiatric and Neuropsychological [F(11,2) = 4.51, P = .06]. Post hoc analyses showed a 45.1% Evaluation reduction at 6 mo (P < .01) and a 24.2% at 2 yr after surgery Humor and cognition assessed by UPDRS part I improved (P < .05) in offmedication. UPDRS item 27 (arising from chair) significantly after surgery in onmedication state [F(11,2) = 6.49, significantly improved by 77.3% at 6 mo (P < .001) and by P = .02]. Values decreased by 44.1% at 6 mo (P < .05) and 45.5% at 2 yr (P < .01 – Figure 3B). Likewise, UPDRS item stayed at similar levels at 2 yr (Table 2). ADL, as indexed by 29 (gait) improved by 72.7% at 6 mo (P < .001) and by 31.9% UPDRS part II, also improved significantly [F(11,2) = 11.14, at2yr(P < .05 – Figure 3C). Accordingly, the walking time to P < .01] both at 6 mo (53.7%, P < .01) and 2 yr (38.3%, cover 7 m decreased by 68.6% at 6 mo (P < .001) and 43.2% at P < .05; Table 2). Concerning nonmotor symptoms, pain

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FIGURE 2. Effects of unilateral campotomy on contralateral motor symptoms: A, Significant reduction of UPDRS III scores after 6 mo and 2 yr is observed in offmedication condition, while in onmedication only a transient significant reduction occurred at 6 mo. B and C, Significant effects on all cardinal contralateral motor symptoms in offmedication condition both after 6 mo and 2 yr after surgery as well as in motor fluctuation are present. D, Dyskinesia improved significantly in 7 patients presenting this symptom after surgery. Values are expressed as means ± SEM. UDYSK = unified dyskinesia rating scale. UPDRS (Unified Parkinson Disease ∗ ∗∗ ∗∗∗ ∗∗∗∗ Rating Scale). Values = means ± SEM. ( )P< .05; ( )P< .01; ( )P< .001; ( )P< .0001. was the only symptom that improved significantly after surgery as “slightly” impaired and two patients as “moderately” impaired [F(11,2) = 5.07, P < .01] (Table, Supplemental Digital (mean = 2.0 ± 0.60; 95% CI: 1.62–2.38). A Wilcoxon test Content). VAS scores decreased by 31% at 6 mo (P < .01) and confirmed this significant effect (P < .001). remained stable until 2 yr. Among psychiatric and neuropsycho- logical evaluations, no item changed significantly after surgery, Adverse Events though a trend to improvement in the neuropsychiatric inventory Four patients presented transient somnolence, which resolved was observed (Table, Supplemental Digital Content). in 1 to 4 d. These patients were sleepy and sometimes confused, though able to obey simple commands (score 12 to 14 in the QoL and Impact of PD on Global Health Status ). Lesion volume was larger than average ANOVA revealed a main campotomy effect on QoL in 2 patients (mean volume = 62 mm3), while a transitory [F(11,2) = 6.29; P = .005] (Table 3). Posthoc analyses showed a larger edema was observed in 2 other patients immediately after 52.4% improvement after 6 mo (P < .01), which was still signif- surgery. There was a unique case disclosing contralateral foot icant after 2 yr (37.8%, P < .05). Further analyses showed signif- dystonia that gradually faded over 30 d. In this case, the lesion icant differences after 2 yr in the following PDQ-39 domains: was more lateral and inferior (X = 8.5 mm; Z = 3 mm) than mobility, activity of daily living, emotional wellbeing and bodily average, suggesting an encroachment on the STN. Two men discomfort (Table 3). Concerning the subjective impact of PD on presented with impulsive control disorders (hypersexuality) that global health status, it was considered before surgery as “moder- completely and spontaneously resolved in the 3 following months. ately” impaired by 3 patients, and “very” impaired by 9 patients Short-lasting apathy, characterized by poor emotional reaction (mean = 3.75 ± 0.45; 95% CI: 3.46–4.04). At the final follow- and reduced engagement in activities considered pleasant prior up, two patients scored their impairment as “not at all”, 8 patients to surgery was observed in 2 different patients and resolved 2 wk

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TABLE 2. UPDRS Subitems and Other Motor Variables: Baseline and Postoperative Scores (mean ± SEM) After 6 mo and 2 yr of Follow-up

UPDRS Baseline Postop 6 mo Postop 2 yr ANOVA

PART I – Humor/Cognition 3.4 ± 0.5 1.9 ± 0.6 2.0 ± 0.6 F = 6.50; P = .02 PART II – ADL 21.4 ± 2.5 9.9 ± 1.7 13.2 ± 2.5 F = 11.14; P = .007 PART III – Motor offmed 59.0 ± 4.8 25.8 ± 4.0 33.1 ± 4.4 F = 46.70; P < .001 – Motor onmed 23.3 ± 1.4 13.8 ± 1.1 19.4 ± 1.2 F = 9.54; P = .009 PART IV – Complications 7.6 ± 1.3 3.2 ± 0.7 3.0 ± 0.8 F = 13.01; P = .006 UPDRS III specific items contralateral to surgery (offmed) Rest tremor (item 20) 3.2 ± 0.2 1.5 ± 0.1 1.1 ± 0.2 F = 76.30; P < .001 Postural tremor (item 21) 2.3 ± 0.3 0.1 ± 0.1 0.2 ± 0.1 F = 34.14; P < .001 Bradykinesia (items 23 to 26) 13.1 ± 1.2 4.1 ± 0.8 4.2 ± 0.7 F = 74.24; P < .001 Rigidity (item 22) 3.3 ± 0.2 0.8 ± 0.1 0.4 ± 0.2 F = 140.7; P < .001 UPDRS specific items ipsilateral to surgery (offmed) Rest tremor (item 20) 2.9 ± 0.3 1.9 ± 0.2 3.0 ± 0.2 F = 13.98; P = .006 Postural tremor (item 21) 1.2 ± 0.4 0.3 ± 0.1 1.5 ± 0.2 F = 6.21; P = .013 Bradykinesia (items 23 to 26) 8.7 ± 1.3 6.5 ± 0.9 8.8 ± 1.2 F = 15.23; P = .005 Rigidity (item 22) 2.5 ± 1.4 1.1 ± 1.7 1.7 ± 1.3 F = 6.64; P = .011 UPDRS – axial and gait Axial offmed (items: 18, 19, 27, 29, 30) 9.1 ± 1.0 5.0 ± 0.9 6.9 ± 1.0 F = 11.75; P = .005 Axial onmed (items: 18, 19, 27, 29, 30) 5.5 ± 0.6 3.7 ± 0.4 5.2 ± 0.8 F = 4.51; P = .06 Gait offmed (item 29) 2.2 ± 0.2 0.6 ± 0.2 1.5 ± 0.3 F = 11.35; P = .005 Arising from chair offmed (item 27) 2.2 ± 0.2 0.5 ± 0.2 1.2 ± 0.2 F = 18.25; P < .001 Hoehn & Yahr 2.9 ± 0.2 2.5 ± 0.2 2.6 ± 0.2 F = 4.40; P = .054 Schwab & England ADL scale 68.6 ± 5.0 82.8 ± 4.1 80.0 ± 5.1 F = 10.22; P = .005 UDyRS (7/12 patients–onmed) 36.4 ± 18.4 9.6 ± 7.9 6.4 ± 4.4 F = 5.03; P = .048 Motor fluctuation (10/12 patients (UPDRS III items 36 to 39) 4.91 ± 0.19 1.42 ± 0.15 1.42 ± 0.15 Fr = 24; P < .001 CAPSIT (offmed) Walking time (seconds) 43.6 ± 18.9 13.7 ± 3.0 24.8 ± 10.1 F = 13.4; P = .006 Number of freezing 0.72 ± 0.4 0.45 ± 0.3 1.1 ± 0.5 F = 1.18; P = .168 Number of steps 23.1 ± 5.4 12.0 ± 0.9 17.8 ± 1.3 F = 6.01; P = .013 LED (mg/24 h) 581.8 ± 66.8 481.8 ± 65.4 572.7 ± 59 F = 3.20; P = .08

ADL = activities of daily living; LED = levodopa equivalent dose; UDyRS = Unified Dyskinesia rating scale; UPDRS = Unified Parkinson’s disease rating scale; Fr = Friedman statistics. after surgery. No hematoma, infection or permanent deficit was The rationale of this surgery is based on the interruption of reported. pallidothalamic, nigrothalamic and pallidomesencephalic fibers involved in dysfunctional processes underlying PD.2,7,11,13 In DISCUSSION addition, our campotomies extended towards the ventral-most portion of the V.o.a and V.o.p thalamic nuclei projecting to After unilateral campotomy, we demonstrated a pronounced supplementary motor area. Although limited in volume, this improvement in the contralateral motor features of PD together thalamic involvement may have contributed to motor benefits. Rigidity was the most improved symptom in accordance with with an impressive reduction of both dyskinesias and motor 2,13,14 fluctuation. Similar results are seldom described and parallel other campotomy series. Interruption of cerebellothalamic 14 fibers running in the medial and posterior aspect of FF may have those reported by Jeanmonod’s team. A benefit in gait perfor- 7,19 mance also occurred, suggesting the FF as a potential target taken part on this beneficial effect. to treat axial motor symptoms. Despite PD progression, sever- Results on motor symptoms reported herein appear to be superior to those obtained after unilateral pallidotomy20,21 and ities of ipsilateral rigidity, tremor and bradykinesia at the final 5,22 follow-up were similar to those observed before surgery. No are similar to those after Subthalamotomy. Additionally, difference of motor symptoms in onmedication condition was campotomy allows to spare the STN as much as possible, avoiding permanent postoperative motor adverse effects as observed in a observed between preoperative and 2-yr periods, but the QoL 22 improvement attests a global benefit mainly due to marked recent study. Only one patient exhibited a transient right-foot reduction on both medication-induced dyskinesias and motor dystonia which may be due to an encroachment on the dorso- fluctuation. Campotomy also reduced pain and facilitated ADL medial STN. Of notice, an improvement on motor symptoms without persistent neuropsychological or neuropsychiatric effects. in onmedication state observed at 6 mo was lost at 2 yr. A Finally, a noticeable reduction of the subjective burden of PD on similar trend was also observed in offmedication condition, likely global health was observed. reflecting PD progression.

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FIGURE 3. A, Axial symptoms significantly improved only in offcondition both at 6 mo and 2 yr after surgery. B and C, illustrate this effect in the subitem 27 (arising from chair) and 29 (gait) of the UPDRS both at 6 mo and 2 yr after surgery. D, Significant reduction in the walking time to cover 7 mo persisted up to 2 yr after ∗ ∗∗ ∗∗∗ surgery. Values = means ± SEM. ( )P< .05; ( )P< .01; ( )P< .001.

TABLE 3. ANOVA Showed a Significant Improvement on QoL After Surgery as Measured by the PDQ-39 Scale (total)

PDQ-39 Baseline Postop 6 mo Postop 2 yr ANOVA

Total 43.7 ± 4.4 20.8 ± 5.2 27.2 ± 4.5 F = 6.30; P = .005 Mobility 57.5 ± 7.9 31.1 ± 5.5 33 ± 5.9 F = 5.04; P = .012 ADL 40.5 ± 6.7 15.5 ± 4.6 20.8 ± 4.6 F = 5.97; P = .006 Emotional wellbeing 29.2 ± 4.6 12.3 ± 4.2 14.2 ± 3.8 F = 4.86; P = .014 Bodily discomfort 39.4 ± 6.3 9.1 ± 3.8 19.9 ± 3.9 F = 10.26; P < .001 Stigma 57.4 ± 11.8 31.2 ± 8.3 29.5 ± 10.3 F = 3.27; P = .066 Social support 13.6 ± 5.5 12.1 ± 8.7 4.5 ± 3.1 F = 0.72; P = .489 Cognition 36.9 ± 8.0 22.2 ± 6.1 36.4 ± 10.0 F = 1.03; P = .369 Communication 39.4 ± 6.8 23.5 ± 10.0 37.9 ± 9.1 F = 1.69; P = .215

The following domains significantly improved after 6 mo and 2 yr: mobility, ADL, emotional wellbeing and bodily discomfort. Each dimensionesfrom0to100inalinear scorerang scale, in which zero is the best and 100 the worst. Values = means ± SEM; ADL = activities of daily living.

Improvements in axial symptoms support the FF as a potential led to discrepant results,26 probably due to differential influ- target to treat these symptoms. Anatomical studies have shown ences on highly heterogeneous PPN neurons.27,28 In this respect, that pallidotegmental fibers course through the FF12,23,24 and modulation of PPN inputs by campotomy may provide a more may drive the pedunculopontine tegmental nucleus (PPN) to specific control of axial motor symptoms than stimulation of a dysfunctional state, participating to axial symptoms in PD.25 PPN neurons. Furthermore, effects on cerebellar fibers coursing Attempts to treat them by electric stimulation of PPN neurons through the medial aspect of the FF may account for balance

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improvement, leading to a faster walk despite no change in the Neurologists who are not acquainted with deep brain stimulation number of steps. (DBS) programming. This is one of the several reasons sustaining As to nonmotor symptoms, it is acknowledged that they the use of ablative therapy in movement disorders.38 Furthermore, are underlined by dysfunctional sensory, associative and limbic our results about axial effects need to be refined using more corticobasal gangliathalamic loops.29 Among them, pain was specific scales and gait laboratory methods, especially in patients the only one that improved after campotomy. Several studies with dopa-resistant symptoms. It is also important to consider using different surgical approaches have already reported such an that all patients underwent unilateral campotomy, which preclude effect,30 the origin of which remains to be clarified. The harmless us to discuss about possible benefits and safety issues of bilateral nature of campotomy on neuropsychological and neuropsychi- campotomy. Finally, the lack of tractography techniques in our atric functions suggests that campotomy features a predominant methods is another limitation, since these techniques can improve influence on sensory-motor loops, in contrast to some deleterious both stereotactic targeting and lesion localization. effects reported after subthalamotomies31 or pallidotomies.21,32 A nonsignificant trend to reduce Neuropsychiatric Inventory CONCLUSION scores (see Table, Supplemental Digital Content) was probably due to anxiety improvement. This effect also occurred after palli- Our results show that unilateral campotomy improves QoL dotomy and may be indirectly ascribed to motor improvement.33 of PD patients through its remarkable ability to control most Although transient, 2 patients presented hypersexuality and 2 of motor symptoms, including gait performance. Its impact on others apathy. We did not find a clear anatomical explanation for nonmotor symptoms were limited to a significant reduction in these effects, and suggest that transient edema over limbic parallel pain. The reduction of PD burden on general health, associated circuits could be at their origins. Transient somnolence occurred with its innocuousness on neuropsychological and neuropsy- in 4 patients and was associated with larger lesions in 2 patients chiatric functions additionally show that campotomy may be and postoperative edema in 2 others. Transient dysfunction of the worth considering in some patients requiring ablative surgery38 pallidomesencephalic fibers modulating the reticular activating as well as in candidates for a rescue procedure when DBS system could explain this adverse effect, which also occurred in fails.39 Finally, recent developments of less invasive therapies, other series.13,14 such as MRI-focused ultrasound15 and Gamma Knife (Elekta The large motor improvement led to a significant amelio- AB, Stockholm, Sweden)40 let hope in further refinements of this ration of the following QoL domains: mobility, ADL, emotional ablative technique. wellbeing and physical discomfort. No change on the subitems cognition and communication, associated with no complain Disclosures about cognitive or speech decline after surgery, support the Dr Godinho received salary grant from the International Association for the hypothesis that eventual deficits in these domains did not have Study of Pain (IASP) “IASP early career research grant program.” The authors clinical impact. This benefit on QoL was paralleled by a signif- have no personal, financial, or institutional interest in any of the drugs, materials, icant reduction of the subjective appraisal about PD burden or devices described in this article. on global health. This patient’s assessment is noteworthy since several studies reported that, in some cases, patients are unsat- isfied after surgery for movement disorders, despite a marked REFERENCES 34 motor improvement. The impact of surgical ablative inter- 1. Meyers R. Surgical interruption of the pallidofugal fibers. Its effect on the 35-37 ventions on QoL is very seldom evaluated in PD and, syndrome of paralysis agitans and technical considerations in its application. in the case of campotomy, never assessed through structured NYStJMed. 1942;42:317-325. and validated scales. Thus, benefits of campotomy on QoL are 2. Spiegel EA, Wycis HT, Szekely EG, Adams DJ, Flanagam M, Baird HW, 3rd. Campotomy in various extrapyramidal disorders. JNeurosurg. 1963;20(10):871- difficult to compare to other surgical approaches although they 884. seem to be superior to those reported after pallidotomy. For 3. Velasco F, Velasco M, Maldonado H. Identification and lesion of prelemniscal or subthalamotomy studies, short follow-up limited radiation in the surgical treatment of tremor [Spanish]. Arch Invest Med (Mex). 1976;7(1):29-42. to 12 mo impedes definitive conclusions. Finally, better scores 4. Patil AA, Hahn F, Sierra-Rodriguez J, Traverse J, Wang S. Anatomical structures might have been obtained after staged bilateral surgery. Although in the Leksell pallidotomy target. Stereotact Funct Neurosurg. 1998;70(1):32-37. Jeanmonod’s team has shown that bilateral campotomy is feasible, 5. Patel NK, Heywood P, O’Sullivan K, McCarter R, Love S, Gill SS. Unilateral the specific effect of this procedure on QoL deserves future inves- subthalamotomy in the treatment of Parkinson’s disease. Brain. 2003;126(5):1136- 1145. tigation. 6. Godinho F, Thobois S, Magnin M, et al. Subthalamic nucleus stimulation in Parkinson’s disease: anatomical and electrophysiological localization of active contacts. JNeurol. 2006;253(10):1347-1355. Limitations 7. Gallay MN, Jeanmonod D, Liu J, Morel A. Human pallidothalamic and cerebel- This study has some limitations. Only 12 out of the 19 patients lothalamic tracts: Anatomical basis for functional stereotactic neurosurgery. Brain could be followed during 2 yr, representing only 63% of the Struct Funct. 2008;212(6):443-463. 8. Ilinsky IA, Kultas-Ilinsky K. Sagittal cytoarchitectonic maps of the Macaca mulatta operated patients. Indeed, many patients in our country live far thalamus with a revised nomenclature of the motor-related nuclei validated by from movement disorders center and are followed-up by local observations on their connectivity. J Comp Neurol. 1987;262(3):331-364.

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9. Hirai T, Jones EG. A new parcellation of the human thalamus on the basis of 33. Higginson CI, Fields JA, Tröster AI. Which symptoms of anxiety diminish histochemical staining. Brain Res Rev. 1989;14(1):1-34. after surgical interventions for Parkinson disease? Neuropsychiat Neuropsychol Behav 10. Carpenter MB, Peter P. Nigrostriatal and nigrothalamic fibers in the Rhesus Neurol. 2001;14(2):117-121. monkey. JCompNeurol. 1972;144(1):93-115. 34. Agid Y, Schüpbach M, Gargiulo M, et al. Neurosurgery in Parkinson’s disease: 11. Parent A, Hazrati LN. Functional anatomy of the basal ganglia. I. The cortico- the doctor is happy, the patient less so? J Neural Transm Suppl. 2006;70:409-414. basal ganglia-thalamo-cortical loop. Brain Res Rev. 1995;20(1):91-127. 35. De Bie RM, de Haan RJ, Nijssen PC, et al. Unilateral pallidotomy in 12. Parent A, De Bellefeuille L. Organization of efferent projections from the internal Parkinson’s disease: a randomised, single-blind, multicentre trial. Lancet North Am segment of in primate as revealed by flourescence retrograde labeling Ed. 1999;354(9191):1665-1669. method. Brain Res. 1982;245(2):201-213. 36. Esselink RA, de Bie RM, de Haan RJ, et al. Unilateral pallidotomy versus 13. Magnin M, Jeanmonod D, Morel A, Siegemund M. Surgical control of the bilateral subthalamic nucleus stimulation in PD: a randomized trial. Neurology. human thalamocortical dysrhythmia. II: Pallidothalamic tractotomy in Parkinson’s 2004;62(2):201-207. disease. Thalamus Related Sys. 2001;1(1):81-89. 37. Zimmerman GJ, D’Antonio LL, Iacono RP. Health related quality of life in 14. Aufenberg C, Sarnthein J, Morel A, Rousson V, Gallay M, Jeanmonod D. A patients with Parkinson’s disease two years following posteroventral pallidotomy. revival of Spiegel’s campotomy: long term results of the stereotactic pallidothalamic Acta Neurochir. 2004;146(12):1293-1299. tractotomy against the parkinsonian thalamocortical dysrhythmia. Thalamus Relat 38. Abosch A, Gross RE. Surgical treatment of Parkinson’s disease: deep brain stimu- Sys. 2005;3(2):121-132. lation versus radiofrequency ablation. Clin Neurosurg. 2004;51:296-303. 15. Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D. First 39. Hariz MI, Hariz GM. Therapeutic stimulation versus ablation. Handb Clin experience with MR-guided focused ultrasound in the treatment of Parkinson’s Neurol. 2013;116:63-71. disease. J Ther Ultrasound. 2014;2(1):1-11. 40. Witjas T, Carron R, Krack P, et al. A prospective single-blind study of Gamma 16. Souza RG, Borges V, Silva SM, Ferraz HB. Quality of life scale in Knife thalamotomy for tremor. Neurology. 2015;85(18):1562-1568. parkinson’s disease PDQ-39 - (Brazilian Portuguese version) to assess patients with and without levodopa motor fluctuation. Arq Neuro-Psiquiatr. 2007;65(3b): 787-791. Supplemental digital content is available for this article at 17. Schaltenbrand G, Wahren W, Hassler RG, eds. Atlas for Stereotaxy of the Human www.neurosurgery-online.com. Brain, 2nd ed. Stuttgart, Germany:Thieme; 1977. 18. Jankovic J, McDermott M, Carter J, et al. Variable expression of Parkinson’s disease: A base-line analysis of the DAT ATOP cohort. Neurology. Supplemental Digital Content. Table. Nonmotor, psychiatric and neuropsycho- 1990;40(10):1529-1529. logical evaluations. Pain was the only symptom that decreased significantly after 19. Sakai ST, Inase M, Tanji J. Comparison of cerebellothalamic and pallidothalamic campotomy. Neuropsychiatric and neuropsychological functions did not change projections in the monkey (Macaca fuscata): a double anterograde labeling study. significantly. Values = means ± SEM. Abbreviations: FAB = frontal assessment JCompNeurol. 1996;368(2):215-228. battery; MMSE = Mini-Mental State Examination; WMS-R = Wechsler 20. Fine J, Duff J, Chen R, et al. Long-term follow-up of unilateral pallidotomy in Memory Scale Revised; ROCFT = Rey–Osterrieth Complex Figure test; advanced Parkinson’s Disease. NEnglJMed. 2000;342(23):1708-1714. RAVLT = Ray auditory-verbal learning test; SCOPA = ScaleforOutcomesin 21. Strutt AM, Lai EC, Jankovic J, et al. Five-year follow-up of unilateral Parkinson’s disease-Psychiatric Complications; FAS = fluency of words beginning posteroventral pallidotomy in Parkinson’s disease. Surg Neurol. 2009;71(5):551- by F, A and S. 558. 22. Alvarez L, Macias R, Pavón N, et al. Therapeutic efficacy of unilateral subthala- motomy in Parkinson’s disease: results in 89 patients followed for up to 36 months. J Neurol Neurosurg Psychiatry. 2009;80(9):979-985. 23. Hazrati LN, Parent A. Contralateral pallidothalamic and pallidotegmental COMMENT projections in primates: an anterograde and retrograde labeling study. Brain Res. 1991;567(2):212-223. n this very interesting paper the authors present 6-month and 24. Takakusaki K, Saitoh K, Harada H, Kashiwayanagi M. Role of basal I 2-year clinical outcome data from 12 PD patients who were treated ganglia-brainstem pathways in the control of motor behaviors. Neurosci Res. with unilateral campotomy contralateral to their most symptomatic side. 2004;50(2):137-151. 25. Pahapill PA, Lozano AM. The pedunculopontine nucleus and Parkinson’s disease. They report significant improvement in both off- and on-state motor Brain. 2000;123(9):1767-1783. function at 6 months, which is maintained in the off-medication state at 26. Thevathasan W, Debu B, Aziz T, et al. Movement Disorders Society PPN 2 years. They also note improved gait at both time points and significant DBS working group in collaboration with the world society for stereotactic and improvement in QOL scores as a result of improved motor function and functional neurosurgery. Pedunculopontine nucleus deep brain stimulation in decreased pain. They observed no long-term effects on neurocognitive Parkinson’s disease: a clinical review. Mov Disord. 2018;33(1):10-20. function, though four of the 12 patients suffered somnolence immedi- 27. Zrinzo L, Zrinzo LV, Massey LA, et al. Targeting of the pedunculo- pontine nucleus by an MRI-guided approach: a cadaver study. JNeuralTransm. ately after surgery and two male patients suffered transient hypersexuality. 2011;118(10):1487-1495. The authors are to be commended for their meticulous reporting of 28. Martinez-Gonzalez C, Bolam JP, Mena-Segovia J. Topographical organization of this patient series and the detail with which they describe their operative the pedunculopontine nucleus. Front Neuroanat. 2011;5:1-10. technique so that others may attempt to replicate their results. For me, the 29. Tremblay L, Worbe Y, Thobois S, Sgambato-Faure V, Féger J. Selective most significant and surprising finding is the prolonged impact on gait, dysfunction of basal ganglia subterritories: from movement to behavioral disorders. which is the most disabling and treatment-resistant motor symptom of Mov Disord. 2015;30(9):1155-1170. 30. Cury RG, Galhardoni R, Fonoff ET,et al. Sensory abnormalities and pain in advancing PD. If this finding can be replicated, unilateral campotomy Parkinson disease and its modulation by treatment of motor symptoms. Eur J Pain. would represent a significant advance in the surgical management of 2016;20(2):151-165. PD, allowing tens of thousands of additional patients to benefit from 31. Bickel S, Alvarez L, Macias R, et al. Cognitive and neuropsychiatric surgical intervention each year. One must keep in mind, however, that effects of subthalamotomy for Parkinson’s disease. Parkinsonism Relat Disord. these results are reported in an open-label fashion in a small patient 2010;16(8):535-539. cohort, a circumstance that has misled our field many times in the 32. Trépanier LL, Kumar R, Lozano AM, Lang AE, Saint-Cyr JA. Neuropsycho- logical outcome of GPi pallidotomy and GPi or STN deep brain stimulation in past. Moreover, that an axial motor symptom such as gait would be so Parkinson’s Disease. Brain Cogn. 2000;42(3):324-347. profoundly improved 2 years after a unilateral intervention contradicts

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the prior collective experience of our discipline that axial symptoms such guided Focused Ultrasound (MRgFUS) to create the lesion. Though this as head tremor or cervical dystonia require bilateral intervention in order would exclude the use of MER to localize the target, MRgFUS could be to achieve optimal effect. performed on anesthetized patients, allowing for a well-maintained blind. Consequently, though compelling, these results should be viewed with Regardless, this is a fascinating finding that deserves further exploration. some skepticism and should be tested in a more rigorous fashion before wholesale use. I think the most interesting way this might be accom- Ron L. Alterman plished would be a sham-controlled, double-blind trial employing MR- Boston, Massachusetts

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