stereotactic lesion in the forel's field h: a two-years prospective … · 2019. 3. 28. ·...

RESEARCH-HUMAN-CLINICAL TRIALS

Stereotactic Lesion in the Forel’s Field H: ATwo-Years Prospective Open-Label Study on Motorand Nonmotor Symptoms, NeuropsychologicalFunctions and Quality of Life in Parkinson Disease

Fabio Godinho, MD, PhD ∗ ‡ §

Michel Magnin, PhD¶

Paulo Terzian Filho, MD∗

Paul Reis, MD‡

Osmar Moraes, MD||

Marivaldo Nascimento, MD#

Carlos Costa, MD∗∗

Maira Okada de Oliveira,

PhD∗∗ ‡‡

Maria Sheila Rocha, MD,

PhD∗∗

∗Departmentof FunctionalNeurosurgery,Hospital Santa Marcelina, São Paulo,Brazil; ‡Division of Functional Neurosur-gery, Institute of Psychiatry of Hospitaldas Clínicas, University of São Paulo,Medicine School, São Paulo, Brazil;§Faculdade Santa Marcelina – MedicineSchool, São Paulo, Brazil; ¶Centre deRecherche en Neurosciences de Lyon,NeuroPain lab, INSERM U 1028, UMR5292 – Lyon, Rhône-Alpes, France;||Department of Neurosurgery, HospitalSanta Marcelina, São Paulo, Brazil; #De-partment of Anesthesiology, HospitalSanta Marcelina, São Paulo, Brazil; ∗∗De-partment of Neurology, Hospital SantaMarcelina, São Paulo, Brazil; ‡‡GlobalBrain Health Institute, University ofCalifornia-San Francisco, San Francisco,California

Correspondence:Fabio Godinho, MD, PhD,592, Maestro Cardim,Conj 1101, Bela Vista,São Paulo, Brazil – 01323-001.E-mail: [email protected]

Received,May 20, 2018.Accepted, January 29, 2019.

Copyright C© 2019 by theCongress of Neurological Surgeons

BACKGROUND: Stereotactic lesion in the Forel’s field H (campotomy) was proposed in1963 to treat Parkinson disease (PD) symptoms. Despite its rationale, very few data onthis approach have emerged. Additionally, no study has assessed its effects on nonmotorsymptoms, neuropsychological functions and quality of life.OBJECTIVE: To provide a prospective 2-yr assessment of motor, nonmotor, neuropsycho-logical and quality of life variables after unilateral campotomy.METHODS: Twelve PDpatientswere prospectively evaluated using theUnified Parkinson’sDisease Rating Scale (UPDRS), the Dyskinesia Rating Scale and the Parkinson’s diseasequality of life questionnaire (PDQ39) before campotomy, and after 6 and 24mo. Nonmotor,neuropsychiatric, neuropsychological and quality of life variables were assessed. Theimpact of PD on global health was also rated.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) inoffmedication condition led to a 43.9% reduction inUPSDRS III scores 2 yr after campotomy(P< .001). Gait improved by 31.9% (P< .05) and walking time to cover 7 m was reduced by43.2% (P< .05). Pain decreasedby 33.4% (P< .01), while neuropsychiatric andneuropsycho-logical functions did not change. Quality of life improved by 37.8% (P< .05), in line with a46.7% reduction of disease impact on global health (P< .001).CONCLUSION: A significant 2-yr improvement of motor symptoms, gait performance andpain was obtained after unilateral campotomy without significant changes to cognition.Quality of life markedly improved in parallel with a significant reduction of PD burden onglobal health.

KEY WORDS: neuropsychological tests, pain, Parkinson disease, quality of life, subthalamus, stereotaxictechniques, Forel’s field H

Neurosurgery 0:1–10, 2019 DOI:10.1093/neuros/nyz039 www.neurosurgery-online.com

F ibers connecting basal ganglia struc-tures to the cerebral cortex, thalamusand cerebellum have been very earlytargeted by different neurosurgical approachesto control Parkinson disease (PD) symptoms.1-3

ABBREVIATIONS: AC, anterior commissure; ADL, activities of daily living; DBS, deep brain stimulation; D.im.e,Dorsointermedius externus; FF, Forel’s Field H; L.po, Lateropolaris; PC, posterior commissure; PD, Parkinsondisease; PPN, pedunculopontine tegmental nucleus; QoL, quality of life; SD, standard deviation; SEM, standarderror of the mean; STN, subthalamic nucleus; V.im, Ventrointermedius; V.o.a, Ventro-oralis anterior thalamicnucleus;V.o.p,Ventro-oralis posterior thalamic nucleus;VAS, visual analoguepain intensity scale;UDysRS,UnifiedDyskinesia Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale

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

Many recent approaches confirmed that lesionsextending into fiber tracts coursing in thevicinity of the subthalamic nucleus (STN)and the pallidum gave better clinical resultsthan lesions confined within these nuclei.4,5

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GODINHO ET AL

In addition, when high-frequency stimulation of the STN wasused, the most effective contacts of quadripolar electrodes werelocated in the rostrodorsal part of the STN, close to the zonaincerta and the Forel’s Field H (FF).6 These data emphasizethat functional modulation of subthalamic fibers is an importantfactor to achieve a satisfactory motor improvement in PD, usingeither lesion or electrical stimulation.Among the subthalamic fiber tracts, the FF and its vicinity

comprise a complex bundle of pallidofugal, cerebellothalamicand pallidomesencephalic axons.7-9 Pallidothalamic fibers projectpredominantly onto Lateropolaris (L.po), Ventro-oralis anterior(V.o.a) and Ventro-oralis posterior (V.o.p) thalamic nuclei, whilecerebellar fibers terminate preferentially into the Ventrointer-medius (V.im) andDorsointermedius externus (D.im.e.) thalamicnuclei (Hassler nomenclature). These thalamic nuclei project tomotor, premotor and supplementary motor cortical areas.10,11 Asto the pallidomesencephalic fibers, they project to mesencephaliclocomotor area and are likely involved in axial motor functions.12Despite these anatomical considerations, only one surgical teamhas reported results based on the direct approach of the FF inPD patients during the last 5 decades.13-15 Using stereotacticlesions centered at the FF (campotomy), significant reductionsof tremor, rigidity and bradykinesia were reported.14 However,no study so far analyzed the possible effects of campotomy onnonmotor symptoms, cognitive functions and quality of life(QoL) in PD patients. In this study, we performed a compre-hensive and prospective evaluation of motor and nonmotorvariables in 12 PD patients after unilateral campotomy followed-up for 2 yr. We hypothesized that reduction in motor symptomswould result in significant improvement in QoL after surgery,while neuropsychological and neuropsychiatric effects would belimited or absent.

METHODS

PatientsWe enrolled 12 out of 19 right-handed patients with advanced PD

in this prospective open-label clinical trial. Data from 7 patients wereexcluded as they lived far away from our center and were followed-upby local Neurologists. All patients were recruited and operated on at asingle hospital from January to July 2014. Clinical and imaging datafrom each subject was identified by 2 digits to assure confidentiality.Exclusion criteria were major psychiatric illness, PD dementia, previousintracranial surgery, major clinical disorders and poor clinical responseto levodopa challenge (motor scores reduction in the Unified Parkinson’sDisease Rating Scale – UPDRS III – below 30%). This clinical trialadheres to the Standard Protocol Items: Recommendations for Interven-tional Trials – 2013 (SPIRIT) guidelines and was approved by the insti-tutional review board. All written informed consents were obtained bythe first author.

This study is registered in the Brazilian Clinical Trials Registry(http://www.ensaiosclinicos.gov.br/rg/RBR-9rh8vr/5 Register Number:RBR-9rh8vr).

Clinical, Neuropsychological and NeuropsychiatricAssessments

Primary outcomes were motor symptoms and QoL at 6 mo and2 yr after surgery (means ± SEM). Secondary outcomes were neuropsy-chological, neuropsychiatric and nonmotor symptoms. Evaluations wereperformed preoperatively, 6 and 24 mo after surgery using UPDRSand Hoehn and Yahr (H&Y) scales, the CAPSIT-PD recommendedby the core assessment program for intracerebral transplantation andthe Unified Dyskinesia Rating Scale (UDysRS). We assessed painintensity through visual analogue pain intensity scale – VAS, theoverall nonmotor symptoms (nonmotor symptoms scale), fatigue severity(fatigue severity scale) and sleep quality (SCOPA-sleep). Neuropsy-chiatric evaluation excluded dementia and other major psychiatricdisorders using the Neuropsychiatric Inventory, Scales for Outcomesin PD – Psychiatric Complications (SCOPA-PC) and Beck DepressionInventory. The neuropsychological evaluation comprised tests recom-mended by the movement disorders society. QoL was estimated throughthe Brazilian version of PD QoL questionnaire – PDQ-39.16 Thesubjective impact of PD on global health was rated preoperativelyand at 2 years according to a 5-point Likert scale as follows: 1 –not at all, 2 – slightly, 3 – moderately, 4 – very, 5 – extremely. Allmotor scales were performed in off and onmedication conditions, whilenonmotor functions were evaluated only in onmedication condition.Adverse events were collected and reported according to the MedicalDictionary for Regulatory Activities, version 17 (MedDRA 17.0 – 2014).If no spontaneous complaints have occurred, an active inquiry wasperformed.

Surgical ProcedureAnatomical targeting was performed by fusing a stereotactic tomog-

raphy with a nonstereotactic volumetric 1.5T Magnetic ResonanceImaging (MRI). The FF localization was estimated as following: X = 7.5mm from the lateral border of the third ventricle at the anteriorcommissure – posterior commissure level (AC–PC); Y= 1 mm posteriorto the midcommissural point; Z = 1 mm inferior to the AC–PClevel.17 Microelectrode recordings were performed using a set of 2 or3 parallel tungsten microelectrodes (microTargeting R© electrodes, FHC,Greenville, Massachusetts). Recordings were started at 5 mm above theanatomical target and performed every millimeter until recording spikesfrom STN neurons. STN cell firings were used as an internal marker,not only to estimate the FF position (anterior, medial and superiorto STN) but also to avoid as much as possible STN lesions. Macros-timulation (130 Hz, 100 μs, 1 to 3 V) and neurological assessmentbegan 5 mm above the target and were performed every millimeter ona trajectory lacking STN spikes. Therefore, campotomies were alwaysperformed medially to the electrophysiologically defined STN. In thesuperoinferior axis, the electrodes were placed 1 mm superior to thebeginning of STN recordings and contralateral to the worst clinicalside. One single radiofrequency lesion was made by means of a 1.1 mmdiameter and 5.0 mm length exposed tip electrode. Special attention wasdrawn to avoid the mammillothalamic tract, which is located slightlymedial and anterior to FF. A test at 50◦C during 60 s was followed by adefinitive lesion (75◦C, 60 s) over the trajectory yielding the best clinicalresponses after macrostimulation (Cosman RFG 4 A R©, Burlington,Massachusetts).

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CAMPOTOMY IN ADVANCED PARKINSON DISEASE

Postoperative ManagementPatients were discharged 3 d after surgery on average. We repeated a

nonstereotactic MRI 6 mo after surgery and fused it with the surgicalstereotactic tomography to determine the mean volume ± 1 standarddeviation (SD) and the corresponding mass center of the lesion.

Statistical AnalysisData were expressed as means and standard errors of the mean

(SEM), except for the anatomical characteristics of the lesions (meansand Standard Deviation – SD). They were tested for normality usingD’Agostino & Pearson test. One-way repeated-measures Analyses ofVariance (ANOVA) were applied on normal distributed variables, whilethe Friedman test was applied on skewed distributions. Degrees offreedomwere corrected using theG–G (Greenhouse–Geisser) ε for corre-lated measures. Tukey’s range test was used to assess significant differ-ences between periods of analysis (preoperative, 6 mo and 24 mo).Subjective global impression scores about health status were comparedbetween preoperative and 24-mo postoperative periods using aWilcoxonmatched-pairs test. Analyses were performed using the Graphpad Prism6.0d software with a two-tailed P < .05 considered as significant.

RESULTS

Patient CharacteristicsThe distribution of PD phenotypes, as defined by Jankovic et

al,18 is shown in Table 1. Ten patients had severe motor fluctua-tions, while 7 had levodopa-induced dyskinesias.

Mean Volume and Anatomical Localization of theCampotomyThe average height (6.0 ± 2.3 mm) and diameter (3.0 ± 1.8

mm) of the lesion corresponded to a mean volume of 30mm3 ± 12 mm3 after 6 mo. A typical lesion is illustrated inFigure 1A. Since the lesions were placed 1 mm above the electro-physiologically defined dorsal STN and this later varies signifi-cantly among patients, the relationship between lesions and thesurrounding structures is difficult to show in the superoinferior

axis by means of atlas. Given this consideration and in order toensure a complete covering of the FF, an eventual encroachingof the extreme ventral border of overlying thalamic nuclei V.o.aand posterior (V.o.p) may have occurred, as shown in Figure 1Band 1C.

Motor Variables, Activities of Daily Living (ADL) andDrug-Induced ComplicationsANOVA showed a main campotomy effect on UPDRS III

scores both in off [F(11,2) = 46.70, P < .001] and on[F(11,2) = 9.53, P < .01] medication states (Figure 2A andTable 2). Posthoc offstate analyses showed a 56.3% reduction at6 mo (P < .0001) and a 43.9% reduction at 2 yr after surgery(P< .001). In onstate, a significant improvement between preop-erative and 6mo after surgery (40.7%, P< .01) was only observed(Figure 2A). Rest tremor, rigidity and bradykinesia contralateralto campotomy had a sustained and significant improvement inoffmedication condition (Figure 2B and 2C; Table 2). Ipsilateralbradykinesia, tremor and rigidity were also significantly amelio-rated after 6mo, but returned close to preoperative levels after 2 yr(Table 2). Motor fluctuation (items 36 to 39 of the UPDRS) alsoimproved significantly in all 10 patients presenting this compli-cation [Friedman statistics = 24, P < .001], showing a 71%reduction in the first 6 mo (P < .001) which remained stableuntil the final assessment (Figure 2C and Table 2). Furthermore, asignificant reduction of dyskinesia (82.5%, P= .04) was obtainedat the final follow-up in the 7 patients presenting this symptom(Figure 2D and Table 2).The preoperative levodopa equivalent dosage (581.8 ± 66.76

mg/d) showed no significant reduction after surgery[F(11,2) = 3.20, P = .08]. Postoperatively, UPDRS-IV scoresfor drug-induced complications improved significantly[F(11,2) = 13.01, P < .01] both at 6 mo (57.9%, P < .01) andat 2 yr (60.6%, P < .01; Table 2).

TABLE 1. Clinical Baseline Demographics of the Patients TreatedWith Unilateral Campotomy

Variables N Mean± SEM RangeMale/Female 7/5Age at disease onset (years) 50.6 ± 2.3 38 to 61Age at surgery (years) 59.9 ± 2.0 51 to 71Disease duration (years) 9.3 ± 1.5 5 to 21Hoehn & Yahr stage 2.9 ± 0.2 2.0 to 4Schwab and England scores 68.6 ± 5.0 49 to 86Baseline UPDRS – total score 88.1 ± 7.0 49 to 131Levodopa challenge test improvement (%) 56.48 ± 4.1 35 to 79Motor fluctuations/Dyskinesias 10/7Campotomy: right/left 5/7PD 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 midcommissuralpoint), 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 lesionvolume (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.aand 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 SymptomsAs illustrated in Figure 3A, ANOVA showed a main

effect of campotomy on axial symptoms in offmedicationcondition [F(11,2) = 11.75, P = .005], while in onmedicationcondition, a nonsignificant trend toward a reductionwas observed[F(11,2) = 4.51, P = .06]. Post hoc analyses showed a 45.1%reduction at 6 mo (P < .01) and a 24.2% at 2 yr after surgery(P < .05) in offmedication. UPDRS item 27 (arising from chair)significantly improved by 77.3% at 6 mo (P < .001) and by45.5% at 2 yr (P < .01 – Figure 3B). Likewise, UPDRS item29 (gait) improved by 72.7% at 6 mo (P < .001) and by 31.9%at 2 yr (P < .05 – Figure 3C). Accordingly, the walking time tocover 7 m decreased by 68.6% at 6 mo (P < .001) and 43.2% at

2 yr (P < .05 – Figure 3D). Finally, the number of steps in 7 mshowed a transient decrease after 6 mo (P < .05), although thissignificance did not survive after 2 yr (P = .08; Table 2).

Nonmotor, Psychiatric and NeuropsychologicalEvaluationHumor and cognition assessed by UPDRS part I improved

significantly after surgery in onmedication state [F(11,2) = 6.49,P = .02]. Values decreased by 44.1% at 6 mo (P < .05) andstayed at similar levels at 2 yr (Table 2). ADL, as indexed byUPDRS part II, also improved significantly [F(11,2) = 11.14,P < .01] both at 6 mo (53.7%, P < .01) and 2 yr (38.3%,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 inoffmedication condition, while in onmedication only a transient significant reduction occurred at 6 mo. B and C, Significant effects on all cardinal contralateral motorsymptoms 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 7patients presenting this symptom after surgery. Values are expressed as means ± SEM. UDYSK = unified dyskinesia rating scale. UPDRS (Unified Parkinson DiseaseRating Scale). Values = means ± SEM. (∗) P < .05; (∗∗) P < .01; (∗∗∗) P < .001; (∗∗∗∗) P < .0001.

was the only symptom that improved significantly after surgery[F(11,2) = 5.07, P < .01] (Table, Supplemental DigitalContent). VAS scores decreased by 31% at 6 mo (P < .01) andremained stable until 2 yr. Among psychiatric and neuropsycho-logical evaluations, no item changed significantly after surgery,though a trend to improvement in the neuropsychiatric inventorywas observed (Table, Supplemental Digital Content).

QoL and Impact of PD on Global Health StatusANOVA revealed a main campotomy effect on QoL

[F(11,2) = 6.29; P = .005] (Table 3). Posthoc analyses showed a52.4% improvement after 6 mo (P < .01), which was still signif-icant after 2 yr (37.8%, P < .05). Further analyses showed signif-icant differences after 2 yr in the following PDQ-39 domains:mobility, activity of daily living, emotional wellbeing and bodilydiscomfort (Table 3). Concerning the subjective impact of PD onglobal health status, it was considered before surgery as “moder-ately” impaired by 3 patients, and “very” impaired by 9 patients(mean = 3.75 ± 0.45; 95% CI: 3.46–4.04). At the final follow-up, two patients scored their impairment as “not at all”, 8 patients

as “slightly” impaired and two patients as “moderately” impaired(mean = 2.0 ± 0.60; 95% CI: 1.62–2.38). A Wilcoxon testconfirmed this significant effect (P < .001).

Adverse EventsFour patients presented transient somnolence, which resolved

in 1 to 4 d. These patients were sleepy and sometimes confused,though able to obey simple commands (score 12 to 14 in theGlasgow Coma Scale). Lesion volume was larger than averagein 2 patients (mean volume = 62 mm3), while a transitorylarger edema was observed in 2 other patients immediately aftersurgery. There was a unique case disclosing contralateral footdystonia that gradually faded over 30 d. In this case, the lesionwas more lateral and inferior (X = 8.5 mm; Z = 3 mm) thanaverage, suggesting an encroachment on the STN. Two menpresented with impulsive control disorders (hypersexuality) thatcompletely and spontaneously resolved in the 3 followingmonths.Short-lasting apathy, characterized by poor emotional reactionand reduced engagement in activities considered pleasant priorto 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 6mo and 2 yr of Follow-upUPDRS Baseline Postop 6mo Postop 2 yr ANOVA

PART I – Humor/Cognition 3.4 ± 0.5 1.9 ± 0.6 2.0 ± 0.6 F = 6.50; P = .02PART II – ADL 21.4 ± 2.5 9.9 ± 1.7 13.2 ± 2.5 F = 11.14; P = .007PART 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 = .009PART IV – Complications 7.6 ± 1.3 3.2 ± 0.7 3.0 ± 0.8 F = 13.01; P = .006UPDRS 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 < .001Postural tremor (item 21) 2.3 ± 0.3 0.1 ± 0.1 0.2 ± 0.1 F = 34.14; P < .001Bradykinesia (items 23 to 26) 13.1 ± 1.2 4.1 ± 0.8 4.2 ± 0.7 F = 74.24; P < .001Rigidity (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 = .006Postural tremor (item 21) 1.2 ± 0.4 0.3 ± 0.1 1.5 ± 0.2 F = 6.21; P = .013Bradykinesia (items 23 to 26) 8.7 ± 1.3 6.5 ± 0.9 8.8 ± 1.2 F = 15.23; P = .005Rigidity (item 22) 2.5 ± 1.4 1.1 ± 1.7 1.7 ± 1.3 F = 6.64; P = .011

UPDRS – axial and gaitAxial offmed (items: 18, 19, 27, 29, 30) 9.1 ± 1.0 5.0 ± 0.9 6.9 ± 1.0 F = 11.75; P = .005Axial onmed (items: 18, 19, 27, 29, 30) 5.5 ± 0.6 3.7 ± 0.4 5.2 ± 0.8 F = 4.51; P = .06Gait offmed (item 29) 2.2 ± 0.2 0.6 ± 0.2 1.5 ± 0.3 F = 11.35; P = .005Arising 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 = .054Schwab & England ADL scale 68.6 ± 5.0 82.8 ± 4.1 80.0 ± 5.1 F = 10.22; P = .005UDyRS (7/12 patients–onmed) 36.4 ± 18.4 9.6 ± 7.9 6.4 ± 4.4 F = 5.03; P = .048Motor 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 < .001CAPSIT (offmed) Walking time (seconds) 43.6 ± 18.9 13.7 ± 3.0 24.8 ± 10.1 F = 13.4; P = .006Number of freezing 0.72 ± 0.4 0.45 ± 0.3 1.1 ± 0.5 F = 1.18; P = .168Number of steps 23.1 ± 5.4 12.0 ± 0.9 17.8 ± 1.3 F = 6.01; P = .013LED (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 wasreported.

DISCUSSION

After unilateral campotomy, we demonstrated a pronouncedimprovement in the contralateral motor features of PD togetherwith an impressive reduction of both dyskinesias and motorfluctuation. Similar results are seldom described and parallelthose reported by Jeanmonod’s team.14 A benefit in gait perfor-mance also occurred, suggesting the FF as a potential targetto treat axial motor symptoms. Despite PD progression, sever-ities of ipsilateral rigidity, tremor and bradykinesia at the finalfollow-up were similar to those observed before surgery. Nodifference of motor symptoms in onmedication condition wasobserved between preoperative and 2-yr periods, but the QoLimprovement attests a global benefit mainly due to markedreduction on both medication-induced dyskinesias and motorfluctuation. Campotomy also reduced pain and facilitated ADLwithout persistent neuropsychological or neuropsychiatric effects.Finally, a noticeable reduction of the subjective burden of PD onglobal health was observed.

The rationale of this surgery is based on the interruption ofpallidothalamic, nigrothalamic and pallidomesencephalic fibersinvolved in dysfunctional processes underlying PD.2,7,11,13 Inaddition, our campotomies extended towards the ventral-mostportion of the V.o.a and V.o.p thalamic nuclei projecting tosupplementary motor area. Although limited in volume, thisthalamic involvement may have contributed to motor benefits.Rigidity was the most improved symptom in accordance withother campotomy series.2,13,14 Interruption of cerebellothalamicfibers running in the medial and posterior aspect of FF may havetaken part on this beneficial effect.7,19Results on motor symptoms reported herein appear to be

superior to those obtained after unilateral pallidotomy20,21 andare similar to those after Subthalamotomy.5,22 Additionally,campotomy allows to spare the STN asmuch as possible, avoidingpermanent postoperative motor adverse effects as observed in arecent study.22 Only one patient exhibited a transient right-footdystonia which may be due to an encroachment on the dorso-medial STN. Of notice, an improvement on motor symptomsin onmedication state observed at 6 mo was lost at 2 yr. Asimilar trend was also observed in offmedication condition, likelyreflecting 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 (arisingfrom 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 aftersurgery. 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 6mo Postop 2 yr ANOVA

Total 43.7 ± 4.4 20.8 ± 5.2 27.2 ± 4.5 F = 6.30; P = .005Mobility 57.5 ± 7.9 31.1 ± 5.5 33 ± 5.9 F = 5.04; P = .012ADL 40.5 ± 6.7 15.5 ± 4.6 20.8 ± 4.6 F = 5.97; P = .006Emotional wellbeing 29.2 ± 4.6 12.3 ± 4.2 14.2 ± 3.8 F = 4.86; P = .014Bodily discomfort 39.4 ± 6.3 9.1 ± 3.8 19.9 ± 3.9 F = 10.26; P < .001Stigma 57.4 ± 11.8 31.2 ± 8.3 29.5 ± 10.3 F = 3.27; P = .066Social support 13.6 ± 5.5 12.1 ± 8.7 4.5 ± 3.1 F = 0.72; P = .489Cognition 36.9 ± 8.0 22.2 ± 6.1 36.4 ± 10.0 F = 1.03; P = .369Communication 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 dimension score ranges from 0 to 100 in a linearscale, 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 potentialtarget to treat these symptoms. Anatomical studies have shownthat pallidotegmental fibers course through the FF12,23,24 andmay drive the pedunculopontine tegmental nucleus (PPN) toa dysfunctional state, participating to axial symptoms in PD.25Attempts to treat them by electric stimulation of PPN neurons

led to discrepant results,26 probably due to differential influ-ences on highly heterogeneous PPN neurons.27,28 In this respect,modulation of PPN inputs by campotomy may provide a morespecific control of axial motor symptoms than stimulation ofPPN neurons. Furthermore, effects on cerebellar fibers coursingthrough the medial aspect of the FF may account for balance


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improvement, leading to a faster walk despite no change in thenumber of steps.As to nonmotor symptoms, it is acknowledged that they

are underlined by dysfunctional sensory, associative and limbiccorticobasal gangliathalamic loops.29 Among them, pain wasthe only one that improved after campotomy. Several studiesusing different surgical approaches have already reported such aneffect,30 the origin of which remains to be clarified. The harmlessnature of campotomy on neuropsychological and neuropsychi-atric functions suggests that campotomy features a predominantinfluence on sensory-motor loops, in contrast to some deleteriouseffects reported after subthalamotomies31 or pallidotomies.21,32A nonsignificant trend to reduce Neuropsychiatric Inventory

scores (see Table, Supplemental Digital Content) was probablydue to anxiety improvement. This effect also occurred after palli-dotomy and may be indirectly ascribed to motor improvement.33Although transient, 2 patients presented hypersexuality and 2others apathy. We did not find a clear anatomical explanation forthese effects, and suggest that transient edema over limbic parallelcircuits could be at their origins. Transient somnolence occurredin 4 patients and was associated with larger lesions in 2 patientsand postoperative edema in 2 others. Transient dysfunction of thepallidomesencephalic fibers modulating the reticular activatingsystem could explain this adverse effect, which also occurred inother series.13,14

The large motor improvement led to a significant amelio-ration of the following QoL domains: mobility, ADL, emotionalwellbeing and physical discomfort. No change on the subitemscognition and communication, associated with no complainabout cognitive or speech decline after surgery, support thehypothesis that eventual deficits in these domains did not haveclinical impact. This benefit on QoL was paralleled by a signif-icant reduction of the subjective appraisal about PD burdenon global health. This patient’s assessment is noteworthy sinceseveral studies reported that, in some cases, patients are unsat-isfied after surgery for movement disorders, despite a markedmotor improvement.34 The impact of surgical ablative inter-ventions on QoL is very seldom evaluated in PD35-37 and,in the case of campotomy, never assessed through structuredand validated scales. Thus, benefits of campotomy on QoL aredifficult to compare to other surgical approaches although theyseem to be superior to those reported after pallidotomy. Forthalamotomy or subthalamotomy studies, short follow-up limitedto 12 mo impedes definitive conclusions. Finally, better scoresmight have been obtained after staged bilateral surgery. AlthoughJeanmonod’s team has shown that bilateral campotomy is feasible,the specific effect of this procedure on QoL deserves future inves-tigation.

LimitationsThis study has some limitations. Only 12 out of the 19 patients

could be followed during 2 yr, representing only 63% of theoperated patients. Indeed, many patients in our country live farfrom movement disorders center and are followed-up by local

Neurologists who are not acquainted with deep brain stimulation(DBS) programming. This is one of the several reasons sustainingthe use of ablative therapy inmovement disorders.38 Furthermore,our results about axial effects need to be refined using morespecific scales and gait laboratory methods, especially in patientswith dopa-resistant symptoms. It is also important to considerthat all patients underwent unilateral campotomy, which precludeus to discuss about possible benefits and safety issues of bilateralcampotomy. Finally, the lack of tractography techniques in ourmethods is another limitation, since these techniques can improveboth stereotactic targeting and lesion localization.

CONCLUSION

Our results show that unilateral campotomy improves QoLof PD patients through its remarkable ability to control mostof motor symptoms, including gait performance. Its impact onnonmotor symptoms were limited to a significant reduction inpain. The reduction of PD burden on general health, associatedwith its innocuousness on neuropsychological and neuropsy-chiatric functions additionally show that campotomy may beworth considering in some patients requiring ablative surgery38as well as in candidates for a rescue procedure when DBSfails.39 Finally, recent developments of less invasive therapies,such as MRI-focused ultrasound15 and Gamma Knife (ElektaAB, Stockholm, Sweden)40 let hope in further refinements of thisablative technique.

DisclosuresDr Godinho received salary grant from the International Association for the

Study of Pain (IASP) “IASP early career research grant program.” The authorshave no personal, financial, or institutional interest in any of the drugs, materials,or devices described in this article.

REFERENCES1. Meyers R. Surgical interruption of the pallidofugal fibers. Its effect on the

syndrome of paralysis agitans and technical considerations in its application.N Y St J Med. 1942;42:317-325.

2. Spiegel EA, Wycis HT, Szekely EG, Adams DJ, Flanagam M, Baird HW, 3rd.Campotomy in various extrapyramidal disorders. J Neurosurg. 1963;20(10):871-884.

3. Velasco F, Velasco M, Maldonado H. Identification and lesion of prelemniscalradiation in the surgical treatment of tremor [Spanish]. Arch Invest Med (Mex).1976;7(1):29-42.

4. Patil AA, Hahn F, Sierra-Rodriguez J, Traverse J, Wang S. Anatomical structuresin the Leksell pallidotomy target. Stereotact Funct Neurosurg. 1998;70(1):32-37.

5. Patel NK, Heywood P, O’Sullivan K, McCarter R, Love S, Gill SS. Unilateralsubthalamotomy in the treatment of Parkinson’s disease. Brain. 2003;126(5):1136-1145.

6. Godinho F, Thobois S, Magnin M, et al. Subthalamic nucleus stimulationin Parkinson’s disease: anatomical and electrophysiological localization of activecontacts. J Neurol. 2006;253(10):1347-1355.

7. Gallay MN, Jeanmonod D, Liu J, Morel A. Human pallidothalamic and cerebel-lothalamic tracts: Anatomical basis for functional stereotactic neurosurgery. BrainStruct Funct. 2008;212(6):443-463.

8. Ilinsky IA, Kultas-Ilinsky K. Sagittal cytoarchitectonicmaps of theMacacamulattathalamus with a revised nomenclature of the motor-related nuclei validated byobservations on their connectivity. J Comp Neurol. 1987;262(3):331-364.


Dow






arch 2019


9. Hirai T, Jones EG. A new parcellation of the human thalamus on the basis ofhistochemical staining. Brain Res Rev. 1989;14(1):1-34.

10. Carpenter MB, Peter P. Nigrostriatal and nigrothalamic fibers in the Rhesusmonkey. J Comp Neurol. 1972;144(1):93-115.

11. Parent A, Hazrati LN. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev. 1995;20(1):91-127.

12. Parent A, De Bellefeuille L. Organization of efferent projections from the internalsegment of globus pallidus in primate as revealed by flourescence retrograde labelingmethod. Brain Res. 1982;245(2):201-213.

13. Magnin M, Jeanmonod D, Morel A, Siegemund M. Surgical control of thehuman thalamocortical dysrhythmia. II: Pallidothalamic tractotomy in Parkinson’sdisease. Thalamus Related Sys. 2001;1(1):81-89.

14. Aufenberg C, Sarnthein J, Morel A, Rousson V, Gallay M, Jeanmonod D. Arevival of Spiegel’s campotomy: long term results of the stereotactic pallidothalamictractotomy against the parkinsonian thalamocortical dysrhythmia. Thalamus RelatSys. 2005;3(2):121-132.

15. Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D. Firstexperience with MR-guided focused ultrasound in the treatment of Parkinson’sdisease. J Ther Ultrasound. 2014;2(1):1-11.

16. Souza RG, Borges V, Silva SM, Ferraz HB. Quality of life scale inparkinson’s disease PDQ-39 - (Brazilian Portuguese version) to assess patientswith and without levodopa motor fluctuation. Arq Neuro-Psiquiatr. 2007;65(3b):787-791.

17. Schaltenbrand G, Wahren W, Hassler RG, eds. Atlas for Stereotaxy of the HumanBrain, 2nd ed. Stuttgart, Germany:Thieme; 1977.

18. Jankovic J, McDermott M, Carter J, et al. Variable expression ofParkinson’s disease: A base-line analysis of the DAT ATOP cohort. Neurology.1990;40(10):1529-1529.

19. Sakai ST, Inase M, Tanji J. Comparison of cerebellothalamic and pallidothalamicprojections in the monkey (Macaca fuscata): a double anterograde labeling study.J Comp Neurol. 1996;368(2):215-228.

20. Fine J, Duff J, Chen R, et al. Long-term follow-up of unilateral pallidotomy inadvanced Parkinson’s Disease. N Engl J Med. 2000;342(23):1708-1714.

21. Strutt AM, Lai EC, Jankovic J, et al. Five-year follow-up of unilateralposteroventral pallidotomy in Parkinson’s disease. Surg Neurol. 2009;71(5):551-558.

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 pallidotegmentalprojections in primates: an anterograde and retrograde labeling study. Brain Res.1991;567(2):212-223.

24. Takakusaki K, Saitoh K, Harada H, Kashiwayanagi M. Role of basalganglia-brainstem pathways in the control of motor behaviors. Neurosci Res.2004;50(2):137-151.

25. Pahapill PA, Lozano AM. The pedunculopontine nucleus and Parkinson’s disease.Brain. 2000;123(9):1767-1783.

26. Thevathasan W, Debu B, Aziz T, et al. Movement Disorders Society PPNDBS working group in collaboration with the world society for stereotactic andfunctional neurosurgery. Pedunculopontine nucleus deep brain stimulation inParkinson’s disease: a clinical review.Mov Disord. 2018;33(1):10-20.

27. Zrinzo L, Zrinzo LV, Massey LA, et al. Targeting of the pedunculo-pontine nucleus by an MRI-guided approach: a cadaver study. J Neural Transm.2011;118(10):1487-1495.

28. Martinez-Gonzalez C, Bolam JP, Mena-Segovia J. Topographical organization ofthe pedunculopontine nucleus. Front Neuroanat. 2011;5:1-10.

29. Tremblay L, Worbe Y, Thobois S, Sgambato-Faure V, Féger J. Selectivedysfunction of basal ganglia subterritories: frommovement to behavioral disorders.Mov Disord. 2015;30(9):1155-1170.

30. Cury RG, Galhardoni R, Fonoff ET,et al. Sensory abnormalities and pain inParkinson disease and its modulation by treatment of motor symptoms. Eur J Pain.2016;20(2):151-165.

31. Bickel S, Alvarez L, Macias R, et al. Cognitive and neuropsychiatriceffects of subthalamotomy for Parkinson’s disease. Parkinsonism Relat Disord.2010;16(8):535-539.

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 inParkinson’s Disease. Brain Cogn. 2000;42(3):324-347.

33. Higginson CI, Fields JA, Tröster AI. Which symptoms of anxiety diminishafter surgical interventions for Parkinson disease?Neuropsychiat Neuropsychol BehavNeurol. 2001;14(2):117-121.

34. Agid Y, Schüpbach M, Gargiulo M, et al. Neurosurgery in Parkinson’s disease:the doctor is happy, the patient less so? J Neural Transm Suppl. 2006;70:409-414.

35. De Bie RM, de Haan RJ, Nijssen PC, et al. Unilateral pallidotomy inParkinson’s disease: a randomised, single-blind, multicentre trial. Lancet North AmEd. 1999;354(9191):1665-1669.

36. Esselink RA, de Bie RM, de Haan RJ, et al. Unilateral pallidotomy versusbilateral subthalamic nucleus stimulation in PD: a randomized trial. Neurology.2004;62(2):201-207.

37. Zimmerman GJ, D’Antonio LL, Iacono RP. Health related quality of life inpatients with Parkinson’s disease two years following posteroventral pallidotomy.Acta Neurochir. 2004;146(12):1293-1299.

38. Abosch A, Gross RE. Surgical treatment of Parkinson’s disease: deep brain stimu-lation versus radiofrequency ablation. Clin Neurosurg. 2004;51:296-303.

39. Hariz MI, Hariz GM. Therapeutic stimulation versus ablation. Handb ClinNeurol. 2013;116:63-71.

40. Witjas T, Carron R, Krack P, et al. A prospective single-blind study of GammaKnife thalamotomy for tremor. Neurology. 2015;85(18):1562-1568.

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

Supplemental Digital Content. Table.Nonmotor, psychiatric and neuropsycho-logical evaluations. Pain was the only symptom that decreased significantly aftercampotomy. Neuropsychiatric and neuropsychological functions did not changesignificantly. Values = means ± SEM. Abbreviations: FAB = frontal assessmentbattery; MMSE = Mini-Mental State Examination; WMS-R = WechslerMemory Scale Revised; ROCFT = Rey–Osterrieth Complex Figure test;RAVLT = Ray auditory-verbal learning test; SCOPA = Scale for Outcomes inParkinson’s disease-Psychiatric Complications; FAS = fluency of words beginningby F, A and S.

COMMENT

I n this very interesting paper the authors present 6-month and2-year clinical outcome data from 12 PD patients who were treatedwith unilateral campotomy contralateral to their most symptomatic side.They report significant improvement in both off- and on-state motorfunction at 6 months, which is maintained in the off-medication state at2 years. They also note improved gait at both time points and significantimprovement in QOL scores as a result of improved motor function anddecreased pain. They observed no long-term effects on neurocognitivefunction, though four of the 12 patients suffered somnolence immedi-ately after surgery and twomale patients suffered transient hypersexuality.

The authors are to be commended for their meticulous reporting ofthis patient series and the detail with which they describe their operativetechnique so that othersmay attempt to replicate their results. Forme, themost significant and surprising finding is the prolonged impact on gait,which is the most disabling and treatment-resistant motor symptom ofadvancing PD. If this finding can be replicated, unilateral campotomywould represent a significant advance in the surgical management ofPD, allowing tens of thousands of additional patients to benefit fromsurgical intervention each year. One must keep in mind, however, thatthese results are reported in an open-label fashion in a small patientcohort, a circumstance that has misled our field many times in thepast. Moreover, that an axial motor symptom such as gait would be soprofoundly improved 2 years after a unilateral intervention contradicts


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https://academic.oup.com/neurosurgery/article-lookup/doi/10.1093/neuros/nyz039

GODINHO ET AL

the prior collective experience of our discipline that axial symptoms suchas head tremor or cervical dystonia require bilateral intervention in orderto achieve optimal effect.

Consequently, though compelling, these results should be viewed withsome skepticism and should be tested in a more rigorous fashion beforewholesale use. I think the most interesting way this might be accom-plished would be a sham-controlled, double-blind trial employing MR-

guided Focused Ultrasound (MRgFUS) to create the lesion. Though thiswould exclude the use of MER to localize the target, MRgFUS could beperformed on anesthetized patients, allowing for a well-maintained blind.Regardless, this is a fascinating finding that deserves further exploration.

Ron L. AltermanBoston, Massachusetts


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stereotactic lesion in the forel's field h: a two-years prospective … · 2019. 3. 28. ·...

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