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Peduncolopontine nucleus stimulation in progressive supranuclear palsy: a randomised trial
  1. Emma Scelzo1,2,3,
  2. Andres M Lozano4,
  3. Clement Hamani4,
  4. Yu-Yan Poon5,
  5. Amaal Aldakheel1,
  6. Cindy Zadikoff6,
  7. Anthony E Lang5,
  8. Elena Moro1,5
  1. 1 Division of Neurology, CHU Grenoble, Grenoble Alpes University, Grenoble, France
  2. 2 Clinical Center for Neurotechnology, Neurostimulation and Movement Disorders, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
  3. 3 Department of Neurology, Policlinico San Donato, University of Milan, Milan, Italy
  4. 4 Division of Neurosurgery, Toronto Western Hospital, University of Toronto, University Health Network, Toronto, Ontario, Canada
  5. 5 Movement Disorders Center, Division of Neurology, Toronto Western Hospital, University of Toronto, University Health Network, Toronto, Ontario, Canada
  6. 6 Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Dr Elena Moro, Division of Neurology, CHU Grenoble, Grenoble Alpes University, INSERM U1416, 38043 Grenoble Cedex 9, Grenoble, France ; elenamfmoro{at}gmail.com

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Axial signs and cognitive disorders are the major source of disability in progressive supranuclear palsy (PSP). Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN), a structure involved in locomotion and posture control, has showed to improve freezing and falls in patients with Parkinson’s disease (PD).1 In this pilot trial, we investigated the effectiveness and safety of unilateral PPN DBS on gait and balance in patients with Richardson’s syndrome (RS) phenotype of PSP.

Between April 2006 and December 2010, eight patients with RS-PSP were enrolled at the Movement Disorders Center of the Toronto Western Hospital. The study was approved by the University Health Network, and the Toronto Rehab Research Ethics Boards. All patients gave their written consent to the study.

Both the surgical procedure and the PPN DBS programming were similar to those already used in patients with PD.2 Patients were assessed at baseline, and at 6 and 12 months after surgery, when they were randomly assigned to be evaluated both in the OFF and in the ON stimulation condition, after being 1 week in each stimulation condition. Patients and raters were blinded to the stimulation conditions. All assessments were videotaped, and adverse events were recorded. Main outcome was the difference between the ON and OFF stimulation conditions at 6 and 12-month follow-up in gait, postural stability and fall subitems of the PSP Rating Scale (PSPRS). Secondary outcomes were differences in the total scores of the motor Unified Parkinson Disease Rating Scale (UPDRS) and PSPRS; the PSP Staging System (PSPSS) score; rigidity, bradykinesia, arising from a chair and posture UPDRS items; history, mental, bulbar examination, supranuclear ocular motor examination, limb examination and gait/midline examination subscores of the PSPRS; withdrawal, sleep difficulty, disorientation, bradyphrenia and emotional incontinence items of the PSPRS. Differences in the PSP Quality of Life (PSP-QoL) scale (total score and subscores) between the OFF and ON stimulation conditions at baseline and 12 months were also analysed. The Wilcoxon signed-rank test was used for all outcomes (Statistica software). Results were considered significant for p values ≤0.05. The CI was 95%.

The patients’ baseline clinical characteristics are reported in the online supplementary table. Five patients were implanted in the left PPN, and three patients in the right PPN. Seven patients were available for assessment at 6 months (146.8±57.2 days postoperatively), and six patients at 12 months (466.3±144.2 days postoperatively). Three patients could not be evaluated because one had hip fracture after a fall, another had aspiration with laryngeal obstruction and urinary retention while the last one died 9 months after the surgery because of aspiration pneumonia.

Gait, postural stability and falls subitems of the PSPRS did not significantly differ between the OFF and ON stimulation conditions at both 6 and 12 months (p>0.05) (figure 1). Moreover, no significant differences were found in the total motor UPDRS, PSPRS and PSPSS scores, motor UPDRS items, PSPRS subscores and singular items between the OFF and ON stimulation conditions (p>0.05). Lastly, PPN DBS did not significantly improve the PSPQoL scale total score nor the motor and mental subscores (p>0.05).

Figure 1

Effects of unilateral PPN stimulation at 6 and 12 months after surgery in different conditions of stimulation. (A) Histograms represent the mean PSPRS score at baseline (black), and at 6 and 12 months in the OFF (black) and ON (grey) stimulation conditions. (B) Histograms represent the mean total PSPRS and UPDRS part III score at baseline (black), and at 6 and 12 months in the OFF (black) and ON (grey) stimulation conditions. (C) Histograms represent the mean PSPRS subscores (history (I), bulbar examination (III), ocular motor examination (IV), limb examination (V) and gait/midline examination (VI)) at baseline (black), and at 6 and 12 months in the OFF (black) and ON (grey) stimulation conditions. (D) Histograms represent the mean total PSPSS at baseline (black), and at 6 and 12 months in the OFF (black) and ON (grey) stimulation conditions. Error bars represent the SD. Bs, baseline; Mo, months; Off, OFF stimulation condition; On, ON stimulation condition; PSPRS, Progressive Supranuclear Palsy Rating Scale; PSPSS, Progressive Supranuclear Palsy Staging Scale; UPDRS, Unified Parkinson’s Disease Rating Scale.

Perioperatively, one patient had a left frontal haemorrhage followed by partially recovered aphasia, and another patient had an asymptomatic ventricular haemorrhage. During chronic stimulation, no patients reported DBS-induced side effects. Lastly, one patient needed a lead replacement 8 months after surgery because of lead fracture.

Overall, unilateral PPN DBS did not improve gait, balance, falls or any other item up to 1-year follow-up. To our knowledge, this is the largest double-blind study on PPN DBS in patients with PSP. To date, PPN DBS effects on PSP have been described in a few open studies with smaller samples of patients.3–6 One study with two patients with RS-PSP did not find clinical benefit in the UPDRS and PSPRS scores, although a minimal and transient gait improvement was observed.6 The other available studies involved different PSP phenotypes.3 4 6 A modest and transient improvement of gait and freezing was found in three patients with PSP-parkinsonism,3 6 and in one patient with primary progressive freezing of gait disorder.4 Since these phenotypes differ from RS-PSP, they cannot be compared with our results. The most favourable results have been reported in three patients with PSP of unknown phenotype who were treated by unilateral PPN DBS, and improved by approximately 26% in the PSPRS score. Reduction of falls and improvement in daily life activities at 1 year was also reported.5 However, assessments were unblinded, and one patient also underwent globus pallidus internus DBS.5

Possible explanations for our negative results could be the use of unilateral versus bilateral stimulation, and potential electrode misplacement. However, the choice of unilateral surgery was made according to our previous experience on patients with PD,2 and for safety reasons (severe midbrain atrophy with possible increased risk of surgical complications and misplacement). Moreover, we have proved the accuracy of our targeting in two patients with postmortem neuropathological analysis.7

Chronic stimulation itself was well tolerated in our cohort. However, two patients had intraoperative bleeding. Although the risk of lead-vessel conflicts in PPN DBS has already been underlined, we had more surgical complications compared with previous reports. While the reason of bleeding in our patients is unknown, variations in the human pons anatomy and the more severe pons impairment and atrophy in patients with RS could be associated factors.

Our study has several limitations. Our sample, although the largest available, is still small. Moreover, the motor and non-motor assessments performed in this study do not allow excluding minimal clinical improvement that might have been observed through more specific evaluations, such as gait analysis or neuropsychological assessments. Finally, we cannot exclude that bilateral surgery could have been more beneficial.

In conclusion, unilateral PPN DBS was not effective in improving balance, and falls in patients with advanced RS-PSP. A different response to PPN DBS in other PSP phenotypes at an earlier stage of the disease or with bilateral stimulation cannot be excluded. The surgical complications occurred in three patients suggest a possible higher risk of DBS complications that should be better investigated in further studies.

Acknowledgments

The authors thank all patients and their families for their participation in this study.

References

Footnotes

  • Contributors ES and CZ have participated in the collection, analysis and interpretation of data.

    AML and CH have participated in the design and execution of the study and in the interpretation of data. Y-YP has participated in the collection, design, execution and interpretation of data.

    A

    A has participated in the analysis and interpretation of data.AEL has participated in the design, analysis and interpretation of data. EM has participated in the design and execution of the study and in the collection, analysis and interpretation of data.

  • Funding This study was supported by a CurePSP grant.

  • Competing interests EL has received honoraria from Medtronic, Boston Scientific, St Jude, Aleva for consulting and is co-founder of Functional Neuromodulation. CZ has received honoraria or consulting fees from AbbVie, Merz, Teva, Lundbeck, UCB, Acadia and Cynapsus. AEL has served as an advisor for Abbvie, Acorda, Avanir Pharmaceuticals, Bristol Myers Squibb, Cipla, Intekrin and Merck; received honoraria from Medichem, Medtronic, Teva, UCB, AbbVie; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada, Physicians Services Incorporated, W. Garfield Weston Foundation; received publishing royalties from Saunders, Wiley-Blackwell, Johns Hopkins Press and Cambridge University Press; and has served as an expert witness in cases related to the welding industry. EM has received honoraria from Medtronic for consulting services and lecturing and research grant support from Merz and AGIR.

  • Patient consent Obtained.

  • Ethics approval Toronto Rehab Research Ethics Boards.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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