Conditions Associated with <scp><i>On</i></scp>‐State Freezing of Gait

We previously described on-state freezing of gait (on-FOG) as a rare gait phenotype in Parkinson's disease (PD).1 In on-FOG cases, levodopa dosage increases were associated with corresponding increases of freezing of gait (FOG), whereas FOG disappeared in the off state. Two of 4 cases we described in 20121 were subsequently diagnosed as the predominant parkinsonian subtype of progressive supranuclear palsy (PSP-P). Based on these observations, we hypothesized that on-FOG might be a red flag for atypical parkinsonism and potentially aid in the earlier detection of PSP. In 2019, we searched patient databases at Toronto Western Hospital and the University of Cincinnati Medical Center to identify further cases with observed on-FOG. We identified a total of 8 on-FOG cases from approximately 8200 clinical records and referrals within a 7-year period. Three cases fulfilled the diagnostic criteria of PSP-P, supporting our initial hypothesis. These patients were initially suspected to have PD based on typical motor symptoms such as asymmetric bradykinesia and tremor. Of these individuals, 2 underwent chronic levodopa therapy having manifested early falling. The third individual completed a levodopa challenge to screen for deep brain stimulation (DBS) candidacy. Individuals with PSP-P also tended to be slightly older than those with PD (see Table 1). Interestingly, 5 additional cases presenting on-FOG were diagnosed with PD. Of these patients, 4 completed a levodopa challenge and underwent DBS targeting either the subthalamic nucleus (n = 2) or the globus pallidus internus (n = 2). These patients had similar time courses and on-FOG onset, which occurred after DBS. The patient with PD without DBS was older and underwent a levodopa challenge to confirm on-FOG, displaying higher on and off Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores (22 and 34, respectively) compared with patients with DBS (9.6 and 19). For these individuals, FOG worsened at higher doses of levodopa (between 400 and 2700 mg) in contrast to cases seen with diphasic FOG.2 Subsequent dose reduction improved FOG. This was usually done slowly over several weeks, thus confirming the initial diagnosis. The UPDRS Part III scores during off and on states were examined with nonparametric testing and were higher in the PSP group compared with the PD group (see Table 1). Both groups presented diminished UPDRS Part III on-state scores relative to their off-state scores. However, only the PD group revealed a statistically significant change between the on and off states (z = −2.02; P < 0.05). Our observations suggest that on-FOG can be found in selected patients with PSP and as a potential complication of DBS in PD. Individuals with PSP on average exhibited FOG earlier in the disease course.3 PSP is known to share common clinical manifestations with PD,4 including gait-related symptoms.5 Thus, our initial observations suggest that the presence of on-FOG is potentially an early cue for patients whose initial PD diagnosis may develop classic features of PSP. Our findings also suggest that on-FOG can occur post-DBS, thus adding another mechanism to consider in the multifactorial pathophysiology of FOG in post-DBS PD.6 However, given the limited sample of observations presented, further studies are required for both populations. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and CritiqueG.U.S.: 2B, 3A C.M.S.S.: 1C A.J.E.: 1C, 3B B.R.B.: 3B A.F.: 1A, 1B, 3B Ethical Compliance Statement: Informed consent and the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: The authors report no relevant conflicts. This study was funded by the University of Toronto and University Health Network Chair in Neuromodulation to A.F. Financial Disclosures for the Previous 12 Months: G.U.S. and M.C.S.S. have nothing to declare. A.J.E. has received grant support from the NIH and The Michael J. Fox Foundation; personal compensation as a consultant/scientific advisory board member for Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Bexion, Kyowa Kirin, Sunovion, and Supernus (formerly USWorldMeds); honoraria from Acadia, Sunovion, Amneal, and Supernus; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He cofounded REGAIN Therapeutics, owner of a patent that covers synthetic soluble nonaggregating peptide analogues as a replacement treatment in proteinopathies. B.R.B. serves as co-Editor in Chief for the Journal of Parkinson's Disease; serves on the editorial board of Practical Neurology and Digital Biomarkers; has received honoraria from serving on the scientific advisory boards for Abbvie, Biogen, and UCB; has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare, and Bial; and has received research support from the Netherlands Organization for Scientific Research, The Michael J. Fox Foundation, UCB, Abbvie, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, Horizon 2020, and the Parkinson Vereniging. Prof. Bloem does not hold any stocks or stock options with any companies that are connected to Parkinson's disease or to any of the topics in this article. A.F. received honoraria from AbbVie, Abbott, Boston Scientific, Ceregate, Ipsen, Medtronic, and UCB and research support from AbbVie, Boston Scientific, and Medtronic.

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