In their Historical Insight, Peter Koehler and colleagues1Koehler PJ Nonnekes J Bloem BR Freezing of gait before the introduction of levodopa. propose that freezing of gait (FOG) in patients with advanced Parkinson's disease is the result of chronic long-term levodopa use. Furthermore, they notice that, if FOG was present in the pre-levodopa era, it expressed itself as akinetic, not as the shuffling and trembling subtypes seen mostly nowadays. Therefore, they conclude that the high-frequency oscillatory features of FOG are probably induced by levodopa. Although we appreciate this thought-provoking hypothesis, we would like to present some observations that refute it.First, FOG can manifest before levodopa intake. In the Parkinson Progression Marker's Initiative cohort, 23 (5%) of 423 de novo patients had FOG at baseline.2Presynaptic striatal dopaminergic depletion predicts the later development of freezing of gait in de novo Parkinson's disease: an analysis of the PPMI cohort. Also, five (17%) of 30 drug-naive patients from a cohort in sub-Saharan African had FOG.3Cilia R Cereda E Akpalu A et al.Natural history of motor symptoms in Parkinson's disease and the long-duration response to levodopa. After 1 year of levodopa treatment, only one patient reported FOG; after 2 years, still only four patients in this cohort reported FOG, with significantly reduced severity when compared with presentation at baseline.

Second, accurate detection of FOG is challenging even with high-resolution cameras and wearable sensors, particularly for discerning small amplitude high-frequency movements during brief episodes. Hence, we suspect that historical cinematography with all its technical limitations was not optimal for the detection of FOG, particularly that of the trembling subtype.

Third, we found two papers from the pre-levodopa era describing FOG episodes along with correlates, in which FOG triggers varied between patients, and visual cues could temporarily overcome the event.4Effects of mood, motivation, stress and alertness on the performance in Parkinson's disease., 5Stereotactic surgery for the relief of Parkinson's disease. 2. An analysis of the results in a series of 303 patients (413 operations). Also, Koehler and colleagues did not find one film from the pre-levodopa era showing FOG, but FOG does appear to be present in a patient filmed around 1910.6Moving pictures of Parkinson's disease.

Therefore, given our concern that the Historical Insight might induce unfounded so-called levodopa-phobia in some patients, we urge caution when proposing that FOG has increased after the introduction of levodopa. What the piece by Koehler and colleagues does highlight is the great need for reliable datasets on FOG to enable in-depth characterisation of its phenotypes. Longitudinal studies are needed to determine how evolving pathology and dopaminergic therapy interrelate and affect the emergence of FOG as a graded phenomenon reflecting motor and non-motor circuit failure.

MG is funded by the EU's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (838576). ND and AN are supported by funding from the Jacques and Gloria Gossweiler Foundation. PG and AN are funded by the Horizon 2020 Innovative Medicines initiative Mobilise-D project (820820), Industrial Research Funds KU Leuven project (3M200670), Flemish Research Foundation (FWO-G0A5619N), and the Michael J Fox Foundation DeFOG project (16347). WV is supported by research funding of the Flemish Research Foundation.

References1.Koehler PJ Nonnekes J Bloem BR

Freezing of gait before the introduction of levodopa.

Lancet Neurol. 20: 972.

Presynaptic striatal dopaminergic depletion predicts the later development of freezing of gait in de novo Parkinson's disease: an analysis of the PPMI cohort.

Parkinsonism Relat Disord. 51: 49-543.Cilia R Cereda E Akpalu A et al.

Natural history of motor symptoms in Parkinson's disease and the long-duration response to levodopa.

Brain. 143: 2490-25014.

Effects of mood, motivation, stress and alertness on the performance in Parkinson's disease.

Psychiatr Neurol (Basel). 150: 345-3575.

Stereotactic surgery for the relief of Parkinson's disease. 2. An analysis of the results in a series of 303 patients (413 operations).

J Neurol Sci. 5: 343-3756.

Moving pictures of Parkinson's disease.

Lancet. 378: 1773-1774Article InfoPublication HistoryIdentification

DOI: https://doi.org/10.1016/S1474-4422(21)00175-7

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© 2021 Elsevier Ltd. All rights reserved.

ScienceDirectAccess this article on ScienceDirect Linked ArticlesFreezing of gait before the introduction of levodopa

Freezing of gait (FOG) occurs in over half of patients with advanced Parkinson's disease. It is characterised by sudden, brief episodes of inability to produce effective forward stepping that typically occur upon gait initiation or during turning while walking. FOG can be subdivided into three clinically distinguishable phenotypes . The two most common forms, which can be seen both when patients are ‘on’ or ‘off’ their dopaminergic medication, are shuffling forward with very small steps and trembling in place without effective forward motion.

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