Levodopa-Resistant Freezing of Gait and Executive Dysfunction in Parkinson's Disease

Ferraye, Murielle Ursulla; Ardouin, Claire; Lhommée, Eugénie; Fraix, Valérie; Krack, Paul; Chabardès, Stéphan; Seigneuret, Éric; Benabid, Alim‐Louis; Pollak, Pierre; Debû, Bettina

doi:10.1159/000346432

Cited by 23 publications

(12 citation statements)

References 34 publications

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“…It is generally believed that FOG is associated with executive dysfunction and visuospatial changes and that this association is important from a pathophysiological standpoint. 15,16 However, studies have actually demonstrated that these cognitive measures are associated specifically with ONOFF-FOG 10,17–19 but not OFF-FOG. 10,20 This approach could also explain why, for example, FOG severity has been associated with reduced functional connectivity within the ‘executive-attention’ neural network in the ‘resting’ state of some studies 21 but not others.…”

Section: Discussionmentioning

confidence: 99%

Freezing of Gait can persist after an acute levodopa challenge in Parkinson’s disease

McKay

Goldstein

Sommerfeld

et al. 2019

npj Parkinsons Dis.

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Study objectives included testing whether presumed levodopa-unresponsive freezing of gait (FOG) in Parkinson’s disease (PD) actually persists in the presence of adequate dopaminergic dosing and to investigate whether the presence of other parkinsonian features and their responsiveness to therapy varies across patients without FOG (NO-FOG), with levodopa-responsive FOG (OFF-FOG), and with levodopa-unresponsive FOG (ONOFF-FOG). Fifty-five PD patients completed levodopa challenges after >12-h OFF with supratherapeutic doses of dopaminergic medications. Observed responses in FOG, measured with MDS-UPDRS-III during the patient reported full “ON”, were used to classify them as NO-FOG, OFF-FOG, or ONOFF-FOG. Serum levodopa levels were measured. Only those with ≥20% improvement in MDS-UPDRS-III score were included in analyses. Levodopa challenge was sufficient to bring about a full “ON” state with ≥20% improvement in 45 patients. Levodopa-equivalent-dose utilized was 142 ± 56% of patients’ typical morning doses. Overall, 19/45 patients exhibited FOG in the full “ON” state (ONOFF-FOG), 11 were classified as OFF-FOG, and 15 NO-FOG. Linear mixed models revealed a highly significant association between serum levodopa level and total MDS-UPDRS-III score that was similar across groups. The ONOFF-FOG group exhibited significantly higher New-FOG-questionnaire and MDS-UPDRS-II scores compared to the OFF-FOG group. Among MDS-UPDRS-III subdomains significant effects of group (highest in ONOFF-FOG) were identified for other axial parkinsonian features. We found that FOG can persist in the full “ON” state brought about by ample dopaminergic dosing in PD. Other axial measures can also be levodopa-unresponsive among those with ONOFF-FOG only. These data provide evidence that ONOFF-FOG is distinct from responsive freezing.

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Section: Discussionmentioning

confidence: 99%

Freezing of Gait can persist after an acute levodopa challenge in Parkinson’s disease

McKay

Goldstein

Sommerfeld

et al. 2019

npj Parkinsons Dis.

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“…The administration of dopaminergic medications leads to a general improvement in gait abnormalities (Bohnen, Albin, Muller, & Chou, 2011), though FOG cannot be completely ameliorated with dopaminergic replacement (Nutt et al, 2011;Shine, Naismith, & Lewis, 2011). For example, a study has reported that FOG in some PD patients did not respond well to levodopa (Ferraye et al, 2013). In addition, there are currently significant limitations associated with long-term dopaminergic therapy in general, as it often leaded to side effects, such as dyskinesias.…”

Section: Effects Of Dopaminergic Medications and Dbsmentioning

confidence: 99%

Motor symptoms in Parkinson’s disease: A unified framework

Moustafa

Chakravarthy

Phillips

et al. 2016

Neuroscience & Biobehavioral Reviews

305

156

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Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement.

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“…“ l ‐Dopa–unresponsive” FOG may indicate an intermediary subtype in which the effect of dopaminergic stimulation is not strong enough to prevent FOG even if other parkinsonian motor signs are improved in the “on” state. A recent study demonstrated that, when subthalamic nucleus (STN)‐stimulated patients with “off” FOG were contrasted to those who had “ l ‐dopa–unresponsive FOG,” executive function was more impaired in the latter group, likely reflecting greater pathology in non‐dopaminergic circuits. We observed that 23 studies in Table did not report proportions of l ‐dopa–responsive or l ‐dopa–unresponsive freezers and that, in 15 studies, the l ‐dopa equivalent dose (LED) was not provided.…”

Section: Between Group Comparisons: Are There True Freezers and Non‐fmentioning

confidence: 99%

Characterizing freezing of gait in Parkinson's disease: Models of an episodic phenomenon

2013

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Freezing of gait (FOG) is a very disabling and common gait disorder in Parkinson"s disease (PD). The first aim of this paper is to provide a methodological and critical review of the most common research approach to understand FOG, i.e., comparing the behaviour of freezers with that of non-freezers. The review shows that studies often fall short in clearly defining the freezer\non-freezer groups and in controlling for disease severity and other confounders.These problems complicate data interpretation on FOG.The second aim of this paper was to summarize the literature on the potential mechanisms behind the episodic nature of FOG in the following four models: 1) The "threshold model" assumes that FOG occurs when the accumulation of various motor deficits reinforce each other to a point of motor breakdown; 2) The "interference model" proposes that FOG represents an inability to deal with concurrent cognitive, limbic and motor input, causing an interruption of locomotion; 3) The "cognitive model" views FOG as induced by a failure to process response conflict, leading to behavioural indecision; and 4) the "decoupling model" sees FOG as a disconnection between preparatory programming and the intended motor response as a result of which automatic movement generation gets stuck. These four theoretical premises are still incomplete and do not fully explain FOG. The depletion of motor and cognitive reserves and an increasingly complex response to levodopa with disease progression will also impact upon the emergence of the FOG-episodes.3

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Levodopa-Resistant Freezing of Gait and Executive Dysfunction in Parkinson's Disease

Cited by 23 publications

References 34 publications

Freezing of Gait can persist after an acute levodopa challenge in Parkinson’s disease

Freezing of Gait can persist after an acute levodopa challenge in Parkinson’s disease

Motor symptoms in Parkinson’s disease: A unified framework

Characterizing freezing of gait in Parkinson's disease: Models of an episodic phenomenon

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