Freezing of gait in PD has a REM correlate: twice cursed with a shared pathophysiology?

Freezing of gait (FOG) is a common, debilitating feature of Parkinson disease (PD), substantially affecting the patient’s quality of life by limiting independence and causing falls. Although it occurs most frequently in the later stages of PD, it is also seen in 26% of earlystage patients not yet exposed to levodopa. Since FOG lacks correlation with bradykinesia, a nondopaminergic mechanism may explain this affliction. This concept is supported by the failure of dopaminergic therapies to relieve FOG, except for the category of “off” period FOG. REM sleep behavior disorder (RBD), a condition characterized by potentially injurious disruptive behaviors during sleep, and REM sleep without atonia (RSWA), a condition defined by polysomnography, are both strongly associated with PD and may antedate the onset of motor symptoms. Two previous studies have shown an increase in the frequency of FOG in PD patients with RBD, suggesting a shared pathophysiologic link between these 2 conditions. The article by Videnovic et al. in this issue of Neurology® explores the relationship between FOG and RSWA in patients with PD by comparing clinical and polysomnography characteristics of patients with RBD and PD with and without FOG to those of ageand sex-matched controls. Subjects with cognitive impairment (Mini-Mental State Examination [MMSE] scores ,26) were excluded. The main finding was a marked increase in the percentage of tonic EMG activity during REM sleep in both RBD and PD1FOG groups, compared with PD-FOG and control groups. Measures of phasic EMG activity were not different in the PD1FOG group compared to PD-FOG. Based on these findings, the authors suggest that the presence of excessive tonic EMG activity during REM sleep may be predictive of the development of a FOG phenotype of PD, a hypothesis that could be tested in a longitudinal study. The authors suggest that their study provides evidence for a common subset of pathophysiologic changes in PD1FOG and RBD groups. While the study does not address this directly, other data suggest that changes in the neuroanatomical networks in the brainstem, including the pedunculopontine nucleus (PPN) and locus ceruleus, which are components of the mesencephalic locomotor center and postural control circuits, may predispose not only to FOG but also to RBD. Noradrenergic deficits due to locus coeruleus cell loss have been associated with balance impairment, falls, and possibly FOG, and the noradrenergic precursor L-threo-DOPS may be effective in treating FOG. The PPN contains cholinergic, GABAergic, and glutaminergic neurons and participates in both arousal and locomotion. Deep brain stimulation of a caudal PPN region recently proved effective in 5 patients with severe FOG and postural instability. The PPN also controls muscle tone during wakefulness and is responsible for atonia during REM sleep. While gait pattern generation disturbances are undoubtedly central to FOG, recent functional imaging data provide a complex picture, suggesting that FOG reflects a combined motor and cognitive deficit. In particular, a correlation of freezing severity with disruption of the frontostriatal-parietal networks has provided evidence for an important role of executive dysfunction in FOG, perhaps because goal-directed cortical areas are recruited to compensate for basal ganglia gait dysfunction. Patients with PD with polysomnogram-confirmed RBD have a greatly increased frequency of mild cognitive impairment and increased incidence of dementia. Cognitive impairment may be the mediator by which freezing occurs in PD patients with RBD. PD1FOG patients in the authors’ study were somewhat older and had longer disease duration than PD-FOG patients, but they had normal MMSE scores. It is possible that use of the Montreal Cognitive Assessment or more focused executive function tests in this study would have shown at least moderate executive dysfunction in the PD1FOG group. The likely dual pathophysiologic basis for FOG, involving both striatofrontal and downstream corticopontine/brainstem pathways, raises the possibility that early-stage (younger) and late-stage (older) PD1FOG patients may differ to some degree in their primary FOG-related pathophysiology. If so, these groups may respond