Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

Abstract

Background: Freezing of gait (FOG) is a common, disabling symptom of Parkinson's disease (PD), but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers. The main focus of this review is to summarize the possible mechanisms underlying FOG, the risk factors for screening and predicting the onset of FOG, and the clinical trials involving various therapeutic strategies. In addition, the limitations and recommendations for future research design are also discussed. Main body: In the mechanism section, we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG. In the risk factor section, gait disorders, PIGD phenotype, lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence. In the treatment section, we summarized the clinical trials of pharmacological and non-pharmacological treatments. Despite the limited effectiveness of current medications for FOG, especially levodopa resistant FOG, there were some drugs that showed promise such as istradefylline and rasagiline. Non-pharmacological treatments encompass invasive brain and spinal cord stimulation, noninvasive repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) and vagus nerve stimulation (VNS), and physiotherapeutic approaches including cues and other training strategies. Several novel therapeutic strategies seem to be effective, such as rTMS over supplementary motor area (SMA), dual-site DBS, spinal cord stimulation (SCS) and VNS. Of physiotherapy, wearable cueing devices seem to be generally effective and promising.Conclusion: FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration. Several risk factors of FOG have been identified, but need combinatorial optimization for predicting FOG more precisely. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggested that some therapeutic strategies showed promise.

Predicting the onset of freezing of gait in de novo Parkinson’s disease

“…Besides, the clinical feature was associated with many other non-motor symptoms, including daytime sleepiness. While dopaminergic neurons were mostly depleted in PD patients 6 , studies suggested that fatigue was most likely to result from disruption of nondopaminergic pathways 33 . Pavese N et al found that the serotoninergic dysfunction in basal ganglia and limbic circuits was associated with fatigue, which also supported the observed associations between fatigue and other non-motor symptoms 33 .…”

“…Previous studies have concentrated on complex determinants and pathophysiology of FoG 6 . Only a few studies have made efforts to predict FoG onset, especially in newly diagnosed PD patients [7][8][9][10][11][12][13][14][15][16] .…”

“…Non-motor factors included specific cognitive deficits, mood and sleep disorders, which were also found to be associated with FoG occurrence [8][9][10][11][12] . Imaging parameters included striatal dopaminergic denervation, which can be examined through the dopamine transporter (DAT) scans and single photon emission computed tomography (SPECT) imaging 6 . PD patients that had a lower DAT activity in caudate nucleus and putamen were at a higher risk to develop FoG 10 .…”

Anti-Gravity Treadmill Training for Freezing of Gait in Parkinson’s Disease

“…FoG is defined as “brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk” and typically occurs on initiating gait or on turning while walking [ 2 ]. Several therapeutic approaches have been employed in clinical studies and medical practice in order to improve FoG, including: pharmacological therapy; brain, spinal cord and vagus nerve stimulation; and physiotherapeutic approaches using wearable cueing devices, treadmill training, walk-bicycle, or obstacle aquatic training with variable clinical benefit [ 3 ]. Despite the wide number of proposed therapies, FoG is still difficult to treat because many patients do not have a complete response to dopaminergic therapy [ 2 ] and neurostimulation techniques, although promising, may require invasive and expensive technology not always available [ 3 ].…”

“…Several therapeutic approaches have been employed in clinical studies and medical practice in order to improve FoG, including: pharmacological therapy; brain, spinal cord and vagus nerve stimulation; and physiotherapeutic approaches using wearable cueing devices, treadmill training, walk-bicycle, or obstacle aquatic training with variable clinical benefit [ 3 ]. Despite the wide number of proposed therapies, FoG is still difficult to treat because many patients do not have a complete response to dopaminergic therapy [ 2 ] and neurostimulation techniques, although promising, may require invasive and expensive technology not always available [ 3 ]. In this scenario, physiotherapeutic approaches may be easier to apply with a lower risk of side effects and potential cardiovascular benefits.…”