A meta-analysis identifies factors predicting the future development of freezing of gait in Parkinson's disease

Abstract

Freezing of gait (FOG) is a debilitating problem that is common among many, but not all, people with Parkinson's disease (PD). Numerous attempts have been made at treating FOG to reduce its negative impact on fall risk, functional independence, and health-related quality of life. However, optimal treatment remains elusive. Observational studies have recently investigated factors that differ among patients with PD who later develop FOG, compared to those who do not. With prediction and prevention in mind, we conducted a systematic review and meta-analysis of publications through 31.12.2022 to identify risk factors. Studies were included if they used a cohort design, included patients with PD without FOG at baseline, data on possible FOG predictors were measured at baseline, and incident FOG was assessed at follow-up. 1068 original papers were identified, 38 met a-priori criteria, and 35 studies were included in the meta-analysis (n = 8973; mean follow-up: 4.1 ± 2.7 years). Factors significantly associated with a risk of incident FOG included: higher age at onset of PD, greater severity of motor symptoms, depression, anxiety, poorer cognitive status, and use of levodopa and COMT inhibitors. Most results were robust in four subgroup analyses. These findings indicate that changes associated with FOG incidence can be detected in a subset of patients with PD, sometimes as long as 12 years before FOG manifests, supporting the possibility of predicting FOG incidence. Intriguingly, some of these factors may be modifiable, suggesting that steps can be taken to lower the risk and possibly even prevent the future development of FOG.

Fig. 1. Study selection and PRISMA Flow.

Study selection; PRISMA Flow Diagram describing the studies that were initially identified in the search and those that were included in the meta-analysis.

Fig. 2. Summary of significant risk factors for incident FOG according to the type of data available with effect size and 95% confidence interval of random effects models.

In each panel, the factors are organized in alphabetical order. A Standardized mean difference; (B) Relative risk; C Hazard ratio. A list of all of the abbreviations used can be found in the Supplementary Table 1.

Fig. 3. Forest plots of selected significant predictors of the future development of FOG.

A represents one of the anxiety predictors; (B) represents one of the depression predictors; (C) represents the use of medication predictors; (D) represents one of the cognitive domain predictors.

Fig. 4. Summary of the significant predictors of FOG incidence, grouped with respect to those that are putatively modifiable and those that are not.

When possible, we recommend keeping levodopa and LEDD at minimal effective doses. When anti-parkinsonian medications are prescribed, the patient’s response should be carefully monitored. A list of all of the abbreviations used can be found in the Supplementary Table 1.