Levodopa Responsiveness Subtypes of Freezing of Gait: Results Using a Levodopa Challenge

Objective To demonstrate that levodopa-unresponsive freezing of gait (ONOFF-FOG), which is a disabling untreatable feature of Parkinson’s disease (PD), is distinct from responsive/OFF only FOG (OFF-FOG) and potentially has a distinct pathophysiology. Methods Fifty-five PD patients completed levodopa challenges after >12 hours OFF with supratherapeutic doses to classify them as NOFOG, OFF-FOG or ONOFF-FOG. Serum levodopa levels ensured threshold levels were met. An “ON” response was defined as ≥20% improvement in MDS-UPDRS-III score. Main outcome measure was MDS-UPDRS-III based on clinical exam, timed-up-and-go tests and 360° turns. Results 45 patients exhibited an “ON” response to the challenge. Levodopa-equivalent-dose was 142±56% of patients’ typical morning doses. Patients could be classified as: 19 ONOFF-FOG, 11 OFF-FOG, 15 NOFOG. The ONOFF-FOG group exhibited significantly higher NFOG-Q, MDS-UPDRS-II/III scores compared to the OFF-FOG group. MDS-UPDRS-III total varied significantly across medication response states (P<0.01) and groups (P=0.03). Among MDS-UPDRS-III subdomains, significant effects of group (highest in ONOFF-FOG group) were identified for measures of lower extremities and gait. Linear mixed models revealed a highly significant association between serum levodopa level and MDS-UPDRS-III score that did not vary across the groups. There was a highly significant group interaction effect on the association between serum levodopa level with MDS-UPDRS-III item 11 “Freezing of Gait” (P<0.001). Conclusions ONOFF-FOG is a distinct subtype of FOG in PD, as opposed to OFF-FOG. This is an important step in demonstrating that FOG is not a single entity and, in turn, could lead to better understanding of pathophysiology and development of effective therapies.