Background

Freezing of gait (FOG) and gait difficulties are common and disabling disorders in advanced Parkinson’s disease (PD) [1].

Although the pathophysiology of FOG remains poorly understood, dopaminergic and non-dopaminergic pathways are implicated [2–5]. The relationship between FOG and dopaminergic medications is not fully predictable. The spectrum of response ranges from the “Off”-FOG, which is a common manifestation of motor fluctuations associated with low dopaminergic drive and relieved by dopaminergic therapy, and “On”-FOG, which appears under the effect of medications and in some case is even worsened by their administration [6]. There are different types of “On” FOG: (1) “pseudo-on” FOG, occurring during a seemingly optimal “on” state, (2) “drug-refractory” FOG, which is indifferent to changes in dopaminergic medication and (3) “true-on” FOG, which occurs or worsens in the “on” state and may improve after therapy reduction [7].

We evaluated the effectiveness of Levodopa–carbidopa intrajejunal gel (LCIG) in seven non-demented PD patients with prominent episodes of freezing refractory to adjustments of oral therapy.

Patients and methods

Screening the charts of 75 PD patients treated with LCIG at three Italian Movement Disorders centers (Cagliari, Milan, Venice), we identified 7 patients (Table 1) who presented On-FOG before switching from oral Levodopa (O-LD) to LCIG therapy. All patients screened met the PD UK Brain Bank criteria [8] and had shown a sustained response to dopaminergic treatment over the years, with motor fluctuations and/or dyskinesias. None of the patients had significant cognitive impairment (MMSE <24, FAB <13), psychiatric or severe systemic illnesses.

Table 1 Demographic and clinical characteristics of patients
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Assessment of PD disability

The main outcome measures were the UPDRS II and III scores and the FOG Questionnaire (FOGQ).

We also extrapolated and collated the gait and postural stability-specific subscores of UPDRS II (items 13–14–15) and III (items 29–30). Dyskinesias presence and duration were assessed by UPDRS scale item 32.

Levodopa dose (LDD) and Levodopa equivalent dose (LED, including LDD + all antiparkinsonian therapies, such as dopamine agonists, rasagiline, I-COMT) was calculated for each patient during O-LD and LCIG treatment (Table 2).

Table 2 Treatment taken by each patient at baseline (on oral levodopa) and during levodopa continuous intrajejunal gel infusion
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Evaluations were performed in “ON” state either during oral LD (O-LD-ON) (60–90 min after intake of usual morning LD dose) and LCIG (LCIG-ON) (60–90 min after starting LCIG infusion).

FOGQ, based on patient and caregiver assessment, was used to assess the frequency and duration of freezing episodes in both O-LD (FOGQ-O-LD) and in LCIG treatment (FOGQ-LCIG).

Data analyses

The changes in the main outcome measures and in gait-related subscores of UPDRS II and III were analyzed with Wilcoxon test for repeated measures. Significance threshold was set at p < 0.05. Data were analyzed using the Statistical Package for the Social Sciences (version 19; SPSS Inc., Chicago, USA).

Results

Median PD and LCIG treatment duration and doses are reported in Tables 1 and 2.

UPDRS scores recorded under O-LD and LCIG treatment are reported in Fig. 1. All UPDRS subscores related to gait and postural stability significantly improved with LCIG in all patients compared to O-LD (n = 7, UPRDS II total p = 0.018; item 13 falling p = 0.034; item 14 freezing p = 0.026; item 15 walking p = 0.026; UPDRS III total p = 0.027; item 29 gait p = 0.027; item 30 postural stability p = 0.025). The improvement of item 32 dyskinesias was not significant (p = 0.18).

Fig. 1
figure 1

UPDRS scores under O-LD and LCIG treatment

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FOGQ significantly improved (p = 0.017 45.1 %) on LCIG (FOGQ-O-LD 19 ± 1.4; LCIG: 10.4 ± 1.6).

Conclusion

Our results suggest that LCIG could be a useful therapeutic strategy in patients with FOG and gait disturbances refractory to oral therapy. Remarkably, FOGQ and the subscores of UPDRS II and III related to gait and postural stability improved in all patients selected after switching from O-LD to LCIG.

In 4 of our 7 patients, LED was increased after switching from oral therapy, while in 3 the total dopaminergic dose was reduced (Table 2).

We believe the first subgroup (see pt 1; video sections 1–2) represents a sample of “relatively undertreated” patients. In other words, the O-LD dose ensuring a relatively good control of rigidity, bradykinesia and tremor, is insufficient to improve gait disturbances, particularly FOG. On the other hand, further increase of O-LD schedule, needed to relieve gait disorders, was prevented by dyskinesias worsening. In these patients, compared with O-LD, LCIG allowed higher and more stable peripheral LD levels, obtaining greater clinical efficacy and avoiding plasmatic LD peaks and troughs which are associated with dyskinesias or poor tolerability. Indeed, many studies demonstrated a sustained improvement in UPDRS III scores on LCIG compared with oral therapy along with a reduction of dyskinesia scores [9, 10].

By contrast, 3 patients of our cohort (Subgroup 2; see pt 7 in video sections 3–4) also achieved a clear improvement of gait after starting LCIG therapy but, interestingly, the total LD dose on LCIG was lower compared with the pre-infusional O-LD. In these patients, “On-FOG” was possibly due to overstimulation by peak-dose O-LD therapy. This phenomenon may be related to a dysfunction of the “higher-level” locomotor control system, including the basal ganglia and prefrontal cortex circuits, modulated by sensory feedback via afferent pathways (somesthetic, vestibular and visual systems). Dopaminergic overstimulation can lead to dysfunction of fronto-subcortical circuits which prompt “high-order” gait abnormalities, such as difficulties in appropriate foot placement when walking and problems with initiation/maintaining stepping.

“Freezing-on” represents a therapeutic challenge in clinical practice: reduction of O-LD may alleviate FOG, but often results in unacceptable worsening of others PD features and STN-DBS is not recommended considering the lack of benefit on LD refractory symptoms and the potential surgical risks [11]. By contrast, LCIG enables achievement of steady LD plasma concentration, within the individual therapeutic window, avoiding overstimulation of fronto-striatal pathways.

We acknowledge that our sample is small, the study retrospective, the UPDRS evaluation was not blinded to treatment condition and we had no pharmacokinetic data. Nonetheless, the observation that in PD patients with FOG not improved by adjustments of oral dopaminergic therapy continuous stimulation provided by LCIG is helpful in both “On” and “Pseudo-on” FOG has important clinical consequences as it may reduce the risk of falls [12].