Interleaved Stimulation for Freezing of Gait in Advanced Parkinson's Disease
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.314570
Source of Support: None, Conflict of Interest: None
Keywords: Deep brain stimulation, freezing of gait, interleaved stimulation, Parkinson's disease, subthalamic nucleus
Syed M Zafar, Roopa Rajan contributed equally to this work
Freezing of gait (FOG) is a common problem in advanced Parkinson's disease (PD) which contributes significantly to functional disability. Therapeutic options that alleviate FOG are limited. FOG may be Levodopa responsive in the initial stages of treatment. Medication-unresponsive FOG is generally refractory to conventional subthalamic (STN) stimulation., Low frequency STN stimulation was shown to improve gait in a small subset of patients with FOG. Pedunculopontine nucleus stimulation, though a promising approach, has not shown consistent beneficial effects.
Axial symptoms including gait are known to respond to the modulation of frequency of STN stimulation. Interleaved stimulation (ILS) is a programming strategy in which two different contact pairs on the same deep brain stimulation (DBS) lead are activated at the same frequency but with different amplitude and pulse width. In ILS, the programmed contacts are activated in an alternating manner. The stimulation parameters can be modified to change the volume of tissue activated at each contact. An area of tissue activated will theoretically receive overlapping stimulation from the activated contacts, at double the set frequency. This strategy is effective in improving speech, controlling tremor and shaping the current flow to reduce stimulation-induced adverse effects., Unilateral ILS of STN improved FOG in a single patient. Combined ILS of the STN and substantia nigra pars reticulata (SNr) is reported to improve FOG. Given the sensitivity of FOG to frequency of stimulation, we conducted a pilot study to test the effect of ILS of STN on FOG in PD patients with FOG that was unresponsive to conventional stimulation.
We conducted a prospective, single-arm study in advanced PD patients who underwent bilateral STN stimulation in a single center. Subjects meeting all the following inclusion criteria were recruited: (1) PD with motor fluctuations and levodopa-induced dyskinesias who underwent bilateral STN-DBS; (2) Implanted with a pulse generator which allows interleaved stimulation; (3) FOG unresponsive to levodopa and monopolar stimulation at standard (130–150Hz) and low (≤60Hz) frequencies. Subjects meeting any of the following criteria were excluded: (1) symptomatic cognitive impairment; (2) wheelchair bound patients in stimulation ON after DBS; (3) patient and caregivers unable to manage operations of the patient therapy controller satisfactorily, in the judgment of the investigators. All patients had undergone stereotactic guided bilateral STN electrode implantation, with 5-channel micro electrode recording and clinical monitoring for benefits and adverse events. Written informed consent was obtained from all subjects and the study was approved by the institutional ethics committee.
All the programming sessions and assessments were performed in the stimulation-ON, medication-OFF state (12-h overnight withdrawal of all dopaminergic medications). Subjects were selected for ILS according to the algorithm in [Figure 1]. For ILS, the currently active contact (selected based on best response of the cardinal motor signs to conventional stimulation settings) and the contact adjacent to it were activated. For all stimulation parameter changes, it was attempted to maintain the same amount of total energy equivalent delivered using the formula: TEED = [(voltage × pulse width × frequency)/impedance]2. We calculated the TEED in the baseline setting and attempted to maintain the same TEED shared between STN1 and STN2 for ILS. In subjects with suboptimal control of motor symptoms or troublesome dyskinesias with ILS, further adjustment of stimulation parameters and contacts was done. While switching to ILS, in the majority of patients, we used the just adjacent dorsal contact as the additional contact, in an attempt to avoid ventral/SNr stimulation. In some patients, where the dorsal contact revealed side effects or was estimated to be beyond the upper STN border (as per intraoperative electrophysiology/monopolar review) we activated the adjacent ventral contact. Outcome was assessed at baseline, 30 min after switching to ILS and 3 months after switching to ILS. Medication doses were kept unchanged during this period to maintain stable LEDD. The primary outcome measure was the UPDRS part III gait score (item 29). Secondary outcome measures were UPDRS III total scores and patient-reported global change on a 4-point scale. In a subset of patients, we performed the stand-walk-sit test, 30 min after switching to ILS. The Wilcoxon Signed Ranks Test was used to compare the UPDRS III gait scores before and after ILS.
19 subjects were enrolled and all completed the assessment at 3 months. The mean age of the study population was 59.8 ± 8.6 years (7 female).The mean duration of illness was 14.6 ± 4.7 years. Patients were receiving STN stimulation for a median of 24 (range: 12–120) months prior to enrolment. Baseline characteristics are shown in [Table 1]. The stimulation parameters before ILS and individual ILS parameters are shown in [Table 2]. All 19 subjects continued with the ILS settings for 3 months.
UPDRS III gait score
The mean UPDRS III gait (item 29) subscore at baseline was 1.8 ± 0.6 (range: 1–3). At 30 min after ILS, the mean gait score reduced to 1.1 ± 0.8 (range: 0–2, P = 0.017). At 3 months, the mean score (1.2 ± 0.8, range: 0–3, P = 0.048) remained significantly reduced compared to baseline.
The total UPDRS III score remained similar at baseline (18.3 ± 10.2) and at three months (15.4 ± 8.0). At 30 min, 89% (17/19) subjects reported at least “some beneficial response” on FOG. This was sustained at three months in only 74% (14/19), with the rest reporting no benefit. No major stimulation-related adverse events were noted with ILS.
Stand-Walk-Sit (SWS) test
The SWS test was done in five subjects at baseline and 30 min after switching to ILS. There was a significant reduction in the number of freezing episodes at 30 min (mean number of episodes, 1.1 ± 2.5) compared to baseline (2.4 ± 1.1, P = 0.041) [Figure 2]. The time taken for completing SWS also improved (baseline: 41.5 ± 41.8, 30 min: 33.2 ± 31.2, P = 0.043). There was no change in the number of steps taken to complete the task (baseline: 31.0 ± 19.6, 30 min: 29.1 ± 19.6, P = 0.273).
In this preliminary study, ILS was found to be beneficial in improving gait in subjects with advanced PD receiving STN stimulation who had FOG unresponsive to levodopa and conventional stimulation settings. Given that postural instability and number of steps taken remained unchanged after ILS, the improvement in gait can be attributed to improvement in FOG. Majority of the patients (89%) reported improvement in FOG immediately after switching to ILS, and this effect was sustained in 74% even at three months. The overall control of motor symptoms remained stable, as evident from the UPDRS part III scores.
The mechanism of action of ILS is not clear. Specifically, FOG is known to be frequency- responsive as it improves with low frequency (60Hz) stimulation and with ILS during which the effective frequency at the overlapping region is doubled. The beneficial effects may not only be due to a frequency change alone but also due to the alternating stimulation of different tissue volumes at the same frequency which may positively influence the cadence of walking. Alternatively, a large volume of stimulation or higher frequency in the overlapping region may override the inhibitory influence on the cadence of gait. It is also possible that the beneficial effects were due to the ability to optimize stimulation in terms of current delivery and tissue volume beyond what was possible with conventional parameters alone.
Our study has certain limitations; we have chosen a highly select group of patients with FOG unresponsive to conventional and low frequency stimulation. Our results may not hold true for a larger population of PD patients with FOG. We used the UPDRS part III item 29 as a measure of gait without objective gait analysis. However, UPDRS part III is routinely used in clinics worldwide to assess motor functions including gait and it correlates well with accelerometric gait variables in PD. This is a single-arm study and further studies including a control group and blinded outcome assessment are required to establish a true effect. In many patients, further adjustments were required for optimal symptom control which may have led to deviations from the calculated TEED. However, this may be reflective of standard practice in clinical STN stimulation, and studies have previously shown that for narrow pulse width ranges below 100Hz, TEED remains relatively constant despite changes in frequency and voltage. Finally, postoperative imaging was not available in this group to confirm the location of electrodes. Hence, a beneficial effect on FOG due to interleaved stimulation of structures other than the STN, such as the substantia nigra cannot be completely excluded. However, we consider this less likely as all patients experienced good benefit on motor symptoms (other than gait) without adverse effects following STN stimulation prior to enrolment indicating placement within motor area of the STN.
In conclusion, this prospective study provides preliminary evidence that ILS of the STN may be beneficial in alleviating FOG in patients with advanced PD receiving conventional STN stimulation or despite low frequency stimulation. Randomized controlled studies of ILS with blinded objective outcome assessment including a larger number of patients are needed to confirm these findings.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Sree Chitra Tirunal Institute for Medical Sciences and Technology, Comprehensive Care Center for Movement Disorders in-house research funds.
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2]