Intrajejunal Infusion of Levodopa/Carbidopa for Advanced Parkinson's Disease: A Systematic Review

ABSTRACT Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device‐aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open‐label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%–26%) commonly relate to device‐related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well‐controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

A BS TRACT: Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. Advanced Parkinson's disease (APD) is characterized by severe treatment-related motor fluctuations and worsening motor symptoms, significant nonmotor symptoms, impaired quality of life (QoL), and prominent disability. 1 Device-aided therapies, which include intrajejunal infusion of levodopa/carbidopa intestinal gel (LCIG), deep brain stimulation (DBS), and continuous subcutaneous apomorphine infusion, are often initiated in APD for fluctuating response to conventional oral levodopa and adjunct agents (eg, catechol-o-methyl transferase inhibitors), severe dyskinesia, difficulty administering oral medications, or unacceptably high caregiver burden. An intestinal gel consisting of entacapone combined with LCIG has also been studied recently as a means of increasing levodopa plasma concentration. Device-aided therapy uptake has increased recently, 2 possibly related to protocols and insights from experienced practitioners, which helps less familiar clinicians incorporate these options. 3 Each device-aided therapy has merits and drawbacks, necessitating careful consideration of their appropriate selection and use, including attention to individual patient and caregiver needs.
A previous systematic review by Wirdefeldt et al. 4 provided a comprehensive assessment of the effects of LCIG on motor symptoms and dyskinesia, nonmotor symptoms, QoL, and safety. This review concluded that moderately high evidence exists that LCIG reduces fluctuating motor symptoms and improves QoL while pointing out issues with the quality of evidence overall and especially for reduction of nonmotor symptoms. Other systematic and narrative reviews have provided practical recommendations on LCIG, including patient selection, efficacy and tolerability profiles, and contraindications. [5][6][7][8] Despite this, several issues remain incompletely resolved. These include the effect of LCIG on specific motor complications and symptoms, specific nonmotor symptoms (especially impulse control disorders [ICDs] and sleep), activities of daily living (ADL), QoL, and caregiver burden. The optimal duration of administration and timing of initiation in relation to disease progression and patient age also require further attention. Finally, detailed information on discontinuation has been lacking. Physician and patient focus group discussions suggest that evidence-based decisionmaking regarding APD is suboptimal and highlight the importance of individual patient preferences. 9 Consequently, this review aims to address these issues with a focus on more recent evidence.

Search Strategy
Relevant human studies were searched using PubMed (up to November 3, 2020) with the following search terms: "parkinson disease," "parkinson's," "levodopa," "carbidopa," and "infusion." Boolean operators combined search terms using the "OR" operator within categories and the "AND" operator for terms between categories.

Eligibility Criteria
Articles were screened for relevance to LCIG and to: (1) motor complications and individual symptoms of APD; (2) nonmotor symptoms; (3) functioning, QoL, and caregiver burden; (4) optimal timing of treatment initiation and administration duration; (5) discontinuation; and (6) common complications. Articles comprising nonclinical design (eg, pharmacokinetic studies), no reportable relevant data, published >10 years ago or interim results, non-English language, small patient numbers (n ≤10), nonstudy publication types (eg, narrative reviews, letters to the editor), or studies of different disease states were excluded. Citations from recent reviews were reviewed to source additional relevant articles.

Quality Assessment
Quality was assessed using a five-point rating scale modified from the Oxford Centre for Evidence-based Medicine (available at: https://www.cebm.ox.ac.uk/ resources/levels-of-evidence/ocebm-levels-of-evidence) for ratings of individual studies and based on study type: 1 = properly conducted randomized clinical trial, systematic review with metaanalysis; 2 = well-designed controlled trial without randomization, prospective comparative cohort trial; 3 = case-control studies, retrospective cohort studies; 4 = case series, cross-sectional studies; and 5 = case reports, opinion of respected authorities. Studies were also assessed in terms of susceptibility to bias and other limitations as reported in the publication or assessed by the authors. However, no quantitative analyses of treatment effects were conducted. Figure 1 shows the search process and results, including reasons for article exclusion. After screening and eligibility assessment, 56 core articles were included (Table S1)

Effects of LCIG on Dyskinesia
The effects of LCIG on motor complications were assessed in a US pivotal 12-week double-blind study of patients with APD of approximately 10 to 12 years in duration, 10 which compared LCIG with oral levodopa/ carbidopa, and a 52-week open-label extension study. 11 Recent observational studies demonstrate that LCIG reduces OFF time and increases ON time with no disabling dyskinesia (ie, without troublesome dyskinesia) typically by approximately 4 hours for each endpoint over mean administration periods of up to 10 years (Table 1). [12][13][14][15][16][17][18] A metaanalysis supports these results but showed no reduction in ON time with troublesome dyskinesia. 19 Regarding the effect of LCIG on troublesome dyskinesia, recent studies, including a post hoc analysis of the pivotal GLORIA registry trial, suggest LCIG has greater benefits in reducing dyskinesia among patients experiencing greater dyskinesia episodes at baseline, [19][20][21] possibly because of patient characteristics and the altered mode of delivery, which has been suggested to achieve more constant blood levels 22 and an increase in the threshold for levodopa-induced dyskinesia. 23 In a comparative study of LCIG and DBS, both procedures improved mean waking OFF time in association with improvements in Unified Parkinson's Disease Rating Scale Part II (UPDRS II), UPDRS III, and UPDRS IV, 24 and LCIG has also been shown to be potentially beneficial in DBS patients who have refractory symptoms. 25 Diphasic dyskinesia associated with LCIG was specifically reported in a small number of articles. In one study (n = 33), four patients (12.2%) with disease duration of 14 to 21 years and motor complications for 8 to 10 years experienced disabling diphasic dyskinesia after LCIG initiation. 26 Patients were managed by increasing morning and continuous LCIG flow generally followed by combination dopamine agonists and sustainedrelease levodopa formulations during bedtime. A more recent retrospective cross-sectional survey of patients with atypical phenomenology (eg, biphasic-like dyskinesias) reported atypical (long-lasting) biphasic,  biphasic-like (continuous), or mixed (peak-dose and continuous biphasic) dyskinesias after levodopa infusion in 30 of 208 patients (14.4%). 27 Increasing the dopaminergic load improved biphasic-like dyskinesia in about half of affected patients, whereas mixed dyskinesias had the worst outcome and a high discontinuation rate.

Effects of LCIG on Axial Symptoms and Gait
Axial symptoms (eg, dysarthria, dysphagia, dyspnea, and balance/walking difficulties) are largely mediated by nondopaminergic pathways and are difficult to treat with levodopa. 28 An open-label study suggested that LCIG improves freezing of gait (FOG) and other gait/ balance parameters, 29 as confirmed more recently in larger populations 30,31 and during periods of over 4 years in patients with disease duration of 18 years at end of follow-up. 32 Over long-term follow-up, axial scores and FOG gradually deteriorated, although milder disease severity predicted better axial outcomes, whereas lower baseline axial response to levodopa predicted a worse outcome in terms of FOG and lower long-term ADL independence.

Effects of LCIG on Nonmotor Symptoms
Nonmotor symptoms in APD, including neuropsychiatric symptoms, cognitive dysfunction, hyposmia, pain, fatigue/sleep disturbances, autonomic dysfunction, and weight loss, have a major impact on QoL and also increase caregiver burden. [33][34][35] The effect of dopaminergic therapy on nonmotor symptoms correlates with motor response in APD, 36 highlighting the importance of optimizing dopaminergic therapy to reduce the impact of nonmotor and motor symptoms.
Final results of large registry and open-label studies confirm LCIG improves numerous nonmotor symptoms as evidenced by significant reductions in total Non-Motor Symptoms Scale (NMSS), individual domain items, and other measures. 12,16,[37][38][39][40][41] Individual domains that consistently showed improvement in two studies of patients with a mean disease duration of 12.5 to 13.9 years and mean total NMSS of 69.2 to 95.5 included "sleep/ fatigue," "gastrointestinal tract," and "miscellaneous." [37][38][39] In a post hoc analysis of the 24-month GLORIA registry trial (n = 375) of LCIG in routine clinical practice, 39 the median change in NMSS total score for the overall population (−18.0, n = 170) was positively correlated with the baseline NMSS score. Further, baseline NMSS >80 was associated with the greatest proportion of responders as assessed by a decrease in NMSS ≥30 (47% vs ≤28% for other baseline NMSS groups).

Effects of LCIG on Sleep
Large-scale patient surveys suggest sleep disturbances are the most disruptive nonmotor complication of APD. 42 Improvements in the Parkinson's disease sleep scale (PDSS) score were noted in a retrospective, openlabel study (n = 14, age: 67.0 AE 11.5 years, disease duration: 12.9 AE 4.8 years) of LCIG, which found that the PDSS improved by 14% (P = 0.008) from baseline after mean follow-up of approximately 24 months. 43 An analysis of 12 LCIG-treated patients (age: 71.7 AE 4.8 years, disease duration: 16.9 AE 4.4 years) support these results, showing PDSS scores improved by 34.0% (P = 0.005), disturbed sleep improved by 31.7% (P = 0.005), and motor symptoms at night improved by 27.9% (P = 0.017) after 2 to 4 months of treatment. 44 In addition, an open-label, prospective trial (n = 15, age: 67.0 AE 6.0 years, disease duration: 12.0 AE 5.0 years), in which patients reported sleep problems (PDSS-2 total score ≥ 11), revealed that only seven patients reported sleep problems (P = 0.021) 1 year after LCIG initiation, in association with clinically meaningful total PDSS-2 reductions. 16 Finally, a subanalysis of the GREENFIELD study found a significant improvement in mean PDSS-2 from baseline (25.0 AE 10.4) to visit 3 (22.7 AE 10.1, P < 0.01). 17 Thus, LCIG generally improves sleep problems measured by PDSS probably because of improvement of nocturnal motor symptoms. Improvements in the NMSS sleep/fatigue domain were linked to QoL improvements in a post hoc analysis of the GLORIA registry study. 39 Effects of LCIG on ICD ICD (eg, compulsive gambling, binge eating) are common complications of dopamine replacement therapy associated with demographic and clinical risk factors (eg, younger age at onset, more frequent dyskinesia) that greatly impair patient functioning and QoL and are especially disruptive for caregivers. 45 An observational study (n = 19) showed that six of eight LCIG-treated patients with ICD had resolution of their disorder, 46 while a larger, more recent, prospective, observational study (n = 62, age: 72.7 AE 7.0 years, disease duration: 13.5 years) with 6-month follow-up found LCIG progressively and significantly improved ICD, including a 64% reduction in the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale score. 47 The GREENFIELD study (n = 145) showed significant improvements compared with baseline in the total Questionnaire on Impulsive Disorders (QUIP-RS) score and, in patients receiving LCIG for <1 year before the first visit, the QUIP-RS subitems sexual behavior, eating, and medication use. 17 These improvements were considered to be caused by reduction of dopamine agonists.

Effects of LCIG on ADL, QoL, and Caregiver Burden
Depression, disability, impairments in physical function, especially FOG and postural immobility, and sleep disturbances are important determinants of QoL in PD, whereas specific motor symptoms (eg, tremor) have relatively minor influence. 42,48,49 A considerable number of studies indicate that LCIG positively affects QoL (Table 2). [12][13][14]16,17,37,38,40,[50][51][52] Correlation analyses in one open-label, observational, prospective study (n = 12; age: 73.8 AE 7.9 years; disease duration: 12.8 AE 5.0 years) did not show significant relationships between clinical conditions and QoL or between levels of anxiety, depression, and burden with caregiver QoL, possibly because of small patient numbers. 50 In a post hoc analysis of the GLORIA registry study (n = 233), moderate positive correlations were found between the NMSS total score and Parkinson's Disease Questionnaire (PDQ)-8 total score (r = 0.46, P < 0.0001), improvements of the sleep/fatigue domain and PDQ-8 total score (r = 0.32, P = 0.0001), and the mood/cognition domain and PDQ-8 total score (r = 0.37, P < 0.0001) during a 2-year period. 39 Most recently, a prospective, open-label study of 12 patients followed for 6 months reported that LCIG improved individual QoL in both patients and caregivers as assessed by the Schedule for the Evaluation of Individual Quality of Life Questionnaire. 51 This improvement was observed despite no significant change in health-related QoL, as assessed by the PDQ-39, and was thought to be influenced by psychological factors given that family and relationships were rated highly by both patients and caregivers. ADL have been assessed in open-label studies of LCIG, mostly via UPDRS II scores and the Schwab and England Activities of Daily Living scale. In one study of 37 patients, the median Schwab and England Activities of Daily Living score increased significantly from 50 at pretreatment to 80 after 3 months of LCIG treatment (P < 0.001), 14 and patients went from being dependent and having difficulties with all activities to being completely independent in most chores. Similarly, UPDRS II scores increased significantly in several other studies, including at periods as early as 3 months after baseline and over longer periods of followup. 15,17,21,38 Hence LCIG may improve ADL along with improvements in motor complications. LCIG has also recently shown beneficial effects on workplace participation in a retrospective study from three centers in Sweden and Denmark in which most patients could perform workplace activities to the same extent or more 5 years after treatment introduction. 53 Few studies have assessed caregiver burden of patients receiving LCIG. The effect of LCIG on caregiver burden has been commonly assessed by the Zarit Burden Interview (ZBI) and depression or anxiety indices. Over long-term follow-up in one observational study of LCIG (n = 37), ZBI scores significantly improved by 20% at 3 months in 9 patients (P = 0.042), although improvement was lower and nonsignificant after 1 year. 14 A similar open, prospective study (n = 12, age: 73.8 AE 7.9 years) also found improvements in caregiver burden, anxiety, depression, and QoL. 50 In a more recent cross-sectional, epidemiological study conducted among 126 patients (age: 69.3 AE 8.0 years) and their caregivers (age: 57.9 AE 12.9 years), ZBI scores tended to be lower among LCIG-treated patients than those treated with continuous subcutaneous apomorphine infusion or standard of care. 54 LCIG appears to have a favorable impact on caregiver burden, 55-57 although more well-designed prospective studies are needed.

Optimal Timing of Treatment Initiation and Diurnal Administration Duration
Optimal Age Range for LCIG Initiation Previous recommendations suggested that age does not affect LCIG efficacy despite being preferred in older, frail patients because of improved tolerability 58 and a greater ability to discontinue treatment if necessary. However, studies to date provide conflicting conclusions and suggest that earlier LCIG initiation in younger patients and those with shorter disease duration may improve outcomes. 59 One prospective, open-label study (n = 28, age: 67.6 AE 6.1 years, disease duration: 15.5 AE 4.0 years) of 24-month LCIG treatment concluded that younger patients had better outcomes in terms of OFF time response (>50% improvement in UPDRS item 39). 29 However, although statistically significant (P = 0.039), the difference in mean age was <2 years between responders and nonresponders, and patient numbers were low (12 and 5 patients, respectively). A larger, retrospective analysis (n = 113, median age: 65 years, median disease duration: 12 years) of LCIG in a real-world setting found men ≤60 years old had greater improvements in mean OFF time (89.8%) than men >60 years old (82.6%), although this difference was not observed in women (81.9% vs 83.2% for ≤60 vs >60 years old, respectively). 60 Further, analysis of the GREENFIELD study found that younger age correlated with slightly more disabling complications, and shorter disease duration (<13 years) led to better outcomes for motor complications and ADL. 17 These results are partly supported by a retrospective analysis of 177 patients who reported significantly greater reduction in OFF time among patients with disease duration less than 10 years than in patients with disease duration of 10 years or greater (−38% vs −29%, P = 0.021). 61 In contrast, a recent analysis of a 54-week phase III study (n = 324) that examined responder and nonresponder characteristics suggested that age and disease duration do not influence LCIG response. 40 Overall, effects of age or duration of disease on LCIG outcomes appear modest, despite evidence suggesting shorter disease duration may improve outcomes.

Optimal Duration of Diurnal Administration with LCIG
Few studies have compared the approved 16-hour LCIG infusion with 24-hour infusions, which may be  16-hour infusion) found that the incidence of de novo adverse events was not significantly increased by the longer infusion period. 63 In contrast, total UPDRS IV and complexity of motor fluctuations subscore were significantly reduced after approximately 1 year with 24-hour infusion compared with 16-hour infusion. Despite these suggested benefits, current evidence suggests 24-hour LCIG infusions should remain limited to certain situations (eg, unresponsive motor complications, severe nocturnal disability). Larger studies are needed to determine benefits of diurnal infusion versus potential drawbacks, apart from expected increases in dosage and medication costs.

Discontinuation
Previous evidence summaries have highlighted the complexity of LCIG discontinuation, including a lack of consensus regarding the effects of age and other variables. 7 Real-world use studies involving large patient numbers and long-term follow-up periods provide the most robust evidence regarding the rate and characteristics of LCIG discontinuation (Table 3). 15,66,67,[69][70][71] In an integrated safety analysis from four prospective multicenter clinical trials, discontinuations related to adverse events were seen in 17% of 412 patients enrolled in open-label studies. 66 A retrospective review of 905 patients included in a survey of Italian specialists on clinical and practical aspects of LCIG therapy reported an overall discontinuation rate of 25.7%, with 9.5% of discontinuations in the first year. 70 This annual rate is similar to that of an open-label phase III study of 262 patients with a disease duration of approximately 10 years who completed a 12-week double-blind study and 52-week open-label extension or a separate 54-week open-label study. 15 More recently, a long-term, retrospective, longitudinal study of 105 consecutive patients with a total mean levodopa-equivalent daily dose of 1148 mg reported a comparable discontinuation rate of 22% after a mean treatment duration of 3.0 AE 2.6 years. 64 Analysis of mortality predictors showed that mortality was not significantly different between patients who discontinued and those who continued LCIG, nor did it correlate with the number of serious adverse events, whereas lower Mini-Mental State Examination score at the start of LCIG did predict higher mortality. Another retrospective study of 204 patients observed over a 10-year period reported a highly similar discontinuation rate (21%), which was linked to a more severe clinical picture in terms of motor symptoms and cognitive decline, greater incidence of peripheral neuropathy, and shorter disease duration at baseline. 65 Indeed, approximately half of the patients who dropped out were receiving 24-hour infusion. A slightly lower discontinuation rate (18.4%) was noted in a recent retrospective cohort study of 98 patients receiving long-term LCIG (age: 66.2 AE 8.2 years; disease duration: 12.3 AE 5.4 years), which also conversely reported that shorter disease duration at baseline was associated with a lower rate of discontinuation. 68 Discontinuation rates were also noted to be lower among patients receiving LCIG monotherapy compared with LCIG polytherapy in a post hoc analysis of the GLORIA registry study. 21 Complications related to the device, lower than expected efficacy, and death tended to be the most consistently noted events leading to discontinuation throughout relevant studies. 20,[64][65][66]68,70 Complications of LCIG Complications of LCIG are generally divided into device-or procedure-related issues and those arising from levodopa/carbidopa administration. Device-related complications were commonly noted in the literature reviewed and especially included dislocation, migration, occlusion, and kinking of tubing, deterioration of connectors, and accidental removal. 10,12,15,20,21,24,37,43,61,66,67,69,72 Procedure-related complications were typically less common, but prominent among these were stomal and other infection, abdominal pain, granuloma formation, and pseudoperitoneum. 15,16,24,25,37,38,66,67,72,73 Levodopa-related complications associated with LCIG noted in the literature included hallucinations, confusion, psychotic disorders, insomnia, falls, and dyskinesia. 15,16,21,24,25,38,63,66,67,69,[72][73][74] In addition, weight loss and peripheral neuropathy were noted throughout the literature and have been specifically assessed in several studies. In two separate observational studies of patients with long-term disease duration of approximately 15 years, mean weight losses of 3.0 kg over 32 months and 7.6 kg over 52 months were reported. 37,75 Another long-term study reported similar levels of weight loss, and although almost half of all patients had weight loss ≥7.0%, only 3.8% of patients had serious weight loss. 15 One open-label, observational study found that the extent of weight loss correlated significantly with the percentage of the waking day spent with dyskinesia, whereas nutritional status correlated with motor symptom severity, dysphagia, and levodopa-equivalent daily dose. 15 Regarding peripheral neuropathy, an earlier prospective observational study reported more severe neurographic abnormalities in 15 patients who had received LCIG for an  42.4 (24-72) months. 78 The authors suggested that chronic vitamin B supplementation may stabilize newonset and preexisting peripheral neuropathy, even if it is not able to fully prevent new cases.

Discussion
The findings of this review corroborate those of previous reviews and literature-based recommendations, although more recent data have clarified issues that may affect device-aided therapy selection. In Europe, LCIG has been available since approval in 2004, whereas the US Food and Drug Administration provided approval in 2015. More recent evidence suggests LCIG is associated with benefits for nonmotor symptoms (particularly sleep and ICD), QoL, and functional activity, which have become prioritized as the need for device-aided therapies expands. A randomized 26-week study comparing LCIG with optimized medical treatment with regard to nonmotor symptoms is also nearing completion (ClinicalTrials.org: NCT02549092), which will assess changes in the PDSS-2 total score and NMSS total score in addition to multiple secondary outcomes, including impulsivity, depression, and pain. The mechanisms by which LCIG improves sleep and fatigue are potentially harder to understand than with DBS but may relate to treatment "simplification." 16,79 Larger studies are needed to clarify the sleep benefits of LCIG, but it is reasonable to propose that LCIG does not worsen sleep quality and may provide at least subjective improvements. Further studies examining ICD, including LCIG-related mechanisms such as reductions in pulsatile dopaminergic stimulation, are also needed.
The effect of device-aided therapies on caregiver burden has become a focus of research given its practical importance. Improvement in caregiver burden with LCIG might relate to improved mobility, which reduces the need for physical care, 50 and improvement in nonmotor phenomenon (eg, sleep disturbances, ICD). 54 Finally, research on device discontinuation is of significant practical value to both physicians and patients/ caregivers. Complications prompting LCIG discontinuation are more common than those for DBS but generally less serious, and the ability to easily discontinue LCIG after repeated complications or lack of efficacy may be a feature of this device-aided therapy.
Overall, treatment selection should consider individual patient circumstances with input from caregivers. Our review suggests LCIG appears favorable for addressing both motor and nonmotor symptoms of APD. Effects of LCIG on caregiver burden and nonmotor symptoms, including impulsivity, should also be taken into account. In addition, a shorter duration of disease may affect the response to LCIG treatment, 80 but lifelong cost-effectiveness should be considered at the same time. The main limitations of this review are related to the quality of the evidence of included studies, lack of consistency in reporting among similar studies, and the decision to limit our search to a single database. Limitations of the current evidence also include a lack of studies directly comparing different alternatives. Despite difficulties in conducting such studies, greater consistency in trial design and reporting may make indirect comparisons and pooling of results more reliable. Further, although the underlying mechanisms that explain the benefits of different devices are known to some extent, few studies have specifically examined this aspect of treatment. On a positive note, later studies have correlated benefits and outcomes with baseline patient characteristics, which should give practical assistance to clinicians in relation to treatment selection.