LCIG in treatment of non‐motor symptoms in advanced Parkinson’s disease: Review of literature

Abstract Background For managing nonmotor symptoms (NMS) in advanced Parkinson's disease (PD), levodopa–carbidopa intestinal gel (LCIG) infusion is of interest as it shows lesser plasma fluctuations of both drugs as compared to oral levodopa–carbidopa (LC). Objectives To highlight LCIG effect in NMS among advanced PD patients and appraise the currently available literature. Methods PubMed screening (till 2020) of 184 articles was done, of which 51 were selected. Among them, 23 original articles relevant to the research question were included, of which 6 were then excluded after careful reading of full articles. The 17 relevant studies of the review provide Grade C level of evidence of efficacy. Results LCIG is beneficial in improving or relieving various NMS especially (mood, cognition/memory, sleep, gastrointestinal symptoms, urinary symptoms, and quality of life questionnaires) in patients with advanced PD. Amelioration of motor functions or direct relations may lead to improvement in NMS PD patients using LCIG. Adverse events noted in patients treated with LCIG include pneumoperitoneum, abdominal pain, stoma infection, reversible peripheral neuropathy, local tube problems, impulse control disorder, and weight loss. Serious adverse events were mostly found to be unrelated to LCIG. Conclusions LCIG provides an uninterrupted intestinal levodopa infusion by percutaneous endoscopic gastrojejunostomy (PEG‐J). It effectively decreases plasma fluctuations of levodopa and reduces motor instability and NMS burden in advanced PD. However, adequate dose modification and individualization of therapy are essential for optimal effect.


| INTRODUC TI ON
Parkinson's disease (PD) is one of the most common neurodegenerative disorders that majorly affect elderly individuals. Degeneration of dopamine-producing brain cells (owing to their high energy demands) leads to the development of PD (Mamelak, 2018;Benamer, de Silva, Siddiqui, & Grosset, 2008). According to the Global Burden of Diseases, Injuries and Risk Factors Study (2016), globally 6.1 million people suffered from PD (Collaborators GBDPsD, 2018). The primary motor symptoms observed in PD patients include tremors, bradykinesia (slow movement), muscle stiffness (rigidity), and postural instability. Apart from motor symptoms, nonmotor symptoms (NMS) associated with PD are depression, anxiety, sleep disturbances, constipation, fatigue, cognition loss, urinary complications, and impairment of olfaction (Al-Mubarak et al., 2015;Luquin, Kulisevsky, Martinez-Martin, Mir, & Tolosa, 2017;Shrestha et al., 2017). Advanced PD is characterized by further progression in motor and functional deterioration, and worsening of motor and NMS complications. For patients with advanced PD, conventional therapy may not be enough for the management of the condition (Al-Mubarak et al., 2015;Luquin et al., 2017;Shrestha et al., 2017).
Various alternative therapies known as "device-aided treatments" are available for the management of motor symptoms; however, NMS are not focused by the presently available therapies (Kelberman & Vazey, 2016;Luquin et al., 2017).
Nonmotor symptoms may result from dopaminergic or nondopaminergic neurotransmissions, thus cannot be completely improved with dopamine replacement therapy alone (such as levodopa alone), the gold standard for treatment of PD (Tomlinson et al., 2010;Tsui & Isacson, 2011). Moreover, higher doses of levodopa may complicate PD and lead to NMS (Tomlinson et al., 2010). Furthermore, there is a need to resolve the significant challenge associated with oral levodopa-carbidopa (L-C), that is, the variability and fluctuations in levodopa-carbidopa plasma concentration. This has encouraged researchers to evaluate the efficacy and safety of levodopa-carbidopa intestinal gel (LCIG) infusion.
Studies suggest that both drugs (levodopa and carbidopa) when given as infusion gel show minor variation and fluctuations in plasma concentration compared to levodopa-carbidopa-oral and are therefore of great importance in improving NMS associated with PD (Othman, Rosebraugh, Chatamra, Locke, & Dutta, 2017).
Thus, to highlight the effects of LCIG in treatment of NMS among advanced PD patients, we conducted this study appraising the currently available literature for identifying gaps in the available evidence.

| Ethical compliance statement
The authors confirm that the approval of an institutional review board and informed patient consent was not required for this work.
The objective was addressed using a structured, evidence-based, critically appraised topic (CAT) format. This includes structuring a focused and answerable clinical question, search strategy, identifying and evaluation of evidence, reporting and interpretation of results, and bottom-line clinical conclusions.
Structured Question: Is LCIG effective for the treatment of NMS in advanced PD?

| Search strategy
We searched the electronic database PubMed till 2020 to identify relevant studies performed using the search terms: levodopa AND carbidopa AND Parkinson's disease AND non-motor; levodopa AND carbidopa AND Parkinson's disease AND non-motor symptom; levodopa AND carbidopa AND Parkinson's disease AND non-motor symptoms AND efficacy. Original research articles, case reports, and systematic reviews were considered for inclusion in the present CAT. Further, all animal studies, letters to editors, and narrative reviews were excluded. Only articles published in the English language were considered for inclusion. No time limit was applied for searching articles.

| Identified evidence
Our literature search resulted in 184 articles on PubMed. Of these, 51 articles were selected, and 133 were excluded. Original research articles were preferred over other study types. Review articles were not excluded from the search initially to identify relevant articles from the bibliography of these articles. The titles and abstracts of all the articles were screened to identify the relevant ones. Full texts of all potentially relevant articles were procured for further screening. The bibliographies of these articles were examined for any additional pertinent citations. After going through the shortlisted 51 articles, 38 were original research articles, one was a case report, four were systematic reviews, seven were letters to the editor, and one full article was in non-English language. Of these 38, 23 original articles, providing data relevant to the research question, were included. Among them, 17 papers commented on effect of LCIG treatment on NMS in PD patients. The excluded 6 articles focused on the stability of plasma levodopa levels and bioavailability (two articles), while one reported cost-effectiveness analysis. Another two articles discussed the beneficial effects of the addition of entacapone to levodopa and carbidopa therapy. One article was excluded due to inconsistent screening of NMS, hence excluded. The detailed study selection criteria are illustrated in Figure 1.

| Evaluation of evidence
Selected articles demonstrated the effect of LCIG on patients with PD, wherein an improvement in NMS was observed in most of the articles. These studies demonstrated that the intestinal gel formulation helps in bypassing gastric emptying and overcoming fluctuation in plasma drug levels. The study characteristics of all the articles included in the present CAT are presented in Table 1.

| Nervous system (CNS) symptoms
Among the NMS of the CNS, the impact of LCIG on mood changes was reported in nine studies. Of these, Valldeoriola et al. (2016) evaluated the effect of LCIG on both motor and nonmotor symptoms in 177 patients and showed that flat mood improved in 99 (56%) patients with LCIG. Bellante et al. (2016) in their prospective, observational study reported mood improvement in nine of ten study patients, which were significant after two months of treatment with LCIG (p < .01). NMSS domain 3 for depression was improved in a study by Fasano et al. (2012)  An improvement in anxiety was reported in three of 17 studies. Bellante et al. (2016) observed improvement in seven of ten patients, with significant improvement after one month of treatment (p = .06). A longitudinal analysis of 53 patients showed significant improvement in Beck Anxiety Inventory (BAI) between baseline and follow-up visits (Wetmore et al., 2019). Psychiatric symptoms were significantly improved as revealed by the significant reduction of UPDRS-I, Neuropsychiatric Inventory (NPI), Questionnaire for ICD in PD (QUIP), and specific items of NMSS, overall there was a significant improvement of depressive symptoms and psychiatric SE caused by dopamine agonist (DA) (i.e. delusions and ICD; Fasano et al., 2012). As per a study by Buongiorno et al. (2015), number of patients with hallucination/ psychosis at baseline slightly increased during treatment from 10 increased to 13.      Buongiorno et al. (2015) from baseline to last visit in the percentage of patients.
Patients treated with LCIG may significantly improve some spe-  Honig et al. (2009)

| Gastrointestinal tract symptoms
Various studies showed improvement in gastrointestinal tract (GIT) symptoms, of which Buongiorno et al. showed a decrease in the number of patients with constipation from baseline (58%) to during the last visit (46%, p < .0001; Buongiorno et al., 2015).
Gastrointestinal (GI) symptoms improved in six studies (Standaert et al., 2017). A study by Honig et al. (2009)  Drooling/dribbling improved in one study by Honig et al. (2009) in terms of a decrease in the number of patients with symptoms and symptom score from baseline to six months, respectively.

| Systemic symptoms
Thirty-eight percent of patients included in the study conducted by Blaise et al. (2020) experienced a weight loss; about half of these lost more than 7% of their initial weight (Wang et al., 2018), between 6.7% and 24.3% of patients treated by LCIG experience weight loss De et al., 2017). However, these studies did not report data on enteral nutrition. Parkinson's Fatigue Scale (PFS-16) was significantly improved between baseline and follow-up after 6 months in the study by Wetmore et al. (2019).
The effect of LCIG on pain in PD patients was evaluated in three of 17 studies included in the CAT. As per a study by Honig et al. (2009), an improvement in miscellaneous symptoms including pain was noted (p = .0004). Buongiorno et al. (2015) showed a reduction in the number of patients with painful paresthesia from baseline (48%) to last visit (30%, p < .0001).
Excessive sweating/hyperhidrosis improved in two of the 17 studies included. A study by Fasano et al. (2012) reported a significant improvement in excessive sweating as assessed by NMSS domain 9 (p = .00097). Another observational, prospective study by Buongiorno et al. (2015) demonstrated a significant decrease (p = .0015) in the percentage of patients with hyperhidrosis from baseline (60%) to last visit (33%).

| Urinary symptoms
Urinary symptoms improved in a total of three studies and a trend for improvement in one (Cáceres-Redondo et al., 2014). While the GLORIA registry reported the effect of LCIG therapy on urinary symptoms at month 12 from baseline (−2.8 ± 8.7, p = .0199), the study did not report the effect on these outcomes at month 24
A long-term global study assessed the effectiveness of LCIG in 375 patients across 18 countries. The study reported significant improvement in UPDRS II, UPRDS III "On" scores, total NMSS, and PDQ-8 from baseline to follow-up at month 12 (p = .0107, p = .0128, p = .0014 and p = .0100; Antonini et al., 2015).

| Adverse events of LCIG
Various AEs found to occur in clinical studies include pneumoperitoneum, abdominal pain, stoma infection, gastrostomy, reversible peripheral neuropathy, local tube problems, ICD, weight loss, and worsening of dysphagia Wetmore et al., 2019;Buongiorno et al., 2015;Antonini et al., 2015;Krüger et al., 2017;Valldeoriola et al., 2017). Serious adverse events were mostly found to be unrelated to LCIG (Palhagen et al., 2012;Wang et al., 2018) The details of the AEs reported in various studies are presented in Table 1.
A study assessing the long-term response to LCIG (mean observation time of 22 months and a maximum of 48 months) reported that 28 patients discontinued the study with reasons being stated as inefficacy (n = 13) or AEs related to the drug (n = 8). The AEs reported were severe dyskinesias, symptomatic orthostatic hypotension, bothersome sleepiness, uncontrolled punding, and anorexia.
The study showed a significant increase in the percentage of the day with dyskinesias after the treatment (30% before treatment versus 40% in LV, p = .019). But when analyzed by dividing the study population into two groups (group 1: less than 50% of the day with dyskinesia versus group 2: more than 50% of the day with dyskinesia), group 2 showed significant improvement in the percentage of day with disabling dyskinesias (p = .04). It is important to conduct more studies with various patient profiles to assess, which responds better to LCIG treatment (Buongiorno et al., 2015).
A study from the Middle East assessing the safety of LCIG in PD patients reported 78.8% of the patients to have developed at least one AE. The complications reported were stoma infection (n = 2); maculopapular rash (n = 1); pump replacement (n = 5) in lieu of breakage or malfunctioning; and tube replacement (n = 12) resulting from accidental tube dislocation/slippage outside the body, tube dislocation to the stomach, and tube blockage due to knot formation.
However, these were minor device-related AEs and not classified as serious .
One-third of the patients assessed in a study by Krüger et al. (2017) experienced an AE possibly related to LCIG, as rated by the study investigator. Two patients (3.1%) died during the study, and causes of death were cardiac failure and sudden death; both deaths were deemed by the investigator as having no reasonable possibility of being related to LCIG; seven patients (11.1%) discontinued LCIG treatment because of AES (Krüger et al., 2017).
A recent meta-analysis of 8 studies reported heterogeneity in nonserious adverse event (AE) (I 2 = 52%, p = .06), while no heterogeneity was reported in serious AE (I 2 = 0%, p = .76). No incident of death was reported in most of the included studies. However, one study reported four deaths (control, n = 2, and LCIG, n = 2).
Investigator classified the relationship of death to study drug as unlikely related (n = 1) to medications, unrelated (n = 2), and possibly related (n = 1; cardiac arrest; Wang et al., 2018).
A retrospective analysis of data on AEs in patients treated with LCIG at a French university medical center showed that 90% of patients experienced at least one AES. Most of them were related to PEG-J or affected the gastrointestinal tract, device-related AES was frequent in 63.5% of patients, and dopa therapy-related AES occurred in 48% of patients (Blaise et al., 2020).
Thus, all these relevant studies provided Grade C level of evidence for LCIG efficacy.

| CON CLUS IONS
The

ACK N OWLED G M ENTS
The authors acknowledge Turacoz Healthcare Solutions, Gurugram, India (www.Turac oz.com), for writing support.

CO N FLI C T S O F I NTE R E S T
Walaa A. Kamel and Jasem Y. Al-Hashel have received honoraria for research support from AbbVie.

AUTH O R S ' CO NTR I B UTI O N
Both the authors contributed to conception, organization, and execution. Both the authors contributed to manuscript drafting and revision. All authors approved the final version of the manuscript and agree to be accountable for the content of the work.

A FFI R M ATI O N
The authors confirm that the work is consistent with the journal ethical guidelines.

PEER R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.1757.