Levodopa-carbidopa intestinaL geL therapy in parkinson’s disease: procedure compLications

Objectives. Continuous delivery of levodopa-carbidopa intestinal gel (LCIG) represents a gold standard option for the treatment of advanced PD and the benefits of intestinal gel delivery are significative superior from those obtained with available medical therapies. We aimed to investigate the percutaneous endoscopic transgastric jejunostomy (PEG-J) use and the occurrence of procedural complications in a group of patients diagnosed with PD Hoehn and Jahr 3 and 4 stages, receiving LCIG therapy. Materials and methods. We performed an observational retrospective cohort study on 24 PD patients recruited from a single regional tertiary center in Cluj-Napoca, Romania, between 2009 and 2019. We included PD patients with Hoehn and Jahr 3 and 4 stages under LCIG therapy. results. PEG-J replacement was found in 54.2% of the patients. Erythema and inflammation at the level of stoma (37.5%) and allergic reactions (20.8%) were the most common complications. The most frequent reason for PEG-J replacement was tube dislocation (20.8%), and rarely the plied tube, the excess of adipose tissue, or bezoar (4.3% each). A third of the patients received PEG-J therapy during the night, after a median time of three years, after PEG-J initiation. A quarter of all the subjects had their Levodopa-Carbidopa therapy interrupted. The median time untill interruption was one year. The reasons for the interruption were patient, or patient’s relative refuses, for a sixth of the cases, or gastric polyps, in very few cases. conclusions. The most frequent complication of LCIG delivered by PEG-J was erythema and inflammation at the level of stoma. However LCIG therapy discontinuation was in particular due to the decision of the patient or relatives.


INtrODUctION
Parkinson's disease (PD) is a chronic and progressive movement disorder and the second-most common neurodegenerative disorder in the world [1][2][3][4]. in 2015, 6.2 million people were diagnosed with PD, with 117,400 deaths/year globally [3].
PD is associated with progressive disability and mobility-related impairments with increased mortality and decreased quality of life for patients and their families [5][6][7][8][9][10]. if the onset of the disorder ap-pears in the fifth decade, it is called early-onset PD, but the disease typically occurs in people in the seventh decade. the symptomatology is dominated by the motor fluctuations and the alteration between "on" (mobility often with dyskinesia) and "off" (immobility) episodes [4]. levodopa and carbidopa represent the primary therapy of PD. Because their absorption is made in the small bowel, a decreased level of absorption leads to a low quantity of dopamine in striatal level, with the primary clinical manifestation represented by an "off" episode. The narrowing of the therapeutic window, after a period of efficient oral therapy, is a significant source of severe complications, including memory loss, hallucinations, delusions, sleep disturbances, anxiety, constipation or diarrhea, fecal incontinence, dysphagia, and dyskinesia.
the most crucial goal of PD therapy is to reduce "off" episodes without inducing the development of dyskinesia. levodopa-carbidopa intestinal gel (lcig) continuous administration through an intrajejunal percutaneous gastrostomy tube, has the effect of a more consistent dopaminergic stimulation in the brain and noticeable clinical improvement [4][5][6][7][8][9][10]. continuous delivery of lcig represents a gold standard option for the treatment of advanced PD, and the benefits of intestinal gel delivery are significantly superior from those obtained with available medical therapies.
nevertheless, there are gastrointestinal complications associated with this method of drug administration.
this study aimed to investigate the Peg-J use and the occurrence of procedural complications in a group of patients diagnosed with PD Hoehn and Jahr 3 and 4 stages, receiving lcig therapy.

study design and setting
We performed an observational retrospective cohort study on 24 patients diagnosed with PD from a single third level center, in cluj-napoca, romania, between 2009 and 2019.

Patients
inclusion criteria were PD patients with Hoehn and Jahr 3 and 4 stages receiving lcig treatment. exclusion criteria were: unclear diagnosis of PD, other parkinsonian syndromes, neurodegenerative diseases, concomitant narrow-angle glaucoma, having contraindications for the placement of a nasogastric probe or jejunal tube and oncological diseases.

Variables
The data was collected from medical files and the electronic records of the hospital. We collected demographic data (age, gender, place of residence), PD symptoms and stadialization (disease duration, Hoehn and Yahr at baseline, UPDrs ii and iiiinitially), Peg-J (percutaneous endoscopic transgastric jejunostomy) use, interruption and reasons for interruption during night, Peg-J placement refusal reason, interruption of intrajejunal levodopa-carbidopa therapy, Peg-J interruption motive, Peg-J complications, Peg-J replacement, and reasons for replacement. The unified Parkinson's disease rating scale (UPDrs) is commonly used to assess the clinical evolution of Parkinson's disease, both in hospitals but also in studies [5].

statistical analysis
categorical data were presented as counts and percentages. continuous data were presented as means and standard deviations (for non-skewed data) or medians and quartiles (for skewed data). all statistical analyses were performed with the r environment for statistical computing and graphics (r Foundation for statistical computing, Vienna, austria), version 3.6.1 [7].

Ethics statement
the study was performed in agreement with the Declaration of Helsinki and was approved by the "Iuliu Hatieganu" University of Medicine and Pharmacy ethics committee. rEsULts the study included 24 subjects with a mean age of 70.1 years (standard deviation of 7.7, ranging from 55 to 85 years). there were 13 males (54.2%), the majority having urban residence (21 -87.5%).
a third of the patients received Peg-J therapy during the night, after a median time of three years, after Peg-J initiation (see table 1). a quarter of the subjects in this group had interrupted the therapy after a median time of one year, mainly due to patients, or patients' relative request. a quarter of all the subjects had their lcig therapy interrupted. the median time till interruption was one year. the reasons for the interruptions were patient, or patient's relative refuses, for a sixth of the cases, or gastric polyps, in very few cases.
Peg-J replacement was found in half of the patients. Erythema and inflammation at the level of stoma and allergic reactions were the most common complications. the most frequent reason for Peg-J replacement was tube dislocation and rarely the plied tube, the excess of adipose tissue, or bezoar. DIscUssIONs this study succeeded in its aim to investigate the Peg-J use and the occurrence of procedure complications in a group of patients diagnosed with PD Hoehn and Jahr 3 and 4 stages, receiving lcig therapy.
several removals of Peg-J by the patient suggest severe mental deterioration, and discontinuation of lcig can be considered an option. the results were similar to our study, Peg-J removals and peristomal complications being the most frequent complications.
the decision for withdrawal of lcig might be difficult sometimes, but in most cases, at this moment, there is no benefit for the health of the patient. a close collaboration between the neurology, psychiatry, and gastroenterology department is mandatory to overcome difficult decisions like this. a study performed by Fernandez H et al. analyzed the safety and efficacy of LCIG in patients with advanced PD experiencing severe motor fluctuations defined as ≥3 hours of daily "off" episodes at baseline written in the PD symptom diary, despite optimized treatment with available PD medications [12]. the intrajejunal tube was well tolerated and only 7.6% of the patients withdrawn from the study because of adverse effects [12].
A study performed by Saddi MV et al. compared two different methods of continuous intrajejunal delivery of levodopa/carbidopa. The first method, percutaneous endoscopic gastrojejunostomy (Peg-J) and the second, radiologically inserted gastrojejunostomy (RIG) are safe and efficient procedures for gastrojejunal tube placement [13]. Because the incidence of adverse events and complications were similar in both groups, the conclusion was that rig technique is as safe and effective as Peg-J, and it can be used for patients who require lcig when the endoscopic procedure is not recommended, or the patient does not tolerate Peg-J [13].
Having taken into account the clinical results of the research and also the similar findings of other studies, this study enhances the present knowledge with more evidence supporting the important frequency of complications due mainly to replacement of Peg-J, also frequent interruptions, primarily due to patient or relative refuse. cONcLUsIONs the most frequent complication of lcig delivered by PEG-J was erythema and inflammation at the level of stoma. lcig therapy was interrupted primarily due to the patient or relative refuse. the most frequent reason for Peg-J replacement was tube dislocation, and rarely the plied tube, the excess of adipose tissue, or bezoar. a third of the patients received Peg-J therapy during the night, after a median time of three years, after Peg-J initiation.