Infusion treatments and deep brain stimulation in Parkinson's Disease: The role of nursing

Geriatric Nursing xx (2016) 1e6

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Feature Article

Infusion treatments and deep brain stimulation in Parkinson’s Disease: The role of nursing A. De Rosa, MD, PhD a, *, A. Tessitore, MD, PhD b, L. Bilo, MD a, S. Peluso, MD a, G. De Michele, MD a a b

Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, via Pansini 5, 80131 Naples, Italy Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 March 2016 Received in revised form 9 June 2016 Accepted 13 June 2016 Available online xxx

Parkinson’s Disease (PD) represents one of the most common neurodegenerative disorders in the elderly. PD is caused by a loss of dopaminergic cells in the substantia nigra pars compacta. The motor cardinal signs include a resting tremor, bradykinesia, rigidity and postural reflex impairment. Although levodopa represents the gold standard also in the advanced stage of the disease, over the years most patients develop disabling motor fluctuations, dyskinesias, and non-motor complications, which are difficult to manage. At this stage, more complex treatment approaches, such as infusion therapies (subcutaneous apomorphine and intraduodenal levodopa) and deep brain stimulation of the subthalamic nucleus or the globus pallidus internus should be considered. All three procedures require careful selection and good compliance of candidate patients. In particular, infusional therapies need adequate training both of caregivers and nursing staff in order to assist clinicians in the management of patients in the complicated stages of disease. Ó 2016 Elsevier Inc. All rights reserved.

Keywords: Parkinson’s Disease Advanced treatment Nursing Deep brain stimulation

Introduction Parkinson’s Disease (PD), the second most common neurodegenerative disorder after Alzheimer’s Disease, is a progressive condition characterized by dopaminergic neurons degeneration in the substantia nigra pars compacta of the midbrain and the presence in the brainstem and the cortex of Lewy bodies (LB), cytoplasmic inclusions mainly composed of a-synuclein fibrils.1 The mean age at onset is 60 years. The prevalence of PD in industrialized countries is generally estimated at 0.3% of the entire population and about 1% in people over 60 years of age.2 The incidence is agerelated, raising from 17.4 in 100,000 person-years between 50 and 59 years of age to 93.1 in 100,000 between 70 and 79 years.1 Men are affected 1.5 times more frequently than women, but some studies do not confirm a significant gender-related difference in the prevalence of the disease.2 The main clinical feature of PD is a progressive motor impairment, typically asymmetric at onset and characterized by slowness of movement (bradykinesia), rest tremor, muscle rigidity and postural instability.1 Most patients also show non-motor features,

The authors have no conflict of interest to report. * Corresponding author. Tel.: þ39 081 7464348; fax: þ39 081 5463663. E-mail address: [email protected] (A. De Rosa). 0197-4572/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.gerinurse.2016.06.012

including autonomic dysfunction, gastrointestinal disorders (drooling, dysphagia, constipation), dementia, psychiatric disturbances, sensory symptoms, and sleep disturbances.3 A prolonged positive response to levodopa treatment supports the diagnosis and is useful to differentiate PD from other types of Parkinsonism.1 Levodopa represents the gold standard of PD treatment and remains the most effective drug even in the advanced stages of the disease. However, over time motor fluctuations and dyskinesias may develop, appearing in about 40% of patients after 4e6 years of treatment.4 The motor fluctuations and dyskinesias depend on drug dose, clinical severity and disease duration, and often result refractory to the traditional non-invasive oral treatment.5 Therefore, new therapeutic modalities have been developed for the advanced stages of the disease, such as Deep Brain Stimulation (DBS), Continuous Subcutaneous Apomorphine Infusion (CSAI) and Levodopa-Carbidopa Intestinal Gel (LCIG), which allow a minimization of motor complications through a more constant stimulation of the striatal dopamine receptors, in an attempt to mimic the normal physiological condition. All three procedures should be performed according to strict inclusion and exclusion criteria, and require a careful selection of candidate patients and accurate monitoring of the possible side effects. The aim of this review is to focus on these complex therapies, highlighting implementation rules, effectiveness, indications, contraindications (Table 1), side effects, complications, the costs of the

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Table 1 Indications and contraindications of deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion (CSAI) and levodopa/carbidopa intestinal gel (LCIG) infusion.

Indications “On-off” fluctuations, “off” state Dyskinesias L-dopa resistant axial signs Contraindications Age >75 years Mild-moderate dementia Severe dementia Psychosis Severe depression Orthostatic hypotension Severe systemic disease Severe brain atrophy and or leukoencephalopathy Previous major abdominal surgery Peripheral neuropathy No caregiver support

DBS

CSAI

LCIG infusion

Yes Yes No

Yes Yes Yes/No

Yes Yes Yes/No

Yes Yes Yes Yes Yes No Yes Yes

Yes Yes/No Yes Yes No Yes Yes No

No No Yes No No No Yes/No No

No No Yes/No

No No Yes

Yes Yes/No Yes

three procedures, and the role of nursing in patient management (Table 2). Deep brain stimulation In the 80s, Benabid and coworkers showed that thalamus “stimulation” by an electrode implanted in the brain and connected to a high-frequency stimulator localized in a thoracic subcutaneous pocket was as efficient at reducing the tremor as lesional procedures.7 Over time, the globus pallidus internus (GPi) and the subthalamic nucleus (STN) were found to be more effective targets than the thalamus in controlling the main signs of PD, such as rigidity and bradykinesia, in addition to tremor. The DBS clinical effect consists of a motor symptom improvement similar to that obtained with supra-maximal doses of levodopa, but with better control of motor fluctuations and dyskinesias.8 The mechanism of action of DBS is unclear and widely debated. It has been hypothesized that the stimulation exerts an inhibitory synaptic effect and regulates the electric and biochemical activity of the cells in the basal ganglia, modifies the firing rate and pattern of the neuronal pool and suppresses the abnormal rhythmic oscillation between the cortex and the basal ganglia.9 These changes are able to modify local neurotransmitter release and increase brain blood flow and neurogenesis.9

To date, there is evidence that stimulation of both STN and GPi DBS improves motor function without any significant differences, even if STN stimulation allows a significant dopaminergic medication reduction, which is useful in patients who present severe dyskinesias, but, on the other hand, it leads to a faster cognitive decline.10,11 Several randomized controlled clinical trials showed that STN-DBS was able to control motor symptoms and complications, and also improved the self-reported quality of life better than the best conventional treatment up to 5e6 years after the electrodes implantation.12 Until now, few studies have investigated the long-term efficacy and safety of STN-DBS. Recently, an 11 year follow-up checked the STN-DBS long-term outcome in 26 PD patients.13 Up to the latest visit, the motor complications still appeared well controlled as compared to the baseline assessment. The dyskinesias showed an 84.6% improvement, and the reduction of motor fluctuations was still relevant (65.8%).13 Procedure The following description is based on the experience of the Grenoble team but the steps and the operative technique may vary according to the clinical setting and the experience of surgical staff.14 The withdrawal of antiparkinsonian medications at least 12 h prior to the DBS procedure is recommended. The STN target is visualized and established by brain stereotactic MRI.14 Microelectrodes are introduced stereotactically into the STN and electrophysiological assessment is performed to localize the target more easily. Patients undergo this procedure under local anesthesia, in order that the neurologist may immediately evaluate the motor benefit and possible side effects resulting from stimulation. However, general anesthesia may be used to decrease the stress and pain for the patient. When the ideal localization has been identified, the microelectrodes are removed and two chronic leads with four contacts each are placed on and fixed to the skull. Immediately after, or a few days later, the leads are connected to a stimulator which is implanted under general anesthesia in a subcutaneous pocket in the subclavicular area (Fig. 1A).14 Programming of the best stimulation parameters usually lasts for several weeks and requires accurate and extensive work by neurologists trained in PD pharmacological management, and both technical aspects and possible complications of DBS. The optimal stimulation is obtained when the selected parameters and contacts induce the best control of motor symptoms and complications, and the lowest occurrence of side effects. The optimization of stimulation requires some months, with a progressive reduction of

Table 2 Adverse events, complications, costs and nursing role related to deep brain stimulation (DBS), continuous subcutaneous infusion of apomorphine (CSAI) and levodopa/ carbidopa intestinal gel (LCIG) infusion. Costa

Side effects

Procedure Device complications complications

DBS

Cognitive dysfunction, mood disorders, axial signs worsening

Intracranial hemorrhage

Skin erosion, infection, lead fracture V 88,014 or migration $ 97,149

CSAI

Nausea, vomiting, postural hypotension, bradycardia, subcutaneous nodules, neuropsychiatric disorders

None significant

Malfunction, occlusion

V 141,393 $ 156,069

Pump malfunctioning, occlusion, disconnection, kinking, jejunal incarceration, tube leakage

V 233,986 $ 258,273

Surgical risk LCIG Duodenal ulcer, secretion from the stoma, infusion granuloma, abdominal pain, transient or persistent infections of ostomy, intestinal occlusion, peripheral neuropathy a

Mean cumulative 5 year cost per patient.6

Nursing role Patients selection, preoperative and intraoperative physical and psychological support, parameter programming, evaluation of side effects Patients selection, assisting the neurologist during the challenge test and continuous infusion, training of caregivers about skin hygiene rules, performing subcutaneous injections, management of subcutaneous nodules Patients selection, pump management, ostomy dressing, weight monitoring

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Fig. 1. A) Deep Brain Stimulation: the two electrodes placed in the basal ganglia are fixed to the skull and connected to a stimulator implanted in a subcutaneous pocket in the subclavicular area (https://www.tga.gov.au/alert/medtronic-deep-brain-stimulation-and-spinal-cord-stimulation-devices-multiple-models). B) Pump for subcutaneous apomorphine infusion is connected to a needle inserted in the skin of the abdominal wall.* (http://www.hopeparkinson.org/uploads/pagesfiles/404.pdf). C) The pump containing levodopacarbidopa gel (Duodopa) is connected to the distal duodenum and jejunum via a small tube placed through a percutaneous endoscopic gastrostomy/jejunostomy (PEG/J).* (http:// www.epda.eu.com/EasySiteWeb/GatewayLink.aspx?alId¼16254). *The pumps are lightweight and the patients can easily wear them using a shoulder strap.

dopaminergic treatment.15 See Refs. 14 and 15 for a more detailed description of the parameter settings. Patient selection The CAPSIT-PD protocol has been constituted in order to determine the steps for selection, preoperative evaluation and post-operative follow-up of candidate patients for DBS.16 Levodopa responsiveness represents the best predictor of procedure efficiency. Therefore, patients presenting symptoms mainly resistant to levodopa, such as postural instability, speech and gait disorders, should be not eligible for DBS, which may progressively worsen axial signs. Concerning age, to date there is not sufficient evidence to establish a definite limit, but some authors suggest a cut-off of 75 years, because procedure efficacy and safety have not been sufficiently studied above that age.17 Although DBS has usually been reserved for patients in advanced stages of the disease, the findings of a recent multicentre randomized trial, the EARLYSTIM trial, showed that STN-DBS performed early in the disease course (mean disease duration 7.5 years, with motor fluctuations for <3 years) improved patients’ quality of life and several secondary outcome measures more than the best medical therapy.18 The disease duration recommended by the CAPSIT-PD protocol should be at least 5 years, in order to avoid the risk of including patients with levodopa-responsive atypical Parkinsonism. Cognitive impairment represents a contraindication for STN-DBS surgery, which has been reported to cause a worsening in verbal fluency and frontal-executive functions (Table 1).19,20 A systematic assessment for psychiatric symptoms should be performed before the intervention in order to exclude severe depression,21 primary psychotic disorders, uncompensated bipolar disorders and substance abuse. Severe diseases, such as unstable heart disease, serious infections, advanced renal or hepatic failure, or malignancy, represent a contraindication since they may compromise DBS benefits, increase post-surgery complications and reduce life expectancy.11,17 Screening assessment includes a brain MRI to exclude the presence of structural lesions, severe atrophy, leukoencephalopathy or multiple ischemic lacunae, which represent exclusion criteria for surgery.17 Adverse events The most serious early complications related to the surgical procedure are intracranial hemorrhage (1% reported by the

Grenoble group), even though the occurrence of permanent disability is low, and seizures.14,22,23 After surgery, aspiration pneumonia, transient post-operative confusion, delirium and psychosis have been observed, also due to the preoperative withdrawal of dopaminergic drugs.14,22 The most frequent hardware-related complications include skin erosion (1e2.5%), infections (4%), caused by Staphylococcus aureus in 40e60% of cases, lead fracture (3.0%) or migration (2.4%).14,22 The stimulation-related side effects are usually due to diffusion of current to the surrounding nervous structures or suboptimal placement of the electrodes, and consist of tetanic contractions, dysarthria, paresthesias, double and blurred vision, eyelid-opening apraxia, and weight gain.23 These effects are usually controlled by parameters or drug dose adjustment, selection of a contact with fewer side effects, or passage to a bipolar modality, which allows stimulation restricted on the target and limits diffusion to adjacent structures. Other events such as mydriasis, flushing, sweating and gaze deviation are transient, developing habituation with various latencies (from seconds to weeks).11 Dyskinesia represents an early side effect but usually undergoes habituation; it suggests a correct placement of the electrode and may be overcome by decreasing the dopaminergic treatment dosage. As mentioned above, STN-DBS may worsen mood disorders,9,21 cognitive abilities, in particular executive functions and verbal fluency, and axial signs, such as speech, gait and balance abnormalities.24,25 The role of nursing Nursing staff should be familiar with the inclusion criteria for DBS. In the preoperative phase, it should collaborate with the medical team in selecting the candidate patients for DBS and providing adequate and comprehensive information about multidisciplinary assessments (e.g., neurosurgical, psychiatric, neuropsychological, physiatric, nutritional), procedural steps, hospital stay time and possible post-operative complications. A nurse should support and establish a trust relationship with patients and their relatives, ensuring that they have understood the information given by the neurologist and neurosurgeon and possibly clarify any questions.26,27 During the hospitalization period, the nursing staff is essential in order to keep the medical team updated about motor fluctuations and non-motor symptoms, such as pain, sleep, constipation and urinary disorders. The role of nursing is highly important in the

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preoperative and intraoperative period when the patient is in “off” condition due to drug discontinuation, and needs particular physical and psychological support. Since the implantation can last several hours, the operating room nurse should be sensitive to the patients’ various needs, chiefly when they are conscious. Special attention should be paid to sensations of cold or pain caused by the prolonged uncomfortable position, or discomfort due to the “off” condition, side effects due to stimulation, such as dyskinesias, paresthesias, diplopia, tetanic contractions. During the post-operative period, the nurse supports the neurologist in parameter programming, evaluating the effectiveness of stimulation and reporting adverse events promptly.28 After discharge, the nurse should periodically phone or visit the patients at home in order to monitor the effects of stimulation, side effects such as skin infections and erosions, referring them to the medical team, and anticipating follow-up visits, if necessary. Continuous subcutaneous apomorphine infusion The antiparkinsonian properties of apomorphine were shown by Schwab and colleagues in 1951.29 Apomorphine is a dopaminergic agonist which exerts its effect through direct stimulation of striatal postsynaptic dopamine D1 and D2 receptors. The absorption of subcutaneously injected apomorphine is rapid, bioavailability is nearly 100%, and its half-life is short (about 43 min). Its highly lipophilic nature allows fast transit to the central nervous system and explains the fast onset of the clinical response. The motor effect appears within 5e15 min after administration and depends on local factors, such as injection site (the abdominal wall is preferable to the thigh), skin temperature, and subcutaneous tissue thickness.30 Apomorphine may be administered as intermittent subcutaneous bolus to treat predictable or sudden “off” state, or as daily continuous infusion in cases of non-responsive motor complications. A consistent improvement in “off” time with a decrement between 50 and 80% has been reported by clinical studies on CSAI. This treatment is not yet available in the U.S.A., where apomorphine is currently approved only for intermittent subcutaneous administration. In recent years, other promising administration systems have been considered through the delivery of intravenous, oral, nasal, sublingual and rectal formulations.31,32 In a 12-year follow-up study which compared clinical and neuropsychological effects of STN-DBS and CSAI, both were effective on off-time reduction (76% vs 51%) and daily levodopa dose reduction (62% vs 29%), whereas dyskinesias decreased by 81% among subjects undergoing STN-DBS and did not change among those treated by CSAI.33 On the other hand, CSAI did not cause cognitive and psychiatric dysfunctions compared with DBS.34 Moreover, CSAI did not worsen dopa-resistant motor axial symptoms such as postural instability and gait disorders, which may occur or worsen after STN-DBS.35 Procedure Before beginning CSAI, all dopamine agonists should be discontinued overnight. Levodopa may be withdrawn, or kept at the same dosage only in the morning and evening. Premedication with domperidone should be started one day before the infusion at a dose of 10 mg up to three times a day in order to avoid potential adverse events, such as vomiting and hypotension.36 Domperidone administration should not normally be prolonged more than one week so as to avoid cardiovascular side effects such as QT prolongation and arrhythmias.36 Apomorphine is delivered by an appropriate pump connected to a needle inserted in the skin of the abdominal wall (Fig. 1B). The initial dosage is 1 mg/h, increasing by 0.5 mg/h every 2e4 h, depending on tolerability and clinical

benefit.37,38 The infusion may be prolonged for 16 h in daytime only and should be discontinued at night.36 The daily average dosage is 4e7 mg/h.36 Patient selection Patients with contraindications to STN-DBS, such as moderate cognitive impairment, levodopa-unresponsive axial symptoms, speech disorders, and severe mood disorders may be candidates for CSAI. This treatment should be not considered for subjects of advanced age, lacking social or familial support, or affected by severe dementia or psychosis, orthostatic hypotension, systemic disease (hepatic, renal or cardiac failure).39 Caution is required for patients affected by diabetes or presenting cellulitis or other skin diseases. Adverse events Nausea, vomiting, and cardiovascular events, such as bradycardia and postural hypotension may be avoided by premedication and co-administration of domperidone. Other effects induced by peripheral vasodilatation are flushing, sweating, rhinorrhea and lacrimation.30 Neuropsychiatric events such as confusion, hallucinations, psychosis, impulse control disorders, sedation, and sleep attacks may be observed as with other dopamine agonists. Subcutaneous nodules are dose-related and develop in most patients (70% incidence) after long-term therapy with CSAI, but rarely lead to drug discontinuation.38 Hematologic effects are benign transient eosinophilia, positive Coombs direct test and, in a few patients, hemolytic anemia. They require a hematologic follow-up but rarely drug withdrawal.30 The role of nursing The success of CSAI depends on good patient compliance, constant support by caregivers, periodic nursing assessment (also at patients’ homes), and long-term medical follow-up. The nurse should be able to identify patients who could benefit from this treatment. Furthermore, the nurse is critical in order to establish efficient communication with the patients and relatives, and within the multidisciplinary team. The management of the device requires the assistance of a trained team of nurses, capable of handling technical problems (i.e. malfunction, occlusion) and detecting any local skin complications. During the hospital stay, the nurse should assist the neurologist during the apomorphine challenge test and the continuous infusion in order to monitor the drug effectiveness and possible side effects, such as hypotension, vomiting and hallucinations, and support the patient in coping with the physical and psychological discomfort due to the reduction or discontinuation of oral dopaminergic drugs. Before discharge from hospital, the nursing staff should train the patients and/or their family members in the use of the pump and instruct them on correct skin disinfection and prompt recognition of side effects. It is fundamental that the nurse is sure that the patient or caregiver is actually independent in carrying out these tasks. The nurse may suggest several strategies to prevent or minimize skin reactions such as a daily change of injection site with round-the-clock administration, avoiding the periumbilical area, following asepsis and skin hygiene rules, using 29 Gauge soft and fine needles with a 30 cm Teflon cannula and a luer lock connector, performing deep injections, covering the needle by silicone patches, and massaging the needle insertion site after the daily infusion.31 In particular, massages with tea tree oil seem to reduce tissue irritation and inflammation.40 The management of subcutaneous nodules varies depending on the type and severity of the disorder. Topical corticosteroid and fibrinolytic use and lowfrequency ultrasound are recommended for treating mild or fibrous nodules. Infection and necrosis, which are exceptional,

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require antibiotics, surgical drainage or excision and usually determine definitive treatment discontinuation. Duodenal levodopa infusion The introduction of levodopa infusion into the duodenum allows the bypassing of unpredictable oral absorption due to erratic, delayed and incomplete gastric emptying, resulting in less variable plasma concentrations of the drug and continuous, more physiological, dopaminergic stimulation. As the low watersolubility of levodopa required large solution volumes, a methylcellulose gel suspension of micronized levodopa (20 mg/ml) and carbidopa (5 mg/ml) (Duodopa) was recently developed and is now available in several countries.41 LCIG is directly delivered inside the distal duodenum and jejunum via a small tube placed through a percutaneous endoscopic gastrostomy/jejunostomy (PEG/J) for permanent use (Fig. 1C).42e44 LCIG is available in cassettes attached to a portable programmable pump connected to the PEG/J. A standard cassette contains 100 ml of gel, providing up to 2000 mg of levodopa. Several short-term non-blind trials have demonstrated that enteral infusional treatment improves motor fluctuations, reducing the “on” time up to several hours in comparison to oral levodopa administration.43 Some studies in advanced PD patients with a follow-up ranging between 6 and 24 months showed significant improvement in motor complications associated with a progressive reduction of disabling dyskinesias.44e46 One of the main limitations of this therapy is that it is highly expensive.6 Procedure The evaluation prior to implantation, the PEG/J location and the follow-up, require the involvement, constant communication and cooperation within a multidisciplinary team consisting of a neurologist, a gastroenterologist endoscopist, an experienced nurse and a dietician. Gastroenterological assessment is necessary in order to exclude previous gastrointestinal diseases or surgery. Gastroscopy with biopsy is performed so as to detect Helicobacter Pilory (HP) infection. Serum vitamin B12, folic acid, metylmalonic acid and homocysteine levels are evaluated, and motor and sensory nerve conduction studies are usually performed in order to detect the presence of a pre-existing peripheral neuropathy, which may be worsened or caused by LCIG treatment. A 3e4 days test with a nasoduodenal intestinal tube is performed so as to assess the clinical effect on motor symptoms and fluctuations, the tolerability and compliance of the patients, and to adjust the dose.47 If a good response is observed, the nasoduodenal tube is removed and the PEG/J is positioned under local anesthesia with the aid of a gastroscopy, which is useful for establishing the appropriate site. Prophylactic antibiotic therapy is administered after implantation so as to prevent peristomal skin infections. The assessment of the correct positioning of the PEG/J is carried out by performing an abdomen X-ray. If the procedure is conducted properly, the infusion is started after the discontinuation of other antiparkinsonian drugs. Usually, the pump is connected in the morning, giving a bolus starting dose between 2.5 and 7 ml.48 The mean daily maintenance dose is calculated according to the previous oral dose and detracting the morning dose, and ranges between 2.4 and 5 ml/h (48e100 mg/h of levodopa). Extra bolus doses between 0.5 and 2 ml may be required if an off-state occurs during the day.48 Duodopa is usually administered in monotherapy, but, if necessary, other antiparkinsonian drugs may be added. Gastroscopy should be repeated and the PEG/J evaluated for possible replacement each year.

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Patient selection According to a proposed algorithm for patient selection, LCIG treatment is recommended in PD subjects who are levodoparesponsive but with insufficient control of motor fluctuations and dyskinesias, despite optimal oral/transdermal therapy.37 Elderly patients without severe cognitive decline and/or severe dopaminergic psychosis may be contemplated for LCIG.39 Patients with mild or moderate depression and anxiety may be considered. Severe coagulopathy, previous gastrectomy, gastroenteroanastomosis or other abdominal surgery, and ascites represent a contraindication.49 A pre-existent peripheral neuropathy should be carefully checked and the risk/benefit ratio taken into account. The availability of reliable caregivers and the patients’ ability to manage the pump, tolerate the surgical procedure and the pump weight are essential. Adverse events Beyond the typical side effects caused by levodopa therapy, such as psychosis, confusion, somnolence and dyskinesias, the more frequent adverse events are related to the device and the surgical procedure. Possible complications related to the PEG/J are peritonitis, described in 4.5% of cases,50 duodenal ulcers, secretion from the stoma, granuloma, abdominal pain, mild or severe, transient or persistent stoma infections, and intestinal occlusions.46 A frequently reported side effect is the accidental removal of the PEG/J (55% of cases).46 An association between LCIG infusion and the development of a subacute/chronic, mainly sensitive, axonal peripheral neuropathy has been observed.51 This finding is associated with low vitamin B12 and folic acid levels, and high homocysteine and methylmalonic acid levels, and may be due to malabsorption caused by the levodopa gel formulation.52 The role of nursing During the hospitalization state, the nurse should support the patients during the test phase because they may be in “off” condition, assist the neurologist in establishing the optimal therapeutic dose of Duodopa, and monitor treatment response and side effects. After the PEG/PEJ implantation, the nursing staff should take care of the device management, cassette mounting, turning on and off the pump, the administration of bolus doses according to the patient’s symptoms, and cleaning the stoma. At the moment of discharge, the nurse should educate and train the patients and their caregivers in the management of the pump. During the follow-up, the nurse should carefully monitor, register any issues such as body weight loss or nausea (which may suggest a device dislocation), and report possible serious side effects to the center where the device has been implanted or to the neurologist in charge of the patient. The timely detection and management of local stomal complications, such as granuloma, retraction, dermatitis, and abscess require nursing staff experienced in wound care and enteral nutrition. The nursing team should be trained in ostomy dressing and in preventing local adverse events, ensuring correct hygiene and protecting the peristomal skin. Furthermore, they should be able to classify the complications (ulcerative, proliferative, erosive, and hyperemic), establish what abdominal areas are involved, and choose and perform the most suitable dressings for the lesion, such as hydrogel, hydrocolloids, alginate silver and polymeric membrane dressings. Conclusions Each non conventional therapy for advanced PD proved to be efficient and generally safe in managing motor fluctuations and

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dyskinesias, although, to date, DBS has shown a higher level of evidence. A good outcome and a lower frequency of adverse events strictly depend on correct candidate selection and careful assessment of inclusion and exclusion criteria. Multidisciplinary approach, long-term follow-up and constant support for the patients and caregivers are mandatory. After discharge, periodic nursing visits at home should be ensured so as to monitor the treatment’s effectiveness and adverse events, in particular for CSAI and LCIG. The role of the nursing staff should not be limited to medical care, but must also be intended to facilitate communication between patients and clinicians, interaction between different care providers, and finally to support and educate patients and caregivers. Acknowledgments The authors thank Josh Williams for checking the English of this article. References 1. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet. 2009;13:2055e2066. 2. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525e535. 3. Chaudhuri KR, Schapira AHV. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8:464e474. 4. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30:80e89. 5. Jankovic J. Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord. 2005;20:S11eS16. 6. Valldeoriola F, Puig-Junoy J, Puig-Peiró R, Workgroup of the SCOPE study. Cost analysis of the treatments for patients with advanced Parkinson’s disease: SCOPE study. J Med Econ. 2013;16:191e201. 7. Benabid AL, Pollak P, Louveau A, et al. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol. 1987;50:344e346. 8. Krack P, Pollak P, Limousin P, et al. Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain. 1998;121:451e457. 9. Chen XL, Xiong YY, Xu GL, et al. Deep brain stimulation. Interv Neurol. 2012;1: 200e212. 10. Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2010;362:2077e2091. 11. Okun MS. Deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2012;367:1529e1538. 12. Volkmann J, Albanese A, Antonini A, et al. Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review. J Neurol. 2013;260:2701e2714. 13. Rizzone MG, Fasano A, Daniele A, et al. Long-term outcome of subthalamic nucleus DBS in Parkinson’s disease: from the advanced phase towards the late stage of the disease? Parkinsonism Relat Disord. 2014;20:376e381. 14. Benabid AL, Chabardes S, Mitrofanis J, et al. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol. 2009;8:67e81. 15. Picillo M, Lozano A, Kou N, Puppi Munhoz R, Fasano A. Programming deep brain stimulation for Parkinson’s disease: the Toronto Western hospital algorithms. Brain Stimul. 2016;9:425e437. 16. Defer GL, Widner H, Marie RM, et al. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord. 1999;14:572e584. 17. Lang AE, Houeto JL, Krack P, et al. Deep brain stimulation: preoperative issues. Mov Disord. 2006;21:171e196. 18. Deuschl G, Schüpbach M, Knudsen K, et al. Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson’s disease: concept and standards of the EARLYSTIM-study. Park Relat Disord. 2013;19:56e61. 19. Alegret M, Dunque C, Valldeoriola F, et al. Effects of bilateral subthalamic stimulation on cognitive function in Parkinson disease. Arch Neurol. 2001;58:1223e1227. 20. Dujardin K, Defebvre L, Krystkowiak P, et al. Influence of chronic bilateral stimulation of the subthalamic nucleus on cognitive function in Parkinson’s disease. J Neurol. 2001;248:603e611. 21. Berney A, Vingerhoets F, Perrin A, et al. Effect on mood of subthalamic DBS for Parkinson’s disease: a consecutive series of 24 patients. Neurology. 2002;59: 1427e1429. 22. Fukaya C, Yamamoto T. Deep brain stimulation for Parkinson’s disease: recent trends and future direction. Neurol Med Chir (Tokyo). 2015;55:422e431.

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