Identification of patients with advanced Parkinson's disease suitable for device-aided therapy (DAT)

Advanced Parkinson's Disease

After diagnosing Parkinson's disease, there follows a relatively short period of stabilization achieved with the administration of levodopa and other medications. However, over time, motor complications may arise, and the existing oral and transdermal treatments may no longer suffice to eliminate OFF states. The disease thus progresses to an advanced stage. In this stage, the patient spends most of the time with PD.

For advanced PD, it is necessary to optimize the treatment regimen to ensure continuous dopaminergic stimulation, which means therapy using medical devices (DAT − device-aided therapy). This includes deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or levodopa infusion directly into the upper jejunum. This also includes intestinal gel containing levodopa and carbidopa (LCIG) and intestinal gel containing entacapone, which increases the bioavailability of levodopa (LECIG).¹

To optimally utilize DAT, it is necessary to timely identify patients who might benefit from this treatment and refer them to a movement disorder specialist. These specialists have created several recommendations and tools that should standardize the process of identifying patients with advanced PD and determine which DAT is most suitable for each of them. ¹

Tools for Identifying Patients with Advanced PD and Suitable DAT

In 2018, a group of specialists from 10 European countries created the 5-2-1 criteria to define advanced PD.² These criteria apply to patients treated with levodopa at least 5 times daily, who spend at least 2 hours awake in the OFF state and have at least 1 hour daily of bothersome dyskinesia. Characteristics of patients for whom DAT is suitable include:

• From motor symptoms:
  • Presence of bothersome dyskinesia and OFF states
  • At least 2 hours of OFF state daily
  • OFF state with postural instability
  • Dystonia with pain
  • Freezing of gait during OFF state
• From non-motor symptoms: sleep disorders
• From functional difficulties: limitation of daily activities²

Another tool for identifying patients with advanced PD suitable for DAT is NAVIGATE-PD,³ created by 103 experts from 13 countries. The main conclusions of this consensus are:

• Patients treated with levodopa > 5 times daily, who have bothersome OFF states > 1–2 hours daily even with optimal oral/transdermal levodopa treatment, should be referred to a movement disorder specialist, even if the duration of PD is < 4 years.
• Indication for DAT includes cognitive decline associated with non-motor fluctuations. With mild cognitive decline, DBS can be cautiously used; otherwise, intrajejunal levodopa infusion is suitable for both therapeutic and palliative strategies.
• Indication for DAT includes insufficient control of motor complications (or pharmacoresistant tremor in the case of DBS). For patients over 70 years with mild to moderate cognitive impairment, severe depression, or other DBS contraindications, intestinal gel with levodopa or subcutaneous apomorphine infusion is suitable.³

An online tool that doctors can use to identify PD patients inadequately compensated by oral treatment is the MANAGE-PD⁴ tool available on the website www.managepd.eu. This validated tool, published in 2022, allows doctors to classify a PD patient into three categories:

1. Adequately compensated on the current therapeutic regimen.
2. Inadequately compensated, for whom optimizing treatment outside of DAT could be beneficial.
3. Inadequately compensated, for whom DAT could be beneficial.

The tool has two parts, assessing the occurrence, frequency, and severity of symptoms. The first part, consisting of 5 yes/no questions, shows whether the patient is adequately or inadequately compensated on the current therapy (i.e., distinguishes category 1 from categories 2 and 3). For inadequately compensated patients, it proceeds to part 2, which, through the assessment of 10 domains, distinguishes category 2 and 3. Category 3, i.e., patients for whom DAT is suitable, is determined based on the use of ≥ 4 doses of levodopa daily and threshold values of symptom frequency and severity in each domain (see figure).⁴

Figure MANAGE-PD tool for identifying PD patients inadequately compensated and patients suitable for DAT⁴

Contraindications for DAT

A relative contraindication for any DAT is non-compliance with non-invasive treatment, while an absolute contraindication is insufficient response to levodopa. Relative contraindications for DBS also include age > 70–75 years, severe depression, and conditions increasing surgical risk, including cardiomyopathy. Absolute contraindications include dementia and severe brain atrophy.

Apomorphine infusions are relatively contraindicated in patients with cognitive impairment or dementia or with a history of dopaminergic dysregulation and absolutely contraindicated if the patient or caregiver cannot administer the treatment independently.

Intestinal levodopa infusions should not be used by patients with preexisting peripheral neuropathy, dopaminergic dysregulation, moderate to severe dementia, and frail patients unable to carry the pump. Absolute contraindications for intestinal infusions include only patients unable to self-administer the medication or with contraindications for abdominal surgery.³

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Sources:
1. Nyholm D., Jost W. H. Levodopa-entacapone-carbidopa intestinal gel infusion in advanced Parkinson's disease: real-world experience and practical guidance. Ther Adv Neurol Disord 2022 Jun 26; 15: 17562864221108018, doi: 10.1177/17562864221108018.
2. Antonini A., Stoessl A. J., Kleinman L. S. et al. Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson’s disease: a multi-country Delphi-panel approach. Curr Med Res Opin 2018; 34 (12): 2063–2073, doi: 10.1080/03007995.2018.1502165.
3. Odin P., Ray Chaudhuri K., Slevin J. T. et al. Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson’s disease: consensus from an international survey and discussion program. Parkinsonism Relat Disord 2015; 21 (10): 1133–1144, doi: 10.1016/j.parkreldis.2015.07.020. 
4. Antonini A., Odin P., Schmidt P. et al. Validation and clinical value of the MANAGE-PD tool: a clinician-reported tool to identify Parkinson’s disease patients inadequately controlled on oral medications. Parkinsonism Relat Disord 2021; 92: 59–66, doi: 10.1016/j.parkreldis.2021.10.009.