Pathophysiology, Patient Burden, and Recognition of OFF Episodes of Parkinson Disease

Introduction

Parkinson disease (PD) is a progressive neurologic disorder characterized by multiple motor and nonmotor symptoms.¹ Motor symptoms of PD include bradykinesia, tremor, and rigidity; nonmotor symptoms include autonomic dysfunction, gastrointestinal dysmotility, cognitive and neurobehavioral abnormalities, and sensory disturbances. From 1990 to 2015, the number of people with PD doubled to over 6 million worldwide.² Driven by an aging population and perhaps increasing incidence, that number is projected to double again to over 12 million by 2040.²

Levodopa is the “gold standard” of PD treatment; however, after several years of treatment, the majority of patients experience a shortened ON response to each dose and “OFF episodes” emerge.³ OFF episodes begin when the ON benefit of a levodopa dose wanes and motor and/or nonmotor symptoms re-emerge. OFF episodes are common in the morning but can happen at any time of day.^4,5 These episodes can have a significant impact on a patient’s daily functionality and quality of life. Lack of awareness and recognition of OFF episodes can impede optimal clinical management.⁶ This report addresses how the progressive pathophysiology of PD contributes to OFF episodes and consequent patient burden, and how the use of assessment tools can identify OFF symptoms to improve their recognition.

Prevalence of and Risk Factors Associated With OFF Episodes

Motor fluctuations have been reported to occur in 40%–50% of patients treated with levodopa for 5 years and two-thirds or more of patients treated for 10 years or more.^7,8 In a survey of approximately 3,000 people with PD conducted by The Michael J. Fox Foundation for Parkinson’s Research, more than 90% of respondents reported that they have at least 1 OFF episode per day, and nearly 65% reported being OFF for 2 or more hours per day.⁹ In a survey of patients living with PD for more than 6 years (since symptom onset), participants ranked fluctuating response to their medication as their most troubling symptom.¹⁰ The major risk factors for OFF periods and dyskinesia include younger onset of PD, disease severity, disease duration, and dosage and duration of levodopa therapy.^11,12

Pathophysiology of PD and Its Treatment

The etiology of PD is not known, but is believed to be related to an interaction between genes and the environment.^13,14 Widespread synuclein degeneration occurs throughout the neuraxis, including central, enteric, and autonomic neurons. Although the cause of PD remains elusive,¹⁵ motor symptoms reflect degeneration of dopaminergic neurons of the substantia nigra pars compacta, resulting in reduced striatal dopamine. As striatal dopamine is lost, hallmark symptoms of PD emerge—ie, bradykinesia, tremor, rigidity, and, later, postural impairment.¹⁶

Levodopa and OFF periods. Levodopa (administered with the peripheral decarboxylase inhibitor carbidopa) is the cornerstone symptomatic therapy for PD. Levodopa provides robust symptomatic benefit to most patients with PD, and its use is associated with reduced morbidity and prolonged survival rates.¹⁷ In the first few years of levodopa therapy, this robust benefit is consistent throughout the day, even when doses are delayed or missed, often referred to as the “honeymoon phase.”^18,19 However, after approximately 5 years, OFF episodes have emerged in about 50% of patients, and the prevalence increases over time.²⁰

Because duration and dose of levodopa are risk factors associated with emergence of OFF episodes (and dyskinesia),^21,22 some clinicians and patients are hesitant to begin therapy (“levodopa phobia”).²³ However, there remains no evidence that levodopa is toxic or causes motor complications. Rather, evidence suggests that OFF episodes occur due to striatal denervation and enteric dysmotility.^24,25 The short half-life of levodopa coupled with reduced striatal buffering capacity, with progressive loss of striatal neuroterminals, results in a short-duration response to doses of levodopa. Onset of levodopa symptom benefit becomes more and more variable, reflecting GI dysmotility due to delayed gastric emptying of levodopa (which is absorbed only in the small intestine) and competitive transport by dietary-neutral amino acids across the intestinal lumen and the blood brain barrier; gut pathogens can also impair the absorption of levodopa.²⁵

As the disease progresses, response to each dose of levodopa becomes more variable in onset and shorter in ON duration. This leads to multiple periods of ON alternating with OFF episodes, which become increasingly unexpected and disruptive.¹⁷

Individuals described dealing with OFF episodes in the following ways:

Patient Perspectives

“My entire body goes stiff… my mouth is often forced open in a painful position, or my mouth is forced closed with my tongue stuck out.”²⁶

“The various off-and-on states is what makes this disease so hard to live with.”²⁶

“Timing of medications requires planning at all times.²⁶

AV 1. Predictors of Nonadherence With Pharmacotherapy in Patients With Parkinson Disease (00:43)

Based on Richy et al.²⁷

The Cost of Medication Noncompliance

The occurrence of OFF episodes should not be confused with symptom burden due to lack of adherence to treatment. A retrospective analysis²⁷ of nearly 16,000 patients with PD over 4 years showed that almost half (46%) were nonadherent to their prescribed medication (AV 1).²⁷ Noncompliance may increase the burden on the health care system because of greater resource usage. The study²⁷ revealed that nonadherent patients incurred higher mean costs associated with emergency department and inpatient visits, driving the total all-cause annual health care mean cost to $84,949 for nonadherent patients vs $77,499 for adherent patients (P < .0001).²⁷

Clinicians who treat patients with PD may contribute to a reduction of the overall health care system burden by discussing the importance of treatment adherence. A randomized controlled trial²⁸ of 83 patients with PD showed that medication adherence improves if patients are educated about the effect of regular medicine intake. Forty-three patients (52%) were randomly assigned to receive counseling about the timing of their medication doses, and 40 (48%) were controls. The difference in adherence to recommended dosage timing pre- to post-intervention was 13.4% greater in the intervention group (CI 5.1 to 21.7, P = .002).²⁸

Case Practice Question 1

Marvin has had PD for 8 years and is at the clinic for a treatment check-up. He reports experiencing the below problems. According to a patient study, which problem would you expect Marvin to describe as the most troubling?

1. Drooling
2. Sleep issues
3. Medication response fluctuations
4. Tremor

Discussion of the Case Practice Question

Preferred Response: C.

Explanation: Marvin is experiencing several changing motor and nonmotor symptoms as his disease has progressed. In a study by Politis et al,¹⁰ more patients rated “fluctuating response to PD medication” as their most bothersome symptom than any other symptom.

AV 2. Frequency and Disability of Nonmotor Fluctuations in Parkinson Disease (00:43)

Data from Witjas et al.³²

The Burden of OFF Episodes

Because of the disruption caused by OFF episodes, patients often try to schedule their day around when they think they’re going to be ON or OFF. In our clinical experience, managing OFF episodes is one of the biggest challenges we face in treating patients with PD over the duration of the disease.

The types of motor fluctuations a patient may experience include the following^4,29–31:

• Morning OFF (or morning akinesia)
• Delayed ON (eg, postprandial akinesia, suboptimal ON, dose failure)
• End-of-dose wearing OFF (predictable)
• Nocturnal akinesia
• ON-OFF phenomena (unpredictable)

In the survey⁹ of approximately 3,000 people with PD, the average patient rating of the disability/impact of OFF states on a scale of 0 to 10 (with 10 being the highest) was 6.58. Chapuis and colleagues²⁹ reported that the impact of motor fluctuations on a patient’s quality of life is significant (P < .05). Using the Parkinson’s Disease Questionnaire (39-item version, PDQ-39), patients assessed their difficulties with PD across 8 dimensions of daily living. Patients reported that their most strongly affected dimensions were Mobility, Activities of Daily Living, Stigma, and Communication. Nocturnal akinesia led to a deterioration of all 8 dimensions of the PDQ-39.²⁹

In our clinical experience, OFF episodes may become problematic for patients because of motor symptoms; however, nonmotor symptoms can also be debilitating and often signal the onset of an OFF time (AV 2).³²

Caregiver Burden Associated With OFF Episodes

The time that patients with PD spend in OFF states significantly increases caregiver burden.³³ A study³³ conducted as part of the National Parkinson Foundation Quality Improvement Initiative (NPF-QII) examined patient quality of life using the PDQ-39 and measured caregiver burden using the Modified Caregiver Strain Index (MCSI). Of the nearly 400 patients, more than half reported OFF time. The MCSI subscore of interpersonal strain was significantly worse for caregivers of patients with OFF time (P < .03), and the number of hours of OFF time significantly correlated with physical strain and time constraints on the MCSI (P < .02).

A survey³⁴ of patients and their care partners revealed that only a quarter of care partners have ever discussed the impact of the patient’s symptoms on their own life at any appointment. A similar proportion of care partners indicated that they are not currently asked by clinicians about the impact of the patient’s OFF symptoms on their own lives, but they would like to be.

Care partners have described the impact that their loved ones’ OFF episodes have on their lives in the following ways:

Family Perspectives

“It’s an added weight about dealing with him and with his situation, so yeah it impacts my life, it adds to the stress… if it was more predictable, I would probably get myself really prepared…[but] because it’s so unpredictable, I think it’s more stressful.”³⁵

“It’s frustrating when you really cannot do a whole lot, where she is dependent upon certain physical activities and medication to try to snap out of the ‘off’ time.”³⁵

It is important to take into consideration the huge burden that OFF episodes place on not only the patient but also their families. In our clinical experience, the time that a patient spends in OFF periods over the course of a day can add up and account for a quarter, a third, or sometimes half of a waking day.

Early Recognition of OFF Episodes

Wearing-off can occur at the early stages of the disease and is also frequently underestimated in routine clinical evaluation.³⁶ The early detection of wearing-off in Parkinson disease (DEEP) study³⁶ included 617 patients with a mean anti-Parkinson treatment duration of 6.6 ± 4.6 years; 87% of patients were on levodopa treatment. Whereas clinicians identified the presence of wearing-off in only 57% of patients, 67% of patients identified wearing-off by a self-administered questionnaire, the Wearing-Off Questionnaire (WOQ-19). Neurologists diagnosed wearing-off in 22% of patients with less than 2.5 years disease duration, but 42% were identified by the WOQ-19. The number of wearing-off symptoms, both motor and nonmotor, increases along with disease duration and negatively affects the patient’s quality of life.³⁶

Assessment tools. A survey³⁴ of patients and their care partners indicated that less than half of patients discuss OFF symptoms at every appointment. To facilitate communication with patients and care partners about OFF periods, practitioners can use questionnaires, such as the WOQ-19.³⁴ Talking with patients can elicit information not provided by a tool, however.³⁷ OFF episodes can sometimes be predictable; if the patient can identify specific times when they are OFF, their medicine dosing can be adjusted accordingly. Talking with care partners may also provide helpful insight for clinicians and elicit more information about a patient’s OFF symptoms than talking with only patients.³⁴

Bringing a patient into the clinic for observation for 8 hours is not practical. During the time they do spend in the office visit, the patient’s clinical state may look different than when they are at home. Patients can complete a pre-visit, paper-based motor symptom diary, which is often used in clinical trials, but it can be cumbersome.³⁸ In our clinical experience, the patient sometimes fills in the diary in the parking lot or clinic waiting room rather than actually filling it in at home on a daily basis. An electronic diary has proved to be more reliable for ON-OFF state identification and classification.³⁸

In our practices, we sometimes ask the patient to record short videos of themselves at home—especially when they are not sure if they are OFF or not—and then we watch it together in the clinic to determine if they are OFF or dyskinetic.³⁹ Increasingly, patients use wearable technology such as a smart watch to detect OFF time, or they use a smart phone to record OFF time. Wearable sensor systems may also be useful, but their widespread use  is currently limited.⁴⁰

Case Practice Question 2

Angela has had PD for 5 years, and her husband Tom is her care partner. When making an appointment, Tom expresses concern that Angela is experiencing what he believes to be OFF periods. What would you recommend that they do before the upcoming appointment?

1. Angela or Tom should record her symptoms in a diary either on paper or her smartphone.
2. Tom should video-record Angela’s movements at home when he believes she is in an OFF period.
3. Angela should arrive early for the appointment and fill out a WOQ-19.
4. All of the above.

Discussion of the Case Practice Question

Preferred Response: D

Explanation: A pre-visit diary, a video segment of a patient who may be experiencing an OFF episode, and/or a self-reported WOQ-19 are all beneficial assessment tools to improve identification of and communication about OFF periods among patients, care partners, and clinicians.^34,38,39

Conclusion

In patients with PD, OFF episodes are common but often under-recognized; they include both motor and nonmotor symptoms and can occur at any time of day. These episodes negatively impact a patient’s functionality and quality of life and place a significant burden on their care partners. By implementing assessment tools such as questionnaires (eg, the WOQ-19), patient diaries, and brief home videos, clinicians can facilitate communication with patients and care partners about OFF episodes and recognize the symptoms earlier.

Clinical Points

• Facilitate communication with patients and their care partners about OFF episodes.
• Use tools to assess patients for motor and nonmotor symptoms associated with OFF episodes.

References

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© Copyright 2020 Physicians Postgraduate Press, Inc.

CME Background Information

Supported by an educational grant from Sunovion Pharmaceuticals Inc.

Participants may receive credit by reading the activity, scoring 70% or higher on the posttest, and completing the evaluation.

Objective

After completing this educational activity, you should be able to:

• Consider how the pathophysiology of Parkinson disease (PD) contributes to patient burden and OFF periods
• Identify signs of OFF periods by incorporating questionnaire use and care partner information into the clinical evaluation

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The Accreditation Council for Continuing Medical Education (ACCME) defines a commercial interest as any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. The ACCME defines relevant financial relationships as financial relationships in any amount occurring within the past 12 months that create a conflict of interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosures are as follows:

Dr Isaacson is a consultant for, has received grant/research support from, has received honoraria from, and is on the speakers/advisory boards for AbbVie, Acadia, Acorda, Adams, Addex, Allergan, Amarantus BioScience, Axovant, Benevolent AI, Biogen, Britannia, Cerecor, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Jazz, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, Thereavance, UCB, US WorldMeds, and Zambon.

The Chair for this activity, Rajesh Pahwa, MD, is a consultant for Abbott, AbbVie, Acadia, Acorda, Amneal, CalaHealth, Global Kinetics, Impel Neuropharma, Kyowa, Lundbeck, Mitsubishi, Neurocrine, Prilenia, Sunovion, and US WorldMeds; has received grant/research support and honoraria from and is a member of the speakers/advisory boards for Abbott, AbbVie, Addex, Biogen, Biohaven, Boston Scientific, EIP, Global Kinetics, Impax, Initec, Eli Lilly, Neuroderm, Neuraly, Parkinson’s Foundation, Pharma2B, Prelinia, Roche, SIS Labs, Sun Pharma, Sunovion, Theranexus, Theravance, US WorldMeds, and Voyager.

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Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit(s)™ from organizations accredited by the ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1.0 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This brief report activity was published in October 2020 and is eligible for AMA PRA Category 1 Credit™ through October 31, 2022. The latest review of this material was September 2020.

Statement of Need and Purpose

Physicians and patients are not communicating clearly about OFF episodes, and detection through clinical evaluation alone is less accurate than if an assessment tool is used. Neurologists, therefore, need education on the use of assessment tools, facilitating good communication with patients and care partners, and risk factors for OFF periods. Because therapeutic strategies for OFF episodes have expanded, and guidelines were recently updated, clinicians also need education from experts about new treatment strategies for OFF episodes and current guidelines. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on Parkinson disease.

Disclosure of Off-Label Usage

Dr Pahwa has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents or device therapies that is outside US Food and Drug Administration–approved labeling has been presented in this activity.

Review Process

The faculty members agreed to provide a balanced and evidence-based presentation and discussed the topics and CME objectives during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by the Chair and a peer reviewer who is without conflict of interest.

Acknowledgment

This activity is derived from the teleconference series “Recognizing and Managing OFF Periods in Patients With Parkinson Disease,” which was held in May–July 2020 and supported by an educational grant from Sunovion Pharmaceuticals Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.