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OFF PERIODS:

A SHATTERING REALITY

KNOW THE FACTS

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Parkinson’s disease is a progressive, neurodegenerative, multisystem disease1

Parkinson’s disease (PD) is a multisystem disorder typically defined by a progressive loss of dopaminergic neurons in the substantia nigra.1,2 By the time of diagnosis, individuals have lost a significant number of dopaminergic neurons—evidence suggests 60-80% of dopaminergic neurons degenerate before clinical features emerge.23 As PD progresses, neurodegeneration continues, with further loss of dopaminergic neurons and dopamine.2 The progression of disease reduces the brain’s ability to store and release dopamine when it is needed.2,3

The characteristic motor symptoms of Parkinson's disease are bradykinesia, tremor and rigidity, all of which are related to the degeneration of dopaminergic neurons in the substantia nigra. However, these symptoms are only one aspect of this multifaceted and complex disorder. It is now suggested that Parkinson's related degeneration is widespread in both the central and peripheral nervous systems.1

Evidence is mounting that many non-nigral sites produce a number of clinical signs and symptoms of Parkinson’s disease.1

Elmer on Parkinsons

...When a person is brand new to our clinic, we focus just like a laser on educating them about their disease.

Lawrence Elmer, M.D., Ph.D., Movement Disorder Specialist

Professor of Neurology and Medical Director of the Center for Neurological Health


DOPAMINE LEVELS IN A NORMAL AND A PARKINSON'S AFFECTED NEURON

Dopamine levels in a normal neuronDopamine levels in a Parkinson's affected neuron

Non-nigral neurodegeneration and non-motor symptoms4

A number of associations have been suggested between symptoms of PD and neurodegeneration beyond the substantia nigra4:

depression

Depression, for example, may be caused by a reduced number of serotonin 5-hydroxyindolacetic acid (5-HT) neurons in the dorsal raphe nucleus and reduced dopamine neurons in the ventral tegmental area

cognitive dysfunction

Depleted dopamine in the head of the caudate nucleus may trigger cognitive dysfunction

hallucination and psychosis

Hallucination and psychosis may be related to the degeneration of the dopaminergic system in the prefrontal region

going to bed

Sleep disorders, which occur in over one third of PD patients, may reflect lower brain stem involvement

Symptom progression during treatment

As Parkinson’s progresses, neurodegeneration of both the central and peripheral nervous systems continues, contributing to fluctuations in symptom control, even with optimized treatment.1,2,5

Elmer on Parkinsons

Probably the most bothersome are the symptoms such as depression and anxiety...that is the most devastating for somebody who is trying to live a full life.

Lynn H., Living with Parkinson's Since 2010

Member of Michael J. Fox Foundation Patient Council & Lead Member of Shaker's Anonymous (CT-Based Support Group)


dopaminergic neurons in the brain

People with Parkinson’s have likely already lost ~60-80% of Dopaminergic neurons by first onset of symptoms23


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Return of Symptoms: OFF Periods

Many people with Parkinson’s disease fluctuate between periods in which symptoms are controlled and periods in which they return.3,6 This is commonly referred to as ON and OFF periods. The progression of Parkinson's disease contributes to the return of symptoms and this can occur despite optimized treatment.7,8

RE-EMERGENCE OF PD SYMPTOMS CAN OCCUR DESPITE OPTIMIZED TREATMENT3

Re-emergence of PD Symptoms can occur during treatmentRe-emergence of PD Symptoms can occur during treatment

Clinicians often identify OFF periods as the re-emergence of Parkinson's motor symptoms, particularly slowness of movement, tremor and rigidity.3 However, in some cases, the presence of non-motor symptoms may predominate. Symptom variability among patients during OFF periods can make its recognition challenging.9

Symptoms can return despite treatment

Over time, both motor and non-motor symptoms become increasingly difficult to control, despite treatment, due to inadequate and variable levels of dopamine.2,5

Mike on Parkinsons

For me, OFF periods, I feel disconnected with my mind and body.

Michael B., Living with Parkinson's Since 2011

Board Member and Member of Connecticut Advocates for Parkinson's


COMMONLY REPORTED SYMPTOMS EXPERIENCED DURING OFF PERIODS INCLUDE

Motor Symptoms3

motor symptoms
  • Tremor
  • Balance Difficulties
  • Slowness of Movement
  • Reduced Dexterity
  • Stiffness

Non-motor
Symptoms3,10

non-motor symptoms
  • Anxiety
  • Irritability
  • Cloudy Mind / Slowness of Thinking
  • Fatigue
  • Mood Changes
  • Cognitive Dysfunction
  • Hallucination

Statistics about OFF periods

Currently, it is estimated that approximately 350,000 people with Parkinson’s in the United States experience OFF periods.11-13 They can occur throughout the day, can be unexpected, and may appear more often over time.3,7,14

As the disease progresses, people with Parkinson’s will experience symptom return.7,8

50%

In a study of 617 Parkinson's patients, ~50% of a subset with disease duration of ≤ 5 years (n=185) experienced OFF symptoms7

96%

Another study following people with Parkinson's for 15 years after diagnosis found that 50 out of 52 (96%) experienced OFF periods8

Time spent in OFF periods can really add up. In a 2014 survey of more than 3,000 people with Parkinson's conducted by the Michael J. Fox Foundation, two-thirds of respondents reported having more than two hours of OFF time per day. Twenty-two percent of those surveyed were OFF 2-3 hours a day, 20% were OFF 3-4 hours a day, and 22% were OFF more than 4 hours a day. That translates to15:

22% were OFF 60-90 hours per month22% were OFF 60-90 hours per month
20% were OFF 90-120 hours per month
22% were OFF more than 120 hours per month22% were OFF more than 120 hours per month

The unpredictability and frequency of OFF periods negatively impact the lives of patients with Parkinson’s, affecting their quality of life.16

~70%
at least twice a day

~70% of approximately 3,000 people with Parkinson’s who participated in a 2014 Michael J. Fox Foundation survey reported OFF periods at least twice a day.15

at least twice a day


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Quality of life and OFF periods

Symptoms of Parkinson's are both motor and non-motor. Non-motor symptoms of Parkinson’s can be physical and affect many functions of the body (eg, constipation, sweating problems, gastric dysmotility).4 OFF periods negatively impact quality of life for people living with Parkinson’s, with the impact being physical, emotional, and psychological.16,17

Physical impact

During OFF periods, people living with Parkinson's are left with restricted movement or uncontrolled movement.2

Unexpected symptoms can affect everyday life, for example16:

walking

Reduced mobility

activities of daily living

Complicating activities
of daily living
(eg, eating, caring for oneself)

stop

Avoiding activities

Emotional and psychological impact

For some people living with Parkinson’s, non-motor symptoms can be just as upsetting as motor symptoms.9

Elmer on Parkinsons

I had to stop working because of the disease, and that was heartbreaking. If you can keep working and keep your life going...then keep doing it. Don't give up.

Brenda V., Living with Parkinson's Since 2012

Board of Directors for the Connecticut Advocates for Parkinson's


Non-motor symptoms that may affect the lives of people with Parkinson's during OFF periods include3,10:

  • Anxiety
  • Irritability
  • Fatigue
  • Mood Changes
  • Cognitive Dysfunction
  • Hallucination
  • Cloudy Mind / Slowness of Thinking
88%

In a small study of 50 patients with Parkinson's, 88% reported anxiety during an OFF period.10

Health-related quality of life may worsen as OFF periods increase18,19

In a small prospective study, 40 people living with Parkinson's (8 patients in each Hoehn and Yahr stage) were followed for a 3 month period. OFF time and its effect on patients' health-related quality of life (HR-QOL) was evaluated. OFF time was determined via the Unified Parkinson's Disease Rating Scale Part IVB and the Sickness Impact Profile (SIP) was used as a measure to quantify HR-QOL. As time spent in OFF increased, a stepwise decrease in quality of life was reported by these patients. A higher SIP score reflects a lower HR-QOL.18,19

Impact of OFF periods on health-related quality of life evaluated by the Sickness Impact Profile18

Health-related quality of life worsens as OFF periods increaseHealth-related quality of life worsens as OFF periods increase

The impact of Parkinson’s disease

On September 22, 2015, the US Food and Drug Administration (FDA) held a public meeting for individuals living with Parkinson’s, their care providers, as well as other representatives to hear their perspectives on the most significant effects of the disease.* When discussing OFF periods, most participants described living with both daily motor and non-motor symptoms and expressed that the symptoms impact all aspects of their lives. A few individuals emphasized the unpredictability that OFF time brought into their lives on a daily basis. Participants brought up limitations in performing at work, caring for self and family, and maintaining relationships.20

*This includes a range of experiences and may not completely represent all individuals with PD.

Because of the multifaceted impact of OFF periods on patients with Parkinson’s disease, the recognition of these periods—while challenging—becomes an important part of ongoing disease management.9

Elmer on Parkinsons

As a person explains their OFF period, it's more of a sad testimony, because you're sharing what you're missing in life.

Steven D., Living with Parkinson's Since 2005

Co-Chair of the PwP Advisory Board & Founder and CEO of the Connecticut Advocates for Parkinson's (CAP)


Two or more hours a day

In a 2014 survey conducted by the Michael J. Fox Foundation, 64% of approximately 3,000 people living with Parkinson's reported that they spent two or more hours per day in OFF periods15


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Effectively communicating with patients

Help your patients uncover the troublesome symptoms of OFF periods9

physician patient conversation

Both physicians and patients agree: OFF periods can be one of the most difficult aspects of Parkinson’s disease. It’s understood that recognizing the symptoms of OFF periods is challenging because of a variety of reasons, including interpatient symptom variability and reliance on patient reporting.9

People with OFF periods may not discuss their symptoms or communicate the impact of the symptoms to their healthcare provider as they may be unaware that the changes they are experiencing are a result of OFF periods. Because patients may not recognize the more subtle changes they are experiencing as symptoms of OFF periods, enhancing communication around the full spectrum of symptoms is important.9

Gary speaks on Parkinson's

Your neurologist...can't guess what your symptoms are, they can't guess what you're feeling, they can't guess what you're going through when you're OFF.

Gary R., Living with Parkinson's since 2008

Member of PatientsLikeMe Team of Advisors;
MJFF Ambassador, Research and Public Policy Advocate


People with PD may not9,14:

OFF periods
  • Discuss the timing of their motor symptoms or realize that motor symptoms occur during OFF periods
  • Be aware that non-motor symptoms could be linked to OFF periods
  • Be aware that there may be variations during the day as symptoms may improve and then re-emerge

In addition, patients may try to be at their best for office visits.

Enhancing the dialogue

To overcome these challenges, having a productive conversation about the impact of symptoms, not simply the presence of symptoms, can help.9

caregiver to a Parkinson's patient

Having a caregiver present may give you additional perspective on what your patient is experiencing.

keeping a diary

Encouraging patients to keep a diary between visits can help get a more complete picture of when Parkinson’s symptoms occur.21

Proactively and directly inquire if individuals with Parkinson’s disease are experiencing OFF periods. Early recognition and enhancing communication regarding the full spectrum of symptoms are important to best understand a patient's needs.9,22

Steve speaks on Parkinsons

...care partners really do bring a lot to the table, as far as giving additional clarity to what they're seeing at home on symptoms and conditions.

Steven D., Living with Parkinson's since 2005

Co-Chair of the PwP Advisory Board & Founder and CEO of the Connecticut Advocates for Parkinson's (CAP)


patient assessment

Changing the conversation: Learn about the importance of bringing together the circle of care to improve conversations about Parkinson's.


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...When a person is brand new to our clinic, we focus just like a laser on educating them about their disease.

Lawrence Elmer, M.D., Ph.D., Movement Disorder Specialist


Probably the most bothersome are the symptoms such as depression and anxiety...that is the most devastating for somebody who is trying to live a full life.

Lynn H., Living with Parkinson's Since 2010


For me, OFF periods, I feel disconnected with my mind and body.

Michael B., Living with Parkinson's Since 2011


I had to stop working because of the disease, and that was heartbreaking. If you can keep working and keep your life going...then keep doing it. Don't give up.

Brenda V., Living with Parkinson's Since 2012


As a person explains their OFF period, it's more of a sad testimony, because you're sharing what you're missing in life.

Steven D., Living with Parkinson's Since 2005


Your neurologist...can't guess what your symptoms are, they can't guess what you're feeling, they can't guess what you're going through when you're OFF.

Gary R., Living with Parkinson's since 2008


...care partners really do bring a lot to the table, as far as giving additional clarity to what they're seeing at home on symptoms and conditions.

Steven D., Living with Parkinson's since 2005


OFF periods for me are best defined as not knowing...what is going to happen.

Israel R., Living with Parkinson's Since 2007


Lawrence Elmer, M.D., Ph.D., Movement Disorder Specialist

Lynn H., Living with Parkinson's Since 2010

Michael B., Living with Parkinson's Since 2011

Brenda V., Living with Parkinson's Since 2012

Steven D., Living with Parkinson's Since 2005

Gary R., Living with Parkinson's Since 2008

Steven D., Living with Parkinson's Since 2005

Israel R., Living with Parkinson's Since 2007

1. Langston JW. Ann Neurol. 2006;59(4):591-596. 2. Olanow CW et al. Neurology. 2009;72(21 suppl 4)S1-S136. 3. Stacy M et al. Mov Disord. 2005;20(6):726-733. 4. Hou J-GG et al. Int J Gerontol. 2007;1(2):53-64. 5. Hametner E et al. J Neurol. 2010;257(Suppl 2):S268-S275. 6. Olanow CW et al. Nat Clin Pract Neurol. 2006;2(7):382-392. 7. Stocchi F et al. Parkinsonism Relat Disord. 2014;20(2):204-211. 8. Hely MA et al. Mov Disord. 2005;20(2):190-199. 9. Pahwa R et al. Curr Res Med Opin. 2009;25(4):841-849. 10. Witjas T et al. Neurology. 2002;59(3):408-413. 11. Statistics on Parkinson's. Parkinson's Disease Foundation. http://www.pdf.org/en/parkinson_statistics. Accessed April 2017. 12. Ahlskog JE et al. Mov Disord. 2001;16(3):448‐458. 13. Decision Resources. Parkinson's Disease (Report: January 2015). 14. Stacy M et al. www.medscape.org/viewarticle/701955. 2009. Accessed April 2017. 15. The Michael J. Fox Foundation Survey of Parkinson’s Patients’ Off Time Experience, July 2014. 16. Hechtner MC et al. Parkinsonism Relat Disord. 2014;20(9):969-974. 17. Brown RG, et al. J Psychosom Res. 2015;78(2):143-148. 18. Dodel RC et al. Pharmacoeconomics. 2001;19(10):1013‐1038. 19. Dodel RC et al. Pharmacoeconomics. 1998;14(3):299‐312. 20. The Voice of the Patient: Parkinson's Disease. Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA). May 2016. http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM498266.pdf. Accessed April 2017 21. Parkinson’s Symptoms Diary. National Parkinson Foundation. http://www.parkinson.org/sites/default/files/CaringandCoping_WORKSHEETS_Parkinson's%20Symptoms%20Diary_form.pdf. Accessed April 2017. 22. Cheng EM et al. Neurology. 2010:75:2021-2027. 23. Fearnley et al. Brain. 1991;114(2283-2301).