OFF episodes: a component of PD

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and non-motor symptoms.1,2

ON occurs in patients with PD when their medication is working to treat their symptoms.3

Current PD treatment strategies center on the use of levodopa (the gold standard) and other dopaminergic agents to help keep a patient ON (ie, experiencing a usual response to medications).4

OFF episodes affect the majority of patients with PD

During OFF episodes, patients with PD experience a change in their clinical state, as motor and/or non-motor symptoms return or worsen.3

Development of motor complications, including OFF episodes and dyskinesias in Parkinson’s disease, is believed to be primarily related to:

  • Natural progression of the disease (ie, progressive neurodegeneration)5
  • Intermittent use of levodopa to treat the underlying motor symptoms5*

*Exogenous levodopa may produce intermittent (ie, pulsatile) stimulation of postsynaptic neurons. This type of activity is thought to cause changes in postsynaptic receptors that may contribute to the development of motor complications.

The majority of patients with PD develop OFF episodes

74% of patients report motor complications after 4 years of antiparkinsonian treatment6†

100% of patients experience motor complications after 10 years of antiparkinsonian treatment7,8‡

Results from a multicenter, parallel-group, double-blind, randomized controlled trial in 301 patients with early PD (150 treated with levodopa, 151 treated with pramipexole) assessed via observation and using the UPDRS, the Parkinson’s Disease Quality-of-Life scale, and the EuroQol Visual Analog Scale (VAS).

Based on conservative estimates indicating that 10% of patients with PD will develop motor complications per treatment year.

OFF episodes extend beyond motor symptoms

OFF episodes may include a wide variety of both motor and non-motor symptoms.3

OFF symptoms are heterogeneous, both within individual patients and among patients, complicating the diagnosis of OFF episodes.9

Motor symptoms2

Cardinal motor

  • Tremor
  • Bradykinesia
  • Rigidity
  • Loss of postural reflexes

Other motor

  • Flexed posture
  • Reduced blink rate
  • Hypophonia
  • Freezing
  • Microphagia
  • Dysphagia
  • Gait changes
  • Changes in dexterity10
  • Difficulty turning in bed
  • Masked face
  • Hypokinetic dysarthria

Non-motor symptoms are defined as11:

  • Autonomic (ie, dizziness, swallowing difficulties, shortness of breath)
  • Neuropsychiatric/cognitive (ie, depression, anxiety, fatigue)
  • Sensory (ie, pain, restless legs)

Non-motor symptoms of OFF episodes:

  • Are common12
  • May appear before motor symptoms; may mistakenly thought to be associated with aging or comorbid conditions13
  • May be more problematic than motor symptoms14

OFF episodes may occur at any point in the course of PD

Mean number of wearing-OFF symptoms reported by patients using the Wearing-OFF Questionaire (WOQ-19)15§:

Wearing-OFF
Symptoms (n)

Non-motor
symptoms

Motor
symptoms

Total

Reprinted from Parkinsonism Relat Disord, 20, Stocchi F, Antonini A, Barone P, et al; DEEP study group, Early DEtection of wEaring off in Parkinson disease: the DEEP study, 204-211. © 2013, with permission from Elsevier.

OFF symptoms Parkinson's Disease (PD)

When assessments were made using the WOQ-19, 41.8% of patients with <2.5 years’ disease duration experienced symptoms of OFF episodes15§

  • Overall, the average number of OFF symptoms reported in a typical day was 8.7 ± 3.815§
  • Both motor and non-motor symptoms were prevalent in OFF episodes, with a mean number of daily reported OFF symptoms of 5.6 ± 2.1 for motor symptoms and 3.1 ± 2.3 for non-motor symptoms15§

§Based on the DEEP study, which measured the number of wearing-OFF symptoms per day as reported by 634 patients with PD (mean disease duration 8 years) using the Wearing-OFF Questionnaire (WOQ-19). Patient inclusion criteria included being on levodopa and/or dopamine agonist therapy for ≥1 year.

References

  1. Anglade P, Vyas S, Javoy-Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol. 1997;12:25-31.
  2. Fahn S. Parkinsonism: clinical features and differential diagnosis. In: Fahn S, Jankovic J, Hallett M, eds. Principles and Practice of Movement Disorders. Amsterdam, Netherlands: Elsevier Ltd Inc, BV; 2011.
  3. Chou KL, Stacy M, Simuni T, et al. The spectrum of "off" in Parkinson's disease: What have we learned over 40 years? Parkinsonism Relat Disord. 2018 doi: 10.1016/j.parkreldis.2018.02.001. [Epub ahead of print]
  4. Obering CD, Chen JJ, Swope DM. Update on apomorphine for the rapid treatment of hypomobility (“off”) episodes in Parkinson's disease. Pharmacotherapy. 2006;26:840-852.
  5. Thanvi BR, Lo TCN. Long term motor complications of levodopa: clinical features, mechanisms, and management strategies. Postgrad Med J. 2004;80:452-458.
  6. The Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease. Arch Neurol. 2004;61:1044-1053.
  7. Metman LV. Recognition and treatment of response fluctuations in Parkinson’s disease: review article. Amino Acids. 2002;23:141-145.
  8. Marsden CD, Parkes JD, Quinn N. Fluctuations of disability in Parkinson’s disease – clinical aspects. In: Marsden CD, Fahn S, eds. Movement Disorders. London, England: Butterworth; 1981:96-122.
  9. Stacy M, Bowron A, Guttman M, et al. Identification of motor and nonmotor wearing-off in Parkinson’s disease: comparison of a patient questionnaire versus a clinician assessment. Mov Disord. 2005;20:726-733.
  10. Gebhardt A, Vanbellingen T, Baronti F, Kersten B, Bohlhalter S. Poor dopaminergic response of impaired dexterity in Parkinson’s disease: bradykinesia or limb kinetic apraxia? Mov Disord. 2008:23:1701-1706.
  11. Martínez-Fernández R, Schmitt E, Martinez-Martin P, Krack P. The hidden sister of motor fluctuations in Parkinson's disease: a review on nonmotor fluctuations. Mov Disord. 2016;31:1080-1094.
  12. Hou JG, Lai EC. Non-motor symptoms of Parkinson's disease. Int J Gerontol. 2007;1:53-64.
  13. DeMaagd G, Philip A. Parkinson's disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P T. 2015;40:504-532.
  14. Jankovic J. Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord. 2005:20(suppl 11):S11–S16.
  15. Stocchi F, Antonini A, Barone P, et al; DEEP study group. Early DEtection of wEaring off in Parkinson disease: the DEEP study. Parkinsonism Relat Disord. 2014;20:204-211.