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Non-motor symptoms – influencing ‘ON’ and ‘OFF’ in Parkinson’s disease

A broad spectrum of non-motor symptoms is highly prevalent in Parkinson’s disease (PD) which impact tremendously on patients’ quality of life. During a corporate-sponsored symposium at MDS 2018, exactly how large an impact such symptoms present was described. In particular, the role of delayed gastric emptying, its influence on motor ‘OFF’ and ‘ON’ time and how new means of delivering effective therapeutics via alternative, non-oral routes was discussed.

Nobutaka Hattori, Japan, gave an overview of the range of non-motor symptoms that arise in PD and which can cause morbidity and mortality, increase cost of care and are common across all disease stages. Such non-motor symptoms in PD can be:

  • Autonomic  - urinary disorders, sexual dysfunction, sweating, orthostatic hypotension
  • Neuropsychiatric – psychosis, depression, anxiety, apathy, dementia, ICS, delirium, hallucinations
  • Sensory – pain, paresthesia, olfactory disturbance
  • Sleep-related
  • Gastrointestinal
  • Other – fatigue, blurred vision, weight gain.

As Dr Hattori stated, it is very important to identify non-motor fluctuations, for which an adjustment of the dopaminergic treatment may be helpful.

It is very important to identify non-motor fluctuations, for which an adjustment of the dopaminergic treatment may be helpful

For individualized treatment strategies, non-motor symptoms need to be seen in the context of life circumstances and other motor and non-motor symptoms in each patient. Dr Hattori presented a proposal for a comprehensive grading of PD severity that combines motor and non-motor assessments and that might be used to more accurately describe PD severity.

The ‘OFF’ and ’ON’ balance

Stuart Isaacson, USA, described the effects that non-motor symptoms can have on the worsening of motor effects. In particular, the effect delayed gastric emptying, or gastroparesis, has on the balance between ‘OFF’ and ‘ON’ periods.

Motor fluctuations, including end of dose wearing ‘OFF’, delayed ‘ON’ and dose failure are experienced by the majority of patients with PD. Indeed, from the patients’ perspective, as evidenced from a survey of 173 patients with PD of ≥6 year’s duration, while non-motor symptoms predominated over motor symptoms, motor fluctuation was their most troublesome symptom.1 Morning, postprandial and nocturnal akinesias are particularly distressing.

Motor fluctuation was the most troublesome symptom from the patients’ perspective

Motor complications significantly worsen the PDQ-39 Summary Index

Motor fluctuations have a significant impact on patient Quality of Life (QoL). A total of 143 patients with an average duration of 9 years were given the Parkinson’s Disease Questionnaire-39 (PDQ-39) to assess the impact of motor complications on QoL. Motor complications were analyzed by the Unified Parkinson’s Disease Rating Scale Parts IV-A and IV-B and the Abnormal Involuntary Movement Scale and motor complications significantly worsened the PDQ-39 Summary Index. 2

‘OFF’ periods reflect a shift from a long duration response to levodopa to a short-duration response. Initially, the effect of oral levodopa is rapid, reliable and sustained. Typically, onset is around 20 minutes. However, over time things change and progressive loss of nerve cells prevents reuptake and storage of dopamine for later release. Thus, the ‘buffering’ capacity formerly present in the system is lost as dopamine availability in the brain become more variable.

The gradual loss of levodopa ‘buffering capacity’ is compounded by variable absorption of levodopa in the small bowel due to PD-related pathological changes

Gastroparesis leads to erratic drug response

Loss of buffering is compounded by the variable absorption of levodopa in the small bowel due to PD-related pathological changes. Gastroparesis is common in patients with PD. Because the stomach contents are held back from reaching the duodenum, this also delays levodopa absorption, thereby resulting in erratic drug responses. 3,4

With disease progression, along with increased motor fluctuation comes a narrowing of the levodopa’s therapeutic window. A lowering of the dyskinesia threshold also occurs meaning that dyskinesia occurs more often as clinically useful levels of levodopa fail to be obtained.

Morning akinesia and gastroparesis – a link

Gastroparesis is thought to play a role in morning akinesia. The pharmacokinetics of levodopa was assessed in 19 patients with advanced PD (>11 years) with and without a delayed response to the first levodopa morning dose. Considerably lower levodopa plasma concentrations were measured in the group exhibiting gastroparesis compared to those unaffected by this condition, suggesting the difference is due to delayed gastric emptying rather than intestinal absorption of levodopa. 5 Thus, the fine tuning of levodopa dosing that considers gastric emptying is essential in the advanced stages of PD.

Other GI pathologies exist in PD

However, gastroparesis is just one of several gastrointestinal manifestations than can occur in PD that can delay or disrupt the progress of levodopa from the time of its ingestions until it reaches the brain and is converted to dopamine. Given the prevalence of GI pathologies in PD, isn’t it time to seek alternative means of delivery of levodopa other than by the oral route?

Given the prevalence of GI pathologies in PD, isn’t it time to seek alternative means of delivery of levodopa other than by the oral route?

Alternative delivery routes are being investigated

A number of non-oral therapies for patients with advanced PD are approved or under investigation for the treatment of ‘OFF’ episodes which may overcome the challenges of GI absorption. These include subcutaneous, transdermal, intrajejunal, buccal and inhaled formulations. In the future patients with more advanced PD might be able to enjoy more ‘ON’ time than they are currently afforded.

This Symposium was conducted with educational financial support provided by Sunovion.

References
  1. Politis M et al. Mov Disorder 2010; 25:1646-1651
  2. Chapuis S et al. Mov Disorder 2005; 20:224-229
  3. Shapira A Eur J Neurol 2009; 16:932-959
  4. Poewe W et al. Clin Intervent Aging 2010;5:229-238
  5. Chaná P et al. J Neurol Neurosurg Psychiatry 2004;75:1782-1783
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