By Shivani Naik, MD; Murali Kolikonda, MD; Shanti Pittampalli, MD; Steven Lippmann, MD

Funding/financial disclosures. The authors have no conflicts of interest relevant to the content of this letter. No funding was received for the preparation of this letter.

Innov Clin Neurosci. 2018;15(9–10):11–13

Dear Editor:

Parkinson’s disease (PD) is second to Alzheimer’s disease as the most common neurodegenerative disease, with a prevalence of 7.5 million people worldwide.1 The number of people with PD is increasing, with most of them living at home and having the majority of their health concerns addressed by primary care physicians.2 The burden of disease is estimated to rise by 77 percent over the next 20 years.2

PD causes motor and non-motor symptoms (NMS).3,4 These NMS include mood disorders, psychoses, sensory problems, dementias, autonomic dysfunction, pain syndromes, fatigue, and disorders of sleep and impulse control. Beyond the motor presentations (e.g., tremor, bradykinesia, rigidity, and postural and gait instability), NMS can diminish the quality of life for patients with PD. These NMS can be present in all stages of the disease. Frequently, NMS precede motor manifestations of PD.3 The symptoms include olfactory disturbance, rapid-eye-movement sleep dysfunction, depression, and pain. As the disease progresses, NMS often coexist with the motor symptoms of PD.3,4 In advanced stages of the disease, symptoms of autonomic dysfunction and hypotension can increase the likelihood of falls.4 Unfortunately, NMS are under-recognized in patients with PD, and treating these symptoms early in the disease process is key to improving patient care.5

Psychotic symptoms are frequently experienced by patients with PD and can significantly hamper a patient’s quality of life and increase caregiver burden.6 The interplay between antiparkinson medication interventions, associated illnesses, and endogenous PD pathology contribute to the development of psychotic symptoms.6 The pathophysiology of these psychiatric presentations remains unclear. There are many psychoses-inducing risk factors among patients with PD, such as older age, female sex, depression, hyposmia, autonomic dysfunction, excessive daytime sleepiness, and sleep disorders.7 Psychoses that are part of NMS associated with PD usually manifest as visual hallucinations. These hallucinations typically exist in isolation, but other hallucinatory phenomena can also be present. Tactile, auditory, and olfactory hallucinations can occur but are less prevalent. As the disease progresses, visual and non-visual hallucinations can co-exist.8

Treatment recommendations for PD psychoses suggest gradual dosage reduction of dopaminergic medications since dopamine can induce psychotic symptoms.9 Current guidelines endorse prescribing clozapine, in preference over quetiapine. Despite well-recognized side effects, both drugs are frequently utilized in cases of PD psychoses because they do not worsen motor symptoms. Pimavanserin is a newly approved pharmacotherapy for PD psychoses that has demonstrated efficacy.10 Pimavanserin is usually well-tolerated, with relatively few side effects, and does not negatively impact motor functioning.

The pathophysiology of PD extends beyond nigrostriatal and dopaminergic pathways. Degeneration in non-dopaminergic regions, particularly the dorsal motor nucleus of vagus nerve and olfactory regions, often precedes dopaminergic pathway degeneration.3 This could be responsible for the NMS, such as impaired olfaction, constipation, and pain, that often precede motoric dysfunction.

For patients with PD who exhibit motoric dysfunction via the dopaminergic pathway, current PD treatments do not consistently treat NMS.11,12 In the later stages of PD, NMS become more obvious as they increase in prevalence, and often coexist with motor symptoms. The prevalence of NMS at the time of PD diagnosis is 21 percent, and this significantly increases to 88 percent seven years following the initial diagnosis.13 Recognizing and treating NMS in early or in pre-motor stages of PD is critical to improving patient outcomes.

Beyond pharmaceutical management of NMS associated with PD, speech and physical therapy can also improve communication, gait, and cognition.14 These therapies, when administered early in the disease process, especially with physician support, can also benefit a patient’s sleep, pain management, and quality of life. Additionally, co-treatment by a neurologist and primary care physician might improve outcomes for patients with PD and NMS.

Identifying and treating NMS associated with PD improves prognosis. Since NMS affects disease severity and quality of life, early recognition and treatment is beneficial. Screening patients with PD for NMS during regular appointments using questionnaires (e.g., the PD NMS questionnaire) is helpful.15 Finally, continuing education for physicians on the latest diagnosis, treatment, and management options for PD and associated NMS can improve prognosis and quality of life for patients with PD.


  1. Ross GW, Abbott RD. Living and dying with Parkinson’s disease. Mov Disord. 2014;29(13):1571–1573.
  2. Dorsey ER, George BP, Leff B, Willis AW. The coming crisis: obtaining care for the growing burden of neurodegenerative conditions. Neurology. 2013;80(21):
  3. Sethi K. Levodopa unresponsive symptoms in Parkinson disease. Mov Disord. 2008;23 (Suppl 3):S521–533.
  4. Chaudhuri KR, Healy DG, Schapira AHV. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5(3):235–245.
  5. Romenets SR, Wolfson C, Galatas C, et al. Validation of the non-motor symptoms questionnaire (NMS-Quest). Parkinsonism Relat Disord. 2012;18(1):54–58.
  6. Chang A, Fox SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. 2016;76(11):1093–1118.
  7. Lenka A, Herath P, Christopher R, Pal PK. Psychosis in Parkinson’s disease: from the soft signs to the hard science. J Neurol Sci. 2017;379:169–176.
  8. Goetz CG, Stebbins GT, Ouyang B. Visual plus nonvisual hallucinations in Parkinson’s disease: development and evolution over 10 years. Mov Disord. 2011;26(12):2196–2200.
  9. Ffytche DH, Creese B, Politis M, et al. The psychosis spectrum in Parkinson disease. Nat Rev Neurol. 2017;13(2):81–95.
  10. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled Phase 3 trial. Lancet. 2014;383(9916):533–540.
  11. Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol. 2009;8(1):67–81.
  12. Lledo A. Dopamine agonists: the treatment for Parkinson’s disease in the XXI century? Parkinsonism Relat Disord. 2000;7(1):
  13. Bonnet AM, Jutras MF, Czernecki V, et al. Nonmotor symptoms in Parkinson’s disease in 2012: relevant clinical aspects. Parkinsons Dis. 2012;2012:198316.
  14. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet. 2009;373(9680):
  15. Chaudhuri KR, Martinez-Martin P, Schapira AH, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord. 2006;21(7):916–923.

With regards,

Shivani Naik, MD

Research Scholar, Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky

Murali Kolikonda, MD

Neurology Resident, Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky

Shanti Pittampalli, MD

Research Scholar, Department of Infectious Disease, University of Louisville School of Medicine, Louisville, Kentucky

Steven Lippmann, MD

Emeritus Professor, University of Louisville School of Medicine, Louisville, Kentucky