Part 1: Pathophysiology, Symptoms, Burden, Diagnosis, and Assessment

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Supplements and Featured Publications, Parkinson’s Disease: Quality Assessment and Improvement of Care, Volume 14, Issue 2 Suppl

Parkinson’s disease (PD) is a chronic neurodegenerative disease associated with substantial morbidity, increased mortality, and high economic burden. Of importance to managed care is that the number of cases of PD are on the rise, paralleling the advancing age of the population, and misdiagnosis is common. Effective management of PD can minimize disability and potentially improve long-term outcomes, which would minimize long-term healthcare costs and medical resource utilization. This article provides a brief review of the epidemiology, pathophysiology, clinical course, and burden of PD.

(Am J Manag Care. 2008;14:S40-S48)

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disease with a multifactorial etiology. Characterized by hallmark signs of bradykinesia, rigidity, tremor, and postural instability, it is superseded only by Alzheimer’s disease as the most common neurodegenerative disorder.1-5 PD exacts a substantial burden on patients, families of patients, and caregivers,6 and is associated with a significant increase in morbidity and disability; mortality rates are higher and life expectancy lower relative to the general population.5,7-9 The economic burden of the disease is substantial, related to direct/indirect costs and medical resource utilization.6,8,10

Managed care providers and health plans need a broad understanding of PD and its management for 3 principal reasons:

1. The prevalence of PD increases with age.4,11 This is of growing concern, since the number of cases of PD is increasing as a result of the longer life expectancy in many populations, including the United States, with an increased need for healthcare resources.2,12

3. Healthcare costs related to PD are projected to rise dramatically in the near future.10

This 3-part supplement is being provided to managed care providers to assist them in addressing issues relative to improving the care of patients with PD.

EpidemiologyThe prevalence of PD rises from 0.3% in the general US population to 1% to 2% in persons 65 years of age or older; some data indicate a prevalence of 4% to 5% in individuals >85 years.2,4,5 The usual age of onset is the early 60s, although up to 10% of those affected are 45 years of age or younger; the latter group is referred to as “youngonset” PD.5,11 In the United States, there are currently up to 1 million with diagnosed PD, which is greater than the combined number of cases of multiple sclerosis, amyotrophic lateral sclerosis (ALS), and muscular dystrophy.1 About 40,000 cases of PD are diagnosed annually, which by definition does not include the thousands of new cases that remain undetected.1 The lifetime risk of PD in males is 2.0% and 1.3% for women.8 Incidence of the disease appears to be lower in African Americans than Caucasians.5

Etiology and Risk Factors

The pathologic hallmark of PD is degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in depletion of striatal dopamine.2,15 This neurotransmitter regulates excitatory and inhibitory outflow of the basal ganglia.2,5,15

Some surviving neurons contain eosinophilic intracytoplasmic inclusions, or Lewy bodies, which are in part composed of numerous proteins. Protein accumulation is speculated by some to play a prominent role in the pathogenesis of both familial and sporadic PD,2,14-16 and the appearance of proteins in Lewy bodies tends to support this notion. Lewy bodies appear to represent the aftermath of underlying pathology. Evidence suggests these intracytoplasmic inclusions do not appear deleterious to cells, and may even be cytoprotective.2 Neurodegeneration of the SNc can occur in the absence of Lewy bodies in both sporadic and familial cases of PD; conversely, Lewy bodies can be present in the absence of neurodegeneration.2 However, the presence of Lewy bodies is required for pathologic confirmation of a clinical diagnosis of iPD.5

The neurodegenerative process in PD is not limited to the SNc, and neuronal loss with Lewy body formation also occurs in other brain regions,5,15-17 which may account for both motor and nonmotor features of the disease.

Clinical Expression and Course

Table 1

Four cardinal motor manifestations are the central features of PD: (1) resting tremor, (2) bradykinesia (slowness of movement), (3) rigidity often with a cogwheel quality, and (4) postural instability (impairment of postural reflexes), which occurs later in the disease.5,18 Symptoms reported by patients when the dominant hand is involved include micrographia (abnormally small, cramped handwriting) and impairment in other fine tasks, such as fastening buttons. Motor symptoms usually begin asymmetrically but gradually spread to the contralateral side,5,11 although the side of initial involvement tends to remain the most severely affected throughout the course of the disease. Characteristics of these cardinal motor features are shown in .4,5,11,13 Although these features may also be present in other forms of parkinsonism, asymmetric onset, gradual progression, and response to levodopa in the absence of neurologic findings other than parkinsonism are clues that the patient has iPD.

Increasingly, it is recognized that nonmotor symptoms, especially depression, dementia, and psychosis, contribute to excess disability in PD.3,9,21 Nonmotor symptoms dominate the clinical picture as PD progresses and may also contribute to shortened life expectancy.7,9 Most do not respond to, and may be exacerbated by, dopamine replacement therapy.9 Of concern is that, in contrast to motor symptoms, nonmotor symptoms of PD are frequently unrecognized and either untreated or poorly treated in clinical practice, ultimately leading to increased healthcare costs and utilization.9

Depression is frequent in PD and the most common neuropsychiatric disorder, affecting up to 50% of patients.5,9,19-21 Depression is often comorbid with anxiety and can occur at any stage of the illness, including prior to onset of motor symptoms. Other nonmotor features that may occur early in PD are autonomic dysfunction, cognitive impairment, and olfactory dysfunction (hyposmia, a reduced ability to smell odors, or anosmia, which is loss of smell).

Cognitive impairment in PD is characterized by deficits in executive abilities, memory retrieval deficits, and impairments in attention and visuospatial abilities, with advancing age being the primary risk factor.5,19 During long-term follow-up of PD patients, a substantial proportion will eventually develop dementia; a prevalence of 78% was reported in a recent long-term prospective study.20 Dementia is rare in early iPD, and its early occurrence should call into question the diagnosis of PD and may suggest a diagnosis of dementia with Lewy bodies (DLB).5,13 Anosmia and hyposmia are so common in PD that smell-testing is undergoing evaluation as an early biomarker to identify patients at risk of developing PD; loss of smell is also a sign that has usefulness in differential diagnosis, helping to distinguish PD from other conditions.5,9 Anosmia does not respond to dopaminergic therapy.5

Psychosis, specifically hallucinations and delusional thinking, is also common in PD, seen in 15% to 40% of treated patients20 and tending to occur later in the disease course. Although there is a clear association between dopaminergic therapy and psychosis, the etiology of psychosis is complex.20 Other reported risk factors for psychosis include older age, cognitive impairment, visual impairment, sleep disturbances, comorbid depression, and longer duration and increasing severity of PD.19,20

Impulse control disorders (ICDs) (Table 2) are increasingly recognized as a relatively common psychiatric disorder in PD, occurring in up to 10% of patients at any given time. The most commonly reported ICDs in PD are compulsive gambling, buying, sexual behavior, and eating, and their occurrence can be devastating to patients and caregivers. Recent research suggests an association between dopamine agonist use and ICDs in PD.

Other Comorbidity. Nonmotor features are considered comorbidities in PD. However, other more general types of comorbidity have been reported separately in various studies. Some of these nonmotor comorbidities include, but are not limited to, falls and injuries (most notably head trauma and hip fracture); cancer, including malignant melanoma; hypertension, stroke, heart failure, and other cardiovascular disease or disorders; impaired glucose tolerance and diabetes; and pneumonia.22-27 Specific evaluation of these comorbidities is beyond the scope of this review. However, it should be noted that a definite association between these complications and PD remains unclear.

Progression and Mortality. PD is a chronic and slowly progressive disease. Both motor and nonmotor symptoms worsen over time. Prior to the availability of effective symptomatic treatment, the progression of motor symptoms led to severe disability after <10 years of disease.7 Although dopaminergic therapy effectively treats symptoms, whether the long-term outcome is altered has not been established.7

PD is not considered a &#8220;fatal&#8221; disease,1 but mortality in patients with PD selected from the community is generally higher than that of the general population, regardless of levodopa or other therapy.9,28,29 Death is typically caused by secondary complications of the disease; pneumonia is the most common, followed by cardiovascular events (including stroke) and cancer.9,28

Life expectancy in PD mirrors its association with increased mortality. Estimates for life expectancy (LE) and age at time of death (AAD) were calculated based on literature review and comparison with the general United Kingdom population.29 LE and AAD were shown to be reduced for all ages of onset and was greatest in young-onset PD. For the younger cases with onset of PD between 25 and 39 years of age, LE and AAD were 38 years and 71 years, respectively&#8212;each about 10 years shorter than for the general population.

In the Sydney trial,28 mean disease duration from diagnosis until time of death was 9.1 years.

Burden of PD

Stepwise Approach. The diagnosis of PD remains a clinical one. The following 3-step approach is suggested, which is adapted from criteria established by the UK Parkinson&#8217;s Disease Society Brain Bank,5,42 as well as other published diagnostic criteria.

Step 1. Identification of a Parkinsonian Syndrome. Commonly used criteria are the presence of bradykinesia and at least 1 of the following: muscular rigidity, 4- to 6-Hz resting tremor, and/or postural instability.5,42

Step 2. Exclusion of Other Causes of Parkinsonism. Differentiation of PD from other causes of parkinsonism is paramount. This includes separation from secondary (symptomatic) forms and atypical (parkinson-plus) syndromes, which can often be challenging.

SECONDARY OR SYMPTOMATIC forms include drug-induced parkinsonism, most commonly related to antipsychotics and antiemetic agents; postinfectious parkinsonism (eg, sequelae of West Nile viral encephalitis); structural lesions, such as stroke or hydrocephalus; vascular lesions; metabolic conditions, including Wilson&#8217;s disease; trauma (post traumatic parkinsonism); and toxic insults, such as those caused by carbon monoxide, manganese, or 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP).4,5,11,13,43 Prescribed medications frequently implicated in the development of parkinsonism are haloperidol, risperidone, metoclopramide, and prochlorperazine.13

ATYPICAL (PARKINSON-PLUS) CONDITIONS include Alzheimer&#8217;s disease with extrapyramidal signs; progressive supranuclear palsy; multiple system atrophy, such as Shy-Drager syndrome; corticobasal ganglionic degeneration; DLB; spinal cerebellar ataxias; striatonigral degeneration; and ALS/parkinsonismdementia complex of Guam.4,5,11,13

Step 3. Identification of Supportive Features. Several supportive criteria can increase the positive predictive value of the clinical diagnosis of PD against the gold standard of pathology confirmation.5,42 At least 3 supportive features add greatly to diagnostic confidence. Important is a response to an adequate challenge of levodopa, which is required for clinical diagnosis of PD.4,5 Olfactory dysfunction may be highly useful in distinguishing PD from other types of parkinsonism.4

Use of Neuroimaging. Neuroimaging does not play a role in diagnosing PD. Computed tomography and magnetic resonance imaging (MRI) show no specific patterns related to PD4,5 and are not indicated in the patient with typical features of the disease. However, neuroimaging may be useful in patients presenting with atypical features to help rule out other causes of parkinsonism. Some specialists recommend MRI: (1) for patients who present atypically; (2) for patients responding suboptimally to therapy; or (3) if there is concern about alternative etiologies of parkinsonian symptoms.5

Patient Assessment

The number of cases of PD will increase dramatically in the future, accompanied by a rise in medical resource utilization and healthcare costs. Studies have shown difficulties in diagnosing PD and poor recognition of its disabling nonmotor symptoms, suggesting the need to enhance awareness of techniques for both diagnosing and monitoring this disease. More and more patients with PD will be seen by the clinician in years to come, and accurate diagnosis increases the chance of effective treatment and reduced disability over time, which reduces direct and indirect healthcare costs. The comorbid neuropsychiatric nonmotor symptoms of PD, such as depression and cognitive impairment, are particularly important, because they may be more disabling to the patient than motor symptoms. Screening for neuropsychiatric symptoms, and their effective treatment and monitoring, will improve the functioning and HRQOL of the patient with PD, which are primary goals of management.

2. McNaught KS, Olanow CW. Protein aggregation in the pathogenesis of familial and sporadic Parkinson’s disease. Neurobiol Aging. 2006;27:530-545.

4. Rao SS, Hofmann LA, Shakil A. Parkinson’s disease: diagnosis and treatment. Am Fam Physician. 2006;74:2046-2054.

6. Dowding CH, Shenton CL, Salek SS. A review of the health-related quality of life and economic impact of Parkinson’s disease. Drugs Aging. 2006;23:693-721.

8. Leibson CL, Long KH, Maraganore DM, et al. Direct medical costs associated with Parkinson’s disease: a population-based study. Mov Disord. 2006;21:1864-1871.

10. Huse DM, Schulman K, Orsini L, Castelli-Haley J, Kennedy S, Lenhart G. Burden of illness in Parkinson’s disease. Mov Disord. 2005;20:1449-1454.

12. Muller T,Voss B, Hellwig K, Josef Stein F, Schulte T, Przuntek H.Treatment benefit and daily drug costs associated with treating Parkinson’s disease in a Parkinson’s disease clinic. CNS Drugs. 2004;18:105-111.

14. Olanow CW, McNaught KS. Ubiquitin-proteasome system and Parkinson’s disease. Mov Disord. 2006;21:1806-1823.

16. McNaught KS, Jackson T, JnoBaptiste R, Kapustin A, Olanow CW. Proteasomal dysfunction in sporadic Parkinson’s disease. Neurology. 2006;66:S37-S49.

18. Rezak M. Current pharmacotherapeutic treatment options in Parkinson’s disease. Dis Mon. 2007;53:214-222.

20.Weintraub D, Stern MB. Psychiatric complications in Parkinson disease. Am J Geriatr Psychiatry. 2005;13:844-851.

22. Zesiewicz TA, Strom JA, Borenstein AR, et al. Heart failure in Parkinson’s disease: analysis of the United States Medicare current beneficiary survey. Parkinsonism Relat Disord. 2004;10:417-420.

24. Constantinescu R, Romer M, Kieburtz K; DATATOP Investigators of the Parkinson Study Group. Malignant melanoma in early Parkinson’s disease: the DATATOP trial. Mov Disord. 2007;22:720-722.

26. Leibson CL, Maraganore DM, Bower JH, Ransom JE, O’Brien PC, Rocca WA. Comorbid conditions associated with Parkinson’s disease: a population-based study. Mov Disord. 2006;21:446-455.

28. Hely MA, Morris JG,Traficante R, Reid WG, O’Sullivan DJ, Williamson PM. The Sydney multicentre study of Parkinson’s disease: progression and mortality at 10 years. J Neurol Neurosurg Psychiatry. 1999;67:300-307.

30. Reese SL. Psychosocial factors in Parkinson’s disease. Dis Mon. 2007;53:291-295.

32. Pechevis M, Clarke CE, Vieregge P, et al. Effects of dyskinesias in Parkinson’s disease on quality of life and health-related costs: a prospective European study. Eur J Neurol. 2005;12:956-963.

34. Hudson PL,Toye C, Kristjanson LJ. Would people with Parkinson’s disease benefit from palliative care? Palliat Med. 2006;20:87-94.

36. Noyes K, Liu H, Li Y, Holloway R, Dick AW. Economic burden associated with Parkinson’s disease on elderly Medicare beneficiaries. Mov Disord. 2006;21:362-372.

country. Mov Disord. 2006; 21:1755-1758.

39. Guttman M, Slaughter PM, Theriault ME, DeBoer DP, Naylor CD. Burden of parkinsonism: a population-based study. Mov Disord. 2003;18:313-319.

41. Spottke AE, Reuter M, Machat O, et al. Cost of illness and its predictors for Parkinson’s disease in Germany. Pharmacoeconomics. 2005;23:817-836.

43. Singh N, Pillay V, Choonara YE. Advances in the treatment of Parkinson’s disease. Prog Neurobiol. 2007;81:29-44.

45. Unified Parkinson’s Disease Rating Scale. MD Virtual University. www.mdvu.org/pdf/updrs. Accessed October 15, 2007.

47. Den Oudsten BL,Van Heck GL, De Vries J. The suitability of patient-based measures in the field of Parkinson’s disease: a systematic review. Mov Disord. 2007;22:1390-1401.