Parkinson's Disease

Course

The neural degeneration of Parkinson's disease  (PD) may begin many years before clinical signs are manifest. Consequently, onset is so insidious that people with PD can rarely pinpoint when they first noticed symptoms and early symptoms might be so mild that a clinical diagnosis cannot be established.

Some people with PD report that symptoms first appeared during periods of stress, subsided and then reappeared several years later (Goetz et al, 1995). Other people with PD describe a history of disability consistent with Parkinsonism present many years before a definite diagnosis was made. The families of people with PD often recall subtle motor and mental changes that predate the diagnosis by years.

There is much evidence suggesting PD may progress rapidly during the subclinical stage and during the first years after the appearance of symptoms, with slower deterioration thereafter (Poewe and Wenning, 1996). According to the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) Unified Parkinson's Disease Rating Scale (UPDRS) study, motor examination scores declined by 8–9% per year in people with PD who were untreated (The Parkinson’s Disease Study Group, 1989). Imaging studies suggest a similar rate of decline, with an annual loss rate of striatum markers of about 10% – 10-fold higher than that seen in the ‘normal’ ageing brain.

The relationships between progression of disease, symptoms and disability are displayed diagrammatically in Figure 1. During the subclinical phase of PD, the rate-limiting enzyme, tyrosine hydroxylase, increases in expression by 2–3 times and dopamine turnover is increased 3–4 times. This compensating mechanism continues into the early years of the clinical phase. However, as PD progresses, progressive loss of surviving pigmented neurons  in the substantia nigra  overwhelms all compensatory mechanisms (and treatments) and is accompanied by increasing disability until death of the neuron (Clarke, 2001).

Before the introduction of levodopa, PD caused severe disability in 16% of people with PD within 5 years of onset, in 37% during the next 5 years and in 42% of those surviving for 15 years (Fahn, 1995); the mortality rate adjusted for age, sex and race was 3 times that of the general population.

The progression of PD is not uniform and two symptom-based subgroups have been suggested: one dominated by postural instability and gait difficulty, the second by tremor  (Jankovic et al, 1990). Distinguishing features of the tremor group include:

• a family history of tremor
• earlier age of onset
• less functional impairment
• preservation of mental status.

There is a consistent finding that people with PD who have tremor-dominant PD have a better outcome. However, there is little consensus concerning the definition of ‘tremor dominant’, with various studies noting it as the initial symptom, the chief complaint or the only cause of disability with little rigidity or akinesia. By contrast, people with PD who have predominant postural and gait difficulties tend to have a poorer prognosis.

Based on presenting phenomenology and prognosis, it has been suggested that people with early onset PD (EOPD; onset between 21 and 40 years of age) have a variant form of PD. In one large cohort study (n=149), Schrag et al. noted that after a median duration of illness of 18 years, cognitive impairment was found in only 19% of people with EOPD, but was notable in 13% of those younger than 60 years and 43% of those 60 years or older. Age was the most important factor for developing dementia, whilst female sex and positive family history of Parkinsonism also had more modest predictive value. After a disease duration of 10 years or less, only 5% and 30% of people were experiencing falls and freezing respectively, but all patients had developed levodopa-related fluctuations and dyskinesias (Schrag et al, 1998).

Schrag et al. also noted that mortality among people with EOPD, although higher than in people without PD, did not differ from people with late-onset PD (LOPD; onset after 60 years of age). However, the 10 people with juvenile onset PD (onset younger than 21 of years) had a mortality risk about three times that of other people with PD. Provided that people with PD remained chronologically and biologically young, intellectual function and postural reflexes were usually well preserved for many years; whereas, people with EOPD experienced early and frequent occurrence of treatment complications.

A number of reports have suggested a relatively benign prognosis in EOPD and differences from LOPD in initial presentation with, motor symptoms of rigidity and bradykinesia predominant in EOPD, whilst postural instability and gait difficulties are more prevalent in patients with LOPD. EOPD is also characterised by a high prevalence of dystonic phenomena that are both disease and treatment related. Patients show a marked response to low doses of levodopa together with early appearance of motor side effects, including response oscillations and dyskinesias (Gomez et al, 1997).

Whilst phenomenological differences apparently exist between EOPD and LOPD, efforts to define these categorically have not been very successful. It seems most likely that EOPD and LOPD are one and the same disease, with differences arising largely from significant differences in patients’ ages.

Another proposed classification of PD (Hely et al, 1995) is based on the presence of dementia; howevere, estimates of the proportion of patients with dementia vary widely, ranging between 10% and 41%. Evidence from people with EOPD suggests that dementia is most likely age-related.

Whilst younger people with PD seem to experience a slower rate of progression, but are more troubled by motor fluctuations than their older counterparts, untreated PD results in virtually complete immobility and dependence. Death ensues due to aspiration pneumonia, pulmonary embolism or similar complications of prolonged immobility.