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Fast Facts: Parkinson's Disease
By K Ray Chaudhuri, Victor SC Fung
Health Press LimitedCopyright © 2016 K Ray Chaudhuri, Victor SC Fung
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The Parkinson's journey
Prodromal Parkinson's disease
The Parkinson's journey may begin long before diagnosis, as Parkinson's disease is now recognized to have a prodromal period dominated by a number of non-motor symptoms. These are late-onset hyposmia or anosmia, rapid eye movement (REM) behavior disorder, episodes of major depression or anxiety, and excessive daytime sleepiness. This prodromal period could last up to 20 years before awareness of the motor symptoms that mark the initial or 'stable' period of the condition. Those who have the non-motor prodrome will have had unexplained symptoms for years, while those with a dominant motor presentation may have had symptoms for only a few months.
For the clinician, diagnosis is based on clinical presentation, as there is still no reliable diagnostic test. While the cardinal motor symptoms and signs of rest tremor, akinesia and rigidity remain the mainstay of diagnosis, the prodrome of non-motor symptoms described above develops in the majority of patients. At least half of all patients experience mood disturbance with anxiety or depression at some stage of the illness, including in the prodromal phase.
"It was almost a relief to be diagnosed with PD. Up until then I had been told I was suffering from work-related stress and anxiety. I thought it was PD before it was diagnosed so it did not come as a shock. In some ways it was good to know that there was a physical reason why I could no longer cope at work."
Delivering the diagnosis. Care must be taken in how the diagnosis is delivered. Patients are often fearful and may come to the clinician with preconceptions based on information overload from the internet, or a limited understanding or experience of the disease from the media or a relative. It is best to break the news of a patient's diagnosis in the presence of their spouse, partner or other family members.
Often, little information is retained from that first consultation and it is necessary to meet again within 2–3 weeks when the patient's initial shock has subsided.
"When my husband finally emerged from that consultation, his face was completely expressionless. He rushed past me, down the stairs, over the parking lot and I ran after him ... there he sat with his head in his hands and tears streaming down his face."
"Please remember the effects of the diagnosis on the spouse as well. The shock can be just as bad for them and the long-term effects can be severe, as they have to support their loved one as they watch what they go through."
Satisfaction with the initial explanation of the diagnosis has been shown to continue to have an independent effect on quality of life even much later in the illness. Reinforcing the diagnosis and the steps made to confirm it should be followed by provision of information and advice. A sense of optimism must be encouraged.
The disease is only slowly progressive.
There are many effective symptomatic therapies that can help maintain quality of life for the majority of the illness.
Major research efforts are in force to discover additional therapies and, of course, a cure.
Regardless of the stage of the disease, non-motor symptoms, in particular depression or mood disturbance, dominate as the predictor of quality of life. It is useful to guide the patient to a viewpoint whereby the focus is maintaining quality of life, rather than defining themselves by their Parkinson's disease, and it is therefore important to address both non-motor and motor symptoms, and to treat both social and motor disability.
Early-stage stable Parkinson's disease
Many patients who have already been diagnosed will have read on the internet, or will even have been told by another clinician, that treatment is only effective for 5 years. Inevitably, they will conclude that they should delay treatment in order to obtain its benefits when really needed. It is important to recognize the patient who has this misconception in order to unequivocally dispel it.
Patients who may not have fully accepted the diagnosis may be fearful of treatment. It is important to acknowledge this, and to help the patient deal with their fear and denial. Evidence shows that quality of life deteriorates in those who delay treatment compared with those who start it straight away. In early Parkinson's disease, motor and non-motor symptoms can be controlled in a stable fashion with relatively simple medication regimens.
Initial therapy. No treatment has been shown to unequivocally slow disease progression, although the results of the ADAGIO study of early treatment with rasagiline are compatible with a disease-modifying effect (see pages 90–1). Rasagiline, dopamine agonists and levodopa are all reasonable choices for initial therapy, each with their relative benefits and potential side effects. There is also increasing evidence for the benefits of exercise or physical therapy, even in early or mild Parkinson's disease.
"Things that can help ... stay active, both physically and mentally. Talk, sing, go for long walks, do crosswords or sudoku, watch your diet. Above all, remember to smile! Children, especially, do not know how to react if grandpa never smiles at them. It can be done with practice!"
Mid-stage unstable Parkinson's disease
In most patients, the early stable period of disease eventually develops into an unstable mid stage, which remains poorly defined. It is usually the start of unpredictable responses to oral dopaminergic drugs, with the benefit of short-acting drugs (usually levodopa) wearing off from one dose to the next, necessitating incremental treatment over a period of months or years. Patients experience some balance issues, fear of falling, early morning off periods and dyskinesias.
Initially, this may only occur after overnight deprivation (early morning akinesia) but eventually the wearing off symptoms will occur between daytime doses as well. Patients can experience a return of any of their motor symptoms (tremor, slowness or stiffness).
Common non-motor fluctuations are off-period anxiety, depression or fogginess of thought. Around the same time, although not necessarily linked, many patients experience involuntary movements in response to their dopaminergic therapy (dyskinesias). This is most common at peak doses but is also frequently a beginning-of-dose and/or end-of-dose phenomenon (e.g. early morning foot dystonia, diphasic dyskinesias).
The multidisciplinary team has a crucial role during this period to reassure the patient and carer, re-evaluate motor and non-motor symptoms and ensure that appropriate appointments for physiotherapy and speech and language therapy are made. For some patients, assessment of their ability to drive and/or to continue working in a stressful job etc. also needs to be considered at this stage.
Unpredictable fluctuations. Initially, motor and non-motor fluctuations tend to be predictable and can often be managed successfully by adjusting oral medications to try to achieve more constant levels of dopaminergic stimulation. However, over a period of years, the fluctuations can become increasingly unpredictable.
Unpredictable motor fluctuations are especially disabling, as patients begin to lose confidence in their ability to go out, resulting in increasing social isolation. Unpredictable motor fluctuations are probably linked to unpredictable and often delayed gastric emptying. This results in unpredictable gut absorption of levodopa, which is only absorbed after passage through the stomach into the small intestine. Although patients can still improve with adjustments to their oral medications, this usually only offers limited control.
"The Parkinson's Disease Nurse Specialist can play a major role in maintaining quality of life by helping both the patient and carer understand the timing and dosing of medication in relation to the digestive system. Also, being actively involved in optimizing dopaminergic treatment can help to reduce carer stress."
Advanced therapy. It is at this stage that treatment with an advanced therapy (apomorphine, levodopa–carbidopa intestinal gel or deep brain stimulation) should be considered. These bypass or eliminate the need for reliable gastric emptying.
Advanced Parkinson's disease
Mid-stage Parkinson's disease leads on to an advanced stage of disease associated with a range of motor and non-motor functional consequences. In some patients, the final stages of Parkinson's disease may involve the development and delivery of palliative care.
As Parkinson's disease progresses, some of the motor symptoms that once were levodopa responsive (e.g. fine motor skills, postural reflexes, freezing of gait) become only partially or occasionally levodopa responsive. This can result in increasing motor disability and complications such as frequent falls. Cognitive impairment or dementia can develop, as well as psychiatric manifestations such as hallucinations without insight, or even psychosis.
Fortunately, it is increasingly recognized that the major risk factor for these complications is age, rather than simply the duration of Parkinson's disease. Patients should be reassured that regardless of when their Parkinson's disease developed (fifth, sixth or seventh decade), these complications do not tend to occur until patients enter their eighth or ninth decade, so not all patients will reach this stage of Parkinson's disease.
Specialist care. Treatment of this stage of the disease remains the greatest challenge in the modern era. Treatments that can provide some maintenance or enhancement of quality of life are available, but the therapeutic options for many symptoms are limited. It is important that people with Parkinson's disease continue to experience care from a specialist, who can best help navigate the route between over- and under-treatment.
Patient education. Patients should be encouraged to learn about their condition. Patient support groups can help with this (see Useful resources, pages 161–3). Carer stress is common, and must be recognized and managed. Gentle but accurate explanation of what is happening is important so that both patients and carers maintain some sense of control.
"I felt that becoming involved in a patient support group, and wanting to know more, reassured my family who give me enouragement and support on this 'journey'."CHAPTER 2
Epidemiology, pathophysiology and genetics
Parkinson's disease is one of the most common neurodegenerative diseases, but estimating its incidence and prevalence is problematic as there is no 'in-life' marker for idiopathic Parkinson's disease; the diagnosis can only be made with certainty if Lewy bodies (intracytoplasmic aggregations of misfolded protein in the brain) are found in the substantia nigra and other brain regions after death (see pages 19–21). Case ascertainment in community studies is difficult, and often other parkinsonian syndromes may be included.
Incidence and prevalence. 'Incidence' is the number of new cases in a specified time frame, and is not modified by factors affecting survival. Estimates of the annual incidence of Parkinson's disease are in the range of 4–20 per 100 000 individuals. The variability is accounted for by differences in the populations studied and by inclusion or exclusion of other clinical entities, such as essential tremor.
'Prevalence' is the total number of cases in a given population at one time. A widely accepted approximate figure for the prevalence of Parkinson's disease is 200 per 100 000 individuals. In the USA, between 750 000 and 1.5 million people are estimated to have the disease. In the UK, there are approximately 120 000–130 000 diagnosed cases but many more affected individuals may remain undiagnosed; prevalence is predicted to rise to around 160 000 in the next 8 years, largely as a result of increased life expectancy. Worldwide figures are expected to double by 2030, rising from 4.1 million in 2005 to 8.7 million by 2030.
Age, sex and ethnicity. Both the incidence and prevalence of Parkinson's disease increase with age, and the prevalence may be as high as 1 in 50 for patients over the age of 80 years. The disease is estimated to affect 1% of 70-year-olds, but is also seen in younger people, with 10% of cases occurring before the age of 50.
Men are 1.5 times more likely than women to develop the condition.
Parkinson's disease has been found in all the ethnic populations studied; however, sporadic reports suggest that patterns of parkinsonism may differ between different ethnic groups. While well-conducted epidemiological studies in black and some Asian populations (such as south Asia) are still lacking, hospital-based studies and some community studies (e.g. the Copiah County study) have suggested that Parkinson's disease is less common in black populations than other ethnic groups. However, this is not widely accepted.
Mortality. In 1967, Hoehn and Yahr published the first mortality study of Parkinson's disease in the pre-levodopa era. They found that up to 61% of patients were severely disabled or dead after 5–9 years of follow-up, which increased to more than 80% in those followed up for more than 10 years. Overall, in this early study, mortality was three times that expected in the general population. Of more than 20 reports on Parkinson's disease and mortality, 11 reported mortality increases of 1.5–twofold, while the others reported increases greater than twofold.
Several researchers have suggested that disability and mortality in Parkinson's disease show a sex difference, with significantly greater mortality in women. However, there are other studies suggesting a poorer prognosis in men. Berger reported relative risks of death of 3.1 for men and 1.8 for women with the disease, although these figures are much higher than those reported in other studies. A study by Japanese investigators suggested a mean age at death of 71.9 years in men and 74.2 years for women. In Japan, female patients appear to lose approximately 7 years of longevity compared with men once Parkinson's disease is diagnosed.
Although some would say that the life expectancy of patients with Parkinson's disease appears to have been prolonged, their lifespan is still probably less than that of the general population, as indicated in the Japanese study. The cause is complex. Improved survival is thought to be a result of the introduction of effective symptomatic therapy such as levodopa, while decreased or delayed mortality from comorbidity may partly account for the decreased mortality in younger people. Studies have suggested that relative survival for people with Parkinson's disease diagnosed before the age of 60 is similar to that for the general population, but for those who are older at diagnosis relative survival is less than expected.
In general, before the use of levodopa the relative risk of death with Parkinson's disease was about 3.0. The 15-year follow-up study of the Sydney cohort by Hely and colleagues, published in 2005, indicated that modern treatment had reduced this risk to 1.86. However, reassessment of this cohort by the same researchers at 20 years reported a revised risk similar to the pre-levodopa era of 3.1. So the longer people live with Parkinson's disease, the higher the mortality rate. It is also important to note that the surviving patients have significant problems: 83% have dementia.
The confusion regarding mortality in Parkinson's disease may be partly because the disease itself is not a primary or direct cause of death. In the USA, the average annual age-adjusted Parkinson's disease mortality between 1962 and 1984 was estimated as 2 deaths per 100 000 for white men and 1 death per 100 000 for non-white men, 1 death per 100 000 for white women and less than 1 death per 100 000 for non-white women. Mortality increased for persons aged 75 years and older, but declined for those younger than 70 years. Overall, published evidence suggests that mortality for Parkinson's disease increases in the older age groups but decreases for younger ages. The cause of death in Parkinson's disease is most commonly a secondary comorbid disorder. A Japanese study showed that the most common cause of death for all patients, regardless of age, was pneumonia.
Economic burden. Studies suggest that Parkinson's disease adversely affects the health-related quality of life of patients and imposes a significant economic burden on society comparable with that of other chronic conditions such as congestive heart failure, diabetes and stroke. Although it is difficult to measure the specific economic cost of Parkinson's disease, in the UK the annual direct cost of managing patients with Parkinson's disease at home is estimated at around £4189; the cost rises to £19 338 for full-time institutionalization. Furthermore, the total direct cost of Parkinson's disease in patients in 'good health' is three times lower than for those in 'poor health'. These figures do not take into account hidden indirect costs such as loss of income from premature retirement, for both the patient and carer.
The main pathological feature of Parkinson's disease is the degeneration of neuromelanin-containing neurons in the pars compacta of the substantia nigra (Figure 2.1). Examination with the naked eye reveals pallor of this area, which is confirmed microscopically by a marked decrease in the number of neuromelanin-containing cells and the presence of Lewy bodies in the remaining nigral neurons.
Degeneration of pigmented neurons in the brainstem is not limited to the nigra but extends to the locus ceruleus and the dorsal motor nucleus of the vagus.
Lewy bodies are intracytoplasmic eosinophilic inclusions, which are found in several areas of the brain but typically in the neurons of the substantia nigra (Figure 2.2). They are a pathological hallmark of idiopathic Parkinson's disease and are also found in other neurodegenerative diseases, such as dementia with Lewy bodies and Alzheimer's disease. Electron microscopy reveals that Lewy bodies are composed of filamentous material arranged in circular and linear profiles, sometimes radiating from an electron-dense core. Lewy bodies stain positively for ubiquitin and α-synuclein.
Excerpted from Fast Facts: Parkinson's Disease by K Ray Chaudhuri, Victor SC Fung. Copyright © 2016 K Ray Chaudhuri, Victor SC Fung. Excerpted by permission of Health Press Limited.
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