Jolyon Meara
Parkinsonism and Other Movement Disorders
Movement disorders in older adults can be broadly classified into the akinetic-rigid hypokinetic conditions, in which voluntary movement is reduced, and hyperkinetic conditions, in which excess involuntary movements called dyskinesias are present (Box 64-1). Dyskinesias can be further classified into tremor, dystonia, tics, myoclonus, and chorea. This distinction is as not absolute as, for example, in Parkinson disease (PD), the most common akinetic-rigid syndrome, involuntary movements are often present. Akinetic-rigid syndromes are usually associated with poor mobility and difficulty with walking because of the presence of a gait apraxia.
Movement disorders are common in older age and are a significant cause of impairment, disability, and handicap.1 Once diagnosed, these disorders can often be effectively treated. These conditions often present in older people at an advanced stage, and it is not uncommon in older patients acutely admitted into the hospital for other conditions to make the diagnoses of hitherto unrecognized essential tremor, parkinsonism, orofacial dyskinesia, or drug-induced movement disorder.
Akinetic-Rigid Syndromes
The akinetic-rigid syndromes are a group of disorders characterized by parkinsonism, which results from the combination of akinesia, rigidity, and, often but not always, tremor (Box 64-2). Parkinsonism is often associated with impaired balance and a gait apraxia leading to falls and impaired mobility. Levodopa-responsive parkinsonism of unknown cause that has particular clinical features, a characteristic clinical progression, and Lewy body neuropathology in the substantia nigra is called idiopathic parkinsonism or PD and accounts for approximately 70% of cases of parkinsonism.2,3 Other causes of parkinsonism include drugs, vascular disease, and, much less frequently, multisystem degenerative conditions, which include progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. With increasing age, not only does the risk of parkinsonism increase but also the likelihood of parkinsonism having a cause other than PD.
Parkinson Disease
Although PD can present at any age, it rarely occurs outside of old age.4 Cross-sectional prevalence studies of PD and parkinsonism show at least two thirds of subjects to be older than 70 years. PD is usually insidious in onset and may have a long symptomatic phase before eventual diagnosis, with symptoms being mistakenly attributed by patients and their physicians to the inevitability of “old age.” The rate of progression in PD is strongly related to age at onset rather than to disease duration, which explains the often rapidly disabling motor deterioration associated with dementia seen in subjects with onset beginning after 70 years of age (late-onset disease). Minimal signs of parkinsonism may result from normal aging changes in the basal ganglia or incidental Lewy body changes, making the diagnosis of PD in older people even more difficult.5
Clinical Features
Classically PD has been considered a disorder of voluntary motor control, which in young subjects is a reasonable assumption. However, the increasing realization of the widespread nature of neuropathology in PD, coupled with our increasing recognition of nonmotor symptoms, has now led to the concept of PD being a multisystem multiorgan disorder.6 Nonmotor symptoms are increasingly common with disease progression and older age at disease onset and therefore are a major feature of PD in older subjects.7,8,9 Cognitive impairment, often progressing to dementia, is the most powerful factor that determines quality of life in older people with PD. Late-onset PD is probably best thought of as being primarily a dementia associated with poor mobility and a high risk of falls.10,11
Neuropathology
PD is characterized by cell loss and gliosis in the substantia nigra and other pigmented brainstem nuclei that are often visible to the naked eye on sectioning the midbrain.12,13 Aging also results in cell loss in the substantia nigra, although the distribution of cell loss is very different from that seen as a result of PD.14 Surviving cells in the substantia nigra contain typical inclusions in the cytoplasm called Lewy bodies, which are now known to be largely an aggregation of a protein called α-synuclein.15 Most cases of PD diagnosed in life are found to have Lewy bodies in the substantia nigra.16 However, Lewy body pathology in the substantia nigra does not necessarily lead to the clinical picture of PD, and conversely, largely from the studies of familial parkinsonism, other pathologies not involving Lewy bodies can give rise to a clinical picture typical of PD.17,18 Lewy bodies are also found in other specific brain sites outside the brainstem, including the cerebral cortex, olfactory bulb, and enteric plexi.19,20 Lewy bodies can be found in up to 10% of postmortem examinations in older subjects with no apparent history of parkinsonism in life (incidental Lewy body disease). It is unclear whether such individuals, if they had survived, would have developed PD or, because of protective mechanisms, were able to contain the disease process in a subclinical state.21 The role of the Lewy body in the pathology of PD is still unknown, and it is unclear whether the Lewy body represents a defense mechanism or the result of the primary disease process.
PD also involves the ascending serotonergic, noradrenergic, and cholinergic projections to the cortex and basal ganglia.22 Clinicopathologic studies have demonstrated that coexisting neuropathology within the striatum and in other areas of the brain is extremely common in older subjects with histologically confirmed PD.23 Braak and colleagues have proposed that the primary degenerative process in PD, based on the assumption that the presence of Lewy bodies indicates neuronal loss, begins not in the substantia nigra but in the olfactory tracts, lower brainstem, and enteric nervous tissue.24 This model fits well with the increasing recognition that rapid eye movement (REM) sleep disorders, hyposmia, and constipation may precede the motor symptoms of PD by several years. The proposed pattern of disease progression also indicates the potential for interaction with environmental agents via the olfactory system and gut.
Motor Features
Akinesia is the central motor abnormality in PD that refers to a lack of spontaneous voluntary movement, slowness of movement (bradykinesia), and faulty execution of movement.25 Marsden brilliantly described akinesia as the “failure to execute automatic learned motor plans.”26 Voluntary movements tend to be of low amplitude and to show increased fatigability. There is a particular difficulty with sequential and concurrent self-paced movements. When asked to oppose the index finger to the thumb in a tapping motion, patients often start with reasonably fast, large-amplitude movements, but the speed and amplitude then rapidly decrease and the movement fades away. Akinesia in the lower limb is best tested by asking the patient to tap the heel of the foot on the floor as rapidly as possible; in this situation, akinesia can be heard as well as seen. Older patients often find bedside tests for akinesia difficult to execute and may perform poorly because of cognitive impairment, painful arthritis, restricted joint range, and muscle weakness. Action tremor from any cause can interfere with the quality of normal hand and finger movements, and this can make the assessment of akinesia difficult in the presence of essential or dystonic tremor.
Rigidity is an increased resistance of muscle to passive stretch felt by the examiner. Clinically, rigidity is best detected at the wrist joint. The patient is asked to relax as fully as possible while the examiner makes flexion and extension movements of the wrist joint with the patient’s forearm supported. Passive movements of the head can be used to detect axial rigidity. Parkinsonian rigidity is not velocity-dependent and is present to the same degree at all joint positions in flexion and extension (“lead-pipe” rigidity). Activation procedures, akin to the Jendrassik maneuver to enhance tendon jerks, can bring out “activated rigidity” that was not previously present. Transient activated rigidity may be a normal finding in anxious individuals. Activated rigidity in the neck muscles may be the first sign of rigidity in PD. Tremor in the upper limb due to any cause will result in a ratchet-like quality of intermittent resistance at the wrist joint called cogwheel rigidity that is not specific to PD.
Tremor, usually of the hand, is the presenting feature of PD in approximately 70% of cases. Hand tremor characteristically occurs at rest when the postural muscles are relaxed and has a frequency of approximately 4 to 6 Hz. In an anxious patient, postural tremor can easily be misidentified as a resting tremor. Most patients with PD manifest a range of resting, postural, and action tremors. A resting tremor of the hand involving the thumb and index finger described as “pill-rolling” and often brought out when the patient is observed walking is very suggestive of PD or drug-induced parkinsonism. Tremor usually begins insidiously in one hand before spreading to the leg on the same side. After a further delay of sometimes a year or more, the opposite hand and leg become affected. In rare cases, PD can present with tremor alone (tremor-dominant PD) with variable degrees of mild rigidity and akinesia found on examination. Tremor-dominant PD is a slowly progressive disorder and can be very difficult to distinguish from essential and dystonic tremors. Individuals with a diagnosis of PD recruited into trials of neuroprotection in PD, who are subsequently found to have no evidence of nigrostriatal dysfunction on positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans, may well have dystonic tremor.
Postural balance can be assessed clinically by asking the patient to stand and then gently pushing the patient forward from behind, with the other hand in front to prevent a fall. Falls or feelings of imbalance strongly suggest the presence of impaired righting reflexes, even if this is not evident at the time of examination. Axial motor disturbances leading to gait disturbance, dysphagia, and dysarthria are a feature of late-onset PD and often respond poorly to drug treatment.
In older people with PD, the severity of clinically elicited motor signs, the benchmark of disease severity in clinical research trials, is often poorly correlated with functional impairment and handicap in daily living. For example, despite the bedside demonstration of severe akinesia in the clinic, one patient still managed to make breakfast that day, albeit slowly, and was able to make the arduous journey to the hospital.
Nonmotor Features
Nonmotor symptoms, particularly hyposmia, sleep disorder, and constipation, may predate the onset of motor symptoms by many years. Nonmotor features of PD are varied and, with disease progression, dominate the clinical picture.9,27 In late-onset PD, nonmotor features are usually advanced by the time of diagnosis and progress more rapidly than in earlier-onset disease. Autonomic system involvement leads to postural hypotension, urinary incontinence, sexual dysfunction, constipation, and abnormalities of sweating.28 The progression of PD pathology in the cerebral cortex leads to a range of neuropsychiatric and cognitive problems, including dementia, psychosis, hallucinations, apathy, and depression.29,30 Sensory symptoms, usually painful in nature and involving the lower limbs, also occur and are difficult to treat successfully. A rating scale for nonmotor symptoms has been developed, but, like so many assessment scales, it is more useful in research settings than in clinical practice.31
Dementia and cognitive impairment are common problems in the management of PD in older adults.32 The cause most frequently appears to be Lewy body pathology in the cerebral cortex.29 Dementia that develops a year or more after parkinsonism is described as PD dementia (PDD), whereas dementia present at the start of the illness is called dementia with Lewy bodies (DLB). These two conditions are generally thought to represent two ends of a spectrum of Lewy body disease.33,34 The situation is more complicated than this with the expansion in the United Kingdom of organized memory clinic care for people with dementia. This has resulted in the identification of individuals with established dementia, who never fulfilled DLB diagnostic criteria, who subsequently develop typical features of PD, and who appear to benefit from cautious levodopa treatment. The risk of dementia in older adults with PD is five times that of age-matched subjects without PD,11 and after 8 years of follow-up the prevalence of dementia may reach nearly 80%.10
Dysthymia, or mild depression, is fairly common in PD,7,35–37 but major depression is unusual in the absence of previous significant depressive illness. The natural history of depression or depressive symptoms in PD and the response to antidepressant drug treatment has been poorly studied.38 Apathy is also frequently described in individuals with PD and may be mistaken for depression.39 A range of nocturnal and daytime sleep disorders is now well described in PD and include REM sleep behavior disorder and excessive daytime sleepiness.40
Visual hallucinations are common in PD and occur early in late-onset disease.41 Rather than simply being side effects of antiparkinsonian medication, visual hallucinations are now thought to be the direct result of Lewy body pathology in the ventral-temporal brain areas, indicating that the second half of the course of the disease has been reached.42,43 Visual hallucinations have been suggested as a useful marker to distinguish PD from non–Lewy body parkinsonism.43
Psychosis in PD usually occurs in older patients with established cognitive impairment or dementia and again indicates the presence of significant cortical disease.44
Delirium in PD is also common in older patients with cognitive impairment and is precipitated by the usual suspects commonly invoked in geriatric practice. All antiparkinsonian medications increase the risk of delirium; this risk is greatest with anticholinergics, dopamine agonists, selegiline, and amantadine. Visual hallucinations commonly occur in conjunction with psychosis or delirium. Delirium has a remarkable but unexplained and little researched effect on motor symptoms in PD. Patients with acute delirium are often hyperactive and wander around the ward despite refusing all antiparkinsonian medication for days at a time. As the delirium lifts and medication is reintroduced, motor function again deteriorates to the previous parkinsonian state of frozen immobility.
Clinical Diagnosis
The diagnosis of PD is a two-stage process that remains heavily dependent on clinical skills.45 First, the symptoms of parkinsonism need to be sought in the history and the signs of parkinsonism established by clinical examination. Progressively small handwriting (micrographia) with the written word disappearing into a shaky line is strongly suggestive of parkinsonism. Difficulty turning over in bed is also a good clue to the early development of axial akinesia. A good witness account, usually from a spouse, is very useful in confirming the often rather general and nonspecific slowing down seen in older patients with PD. The gradual inability to keep up with a spouse on daily routine walks is again a useful early indication of gait disturbance and akinesia. Loss of saliva from the mouth at night (sialorrhea) is also helpful, indicating the presence of akinetic bulbar function. Second, if parkinsonism is detected, consideration has to be given to what type of parkinsonism is present by applying validated clinical diagnostic criteria23,46 (Box 64-3).
In older patients, the diagnosis of parkinsonism can be extremely difficult, even in expert hands, particularly when the clinical picture is complicated by other diseases, cognitive impairment, depression, and atypical features.47 The diagnosis of parkinsonism in acutely ill frail patients in the hospital should be approached with particular caution because, once the patient has recovered from the acute illness, the apparent signs of parkinsonism may not be present. A confident diagnosis of parkinsonism cannot always be made in older people, and sometimes a trial of levodopa at an adequate dosage (at least 600 mg daily) may be required. The use of DaTSCAN-SPECT imaging of the nigrostriatal tract using a radiolabeled tracer for the dopamine transporter may help distinguish atypical postural and action tremors in older patients and lead to the correct diagnosis of PD, essential tremor, and dystonic tremor.48,49
How good are experts at distinguishing PD from other types of parkinsonism? Two important clinicopathologic brain bank studies addressed this problem and demonstrated that diagnostic accuracy for PD at death, when diagnostic accuracy is going to be highest, was only approximately 76%.23,50 Diagnostic accuracy in later cases referred to a brain bank was shown to have improved to approximately 84%.51 The use of stringent clinical diagnostic criteria can improve the specificity for correct diagnosis to over 90% but at the expense of a reduced sensitivity of approximately 70% since true but clinically atypical cases are excluded.
Clinical Subtypes
Clinical observation suggests that subtypes of PD exist, and yet surprisingly little scientific study of this phenomenon has been undertaken (Box 64-4).46,52,53 Late-onset disease tends to progress more quickly than early-onset disease (symptoms before the age of 40 years) and is more often associated with cognitive impairment.54 Patients in the longitudinal DATATOP study who were classified as having rapidly progressive disease were older, had more severe postural imbalance and gait disorder (PIGD group), and exhibited less tremor at study entry than the group with slowly progressive disease. Tremor-dominant disease was associated with less disability, less cognitive impairment, and less depression compared to a group with akinetic rigidity and postural imbalance. The DATATOP analysis suggested that cognitive function and motor deterioration were relatively independent once adjustment for age had taken place.54 However, patients with late-onset disease appear to become demented sooner than patients with early-onset disease of similar duration.55 The risk of disabling levodopa-induced dyskinesias appears to be much lower in patients with late-onset compared with early-onset disease. Motor fluctuations are also less evident in late-onset disease with the possible exception of the end-of-dose “wearing off” of drug benefit.
The clinical expression and progression of PD with age is likely to reflect the impact of additional neuropathology from vascular or Alzheimer type pathology as well as effects of cell loss because of aging.56 Indeed, vascular and Alzheimer type changes in the striatum and cortex may protect older patients from levodopa dyskinesia and motor fluctuations but reduce the therapeutic response to levodopa and increase the risk of cognitive impairment or dementia.
Epidemiology
PD has a strong age-associated risk, and both prevalence and incidence increase exponentially with age.57,58 Whether the incidence of PD truly falls in extreme old age is still unclear. The apparent drop in incidence in extreme old age may reflect diagnostic difficulties or limitations of case ascertainment in small populations. PD affects all racial groups and, after adjusting crude rates to a standard population and allowing for differences in study methodologies, has a fairly uniform worldwide distribution of approximately 110 per 100,000.57 Differences in adjusted prevalence rates may still be explained by differential survival, diagnostic bias, and variable mortality rates. Population-adjusted prevalence rates for PD in European subjects older than age 65 years have been reported as 2.3% for parkinsonism and 1.6% for PD.59 Studies in which all eligible subjects are examined using the total census approach have shown that up to a third or more of subjects ascertained as having PD were medically undiagnosed before the study.60,61 A longitudinal study of 4341 older subjects initially free of parkinsonism reported an average annual incidence rate of 530 per 100,000 for parkinsonism and 326 per 100,000 for PD.62
The strong age-associated risk of PD means that over the next few decades the burden of PD worldwide will increase, particularly in the most populous regions of the Far East and China, where the greatest increase in older people and incident cases of PD will occur.63 The number of people older than 50 years who have PD is likely to double in the 10 countries with the biggest populations over the next quarter of a century.63
Parkinsonism in institutional care has received little research attention despite the fact that 15 years from diagnosis approximately 40% of survivors will need long-term care.9 The prevalence of parkinsonism appears to be high in hospitals, nursing homes, and residential/retirement homes.64 A survey in the United States of 5000 nursing home residents older than 55 years reported a prevalence for medically diagnosed PD of nearly 7%.65 A European study found that 42% of cases of PD in older subjects living in institutions were medically undiagnosed.66 Nursing home residents with PD tended to be more disorientated, depressed, and functionally disabled than residents without PD.67,68 Psychosis and dementia are the two main factors increasing the risk of admission to nursing homes of older people with PD.67,68
Cause
The cause of sporadic PD is unknown but is likely to represent interaction between environmental agents and genetic susceptibility. Potential mechanisms to explain this interaction are suggested by the Braak hypothesis of disease progression,24 the existence of environmental neurotoxins such as 1-methyl-4-phenyl-1,2,2,6-tetrahydropyridine (MPTP),69 and the occurrence of incidental Lewy body disease.
Twin studies suggested that, apart from early-onset disease, genetic mechanisms were relatively unimportant in the causation of PD.70 However, since then, rare monogenic forms of familial parkinsonism have been described, the most common relating to mutations in the LRRK2, Parkin, and PINK1 genes.71 A total of at least 13 genetic loci have been reported that result in dominantly and recessively inherited parkinsonism, usually of early onset and often with clinical features atypical of PD. These genes are most likely to be involved in protein degradation, oxidative stress responses, and mitochondrial function. Neuropathologic findings resulting from these gene mutations are variable but consistently reveal nigral degeneration with or without Lewy bodies. Even when the clinical picture is indistinguishable from PD, as occurs in LLRK2 mutations, the pathologic findings can be remarkably varied. Mutations at the LLRK2 locus result in dominantly inherited PD with reduced penetrance causing an age of onset typical of PD that may account for 1% of “sporadic” cases of PD.72 Overall, approximately 5% of sporadic incident PD may have a clearly defined genetic basis. The relationship between clinical features and progression in early PD and genetic markers for PD is currently under investigation in the large PROBAND study, which is scheduled to close to recruitment in 2016.
Several environmental agents, such as MPTP and manganese, can cause parkinsonism, but no environmental exposure that is widespread enough and persistent enough over thousands of years to cause sporadic PD has yet been found.
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