Parkinsonian Movement Disorders
Edwardm C. Lauterbach
I. Hypokinesias: The Parkinsonisms
A. Classification of hypokinetic parkinsonian disorders
Movement disorders present as hypokinesias and hyperkinesias. Hypokinesias are syndromes of reduced movement and refer to parkinsonian disorders (the parkinsonisms), including Parkinson disease (PD), progressive supranuclear palsy (PSP), multiple system atrophies (MSAs), including those with parkinsonism (MSA-P), dysautonomia (MSA-A), or cerebellar features (MSA-C), corticobasal degeneration ([CBD]), and other conditions. FTDP-17 is a parkinsonism associated with frontotemporal dementia and tau mutations and is discussed in the chapter on Dementia.
The most common movement disorder is PD, described by Parkinson in 1817. The disorder is characterized by disturbances in motor, cognitive, and emotional function. The motor disturbances include bradykinesia, rigidity, loss of postural reflexes, and a 3 to 8 Hz resting tremor. Many patients also develop dementia or depression.
Parkinsonism is also observed in other conditions. Dementia with Lewy bodies (DLB) presents with a dementia attended by features of PD. Normal pressure hydrocephalus (NPH) sometimes presents with rigidity, suggesting a parkinsonian disorder. Drug-induced movement disorders are considered briefly in terms of diagnosis and treatment rather than comprehensively, because they do not constitute the primary focus of this chapter. The reader is referred to the text edited by Watts and Kohler for a comprehensive treatment of this subject.1
TABLE 9.1 Prevalence of Parkinsonian Disorders | ||||||||||
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B. Epidemiology
Known or estimated prevalences of these disorders are shown in Table 9.1. PD is an age-related illness, with a prevalence of 60 per 100,000 between the ages of 65 to 69, 270 between 75 to 79, and 350 between 85 and 90 determined in one study. Men are more often affected with PSP than women.
C. Etiology and pathophysiology
PD is believed to result from degeneration of nigrostriatal tracts projecting from the dopaminergic substantia nigra pars compacta to the striatum. Although the pathophysiology is quite complex, the loss of dopamine results in excessive activation of the inhibitory (“indirect”) basal ganglia pathway, reducing activation of motor cortices. The cause of the dopaminergic degeneration is not known. Typical PD is not inherited, but there are single gene mutations that cause a form of parkinsonism (e.g., PARK1 to 10 mutations, Nurr1, several mitochondria genes, tyrosine hydroxylase, etc.). Oxidant stress and toxin exposure (1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine [MPTP] and rotenone) have also been implicated in PD pathogenesis.
The pathophysiologies of the other parkinsonisms are less well established. MSA is related to nigral and putamenal degeneration, often with at least one other site involved. MSA-P (striatonigral degeneration [SND]) is thought to result from trans-synaptic degeneration of the putamen as a consequence of nigral disease. MSA-A (Shy-Drager syndrome [SDS]) is linked to degeneration of the autonomic nervous system, and MSA-C (olivopontocerebellar atrophy [OPCA]) to olivocerebellar and pontine degeneration.
PSP is associated with widespread neuronal loss and gliosis in the nucleus basalis of Meynert, globus pallidus, subthalamic nucleus, substantia nigra, pedunculopontine nucleus, intralaminar thalamic nuclei, red nucleus, reticular formation, locus coeruleus, superior colliculus, cranial nerve nuclei III and IV, vestibular nuclei, dentate nucleus, and pons, along with midbrain and frontotemporal atrophy.
CBD is associated with neuronal loss and gliosis and Pick pathology in the substantia nigra, frontoparietal cortex, thalamus, subthalamic nucleus, and red nucleus.
DLB is described in Chapter 4, but frontotemporal cortical degeneration and Lewy bodies are prominent features.
D. Diagnosis and differential diagnosis
The diagnosis of PD is based on clinical features including bradykinesia, rigidity (also called extrapyramidal rigidity, plastic
rigidity, lead pipe rigidity), loss of postural reflexes, and a 3 to 8 Hz alternating resting tremor.2 PD is generally diagnosed by the presence of at least two of these four cardinal features. Bradykinesia refers to slowness in movement, such as gait, but is also manifest in slowed finger taps, rapid alternating movements, and foot taps. Unlike upper motor neuron spastic rigidity, the rigidity encountered in PD is not associated with upper motor neuron lesions or signs (e.g., hyperreflexia). The loss of postural reflexes leads to falls and contributes to en bloc turns, festinating gait, and retropulsion and propulsion on neurologic exam. The posture is generally forward flexed (stooped), with arms slightly flexed, diminished arm swing on gait, and small shuffling steps referred to as march en petit pas. Akinesia is hesitancy or inability to initiate a movement. In more advanced cases, akinesia delaying the initiation of gait (start hesitancy) and freezing (motor blocks) that slows or arrests gait in narrow confined passageways can be evident. The 3 to 8 Hz resting tremor (more usually, 4 to 6 Hz) is most apparent when the limb is at rest and diminishes on assuming postures or with activity. Patients with PD can often temporarily suppress their tremor by moving their limb, in contrast to most other types of tremor. The tremor also displays a side-to-side quality (produced by alternating firing of agonist and antagonist musculature), whereas most other tremors have an up-and-down motion when the arms are extended (caused by simultaneous firing of agonist and antagonist musculature). PD presents unilaterally in most cases, although in 20% it presents bilaterally. The facies display diminished expression resembling flattened affect referred to as a poker face or hypomimia and the nasolabial folds are diminished. There is a staring quality, usually with reduced blinking in the untreated state. In contrast to Parkinson-plus syndromes, a relatively good response to levodopa is usually maintained throughout the illness, despite treatment complexities and complications that evolve late in the disease.
The chief differential involves Parkinson-plus syndromes and secondary parkinsonism (symptomatic parkinsonism). In contrast to Parkinson-plus syndromes, PD usually lacks additional neurologic signs and has a good response to levodopa. Magnetic resonance imaging (MRI) is generally unrevealing except for sometimes-apparent midbrain nigral atrophy and I-123 beta-CIT single photon emission computed tomography (SPECT) imaging shows reduced striatal dopamine uptake. In Parkinson-plus syndromes (atypical parkinsonisms), there are additional signs, which may include supranuclear gaze palsy, falls occurring within the first 3 years of illness, autonomic dysfunction, cerebellar signs, other movement disorders including dystonia or myoclonus, apraxia, alien hand sign, and so on. These can define PSP, MSAs (including those with parkinsonism [MSA-P], dysautonomia [MSA-A], or cerebellar features [MSA-C]), CBD, and other conditions. DLB presents with a dementia attended
by early visual hallucinosis, delirial cognitive fluctuations, and one or more features of PD. A problem in considering the differential diagnosis is the capacity of one disorder to sometimes share clinical features of another disorder, and less than unitary correlations between clinical and histopathologic diagnoses. Clinically diagnosed disorders often result in surprises at autopsy, with pathologic findings not infrequently indicating a disease other than the presumed clinical diagnosis. Neuroimaging can at times be helpful in distinguishing these disorders.
Multiple system atrophies. The mean age of onset is 53 years, much earlier than PD. Hence, early age of onset and presentation with a negligible levodopa response, significant dysautonomia (97% in one series) or cerebellar signs suggest MSA, of which there are three types: SND (MSA-P), SDS (MSA-A), and olivopontocerebellar atrophy (OCPA) [MSA-C].2,3 The diagnosis is made by looking for the features of MSA-P, MSA-A, and MSA-C occurring in any combination, with a 9-year median survival. REM behavior disorder ([RBD]; see section IE1j) is often seen in these patients. The absence of supranuclear gaze palsy and cognitive impairment can help exclude PSP in many cases. The putamen in MSA may be hypointense but a hyperintense lateral putamenal border on T2-weighted MRI is specific for MSA and differentiates it from PD when this radiologic sign is present.
MSA-P usually presents with bradykinesia and rigidity but, in contrast with PD, is negligibly responsive to levodopa and early autonomic dysfunction is present. Hyperreflexia, anterocollic dystonia, various types of tremors, sleep apnea with respiratory stridor, and MSA radiologic findings can further distinguish MSA-P from PD.
Signs of dysautonomia are preeminent in MSA-A (SDS) (e.g., erectile dysfunction, orthostatic hypotension, sphincter dysfunction, incontinence, and constipation), unlike in PD. The presence of central and obstructive sleep apneas, especially the latter with vocal cord stridor, can help distinguish MSA-A from PD. Cerebellar or pyramidal signs are present in at least half of the cases, in contrast with PD.
MSA-C often initially presents as an ataxia with mild parkinsonian features. In contrast to PD, upper motor neuron (Babinski sign, hyperreflexia, clonus, spastic rigidity) and cerebellar signs (ataxia, rebound, terminal kinetic tremor (intention tremor), dysdiadochokinesia) may attend parkinsonian features, sometimes with dysautonomic signs. Eventually eye signs (horizontal nystagmus, impaired upgaze and convergence, loss of the vestibulo-ocular reflex), dysarthria, dysphagia, incontinence, upper motor neuron signs, lower motor neuron signs, cerebellar and brainstem atrophy, and
pontine demyelination on MRI T2-weighted images may be evident, distinguishing MSA-C from PD.
Progressive supranuclear palsy. The mean age of onset is 63, later than MSA but earlier than PD, with a 6 to 7 year survival. Diagnostic features include an early broad-based and stiff gait with backward falls and a supranuclear gaze palsy with slow vertical saccades and difficulty looking down.2,4 The latter two features (prominent postural instability with falls within the first year and supranuclear gaze palsy) have the best diagnostic positive predictive value. Other features include axial rigidity (greater than limb rigidity, unlike PD), nuchal dystonia (often with the neck held in extension, contrasting with neck forward flexion in PD), exaggerated nasolabial folds (contrasting with diminished nasolabial folds in PD), dysarthria, dementia, and a poor response to levodopa. Dysarthria, dysphagia, and “emotional incontinence” are other signs common in PSP, usually occurring in late PD. Speech may be characteristically hypernasal, ataxic, and low-pitched, unlike PD. MRI evidence of midbrain and frontotemporal atrophy with third ventricle dilatation is supportive of the diagnosis, contrasting with the midbrain atrophy of PD. In contrast with PD, olfaction is spared.
Corticobasal degeneration. The mean age of onset is 63, with a 6- to 7-year course, like PSP. CBD is a gradually progressive condition recognized by unilateral akinesia and rigidity responding poorly to levodopa, along with apraxia (usually ideomotor apraxia).5,6 The early onset, levodopa response, and apraxia distinguish CBD from PD. Apraxia of some type may occur in 70% of patients with CBD. Other features include cortical reflex myoclonus, limb dystonia, alien limb sign, and occasionally, a cortical sensory loss, none of which are characteristic of PD. A marked cortical asymmetry is apparent on MRI in most cases, and atrophy of the middle one third of the corpus callosum may be present, unlike PD.
Other conditions sometimes presenting with parkinsonism include normopressure hydrocephalus (NPH, characterized by a magnetic apractic gait, early incontinence, occasional rigidity or paratonia, and dementia), heredodegenerative disorders (see Table 9.2), vascular (multi-infarct, Binswanger disease), infectious (e.g., postencephalitic, AIDS, subacute sclerosing panencephalitis [SSPE], prionic), drug induced, toxic (e.g., MPTP, CO, Mn, Hg, carbon disulfide, cyanide, methanol, ethanol), traumatic (e.g., pugilistic), metabolic (e.g., hepatocerebral degeneration), endocrinologic (e.g., parathyroid, hypothyroidism), neoplastic (e.g., tumor, paraneoplastic), structural (e.g., NPH, noncommunicating hydrocephalus, syringomesencephalia), degenerative (hemiatrophy-hemiparkinsonism), and psychogenic disorders (e.g., severe psychomotor retardation, catatonia, conversional). Drug-induced parkinsonism (DIP)
occurs with dopamine D2 receptor antagonists (including metoclopramide) and, less commonly, with other agents (e.g., SSRIs, reserpine). A severe reaction necessitating emergency treatment, neuroleptic malignant syndrome (NMS), can develop with these drugs, and is generally recognized by fever attended by an extrapyramidal syndrome and delirium. Classic features include fever, leukocytosis, elevated creatine phosphokinase,
autonomic instability, and parkinsonian rigidity and tremor, although other types of movement disorders may also occur.
TABLE 9.2 Heredodegenerative Disorders Associated with Secondary Parkinsonism | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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