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Atypical Parkinsonian Syndromes
Atypical parkinsonian syndromes, previously called Parkinson-plus syndromes, are chronic, progressive neurodegenerative disorders characterized by rapidly evolving parkinsonism in association with other signs of neurologic dysfunction beyond the spectrum of idiopathic Parkinson disease (PD). These include early dementia, postural instability, supranuclear gaze palsy, early autonomic failure, and pyramidal, cerebellar, or cortical signs. The most common disorders ( Table 29.1 ) are progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple-system atrophy (MSA), and dementia with Lewy bodies. Unlike idiopathic PD, these uncommon syndromes have poor or transient responses to dopaminergic therapy and consequently a worse prognosis. These disorders are classified as tauopathies and synucleinopathies based on the accumulation of the abnormal proteins tau or alpha-synuclein within neurons and glial cells having various anatomic distributions within the brain.
TABLE 29.1
Atypical Parkinsonian Syndromes
| Syndrome | Abnormal | Clinical Features | Age at Onset (Years) | Genetic | Pathology | Therapy |
|---|---|---|---|---|---|---|
| PSP | Tau | Gait disorder, falls Abnormal eye movements Akinetic-rigid asymmetric parkinsonism Cortical signs Dystonia Action/postural tremor Myoclonus |
55–70 | Sporadic? Familial | Atrophy of BG and brainstem regions Normal cerebral cortex Globose, NFT |
Poor response to dopaminergic medication Botulinum toxin for blepharospasm Supportive therapy |
| CBD | Tau | Alien limb phenomenon Symmetric axially predominant parkinsonism Dysarthria and dysphagia Frontal lobe abnormalities Cognitive impairment |
60 | Sporadic | Atrophy in FP cortex Tau-positive neurons in cortex Swollen and achromatic neurons (ballooned neurons) |
Poor response to dopaminergic medication Botulinum toxin for blepharospasm Supportive therapy |
| FTDP-17 | Tau | Highly variable: behavioral disturbance Cognitive impairment Motor disturbance (later in the disease) Positive family history |
50 | Autosomal dominant | Atrophy in FT cortex, BG, SN, LC Neuronal loss Argentophilic neuronal inclusions |
Poor response to dopaminergic therapy |
| MSA | Alpha-synuclein | Parkinsonism Cerebellar signs Autonomic features Pyramidal features |
60 | Sporadic | Glial and neuronal cytoplasmic inclusions Absence of Lewy bodies |
Poor or marginal response to dopaminergic therapy Fludrocortisone or midodrine for orthostatic hypotension |
BG, Basal ganglia; CBD, corticobasal degeneration; FP, frontoparietal; FT, frontotemporal; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; LC, locus ceruleus; MSA, multiple system atrophy; NFT, neurofibrillary tangle; PSP, progressive supranuclear palsy; SN, substantia nigra.
Tau is found in a hyperphosphorylated form in both PSP and CBD. In normal human brains, tau functions as a microtubule-binding protein as well as a stabilizer of the neuronal cytoskeleton. In the diseased brain, tau is found in glial cells and neurons, where it produces a special cluster of fibrils called neurofibrillary tangles (NFTs). Generally there are six isoforms of tau made by alternative splicing from the tau gene. Tau also accumulates in the less common tauopathy, frontotemporal dementia with parkinsonism (FTPD). This is linked to chromosome 17 (FTPD-17).
Alpha-synuclein is a highly soluble synaptic protein found in the normal human brain. In MSA it typically accumulates as insoluble aggregates within white matter oligodendrocytes as glial cytoplasmic inclusions (GCIs) and in the form of Lewy bodies in DLB. There are no effective therapies for these syndromes.
Progressive Supranuclear Palsy
Clinical Vignette
A 65-year-old writer presented with poor balance starting 2 years earlier. He tripped easily and fell backward multiple times. He also described changes in his speech and in the swallowing of liquids, which was accompanied by coughing. His wife described change in his facial expression and stated that he looked as though he were staring and always had to turn his whole body in turning to the side.
He had described blurred vision while typing on the computer. He was squinting and occasionally had difficulties opening his eyes.
Neurologic examination demonstrated hypertonic facial muscles, which produced facial folds and a worried, astonished expression, dysarthric speech, a vertical more than horizontal supranuclear gaze palsy with preserved oculocephalic reflexes. Blepharospasm, prominent axial rigidity, and mild bradykinesia in all four extremities with minimal cogwheel rigidity and brisk muscle stretch reflexes were also identified. He stood up quickly, nearly falling backward if not assisted. He walked with erect posture and a stiff, wide-base gait. He had no postural reflexes and, during a pull test, fell backward easily.
PSP is a sporadic tauopathy that has a progressive clinical course characterized by parkinsonism with supranuclear gaze palsy ( Fig. 29.1 ), early postural instability, falls, bradykinesia, and dysarthria, all of which are illustrated in this vignette. PSP typically does not respond to dopaminergic therapy. Its prognosis is poor, with a median survival of 5 to 8 years. PSP's etiology, like that of CBD, is unknown. A genetic susceptibility combined with environmental risk factors is suspected. To date, only the H1 MAPT haplotype has been consistently associated with a risk of developing PSP. A recent genome-wide association study identified three additional putative genes associated with PSP: STX6, EIF2AK3, and MOBP.
Pathophysiology
PSP is primarily a subcortical neurodegenerative tauopathy, in contrast to both CBD and FTPD-17, having involvement of the cerebral cortex. Macroscopically, depigmentation is observable within the substantia nigra (SN) and locus coeruleus (LC), as is atrophy of the pons, midbrain, and globus pallidum. Microscopically the most affected regions are brainstem nuclei III, IV, IX, and X; the red nucleus; LC; SN; globus pallidus; and cerebellar dentate nucleus. Tau protein accumulates within neurons as NFT and in glia as spherical neuropil threads ( Fig. 29.2 ).
Clinical Presentation
PSP typically occurs between the sixth and seventh decades of life. Onset before age 40 years is rare. Prevalence is estimated to be about 5 per 100,000. PSP is sporadic in most individuals, but rarely an autosomal dominant inheritance is suggested.
The most common form of PSP is known as the Richardson variant. Patients with this form present with gait instability and a tendency to fall backward unexpectedly; in contrast, neither of these symptoms occurs early on in PD. The parkinsonism of PSP is typically axial and symmetric, unlike the asymmetric often single-limb presentation of PD. Most patients with PSP carry an erect posture, in contrast to the flexed PD stance (see Fig. 29.1 ). Often they lack the typical PD tremor. Dystonia is a common finding, affecting the neck (in the form of retrocollis), limbs, and eyelids (blepharospasm). However, at least five phenotypic variants have recently been described: PSP-parkinsonism, PSP-pure akinesia with gait freezing, PSP-corticobasal syndrome (PSP-CBS) (or primary nonfluent aphasia), PSP-behavioral variant of frontotemporal dementia (FTD), and two other possible PSP variants with features that overlap with either primary lateral sclerosis (PLS) or cerebellar ataxia.
The hallmark of PSP is the classic and characteristic finding of limited vertical eye movements; eventually horizontal supranuclear gaze palsy may also become evident. In this clinical setting, the patient usually does not recognize the loss of eye movement per se but rather perceives these limitations as blurry vision, particularly manifested by difficulties with routine activities such as reading or walking down stairs. Dysarthria and dysphagia are also commonly experienced early in the disease course. Cognitive dysfunction is a later development for most PSP patients.
Diagnosis
PSP and other atypical parkinsonian syndromes—including CBD, MSA, and dementia with Lewy bodies—are often misdiagnosed as PD in the early stages. The most important diagnostic clues are (1) the results of a careful clinical evaluation and (2) a poor response to dopaminergic therapy. There are proposed diagnostic criteria for each disorder, which are used in neurology and movement disorders practice. To date there is no available biomarker for PSP, and brain magnetic resonance imaging (MRI) remains most helpful, showing atrophy of the midbrain and superior cerebellar peduncles. As a result, the brainstem is often beaked and takes on the appearance of a hummingbird or penguin body ( Fig. 29.3 ). Metabolic positron emission tomography (PET) has demonstrated global reduction in cerebral metabolism; 18 F-fluorodopa PET uptake studies have revealed reduced caudate and putamen uptake. Single photon emission computed tomography (SPECT) revealed bifrontal hypometabolism. Other newer methods including diffusion-tensor imaging (DTI) and recent tau PET ligands show promise for detecting tau in PSP.
Treatment
There are no effective specific therapies available for the PSP patient. Although some of these individuals with slowness, stiffness, and balance problems initially may respond to antiparkinsonian therapies such as levodopa or levodopa combined with anticholinergic agents, this effect is usually limited and at best a temporary one. Visual limitations, dysarthria, and dysphagia are usually unresponsive to pharmacologic intervention.
Antidepressant drugs have had modest success in PSP; fluoxetine, amitriptyline, and imipramine are the most commonly used, although their benefit seems to be unrelated to their ability to relieve depression. Botulinum toxin injections are used when blepharospasm is an issue. Physical and occupational therapy are the most important aspects of patient management.
Multiple research studies with potential disease-modifying therapies for PSP have not been successful. PSP has an inexorably progressive course. The average PSP patient has a survival from symptom onset to death of 5–6 years. Head injury and fractures from falls are common. Because of dysphagia, PSP patients are predisposed to other serious complications such as choking and pneumonia, the most common cause of death.
Corticobasal Degeneration
Clinical Vignette
Two years earlier, a 68-year-old retired orthopedic surgeon began having difficulties with fine motor coordination of the right hand. His hand felt stiff and uncoordinated and was occasionally doing things on its own. His family described it as, “His hand elevates and wanders around without a purpose.” When an object was placed in his right hand, he had difficulty releasing it. Later, his right hand tended to close involuntarily and appeared swollen. Eventually he was unable to perform any fine motor tasks with this hand. Treatment with high doses of carbidopa/levodopa (Sinemet) 25/100, total of 15 tablets a day, was ineffective. One year later, he also noted poor balance and started to fall down. His gait was slow and shuffling, and his right arm was held close to his body in a flexed position. A jerky intention-type tremor developed in the right hand; it was particularly noticeable when he attempted to reach for an object. Concomitantly, his family began to observe that he was experiencing word-finding difficulties, memory problems, slurred speech, and swallowing difficulties.
His neurologic examination demonstrated very dysarthric bulbar speech, word-finding difficulties with anomia for uncommonly utilized objects, and an apraxia wherein he could not appropriately use a body part as illustrated or demonstrate how to perform certain common functions such as combing his hair. On cranial nerve examination, he had mild difficulty generating vertical more than horizontal saccadic eye movements. He had a reduced blink frequency. Right arm levitation, dystonic posture of the right arm with irregular jerky tremor, striking rigidity and bradykinesia on the right side, brisker right muscle stretch reflexes, and a right Babinski sign were also seen. He also had positive snout and grasp reflexes. His gait was very stiff and so limited that he was unable to walk without the assistance of two people.
CBD is a rare sporadic neurodegenerative tauopathy. It occurs mainly after age 60 years and shows no population clusters; its incidence, prevalence, and etiology are unknown. The typical presentation is that of an asymmetric progressive akinetic rigid syndrome, dystonia, and alien-hand phenomenon as well as signs of cerebral cortical dysfunction. All of these various CBD manifestations are poorly responsive to levodopa therapy.
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