eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Progressive Supranuclear Palsy

Author: Eric R Eggenberger, DO, MS, FAAN, Professor, Vice-Chairman, Department of Neurology and Ophthalmology, Colleges of Osteopathic Medicine and Human Medicine, Michigan State University; Director of Michigan State University Ocular Motility Laboratory; Director of National Multiple Sclerosis Society Clinic, Michigan State University
Coauthor(s): Zeba F Vanek, MD, MBBS, DCN, Associate Professor of Neurology, David Geffen School of Medicine at UCLA; Director, UCLA Spasticity Clinic
Contributor Information and Disclosures

Updated: Sep 4, 2009

Introduction

Background

Progressive supranuclear palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a neurodegenerative disease that affects cognition, eye movements, and posture.¹ PSP was first described as a clinicopathologic entity in 1964. Characteristics include supranuclear, primarily vertical, gaze dysfunction accompanied by extrapyramidal symptoms and cognitive dysfunction. The disease usually develops after the sixth decade of life, and the diagnosis is purely clinical. Currently, no therapy is proven to be effective.

Pathophysiology

• Pathologically, PSP is defined by the accumulation of neurofibrillary tangles in the brain.² Different rates and patterns of the accumulation of phosphorylated tau protein may account for the variation in clinical phenomena seen in patients with PSP.
• Liao and colleagues suggest that abnormal otolith-mediated reflexes may be at least partly responsible for the frequent falls in patients with PSP. They found that during near viewing, the translational vestibulo-ocular reflex responses in patients with PSP were, on average, only 12% of those of control subjects (p = 0.001). The amplitude of vestibular-evoked myogenic potentials was also significantly reduced in PSP patients compared with normal controls.³

Frequency

United States

A population-based study in New Jersey by Golbe and colleagues revealed an overall prevalence of 1.39 cases per 100,000 population. The male prevalence was 1.53 cases, while the female prevalence was 1.23 cases (both figures are per 100,000 population); this finding was in accordance with a previously noted slight male preponderance. The adjusted prevalence ratio among patients older than 55 years was 7 cases per 100,000 population.⁴

Prevalence data derived from tertiary centers suggest that PSP affects 4-6% of patients with parkinsonism.⁵

International

Incidence has been assessed in Perth, Australia; crude incidence rates are 3-4 per million cases per year, approximately 5% of the incidence of Parkinson disease.⁶

Mortality/Morbidity

• PSP is usually fatal within approximately 6 years of onset, with a range of 2-17 years, based on cohort patients dying under surveillance; life table analysis among Golbe's entire cohort revealed a median disease duration of 9.7 years. Conflicting reports exist regarding the influence of age at diagnosis on survival; Golbe found a tendency for younger patients to survive longer, although this is not a uniform finding among other studies.^4,7
• The primary causes of death in patients with PSP are infections and pulmonary complications (eg, pneumonia) that are frequently related to immobility. Often, the primary morbidity relates to imbalance leading to immobility, although dementia, visual symptoms, and dysphagia are major concerns. Approximately 50% of patients with PSP require some aid to walk within 3 years of the initial symptoms. The usual interval from initial symptom occurrence to the need for a cane or a walker is 3.1 years, and the interval to confinement to a chair or bed is 8.2 years.⁴

Race

Most reported cases have been in whites. The affected cohort in Golbe's 1988 study was comprised entirely of white persons; however, the survey population included only 5.7% black individuals, thus preventing any meaningful analysis regarding race.⁴

Sex

PSP has a slight male predominance in most studies. According to Kristensen, the male-to-female ratio is 1.5:1.⁸

Age

The mean age at onset is approximately 63 years, with a range of 44-75 years.^4,7 The median interval between onset and diagnosis is 3 years, with a range of 6 months to 9 years.

Clinical

History

The first clinicopathologic descriptions of PSP were published in 1963 and 1964 and proved to be remarkably accurate.⁹ Only in the past 15 years have neurologists and basic scientists again focused on this disorder.

• The onset of PSP is insidious, and usually a prolonged phase of vague fatigue, headaches, arthralgias, dizziness, and depression occurs. Patients also develop subtle personality changes, memory problems, and pseudobulbar symptoms, and family members are often a more accurate source of such information than the patient. The initial symptoms can often involve unexplained imbalance or falls. Over time, dysarthria, dysphagia, and visual symptoms ensue.
• In a neuropathologic study, the most common symptoms at disease onset were postural instability and falls (63%); dysarthria (35%); bradykinesia (13%); and visual disturbances such as diplopia, blurred vision, burning eyes, and light sensitivity (13%).¹⁰
• The cardinal manifestations of PSP are supranuclear ophthalmoplegia (see Physical); pseudobulbar palsy; prominent neck dystonia; parkinsonism; behavioral, cognitive, and gait disturbances that cause imbalance; and frequent falls.
• Although presentations vary and early predominance of a particular symptom is not unusual, a greater spectrum of symptoms inevitably ensues over time. Several other features have been reported, including sleep disturbance with insomnia, clumsiness, impaired handwriting, and oscillopsia. Although the full constellation of symptoms occurring in a progressive fashion over time is characteristic, the vertical gaze palsy is the most distinctive single clinical feature.
• Other features that can be prominent include focal or segmental dystonia in the form of limb dystonia or blepharospasm.¹¹
• Patients can also have asymmetric apraxia resembling corticobasal degeneration.¹²
• Micturition disturbances, including urinary incontinence, are common in the later stages.^13,14
• A subset of patients present with a progressive apraxia of speech, nonfluent aphasia, or a combination of the two.¹⁵

Physical

The physical examination emphasizes the clinical features previously outlined. PSP is characterized primarily by motor, cognitive, and visual symptoms. Documentation of cognitive function with attention to executive function is important.

• The cranial nerve examination should include detailed analysis of ocular motility.
  • Slow vertical saccades and square wave jerks are early signs in most patients. The classic gaze palsy in PSP is supranuclear ophthalmoplegia. Supranuclear in this context refers to a lesion above the ocular motor nuclei, thus sparing the ocular motor nuclei, nerve fascicles, and neuromuscular junctional and extraocular muscles. Examination features serve to establish that the infranuclear structures are intact and that the lesion lies within the supranuclear domain. A supranuclear vertical gaze limitation is improved following extravolitional pathway activation, such as the vestibular ocular reflex (VOR) or the Bell phenomenon.
  • The Bell phenomenon consists of upward eye deviation behind closed lids. This can be assessed clinically by partially holding the eyelid open and instructing the patient to try forcefully closing the eye. The vertical VOR can be activated by manually flexing and extending the neck while the patient views a distant target. If the extent of the vertical eye movement limitation is improved with either of these maneuvers, then the lesion is supranuclear in origin.
  • Measurement of ocular alignment in the cardinal positions of gaze at near and distance viewing often discloses the source of any diplopic symptoms.
  • Examination of the eyelid position and movements may yield critical information.
  • The characteristic facies, especially when associated with dysarthria, may provide a nearly pathognomonic clinical picture.
  • Examination of pursuit movements and the extent of ocular rotations are important.
• Often, the earliest symptoms relate to imbalance and dysarthria. The imbalance is part of an extrapyramidal syndrome that is inclusive of poor postural reflexes, axial greater than appendicular rigidity, and dysarthria (monotone with slight hypophonic quality). Resting tremor is unusual.
  • The early appearance of gait and balance dysfunction is in contrast to the course of idiopathic Parkinson disease, in which imbalance tends to occur late in the disease. The gait in individuals with PSP tends to be wider based and unstable; these individuals have a tendency to fall in any direction because of impaired postural reflexes.
  • Bradykinesia with masked facies and a startled expression are frequent findings. Retrocollis may be present; with lid retraction, it enhances the astonished, worried appearance. Increased rigidity without cogwheeling or tremor completes the motor picture.
• Visual symptoms tend to be a relatively early finding, but they may not be present at onset; rarely, they are absent entirely. The earliest eye sign often is slowing of vertical saccades and fast phases. Later, the classic vertical supranuclear ophthalmoparesis occurs; this typically involves downgaze before upgaze. As a supranuclear process, vertical eye movements can still be generated by the VOR until late in the course of the disease, although the Bell phenomenon is usually absent (supraduction with eye closure). Later in the disease course, this ophthalmoparesis affects horizontal, in addition to vertical, eye movements. Complete ophthalmoparesis may ensue late in the course.
  • Additionally, nearly continuous square wave jerks are commonly observed with fixation. Square wave jerks consist of small (<5°) horizontal movements that take the eyes conjugately off target and then return the eye to the target after a brief 180- to 200-millisecond latency. Although occasional square wave jerks are a common finding in elderly individuals and may be normal if unaccompanied by other symptoms, more continuous square wave jerks are often associated with an underlying CNS disease.
  • Convergence eye movements are often impaired, and convergence insufficiency may produce episodic diplopia at near distances. Impaired binocular fusional capacity may produce diplopia related to decompensated phorias. Impaired VOR suppression has also been noted.
  • Several eyelid signs frequently occur in individuals with PSP, including lid retraction, eyelid opening or closing apraxia, blepharospasm, or lid lag.
  • Loss of the fast component of the optokinetic nystagmus can precede gaze palsy.
• Cognitive dysfunction and personality change are common, but they are generally milder in degree compared to primary dementing illnesses such as Alzheimer disease. Slowed cognitive processing, sequencing and planning difficulties, mild memory difficulty, and apathy are typical. These are generally more prominent later in the disease course.
  • Litvan and Mega et al discussed the neuropsychiatric aspects of PSP in greater detail.¹⁶ The investigators administered the Neuropsychiatric Inventory (NPI) to 22 patients with PSP, 50 patients with Alzheimer disease, and 40 controls.
  • The NPI focuses on the presence of delusions, hallucinations, agitation, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability, and abnormal motor behavior.
  • The presence of high apathy scores coupled with low agitation and anxiety scale scores was used to correctly identify patients with PSP 85% of the time.
• Litvan and Agid et al tested the accuracy of 4 proposed clinical diagnostic criteria for PSP.^17,18 These authors applied the proposed diagnostic criteria to autopsy-proven cases, including 24 cases of PSP, 29 cases of Lewy body disease, 10 cases of cortical-basal ganglionic degeneration, 7 cases of postencephalitic parkinsonism, 16 cases of multiple system atrophy, 7 cases of Pick disease, and 12 cases of other parkinsonian or dementing illnesses.
  • None of the criteria demonstrated both high sensitivity and high predictive value. A regression analysis approach revealed that vertical supranuclear palsy with downgaze abnormalities and postural instability with unexplained falls were the most useful diagnostic features.
  • A progressive disease course including these features constituted the mandatory inclusion criteria. Mandatory exclusion criteria included a history of encephalitis, hallucinations, cerebellar signs, noniatrogenic dysautonomia, unilateral dystonia, alien hand syndrome, early cortical dementia, or focal lesions on examination or imaging. These criteria performed better than previously published guidelines, with a mean sensitivity of 57% and positive predictive value of 85%. When applied to data from the patient's last visit to clinic, the criteria revealed a sensitivity of 66% and positive predictive value of 76%.
• The participants in a National Institute of Neurological Disorders and Stroke (NINDS)/Society for PSP conference formulated clinical research criteria for the diagnosis of PSP.¹⁹ They based these new criteria on literature review and then validated them using a clinical data set from autopsy-confirmed cases of PSP.
  • Criteria for possible PSP are as follows:
    • Gradually progressive disorder with onset when the individual is aged 40 years or older
    • Either vertical supranuclear palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset
    • No evidence of other diseases that can explain the clinical features
  • Criteria for probable PSP are vertical supranuclear palsy with prominent postural instability, falls in the first year of onset, and other features of possible PSP, as follows:
    • Symmetric proximal greater than distal akinesia or rigidity
    • Abnormal neck posture, especially retrocollis
    • Poor or absent response of parkinsonism to levodopa therapy
    • Early dysphagia and dysarthria
    • Early cognitive impairment with at least 2 of the following: apathy, abstract thought impairment, decreased verbal fluency, imitation behavior, or frontal release signs
  • Criteria for definite PSP are as follows: History of probable or possible PSP and histopathologic evidence that is typical of the disease
  • The proposed criteria for possible PSP are highly sensitive, while the criteria for probable PSP are highly specific, rendering each useful for different analyses and studies. These attempts at clinical diagnosis will hopefully be supplanted by a reliable and objective diagnostic test in the future.
  • The presence of prominent cerebellar signs, hallucinations or dysautonomia in the absence of drug effect, early cortical dementia features, or unilateral dystonia casts doubt on the diagnosis of PSP and should prompt consideration of other neurodegenerative conditions.

Causes

The cause of PSP remains unknown. Most cases appear to be sporadic. Both environmental and genetic influences have been postulated.

Few epidemiologic studies are available to investigate PSP associations. Golbe and coworkers performed a questionnaire survey on a cohort of 75 patients with PSP and matched controls. Surveyed exposures included hydrocarbons, pesticides and herbicides, urban/rural living, occupation, trauma, education level, maternal age, and family history of neurologic diseases. Patients with PSP were less likely than controls to have completed 12 years of education. The authors speculate that education level may be a marker for more direct risk factors such as early life nutrition or occupational or residency exposure.²⁰

• The role of heredity in the pathophysiology of PSP remains elusive. Although anecdotal reports exist in the literature of apparent familial PSP, several larger series have not noted this association.
  • In one case-control questionnaire, a trend toward relatives with parkinsonism was reported. Tetrud and colleagues reported the occurrence of autopsy-proven PSP in a brother-sister pair.²¹ Both developed parkinsonism in the eighth decade of life and subsequently exhibited typical features of PSP over the next 5 years. Their mother and, possibly, their maternal grandfather experienced a parkinsonian syndrome, while essential tremor was noted in their father and 2 of the brother's 3 children. The probands exhibited typical pathologic features of PSP upon autopsy.
    • Although the current absence of a large kindred with PSP precludes molecular linkage studies, the authors suggest that pairs such as in their report could be pooled for analysis; such occurrences are quite rare.
  • Kaat and colleagues reported that of 57 of 172 patients with PSP (33%) had at least one first-degree relative who had dementia or parkinsonism, compared with 25% of control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13).²² More first-degree relatives with parkinsonism were observed in PSP patients than in controls (OR 3.9; 95% CI 1.99-7.61).  
• Although most cases of PSP appear to be sporadic, rare genetically determined forms may exist.
  • Garcia de Yebenes et al studied a 5-generation family in which PSP was transmitted as an autosomal dominant trait.²³
    • Two instances of male-to-male transmission were found. The proband had the classic presentation of this disorder beginning with axial rigidity, slowness of movement, and gait difficulty. Over the course of 2 years, he progressed to complete vertical gaze palsy, axial dystonia, retrocollis, and generalized severe akinesia.
    • Postmortem examination demonstrated neurofibrillary tangles (NFTs) and gliosis without prominent senile plaques, the same pathology that was observed in the sporadic cases of PSP described by Steele et al.⁹
  • In addition, Garcia de Yebenes et al described 6 other families with multiple affected individuals. These included 2 in which a parent was affected, suggesting autosomal dominant inheritance, and 1 family in which parental consanguinity occurred, suggesting recessive inheritance.²³
  •  In the cohort studied by Kaat and colleagues, 12 of 172 patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission.²²
• The t (tau) protein is important in maintaining neuronal morphology through microtubule binding. Abnormalities of the t protein have been noted in several neurodegenerative diseases. Under abnormal circumstances, the normally soluble t protein may collect in insoluble protease-resistant helical filaments. The exact triggers for the conversion from normal t to the aggregate form are not completely understood.
  • This model shares some characteristics with prion disease (Creutzfeldt-Jakob disease), in which an abnormal insoluble prion protein (PrP) isoform accumulates.
  • Work by Conrad and colleagues has demonstrated the overrepresentation of the homozygous t A0 allele in patients with PSP compared to controls.²⁴
  • Accordingly, the t A0 allele may be a genetic marker of increased susceptibility to the PSP pathophysiology. The t A0 allele status is not required or sufficient to predict the occurrence of PSP, however.
• Although the e4 allele of apoprotein E gene (ApoE) is a significant risk factor for the development of Alzheimer disease and is overrepresented in individuals with Lewy body disease, it is not associated with PSP, Parkinson disease, or alcoholic dementia.

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