Progressive Supranuclear Palsy

Practice Essentials

Progressive supranuclear palsy (PSP) is a neurodegenerative disease (see the image below) whose characteristics include supranuclear, initially 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.

View Image

Sagittal T1-weighted image shows atrophy of midbrain, preservation of pontine volume, and atrophy of the tectum, suggestive of progressive supranuclea....

Signs and symptoms

The onset of PSP is insidious and usually includes a prolonged phase marked by the following symptoms:

• Fatigue
• Headaches
• Arthralgias
• Dizziness
• Depression

Patients also experience subtle personality changes, memory problems, and pseudobulbar symptoms, which are often more evident to the family than to the patient. The initial symptoms can often involve unexplained imbalance or falls.

The cardinal manifestations of PSP are as follows:

• Supranuclear ophthalmoplegia
• Pseudobulbar palsy
• Prominent neck dystonia
• Parkinsonism
• Behavioral, cognitive, and gait disturbances that cause imbalance
• Frequent falls/impaired postural reflexes

Findings on physical examination can include the following:

• Poor postural reflexes, axial rigidity greater than appendicular rigidity, and dysarthria (monotone with slight hypophonic quality)
• Absence of cogwheeling or tremor
• Widely based and unstable gait
• Bradykinesia with masked facies and a startled expression
• Retrocollis may be present

Visual signs and symptoms

• Slow vertical saccades and square wave jerks on ocular examination (early signs)
• Supranuclear ophthalmoplegia (classic gaze palsy in PSP)
• Downgaze typically involved before upgaze
• Improvement in supranuclear vertical gaze limitation after extravolitional pathway activation with the vestibular ocular reflex (VOR) or the Bell phenomenon
• Nearly continuous square wave jerks commonly observed with fixation
• Impairment of convergence eye movements (may cause diplopia)
• Eyelid retraction, eyelid opening or closing apraxia, blepharospasm, or lid lag
• Complete ophthalmoparesis in advanced PSP

Cognitive symptoms

• Slowed cognitive processing, sequencing and planning difficulties, mild memory difficulty, and apathy (generally more prominent in late disease)
• High apathy scores coupled with low agitation and anxiety scale scores on Neuropsychiatric Inventory testing

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of PSP is clinical. Key features typically develop over time. Participants in a National Institute of Neurological Disorders and Stroke (NINDS)/Society for PSP conference have formulated and validated clinical research criteria for the diagnosis of PSP.^[1] In this system, criteria for possible PSP are as follows:

• Gradually progressive disorder with onset at age 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:

• 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
• Histopathologic evidence that is typical of the disease

The workup in patients with suspected PSP is directed principally at eliminating other diagnoses (eg, Whipple PCR to eliminate possible Whipple disease). MRI offers little help in the early stages of PSP, but may reveal the following abnormalities in some advanced cases^{[2, 3, 4, 5, 6]} :

• Atrophy of the midbrain (see the image below) with cisternal and ventricular dilatation
• Thinning of the quadrigeminal plate
• Dilation of the third ventricle
• A nonspecific finding of increase in proton density images in the periaqueductal gray matter, compatible with gliotic changes

Sleep studies in patients with PSP show the following abnormalities, although these are not specific for PSP:

• Diminished total sleep time
• Increased awakenings
• Progressive loss of rapid-eye-movement (REM) sleep^{[7, 8]}
• Decreased REM–to–non-REM (NREM) quotient^{[9, 10]}

See Workup for more detail.

Management

No medication is effective in halting the progression of PSP; however, medications that may provide modest symptomatic improvement include the following:

• Dopamine agonists
• Tricyclic antidepressants
• Methysergide
• OnabotulinumtoxinA: May be useful for rigidity (nuchal rigidity in particular) and dystonia (eg, blepharospasm, bruxism, and focal limb dystonia)^[11]
• Methylcellulose or methyl alcohol eyedrops: For relief of chronic conjunctivitis from reduced blink rate

Physical therapy and rehabilitation medicine involvement may help maximize ambulation safety and facilitate instruction in the use of a walker, wheelchair, or other aids.

See Treatment and Medication for more detail.

• References

Background

Progressive supranuclear palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a neurodegenerative disease that affects cognition, eye movements, and posture.^{[12, 13]} PSP was first described as a clinicopathologic entity in 1964. Characteristics include supranuclear, initially 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.

• References

Pathophysiology

Pathologically, PSP is defined by the accumulation of neurofibrillary tangles in the brain.^[14] Different rates, localizations, and patterns of the accumulation of phosphorylated tau protein may account for the variation in clinical phenomena seen in patients with PSP.

The tau protein

The tau protein is important in maintaining neuronal morphology through microtubule binding. Abnormalities of this protein have been noted in several neurodegenerative diseases. Under abnormal circumstances, the normally soluble tau protein may collect in insoluble protease-resistant helical filaments. The exact triggers for the conversion from normal tau 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 isoform accumulates.

Work by Conrad et al demonstrated the overrepresentation of the homozygous tau A0 allele in patients with PSP compared to controls.^[15] Accordingly, the tau A0 allele may be a genetic marker of increased susceptibility to the PSP pathophysiology. However, the tau A0 allele status is not required or sufficient to predict the occurrence of PSP.

Although the e4 allele of the 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.

Liao et al 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, which suggested that abnormal otolith-mediated reflexes may be at least partly responsible for the frequent falls in patients with PSP.^[16] The amplitude of vestibular-evoked myogenic potentials was also significantly lower in PSP patients than in normal control subjects.

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Etiology

The cause of PSP remains unknown. Most cases appear to be sporadic. Both environmental and genetic influences have been postulated. To date, there have been only a few epidemiologic studies investigating PSP associations.

In a questionnaire survey carried out on a cohort of 75 patients with PSP and matched controls, Golbe et al obtained information on exposures (eg, to hydrocarbons, pesticides and herbicides), urban versus 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.^[17] The authors speculate that education level may be a marker for more direct risk factors (eg, early life nutrition or occupational or residential exposure).

The role of heredity in the pathophysiology of PSP remains elusive. Although there are anecdotal reports in the literature that describe 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 et al reported the occurrence of autopsy-proven PSP in a brother-sister pair.^[18] 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, and 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 those in their report could be pooled for analysis^[18] ; such occurrences are quite rare.

Kaat et al reported that of 57 (33%) of 172 patients with PSP had at least 1 first-degree relative who had dementia or parkinsonism, compared with 25% of control subjects.^[19] More first-degree relatives with parkinsonism were observed in PSP patients than in controls.

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,^[20] finding 2 instances of male-to-male transmission. The proband had the classic presentation of this disorder beginning with axial rigidity, slowness of movement, and gait difficulty. Over a period 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.^[21]

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.^[20] In the cohort studied by Kaat et al, 12 of 172 patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission.^[19]

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Epidemiology

United States

A population-based study in New Jersey by Golbe et al revealed an overall prevalence of 1.39 cases per 100,000 population. The male prevalence was 1.53 in 100,000, whereas the female prevalence was 1.23 in 100,000; this finding was in accordance with a previously noted slight male preponderance. The adjusted prevalence ratio among patients older than 55 years was 7 in 100,000.^[22] Prevalence data derived from tertiary centers suggest that PSP affects 4-6% of patients with parkinsonism.^[23]

International

The incidence of PSP 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.^[24]

Age-, sex-, and race-related demographics

The mean age at onset is approximately 63 years (range, 44-75 years).^{[22, 25]} The median interval between onset and diagnosis is 3 years (range, 0.5-9 years). PSP has a slight male predominance in most studies. According to Kristensen, the male-to-female ratio is 1.5:1.^[26]

Most reported cases have been in whites. The affected cohort in Golbe’s study consisted entirely of white persons; however, the survey population included only 5.7% black individuals, thus preventing any meaningful analysis regarding race.^[22]

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Prognosis

Studies of cohort patients dying under surveillance suggest that PSP is usually fatal within approximately 6 years of onset (range, 2-17 years); life table analysis among the entire cohort of Golbe et al revealed a median disease duration of 9.7 years.^[22] 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.^{[22, 25]}

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, though dementia, visual symptoms, and dysphagia are major concerns. About 50% of patients require some aid to walk within 3 years of the initial onset of 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.^[22]

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Patient Education

The primary educational efforts related to PSP are focused on the patient and family and aimed at fostering an understanding of the disease, the patient’s prognosis, potential complications, and effective coping mechanisms. Many patients and families benefit from contact with and participation in a support group. Further information is available from CurePSP and The Parkinson’s Institute.

For patient education resources, see the Dementia Center, as well as Progressive Supranuclear Palsy.

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History

The first clinicopathologic descriptions of progressive supranuclear palsy (PSP) were published in 1963 and 1964 and proved to be remarkably accurate.^[21] Only in the past 15 years has there been a renewed focus on this disorder among neurologists and basic scientists.

The onset of PSP is insidious and usually includes a prolonged phase of vague fatigue, headaches, arthralgias, dizziness, and depression. Patients also experience subtle personality changes, memory problems, and pseudobulbar symptoms; family members are often a more accurate source of such information than the patient is. 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%).^[27]

The cardinal manifestations of PSP are as follows:

• Supranuclear ophthalmoplegia (see Physical Examination)
• Pseudobulbar palsy
• Prominent neck dystonia
• Parkinsonism
• Behavioral, cognitive, and gait disturbances that cause imbalance
• Frequent falls/impaired postural reflexes

Although presentations vary and early predominance of a particular symptom is not unusual, over time, a wider spectrum of symptoms inevitably ensues. 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 the following:

• Focal or segmental dystonia in the form of limb dystonia or blepharospasm^[28]
• Asymmetric apraxia resembling corticobasal degeneration^[29]
• Micturition disturbances, including urinary incontinence (common in the later stages)^{[30, 31]}
• Progressive apraxia of speech, nonfluent aphasia, or a combination thereof^[32]
• Photophobia (as compared with control subjects)^[33]

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Physical Examination

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

Motor symptoms

Often, the earliest manifestations of PSP relate to imbalance and dysarthria. The imbalance is part of an extrapyramidal syndrome that includes poor postural reflexes, axial rigidity greater than appendicular rigidity, and dysarthria (monotone with slight hypophonic quality). Resting tremor is unusual. Additionally, otolith dysfunction may also contribute to imbalance and falls.

The early appearance of gait and balance dysfunction in PSP may be contrasted with 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 more widely 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 (see the image below). Retrocollis may be present; with lid retraction, it enhances the astonished, worried appearance. Increased rigidity without cogwheeling or tremor completes the motor picture.

View Image

Characteristic facial appearance of patient with progressive supranuclear palsy.

Visual symptoms

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 that is situated 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 after 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 holding the eyelid partially 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 is important.

Although visual symptoms tend to be a relatively early finding, they may not be present at onset; rarely, they are absent entirely. The slowing of vertical saccades and fast phases previously mentioned (see above) is often the earliest eye sign. 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, though the Bell phenomenon is often absent (supraduction with eye closure). Later in the disease course, this ophthalmoparesis affects horizontal as well as vertical eye movements. Complete ophthalmoparesis may ensue late in the course.

Nearly continuous square wave jerks are commonly observed with fixation. These are small (< 5°) horizontal movements that take the eyes conjugately off the target and then return them to the target after a brief 180- to 200-msec latency. Although occasional square wave jerks are common in elderly individuals and may be normal if unaccompanied by other symptoms, more continuous square wave jerks are often associated with underlying central nervous system (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. Pupillary abnormalities include decreased pupillary diameter in darkness when compared with controls.^[34]

Cognitive symptoms

Cognitive dysfunction and personality change are common in patients with PSP, but they are generally milder in degree than those seen in patients with 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 course of the disease.

Litvan et al administered the Neuropsychiatric Inventory (NPI) to 22 patients with PSP, 50 patients with Alzheimer disease, and 40 control subjects.^[35] 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.^[35]

Clinical diagnostic criteria

Litvan et al tested the accuracy of 4 proposed clinical diagnostic criteria for PSP and found that none of the criteria demonstrated both high sensitivity and high predictive value.^{[36, 37]} A regression analysis approach revealed that vertical supranuclear palsy with downgaze abnormalities and postural instability with unexplained falls were the most useful diagnostic features.

In these studies, the 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.^{[36, 37]}

Mandatory inclusion criteria consisted of a progressive disease course including the aforementioned diagnostic features.^{[36, 37]} Mandatory exclusion criteria included a history of encephalitis, hallucinations, cerebellar signs, noniatrogenic dysautonomia, unilateral dystonia, alien hand syndrome, early cortical dementia, or documented focal lesions. These criteria performed better than previous guidelines (sensitivity, 57%; positive predictive value [PPV], 85%). When applied to data from the last clinic visit, they had a sensitivity of 66% and a PPV 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.^[1] They based these new criteria on literature review and then validated them using a clinical data set from autopsy-confirmed cases of PSP.

In this system, 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
• Histopathologic evidence that is typical of the disease

The proposed criteria for possible PSP are highly sensitive, whereas those for probable PSP are highly specific; thus, each set of criteria is useful for different analyses and studies. It is to be hoped that these attempts at clinical diagnosis will 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.

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Complications

The primary complications of PSP are related to the following:

• Impaired balance
• Decreased cognition
• Immobility in late disease

Complications related to falls include orthopedic injury and other posttraumatic problems. Immobility in late disease leads to infectious complications such as pneumonia, urinary tract infection, and sepsis.

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Laboratory Studies

Workup in the setting of suspected progressive supranuclear palsy (PSP) is directed principally at eliminating other diagnoses.

Borroni et al proposed evaluation of tau forms in cerebrospinal fluid (CSF) as a biomarker for PSP.^[38] CSF contains both extended (55 kd) and truncated (33 kd) tau forms, and the truncated-to-extended ratio is significantly lower in PSP than in other neurodegenerative disorders. In this study, the ratio was 0.504 ± 0.284 in PSP patients, 0.899-1.215 in patients with other neurodegenerative conditions, and 0.989 ± 0.343 in controls. In addition, a decreased ratio was correlated with brainstem atrophy, as assessed by voxel-based morphometry. Further study of such biomarker candidates is required before these become incorporated into diagnostic algorithms or criteria.

Whipple polymerase chain reaction (PCR) may be helpful in eliminating the possibility of Whipple disease, a treatable infectious disorder.

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Magnetic Resonance Imaging

Although, magnetic resonance imaging (MRI) of the brain offers little help in the early stages of PSP, it may reveal the following abnormalities in some advanced cases^{[2, 3, 4, 5, 6]} :

• Atrophy of the midbrain (see the image below) with cisternal and ventricular dilatation
• Thinning of the quadrigeminal plate
• Dilation of the third ventricle
• A nonspecific finding of increase in proton density images in the periaqueductal gray matter, compatible with gliotic changes

  View Image

  Sagittal T1-weighted image shows atrophy of midbrain, preservation of pontine volume, and atrophy of the tectum, suggestive of progressive supranuclea....

   

  

   

Righini et al reported the usefulness of assessing the appearance of the superior profile of the midbrain on midsagittal T1-weighted MRI.^[39] The appearance of a flat or concave profile (as opposed to the normal convex profile) was associated with a 68% sensitivity and an 89% specificity for the diagnosis of PSP as compared with the diagnosis of Parkinson disease.

It should be kept in mind that these imaging findings are not pathognomonic of PSP nor early findings; some of their components may be observed in several other diseases in the differential diagnosis.

A study from Hamburg, Germany, reported that an abnormal brain iron accumulation was a marker for ongoing neurodegeneration in both PSP and Parkinson disease, but the 2 conditions differed with respect to the anatomic distribution of this accumulation. The investigators found that regional decreases of T2' relaxation times in parts of the basal ganglia reflecting increased brain iron load were characteristic for progressive supranuclear palsy but not for Parkinson disease.^[40]

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Other Neuroimaging

Neuroimaging is often performed to eliminate other entities in the differential diagnosis. The presence of significant abnormalities (eg, large vessel ischemic disease, hydrocephalus) casts doubt on the diagnosis of PSP. Functional neuroimaging includes positron emission tomography (PET) and single-photon emission computed tomography (SPECT).

PET may help reveal physiopathologic aspects of the disease. PET studies have documented a global cerebral hypometabolism with relative selectivity in the frontal cortex.^{[41, 42, 43]} Regional cerebral blood flow and oxygen metabolism are decreased in the caudate and putamen and impaired in the thalamus and brainstem. PET studies have also documented significantly lowered glucose metabolism in the midbrain of PSP patients as compared with control subjects.^[44]

Fluorodopa (F-dopa) PET has shown reduced F-dopa influx into the caudate and putamen. In idiopathic Parkinson disease, the caudate is affected less severely; therefore, this finding can help in differentiating the 2 conditions.^[45] The costs of PET studies and their limited availability restrict this technique to experimental trials.

In some patients with PSP,¹²³ I-iodobenzamide SPECT has demonstrated reduced striatal dopamine receptor binding.^[46] This finding can be used to distinguish vascular white-matter lesions from PSP.

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Sleep Studies

Sleep patterns are often abnormal in individuals with PSP. Polysomnography shows diminished total sleep time, increased awakenings, progressive loss of rapid-eye-movement (REM) sleep,^{[7, 8]} and decreased REM–to–non-REM (NREM) quotient.^{[9, 10]} REM sleep behavior disorder, consisting of motor activity associated with vivid dreams during REM sleep, also occurs in individuals with PSP.

These abnormalities are not specific for PSP. For example, Sixel-Döring et al found that although polysomnographically recorded sleep is more severely impaired in patients with PSP than in patients with Parkinson disease, Parkinson Disease Sleep Scale scores did not differ significantly between the 2 patient groups.^[47]

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Histologic Findings

The histopathology of PSP involves diffuse brainstem disease. Neuronal loss, neurofibrillary tangles (NFTs), and gliosis affect the reticular formation and ocular motor nuclei. Early pathology is evident primarily in the midbrain; this may explain the early vertical eye movement characteristics. The pontine nucleus raphe interpositus and pedunculopontine and deep pontine nuclei are also affected.

The distribution and ultrastructure of NFTs in PSP are distinct from those of NFTs in Alzheimer disease. PSP is characterized by greater subcortical involvement, with single tubules 15-20 nm wide, whereas Alzheimer disease is characterized by cortically based paired helicoid filaments.

An examination of PSP cases revealed the uniform presence of tau-positive cortical lesions. These were found in highest concentration in the precentral and angular gyrus, primarily affecting the deep cortical layers, and involved both small and large neurons. Again, this pattern differs from the NFT pattern observed in Alzheimer disease. NFT concentration analysis appeared to implicate the pedunculopontine nucleus in lesion spread.

Although NFTs are the histologic hallmarks of PSP, neuropil threads have also been found extensively.

Besides the brainstem structures, the striatum, the medial pallidum, the subthalamic nucleus, and the substantia nigra are also affected.

There remain many unanswered questions about the pathologic features linking PSP, Alzheimer disease, idiopathic Parkinson disease, and, in particular, corticobasal degeneration. Further ultrastructural and genetic studies are needed to reveal the cause and the pathogenesis of the disease.

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Approach Considerations

Treatment of progressive supranuclear palsy (PSP) is challenging at best. Only a few patients respond to dopaminergic or anticholinergic drugs, and responses often are short-lived and incomplete. No medication is effective in halting the progression of the disease; however, several medications, including dopamine agonists, tricyclic antidepressants, and methysergide, may provide modest symptomatic improvement with respect to some of the clinical features.

Electroconvulsive therapy (ECT) may ameliorate motor symptoms in some patients with PSP. However, long hospitalizations and significant adverse effects (eg, confusion) limit the usefulness of ECT.

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Pharmacologic Therapy

The combination of carbidopa and levodopa generally produces no dramatic symptomatic improvement in patients with PSP, in sharp contrast with its effect in patients with idiopathic Parkinson disease. Accordingly, administration of carbidopa-levodopa may serve as a diagnostic test to help eliminate the possibility of Parkinson disease.

Some clinicians think that bromocriptine may have somewhat greater effect in individuals with PSP, though the effect is modest and short-lived in most patients. Tricyclic antidepressants have also been used. Other medications that have been tried with limited success include amantadine and trazodone.

OnabotulinumtoxinA has been found to be useful in the treatment of rigidity (nuchal rigidity in particular) and dystonia (eg, blepharospasm, bruxism, and focal limb dystonia).^[11] It may also be useful for sialorrhea.

A small phase II clinical trial using coenzyme Q10 in patients with PSP showed modest clinical improvement in the short term.^[48]

Chronic conjunctivitis is common in individuals with PSP because of the reduced blink rate in these patients. It can be treated with applications of methylcellulose or methyl alcohol drops in the eyes.

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Consultations

Consultation with a neuro-ophthalmologist or an ophthalmologist may help define the cause and outline the treatment of symptoms such as episodic diplopia.

Consultation with a rehabilitation medicine specialist may assist in maximizing gait stability and safety.

When swallowing starts to become affected, consultation with a speech therapist may help in modifying the diet.

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Diet and Activity

Patients should follow a well-balanced diet. When feeding becomes impossible because of dysphagia and the high risk of bronchoaspiration, patients should be encouraged to accept gastrostomy as a good option.

A double-blind, randomized, placebo-controlled, phase II trial found that supplemental coenzyme Q10, 5 mg/kg/day for 6 weeks, produced favorable changes in cerebral energy metabolites and slight but significant improvement in some measures of motor and neuropsychological dysfunction.^[48]

Gait disturbances and falls are 2 of the major causes of disability in individuals with PSP. Physiotherapy after gait analysis, occupational therapy to find the best solutions to improve mobility, safe exercise programs, and appropriate mobility aids may decrease falls and related morbidity.

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Long-Term Monitoring

To help the patient and family adjust to the changing needs incurred by PSP, close follow-up care should be provided, with particular attention to potential adverse effects related to any medication trials. Often, family-directed education is the most valuable component of clinical visits. Patients and families often benefit from contact with a PSP support group (see Patient Education).

Physical therapy and rehabilitation medicine involvement may help maximize ambulation safety and facilitate instruction in the use of a walker, wheelchair, or other aids.

Preliminary evidence suggests that the combination of balance training complemented with eye movement and visual awareness exercises can be beneficial for enhancing suppression of fixation and gaze shift in patients with PSP.^[49]

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Medication Summary

No effective therapy for progressive supranuclear palsy (PSP) is known. A trial of a dopamine agonist is often undertaken to help eliminate Parkinson disease in diagnostically confusing cases or to provide modest symptomatic improvement.

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Levodopa and carbidopa (Sinemet, Parcopa)

• Dosing, Interactions, etc.

Clinical Context:  The combination of carbidopa and levodopa generally produces no dramatic symptomatic improvement in patients with PSP, in sharp contrast with its effect in patients with idiopathic Parkinson disease. Accordingly, administration of carbidopa-levodopa may serve as a diagnostic test to help eliminate the possibility of Parkinson disease.

Carbidopa-levodopa is available in 10/100, 25/100, 25/250 formulations.

• References

Bromocriptine (Parlodel, Cycloset)

• Dosing, Interactions, etc.

Clinical Context:  Bromocriptine is a semisynthetic ergot alkaloid derivative that is a strong D2 receptor agonist and a weak D1 receptor antagonist. It is approved by the US Food and Drug Administration (FDA) as an adjunct to carbidopa-levodopa; it is less effective than other dopamine agonists. It may relieve akinesia, rigidity, and tremor in Parkinson disease. The mechanism of the therapeutic effect involves direct stimulation of dopamine receptors in the corpus striatum.

Approximately 28% of a bromocriptine dose is absorbed from the gastrointestinal tract and metabolized in the liver. Elimination half-life is approximately 50 hours, with 85% excreted in feces and 3-6% eliminated in urine.

Initiate the drug at a low dosage and individualize. Slowly increase the daily dose until maximal therapeutic response is achieved. If possible, maintain the dosage of levodopa during this introductory period. Assess dosage titrations every 2 weeks to ensure that the lowest dosage producing optimal therapeutic response is not exceeded. If adverse reactions mandate dose reduction, reduce the daily dose gradually in 2.5-mg increments.

• References

Class Summary

Dopamine agonists directly stimulate postsynaptic dopamine receptors to provide benefit against symptoms of Parkinson disease. In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine receptor subtypes is currently unclear.

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Amitriptyline

• Dosing, Interactions, etc.

Clinical Context:  Amitriptyline inhibits reuptake of serotonin or norepinephrine at the presynaptic neuronal membrane, thereby increasing the concentration in the central nervous system.

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Clomipramine (Anafranil)

• Dosing, Interactions, etc.

Clinical Context:  Clomipramine is a dibenzazepine compound belonging to the family of tricyclic antidepressants. The drug inhibits the membrane pump mechanism responsible for the uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons.

Clomipramine affects serotonin uptake while it affects norepinephrine uptake when converted into its metabolite desmethylclomipramine. It is believed that these actions are responsible for its antidepressant activity.

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Doxepin (Silenor)

• Dosing, Interactions, etc.

Clinical Context:  Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by the presynaptic neuronal membrane. It inhibits histamine and acetylcholine activity and has proven useful in the treatment of various forms of depression associated with chronic pain.

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Nortriptyline (Pamelor)

• Dosing, Interactions, etc.

Clinical Context:  Nortriptyline has demonstrated effectiveness in the treatment of chronic pain.

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Desipramine (Norpramin)

• Dosing, Interactions, etc.

Clinical Context:  This is the original TCA used for depression and has been shown to treat chronic pain. These agents have been suggested to act by inhibiting the reuptake of noradrenaline at synapses in central descending pain modulating pathways located in the brainstem and spinal cord.

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Class Summary

Tricyclic antidepressants are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. They have central effects on pain transmission.

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