Progressive Supranuclear Palsy Clinical Presentation

The first clinicopathologic descriptions of progressive supranuclear palsy (PSP) were published in 1963 and 1964 and proved to be remarkably accurate.^[10] 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%).^[16]

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^[17]
• Asymmetric apraxia resembling corticobasal degeneration^[18]
• Micturition disturbances, including urinary incontinence (common in the later stages)^{[19, 20]}
• Progressive apraxia of speech, nonfluent aphasia, or a combination thereof^[21]
• Photophobia (as compared with control subjects)^[22]

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.

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.^[23]

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.^[24] 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.^[24]

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.^{[25, 26]} 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.^{[25, 26]}

Mandatory inclusion criteria consisted of a progressive disease course including the aforementioned diagnostic features.^{[25, 26]} 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.^[27] 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.

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.