Progressive Supranuclear Palsy (PSP)
Progressive Supranuclear Palsy (PSP) is a progressive parkinsonian disease that is often misdiagnosed as Parkinson’s disease or Alzheimer’s disease due to the overlap of its symptoms. PSP is the most common atypical parkinsonian disorder. It gets its name from the brain lesions that occur that control the eye movement.
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Symptoms of PSP vary depending on the areas of the brain that are affected by the disease. Accordingly, there are variable clinical syndromes (presentations) of the disease.
Progressive supranuclear palsy: Richardson syndrome (PSP-RS)
This syndrome is the most common presentation of PSP that typically starts above age 50 with postural instability (balance disturbances) that leads to unexplained falls, often backward without loss of consciousness. Patients may develop gait instability with ataxic quality (broad-based steps). Slowness (bradykinesia) and stiffness (rigidity) are Parkinsonian symptoms that occur in all Parkinson’s disease mimicker disorders. Slowness in daily activities is another feature of PSP. For example, PSP patients often take longer to eat, dress, and bathe. PSP patients with the Richardson syndrome tend to walk, turn, and sit as a “block” because of the trunk stiffness. They also usually develop more neck and trunk (axial) rather than limb slowness and stiffness.
Most of the important symptoms of PSP that lead to its name are found in the eye movements. Vertical supranuclear gaze paresis is a movement limitation of the eyes that results in the inability to aim the eyes properly looking up and down, with the ocular reflexes preserved (see figure below). Gaze paresis usually affects down-gaze first, followed by up-gaze and later horizontal-gaze. Voluntary gaze is often more affected than pursuit gaze. Slowing and eventually reduced amplitude of vertical saccades (rapid eye movements between two stimuli) occur earlier than the paresis. The abnormality in the vertical saccades and gaze paresis can lead to difficulty with reading, eating, walking downstairs.
Light sensitivity (photophobia) is another symptom related of PSP that can be explained in part by a decrease in eye blinking. It can be associated with redness of the eyes and increased tearing and patients may need to wear sunglasses even indoors to avoid the irritating light. Due to the severely decreased blinking and diminished facial expressions (mask face), PSP patients may have an “astonished” or “surprise” face.
Subject attempting to look down voluntarily, but not able to fully do so.
Patients with PSP-RS usually have some degree of apathy (loss of interest) and slowness of thought (bradyphrenia) associated with impaired attention. Other symptoms related to the mental dysfunction are forgetfulness, difficulty in making decisions, impaired abstract thought, and occasionally disinhibition (executive dysfunction).
Dysarthria (poor articulation of speech) and dysphagia (swallowing) are also frequently relatively early in the course of the disease. The disease progresses relatively slowly, but PSP-RS patients have a shortened survival than the general population.
Less common presentations of progressive supranuclear palsy
The clinical presentation of PSP varies depending on the area of the brain affected by the disease. Motor problems are more predominant when the brainstem is more affected, while cognitive changes are more predominant when the cortex (outer layer of the brain) is affected.
Brainstem predominant syndromes
- PSP with Parkinsonism: PSP-P presents as Parkinson’s disease in most aspects with longer disease duration. It is characterized by bradykinesia (slowness of movement), rigidity (stiffness), and sometimes tremor, which tends to be at rest and asymmetric (affecting one side more than the other). The parkinsonism may respond to dopaminergic medication for at least two years, but eventually, response to dopaminergic medication is partial and not sustained. Falls, oculomotor disturbances and cognitive impairment and all the typical features of PSP-RS occur later in PSP-P. In PSP-P, the disease initially progresses more slowly than PSP-RS.
- PSP with pure akinesia and gait failure: PSP-PAGF presents with progressive gait disturbance. These patients have trouble with movement initiation due to difficulty selecting and/or activating motor programs in the central nervous system, a condition called akinesia. Patients may feel as if they are “freezed or glued” to the floor when attempting to walk. The term akinesia is applicable to problems with gait (freezing or difficulty with movement initiation). This form of PSP has a much better prognosis. Speech (stuttering or stammering speech), and handwriting (micrographia or small hand writing) may eventually develop, as well as features of PSP-RS.
Cortical predominant syndromes
- PSP with frontal lobe dementia: PSP-FLD is characterized by prominent personality changes and abulia (lack of initiative and diminished motivation) during the first couple of years.
- PSP with corticobasal syndrome: PSP-CBS is characterized by: the unilateral and asymmetric development of parkinsonism (rigidity and bradykinesia), loss of the ability to execute or carry out learned purposeful movements without clear motor or sensory causes (ideomotor apraxia), involuntary jerks (myoclonus), sustained muscle contractions causing abnormal postures (dystonia), and/or feeling of the limbs as alien (alien limb phenomenon) (see figure). It used to be thought that the corticobasal syndrome was only caused by corticobasal degeneration, but now is known that PSP as well as other disorders may be the underlying cause of these symptoms. It is difficult to differentiate PSP-CBS from corticobasal degeneration presenting with the CBS. The CBS progresses from one side of the body to the other.
- PSP with progressive non-fluent aphasia or apraxia of speech: PSP-PNFA or AOS includes both progressive speech and language impairments. The language disorder observed in this presentation is characterized by decreased fluency and disturbance in formulation of language causing difficulties expressing oneself. Apraxia of speech is characterized by slow, segmented and groping speech with a loss of prosody. This presentation may be followed by the PSP-CBS or the PSP-RS.
The diagnosis of PSP is clinical. It depends on the clinical picture of the disease. However, the brain structural and functional images may play a role in helping to differentiate PSP from other Parkinsonian disorders. Typically, in PSP-RS, the mesencephalon is small, could resemble the shape of a penguin (see figure). SPECT and PET are less useful in practice, and may show dopamine abnormalities in both the putamen and caudate or low glucose metabolism in the frontal lobes, depending on the tracer used.
There is strong evidence that a protein known as “tau” is abnormally aggregated in multiple types of brain cells (neurons, glia) in the brain leading to gradual malfunctioning and death of these cells; the common term is “tauopathy”.
The above image shows tau aggregation in neurons and glia.
The tau aggregation and loss of cells occurs in several areas of the brain to include the subthalamic nucleus, striatum, substantia nigra, pontine tegmentum, oculomotor nucleus, medulla and dentate nucleus. The most specific features for PSP are presence of star-shaped astrocyt¬ic tangles that can be seen with light microscopy and that are stained with an¬tibodies to tau (figure). PSP is considered a sporadic disease; however, it has some genetic component. Environmental causes are being investigated, particularly by Dr. Litvan, who leads a multicenter, NIH funded case-control study to determine whether there are occupational and environmental risk factors for PSP.
Management of PSP starts with the correct diagnosis, through clinical examination by a movement disorder specialist.
Multidisciplinary approach: Since PSP is a gradual progressive disease, it does not cause any sudden symptoms unless there are complications. Currently, the main goal of treating PSP is to prevent complications and improve the quality of life. The most important complications that need to be prevented are falls and chocking. Because of those dangers, a multidisci-plinary approach is essential in the management of PSP. Along with a movement disorder specialist, speech, language, and occupational thera¬pists and dietitians should be involved in the management plan.
Physical therapy: Working with a physical therapist can provide effective measures and techniques to avoid falls and their consequences. Physical therapists can provide tips on ways to improve walking and balance (i.e., using a weighted walker and using low-heal nonstick shoes).
Speech therapy: Speech therapists evaluate the swallowing function (modified barium swallow study) and make sure to prevent chocking in the future by teaching specific techniques like head posturing and modifying diet. In addition, speech therapy can also improve voice projection.
Occupational therapy: Working with an occupational therapist is essential to promote and extend independence. Eating and reading both can be improved in patients with severe limitation of eye movement by using special glasses called prisms to remedy the difficulty of looking down.
Symptomatic treatment: Several drugs have been studied for the treatment of the motor aspects of the PSP. Unlike Parkinson’s disease, treating PSP patients with levodopa usually has no significant benefits, however, if there is parkinsonism, it is important to administer it for at least a month at high doses to be sure of the response. Dopamine agonists do not add any additional benefits and may have more side effects.
Botulinum toxin injections: These can effectively be used to treat various forms of focal dystonia and eyelid drop. These injections may help to decrease the disability and improve quality of life; however there is always the risk of side effects.
Biological treatments: Treatments to slow disease progression are not available, but two recent studies in which UCSD investigators participated, evaluated if medications that inhibit one enzyme (GSK-3beta inhibitors: davunetide and tideglusib) could prevent the “cluttering” (aggregation) of tau could be of benefit. Research in this area is quite active.
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