Progressive supranuclear palsy
Progressive supranuclear palsy is a non late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including loss of balance, slowing of movement, difficulty moving the eyes, and cognitive impairment. PSP may be mistaken for other types of neurodegeneration such as Parkinson's disease, frontotemporal dementia and Alzheimer's disease. It is the second most common tauopathy behind Alzheimer's disease. The cause of the condition is uncertain, but involves the accumulation of tau protein within the brain. Medications such as levodopa and amantadine may be useful in some cases.
PSP was first officially described by Richardson, Steele, and Olszewski in 1963 as a form of progressive parkinsonism. However, the earliest known case presenting clinical features consistent with PSP, along with pathological confirmation, was reported in France in 1951. Originally thought to be a more general type of atypical parkinsonism, PSP is now linked to distinct clinical phenotypes including PSP-Richardson's syndrome , which is the most common sub-type of the disease. As PSP advances to a fully symptomatic stage, many PSP subtypes eventually exhibit the clinical characteristics of PSP-RS.
PSP, encompassing all its phenotypes, has a prevalence of 18 per 100,000, whereas PSP-RS affects approximately 5 to 7 per 100,000 individuals. The first symptoms typically occur at 60–70 years of age. Males are slightly more likely to be affected than females. No association has been found between PSP and any particular race, location, or occupation.
Signs and symptoms
The initial symptoms in two-thirds of cases are loss of balance, lunging forward when mobilizing, fast walking, bumping into objects or people, and falls. Dementia symptoms are also initially seen in about one in five cases.Other common early symptoms are changes in personality, general slowing of movement, and visual symptoms. The most common behavioural symptoms in patients with PSP include apathy, a lack of inhibition, anxiety, and a profound state of unease or dissatisfaction.
Later symptoms and signs can include, but do not necessarily include dementia, slurring of speech, difficulty swallowing, and difficulty moving the eyes, particularly in the vertical direction. The latter accounts for some of the falls experienced by these patients, as they find it difficult to look up or down.
Some of the other signs are poor eyelid function, contracture of the facial muscles, a backward tilt of the head with stiffening of the neck muscles, sleep disruption, urinary incontinence, and constipation. Some patients retain full cognitive function up to the end.
The visual symptoms are of particular importance in the diagnosis of this disorder. Patients typically complain of difficulty reading due to the inability to look downwards. The ophthalmoparesis experienced by these patients mainly concerns voluntary eye movement and the inability to make vertical saccades, which is often worse with downward saccades. Patients tend to have difficulty looking down followed by the addition of an upgaze palsy. This vertical gaze paresis will correct when the examiner passively rolls the patient's head up and down as part of a test for the oculocephalic reflex. Involuntary eye movement, as elicited by Bell's phenomenon, for instance, may be closer to normal.
On close inspection, eye movements called "square-wave jerks" may be visible when the patient fixes gaze at distance. These are fine movements, that can be mistaken for nystagmus, except that they are saccadic in nature, with no smooth phase. Although healthy individuals also make square-wave jerk movements, PSP patients make slower square-wave jerk movements, with smaller vertical components. Assessment of these square-wave jerks and diminished vertical saccades is especially useful for diagnosing progressive supranuclear palsy, because these movements set PSP patients apart from other parkinsonian patients. Difficulties with convergence, where the eyes come closer together while focusing on something near, like the pages of a book, is typical. Because the eyes have trouble coming together to focus at short distances, the patient may complain of diplopia when reading.
A characteristic facial appearance known as procerus sign, with a wide-eye stare, furrowing of forehead with a frowning expression, and deepening of other facial creases, is also diagnostic of PSP.
Signs and symptoms of PSP-RS subtype
PSP-RS is characterized by a combination of motor, ocular, cognitive, and speech-related impairments, that typically emerge in early stages of the disease. Symptoms of PSP-RS usually begin after 60 and steadily progress over time. Clinical symptoms of PSP-RS often include unexplained falls, unsteady gait, bradykinesia, apathy, disinhibition, cognitive dysfunction, difficulty planning or multitasking, slow speech, and impaired ocular movement. PSP-RS is also characterized by unresponsiveness to dopamine therapies often prescribed for those with Parkinson's disease. Patients can present initially with symptoms more characteristic of the PSP-Parkinson subtype which is characterized by asymmetric rigidity, resting tremor, and are more responsive to dopamine therapies such as levadopa compared to PSP-RS. Clinical and pathological differences between PSP-P and PRSP-RS occur within the first year of the disease, with individuals with PSP-RS exhibiting faster progression of symptoms and lower survival rates after diagnosis. Diagnostic criteria distinguish between probable and possible PSP-RS, as definitive diagnosis requires post-mortem neuropathological confirmation. The NINDS-SPSP criteria define probable PSP-RS as requiring both vertical supranuclear gaze palsy and early postural instability with falls, while possible PSP-RS requires either vertical gaze palsy or slowed vertical saccades combined with early falls. PSP-RS effects more males than females, with a male to female ratio of 1.8:1. Symptom progression tends to occur more quickly in PSP-RS than other sub-types with the average disease duration being 5.9 years and an average age of death of 72.1 years.Motor symptoms in PSP-RS
One of the key features of PSP-RS that occurs within the first year of symptom onset, is early postural instability which often leads to unexplained falls. Additionally, patients present with axial rigidity, which is characterized by stiffness in the neck and body. This is often accompanied with bradykinesia which is slowness of movement. Although PSP-RS is often misdiagnosed as Parkinson's disease, tremors are uncommon in PSP-RS. Motor symptoms are often symmetrical in PSP-RS with both sides of the body being affected.Ocular symptoms in PSP-RS
A defining feature of PSP-RS is vertical supranuclear gaze palsy, which is difficulty with voluntary downward gaze. Vertical supranuclear gaze palsy, a symptom characterized by decreased velocity and amplitude of vertical eye movements is often the prominent diagnostic feature of PSP-RS. Approximately 40% of patients with PSP-RS experiencing supranuclear gaze palsy, but it may not present until 3–4 years after disease onset. Individuals with PSP-RS also display other ocular motor symptoms such as dry, red and sore eyes, blurred vision, and difficulty focusing. They may also experience spontaneous and involuntary eye-lid closure or apraxia of the eyelid opening.Cognitive and behavioral symptoms in PSP-RS
Cognitive changes are frequent in PSP-RS compared to other PSP subtypes and include slowed thinking, executive dysfunction, and difficulty with planning or problem-solving. Some patients exhibit apathy, emotional blunting, or involuntary episodes of laughing or crying unrelated to mood. Some studies report that around half the individuals with PSP-RS develop these personality changes within 2-years of diagnosis. Dementia is not typically a dominant feature early on but may develop in later stages.Cause
The cause of PSP is unknown. Fewer than 1% of those with PSP have a family member with the same disorder. A variant in the MAPT gene for tau protein called the H1 haplotype, located on chromosome 17, has been linked to PSP. Nearly all people with PSP received a copy of that variant from each parent, but this is true of about two-thirds of the general population. The H1 haplotype of the MAPT gene has been identified in approximately 94% of individuals with PSP, compared to around 78% in healthy adults. Therefore, the H1 haplotype appears to be necessary but not sufficient to cause PSP. Other genes, as well as environmental toxins, are being investigated as other possible contributors to the cause of PSP.Additionally, the H2 haplotype, combined with vascular dysfunction, seems to be a factor of vascular progressive supranuclear palsy.