Timothy C. Hain,
Chicago IL, USA. Version: 7/2002
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Progressive supranuclear palsy (PSP) is a degenerative neurological disorder of uncertain etiology characterized by gait ataxia, slowing or inability to generate voluntary saccadic eye movements, and axial rigidity. The most characteristic aspect of PSP is an inability to move the eyes, but the first symptom of PSP is usually unsteadiness and falling.
PSP was first described as a distinct disorder in 1964. It is sometimes referred to as Steele-Richardson-Olszewksi syndrome, reflecting the names of the individuals who defined the disorder.
PSP is estimated to affect about 4-6.4/100,000 persons, or about 5-6 percent of persons thought to have Parkinsonism. The incidence rate for new cases for ages 50-99 is 5.3/100,000, the crude incidence rate is 1.1/100K (Bower et al, 1997; Schrag et al, 1999). The peak incidence is in the early sixties. Men are affected slightly more often than women. PSP does not generally run in families, although there are some pedigrees reported.
An illness resembling PSP is very common in Guam, sometimes in association with ALS (amyotrophic lateral sclerosis) and dementia. The cause of Guamanian PSP is unclear although it has been attributed to unusual dietary factors, possibly interaction with genetic factors (Cox and Sacks, 2002). Recently a high prevalence of PSP like illness has been found on the island of Guadeloupe in the French West Indies (Caparros-Lefebre, 1999). In this population, it is suspected that a PSP like illness is related to ingestion of native teas called "soursop" and "sweetsop", both of which are forms of the "custard apple".
A famous person with PSP is Dudley Moore, the actor.
The most frequent first symptom of PSP is several falls over a year. Next patients often develop some stiffness and at this point may be diagnosed as having "atypical Parkinsonism. However, patients with PSP rarely develop the resting tremor and stooped posture characteristic of Parkinsonism.
As the disease progresses, most patients will develop problems controlling eye movement. The eye problems begin with vertical eye movements -- patients may be unable to look downward. This may result in the so-called "dirty-tie" sign, because patients can't see that they are dropping food when they eat. Difficulty in reading is common. Eventually, patients lose the ability to look up and down at all, and usually about a year later, the ability to look from side-side is also lost. Typically, patient with PSP have trouble controlling the sitting down process -- they may "fall into their chair". Swallowing difficulties are also common in PSP (Litvan, 1997), the most common problem being delayed initiation of swallowing. The course of PSP was recently studied (Santacruz et al, 1998).
There are a number of possible "signs" of PSP that will need confirmation. Ghika and Bogousslavski suggested that presymtomatic hypertension is a major feature in the diagnosis of PSP (1997).
It is known that the symptoms of PSP are caused by gradually progressive damage to a group of cells in a part of the brain called the "midbrain". These cells are involved in eye-movements and balance. The cause of the degeneration of these cells is unknown. In addition to the midbrain disease, there is also damage to the basal ganglia (especially globus pallidus), subthalamic nuclei, and the dentate nucleus of the cerebellum. According to Cordato et al (2000), atrophy of the basal ganglia is largely confined to the internal globus pallidus. Cerebral cortex is also affected and decreased metabolism of cerebral glucose correlates with dementia. Cortical benzodiazepine receptors are also decreased (Foster et al, 2000).
Pathologically, gross examination of the brain in PSP shows midbrain atrophy. There is neuronal loss and neurofibrillary tangles in the basal ganglia, diencephalon and brainstem. The substantia nigra, subthalamic nucleus and pontine base are typically involved as well as the ventral anterior and lateral thalamic nuclei. The cerebellar dentate nucleus may show degeneration. Cortical pathology is minimal except for motor areas. See the review in Jellinger (1992) for more detail.
Until recently, the main suspicion for cause fell upon either a virus or a slow toxin. For example, a toxin called "MPTP", a contaminant in a drug of abuse, causes a condition similar to Parkinsonism. It has been speculated that there may be other slow-toxins in the environment, as for example, cycad nut or fruit bat consumption in Guam (Cox and Sacks, 2002) and certain herbal teas used in the Caribbean. With respect to the virus hypothesis, certain variants of Parkinsonism are known to be related to strains of influenza, and it is conceivable that a so-far undescribed virus is the cause of PSP.
Recent genetic studies, however, suggest that some cases of PSP is an autosomal recessive condition that maps to a polymorphism in the tau gene. (Bennet et al, 1998; Higgins et al, 1998-1999; Spillantini and Goedert, 2001). Tau is a microtubule-binding protein that is normally abundant in neurons. There are six different forms of tau in normal human brain. In typical PSP, pathological tau is composed of aggregated 4-repeat (E10+) forms that accumulate in cells and glia in the brain (Searceant et al, 1999; Spillantini et al, 1998). Rojo et al (1999) recently reported 12 pedigrees with familial PSP. Relatives of patients with PSP tend to score more abnormally on screening tests for Parkinsonism (Baker and Montgomery, 2001), supporting either a genetic factor or exposure to a common environmental toxin. Genomic screens in persons with late-onset Parkinsons disease also suggests a linkage a mutation on the Tau gene on chromosome 17q (Martin et al, 2001)
Delacourte et al suggested that tau is not the primary problem in most neural degenerations, but rather is a marker for vulnerable neurons that are damaged in several degenerative diseases (1998). Perhaps consistent with this line of logic, there are a multitude of other "tauopathies" including Alzheimer's disease, Picks disease, ALS-Parkinson dementia complex of Guam, familial "tauopathy" (Murrel et al, 1997) , and corticobasal degeneration (Higgins et al, 1999). There are four distinct kindreds with a mutation on chromosome 17 called N279K, and 50 kindreds having a syndrome called FTDP-17 for frontotemporal dementia and parkinsonism (Arima et al, 2000; Wszolek and Hutton, 2000), that lumps together 9 different mutations (Reed et al, 2000). The tau in PSP is different from that observed in Alzheimer's disease and Picks, both in morphology and tau isoform content, but it resembles the tau in corticobasal degeneration (Di Maria et al, 2000; Houlden et al, 2001) and FDTP-17. PSP certainly need not be entirely genetically determined -- it also seems possible that PSP is partially controlled by genetic susceptability and also partially related to other stressors such as toxins or viruses. Oxidative stress, perhaps related to mitochondrial disorders, is another possibility.
PSP is a clinical diagnosis, meaning that there is no "test" for PSP. PSP is ordinarily diagnosed by a neurologist who has had experience with this condition. There are several very obscure neurological diseases that can be confused with PSP (see table below), and it is wise to seek out a "tertiary care" neurologist who is familiar with PSP. This usually entails being referred to a "movement disorders clinic" in a university hospital setting. Experienced neurologists are generally accurate in making the diagnosis of PSP, being "right" about 90% of the time. Eye movements are always abnormal, but there are numerous other (rare) causes of slowed eye movements. Classically it is taught that in PSP there is an "axial rigidity", meaning that the limbs may be relatively normal while the neck and trunk are rigid. This idea was called into question recently by a paper by Tanigawa that suggested that only the neck is rigid (Tanagawa et al, 1998). Blood tests, CT and MRI scans are usually normal.
All patients with PSP have abnormal vertical eye movements. Patients with PSP rarely have tremor and the stooped posture characteristic of Parkinson's disease. Another degenerative disease, Gaucher's type-III, a metabolic storage disese, also causes a progressive supranuclear palsy, but it begins horizontally. Other disorders that may be mistaken for PSP include corticobasal degeneration, Picks disease, multisystem atrophy (MSA) and diffuse Lewy body disease. Links to pages about these disorders in on the table below. A familial "tauopathy" with dementia closely resembling PSP was recently described (Murrell et al, 1997). Jacob-Creutzfeld disease and related disorders can also present with ataxia and a supranuclear gaze palsy, but the course is generally more rapid and dementia is more severe than in PSP.
Litvan and others (1997) investigated features that differentiate PSP from these other disorders, as gone over in a table adapted and amended form their paper below. While not to be relied upon as absolute criteria, this analysis does point out that gait instability and supranuclear gaze abnormalities are key differentiating features.
|Disorder||Clinical features of of PSP or disease that are different from other degenerative neurological disorders that have impaired vertical eye movements.|
|Parkinsonism||In PSP there is gait instability, absence of tremor dominant disease, absence of response to levodopa or supranuclear gaze abnormality|
|MSA||In PSP there is supranuclear gaze palsy, and increased age at symptom onset. MSA prominantly involves blood pressure control.|
|Corticobasal degeneration||Gait instability, severe (supranuclear) upward gaze palsy, bilateral bradykinesia. PET scanning has been reported to differentiate from PSP (Nagahama et al, 1997).|
Gauchers has more dementia than PSP, usually starts earlier, and the eye movement problems begin horizontally. Gauchers is rarer than PSP and runs in families.
|Picks disease (also known as frontotemporal dementia)||PSP has more gait instability and less dementia.|
|Diffuse Lewy body disease||
PSP has gait instability and supranuclear gaze palsy. Lewy bodies are not increased in PSP (Tsuboi et al, 2001). DLB has characteristic intolerance of medications.
Patients with PSP all progress and the usual life span after diagnosis is 5 years (Bower et al, 1997). Death does not result as a direct effect of the disease but rather from complications such as pneumonia or pulmonary embolism, which may result from inability of the patients to move about and care for themselves. Of course, falling is common in persons with PSP that are still ambulatory. When persons with PSP begin to cough after every meal, this generally indicates that there is considerable danger of pneumonia from aspiration, and a decision needs to be made whether or not to put in a feeding tube.
In a word, no. In particular, there is no drug known that will stop the usual inexorable progression of the disease. Most neurologists will try using drugs for Parkinsonism, such as Sinemet. However, such drugs are mildly helpful in only about 50% of persons with PSP. As disability in PSP is due to neuronal damage, and neurons do not regenerate, stopping progression is presently the main goal of treatment.
Recent studies of specific medications include:
Some neurologists (including the author) prescribe a medication in PSP patients called "seligiline", which was at one point thought to prevent progression in Parkinsonism. Seligiline has not been formally studied in PSP and it is presently unclear whether or not it is helpful. There is some evidence that this drug may inhibit apoptosis (programmed cell death), which might be helpful in PSP. It is our view that this drug is worth trying. It is the authors impression, based on use of this drug in several patients, that seligiline reduces the rate of progression in PSP. Some PSP patients on seligiline develop blood pressure instabilities, which limits its use.
Physical therapy has been reported in a single case report to have a positive effect (Suteerawattananon et al, 2002). In general, while we favor physical therapy, it is unreasonable to expect that it will reverse the ongoing degenerative neurological processes that cause the clinical picture of PSP.
There is a small literature that documents a positive effect of amitriptyline (Elavil), which is an antidepressant medication. This medication is, however, sedating and may also have very adverse effects on thinking.
Drugs like the calcium channel blockers may be also worth trying as they may prevent apoptosis (programmed cell death) as mentioned above for Seligiline. Minocycline, a tetracycline type antibiotic, has recently been shown to be neuroprotective in animal models of stroke, multiple sclerosis, Parkinson's disease and Huntington's disease (Arvin et al, 2002). We know of no studies of these drugs in PSP, however.
Vitamin E may be slightly helpful. In other degenerative neurological disorders, Vitamin E often has a small effect in reducing the rate of progression. The author does suggest it for his PSP patients. It seems possible that agents that reduce oxidative stress (mainly vitamins) might slow the rate of progression in PSP.
Most individuals with PSP and their caregivers attempt to make realistic plans anticipating a slow neurological decline. Patients and caregivers should establish early on their wishes regarding invasive supportive care -- intubation, feeding tubes -- as these issues are almost certain to come up in the course of the disease. As little is understood about PSP, efforts to encourage research into its diagnosis, mechanism and treatment seem highly worthwhile. Patients with PSP should consider donating their brains for autopsy examination at the time of death. In this way, a cure for this condition may eventually be found. The Society for PSP (at Johns Hopkins Hospital), is presently coordinating this effort along with the Mayo Clinic (Jacksonville)