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, or "SRO", syndrome, from the names of the individuals who defined the disorder. Although PSP is rare and has no treatment, it has attracted an immense amount of research activity since being discovered, and there are thousands of papers on this obscure condition.
PSP is one of the "tauopathies" which also includes corticobasal degeneration, Picks disease, Frontotemporal dementia, primary progressive aphasia, and several others. PSP in particular has a 4-repeat tau (4RT) that accumulates in the basal ganglia, brainstem and cerebellum. These disorders can overlap with each other and recent investigators have split PSP into subtypes. PSP-RS was detailed in the NINDS, but now PSP can include PSP-parkinsonism, progressive gait freezing (PSP-PGF), as well as PSP-cortical (PSP-frontal and PSP-Corticobasal). (Jabbari et al, 2020).
PSP can overlap with MSA (multiple systems atrophy) as well, which is not a tauopathy but rather it involves accumulation of alpha-synuclein.
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.
According to Coyle-Gilchrist et al (2016), the prevalence of FTD+PSP+CBD was 10.8/100,000 in two counties in the UK. Age adjusted prevalence between 65-69 was 42.6/100K. FTD, MSA, PSP and CBD are often lumped together in studies like this because they cannot be easily distinguished from each other during life and autopsy data is scarce.
Here at Chicago Dizziness and Balance, we have recorded 22 patients with PSP in our database, that includes roughly 18,000 dizzy patients. This suggests that the chance of encountering PSP in dizzy patients is very low -- about 1/1000.
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). Genetic factors do not appear to contribute substantially to the epidemic of PSP in Guam which "remains enigmatic" (Steel et al, 2015). Regarding diet, 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 toxin present in the diet of the Chamorros in Guam, i.e. cycad seeds, BMAA, has been shown to induce similar brain pathology to PSP in animals (Cox et al, 2015).
Another cluster of PSP patients was recently reported in Northern France, with "severe environmental contamination by industrial metals". (Caparros-Lefebvre et al, 2015).
A famous person with PSP was Dudley Moore, the actor.
The symptoms and natural history of PSP was recently reported by Nath and others (Nath, Ben-Shlomo et al. 2003). 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. Double vision is reported in more than half of all patients (Nath, Ben-Shlomo et al. 2003). 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. Photophobia is reported in 43% (Nath, Ben-Shlomo et al. 2003). 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. Eyelid apraxia occurs in 43% (Nath, Ben-Shlomo et al. 2003).
Typically, patient with PSP have trouble controlling the sitting down process -- they may "fall into their chair". There is evidence for abnormal otolith responses -- small translational-VOR, and reduced VEMPs (Liao et al, 2008). This is probably not the reason however for their unsteadiness.
PSP patients as well as the related FTD patients also may have unusual features to the pitch control of their voices (Nevler et al, 2017).
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).
PSP is probably caused by accumulation of "Tau" which is a neurofibrillary protein. Tau has been renamed as MAPT -- microtubule-associated protein tau. While not "alive", Tau protein variants can be transmitted by innoculation into the spinal fluid of animals, and may be similar to "prion" diseases (such as Mad Cow disease). That being said, human-human transmission of PSP has never been proven. Mutations in the MAPT gene are associated with substantially increased risk. The MAPT H1 haplotype is by far the strongest susceptibility locus. (Heckman et al, 2019)
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. Tau-immunoreactive astrocytes in progressive supranuclear palsy (PSP) have a distinctive morphology and are referred to as tufted astrocytes (TA). 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.
Genetic studies, 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 Parkinson's disease also suggests a linkage a mutation on the Tau gene on chromosome 17q (Martin et al, 2001)
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.The MAPT H1 haplotype is by far the strongest susceptibility locus in PSP. (Heckman et al, 2019) PSP certainly need not be entirely genetically determined -- it also seems possible that PSP is partially controlled by genetic susceptibility and also partially related to other stressors such as toxins or viruses. Oxidative stress, perhaps related to mitochondrial disorders, is another possibility.
Until recently, the main suspicion for cause fell upon either a virus or a slow toxin. In view of recent data above, this is probably wrong. 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. A toxin present in the diet of the Chamorros in Guam, i.e. cycad seeds, BMAA, has been shown to induce similar brain pathology to PSP in animals (Cox et al, 2015). 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.
|Slow downward saccades in a patient with PSP (unpublished data of Dr. Hain). These were recorded with a scleral eye coil.|
Supplemental material Video of slow vertical saccades in patient with PSP (10 meg)
A PSP-like disorder has been reported after surgical repair of the ascending aorta (Mokri et al, 2004). This condition closely resembles PSP, but appears within weeks to months following this type of surgery. This is probably unrelated to the "mainstream" PSP which is associated with Tau.
|Slow downward saccades in a patient with a PSP like syndrome following aortic surgery(unpublished data of Dr. Hain). These were recorded with an infrared oculography system in our dizziness clinic in Chicago.|
PSP is a clinical diagnosis, meaning that there is no absolute "test" for PSP. PSP is ordinarily diagnosed by a neurologist who has had experience with this condition. If anything, limitation or slowing of vertical saccades (see above) is the closest to a "litmus" test. Good recordings of vertical eye movements are not that easy, and to get this done properly requires good equipment
A large number of radiological techniques have been suggested (Golbe, 2004). Several of these depend on documenting subtle shrinkage of the midbrain and related areas using MRI (Paviour et al, 2005).
It has been reported that a particular type of MRI scan, Diffusion-Weighting Imaging (DWI), can differentiate PSP from Parkinsonism based on increased diffusion coefficients in the putamen. However, this type of MRI does not distinguish PSP from the Parkinson variant of multiple system atrophy (MSA). (Seppi, Schocke et al. 2003). In our opinion, while DW MRI should ideally be done as a confirmatory test when the PSP patient presents, there is little clinical usefulness in the DW scan as there are no effective treatments for PSP or MSA, and differentiation of PSP from Parkinsonism is not difficult for an experienced clinician. The superior cerebellar peduncle is also, on average, 20% smaller in PSP than in controls (Paviour et al, 2005). Practically this would seem to be a difficult distinction to make in clinical material.
A subjective observation, called the "hummingbird sign", has to do with recognition of a smaller midbrain on the T2 MRI, and preserved pons. This is said to look like a hummingbird's head. Obviously, this is a subjective call on the part of the person interpreting the MRI. The graphic above is from an article on this subject,(Sonthalia and Ray, 2012).
The same article quoted above, also discusses the "Micky Mouse sign", which involves again atrophy of the midbrain, resulting in an appearance of having 2 ears on the axial MRI, at the level of the cerebral peduncles. Again, this is a subjective call of course.
The ratio of the area of the midbrain to the pons on sagittal MRI has reported to be an accurate method of detecting PSP (Oba and others, 2005), as the midbrain is smaller in PSP. This method was also supported by Massey et al (2013), who suggested that a ratio of 0.52 was "100% specific" for PSP. Although this method is supposedly simple, the methodology of computing "elliptical regions of interest", seems to us to involve considerable subjective judgment on the part of the radiologist and also, the overlap between controls and PSP patients seems to us to be substantial. We suspect that the problem might be the intrinsic doubling in uncertainty involved when dividing one uncertain number by another. We also think it is imprudent to ask a radiology doctor who does not examine the patient, to determine from a somewhat subjective measurement, whether or not a patient has a deadly disease. We think that there would likely be an tendency to "undercall".
Another approach is a spinal fluid test developed in Italy for "truncated Tau forms" (Borroni et al, 2008). This spinal fluid test, not currently available at a clinical test, was reported as extremely sensitive and specific for PSP. As there is no commercial method of doing this test, it's clinical utility is presently absent.
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. General practitioners often misdiagnose PSP as Parkinsonism (Nath, Ben-Shlomo et al. 2003).
Eye movements, particularly saccades (see figure and movie above) are nearly always abnormal, but there are other (rare) causes of slowed eye movements. Shaikh et al (2017) recently reported that saccades are not only slow but also interrupted. This has not been our experience however.
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). There are some unusual tests that may be positive, such as the "applause sign" -- see next section. Blood tests, CT and MRI scans are usually normal.
Tilt table and Valsalva testing may be abnormal in PSP as well as related disorders such as MSA. (Schmidt et al, 2009).
Other recently reported methods include differences in the amplitudes of transcranial magnetic stimulation, and SPECT scan.
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 disease, also causes a progressive supranuclear palsy, but it begins horizontally. Other disorders that may be mistaken for PSP include corticobasal degeneration, Picks disease, multi system atrophy (MSA) and diffuse Lewy body disease. There is also a recently described variant of moronic dystrophy (MD2), which has some resemblance to PSP. MD2 affects tau (Maurage et al, 2005).
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.
MRI may be able to differentiate PSP from Parkinsonism. (Oba and others, 2005) as the midbrain is smaller relative to the pons in PSP than in PD.
Several simple clinical tests have been reported as being commonly abnormal in PSP, but rarely normal in Parkinson's disease(Kuniyoshi et al, 2002). These include a lack of habituation of blinking after a penlight is flashed 7 times in one eye, a sustained head deviation after unidirectional rotation in an office chair for 45 seconds, and the "applause" sign -- the patient is asked to clap exactly three times, sees it demonstrated, but when they perform the test the clapping continues more than 3 times. Of these, the "applause sign" seems most potentially useful, with the head deviation sign also being a reasonable possibility. The head deviation sign may be related to "hanging up in the orbit" -- a sign seen in patients with poor fast phases.
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.
A syndrome superficially resembling PSP was reported recently in stiff-person syndrome (Oskarsson et al, 2008). Like PSP, this single patient had a vertical supranuclear gaze palsy. Unlike PSP, their saccadic performance fatigued with continuous testing (for 340+ seconds). This patient also developed a tremor. This is an interesting observation. As it is not possible to test most patients for 340 seconds, and in fact most patients with PSP have no oculomotor testing at all, it may be worth checking for GAD antibodies in a prospective fashion in patients carrying the diagnosis of PSP.
|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. In PSP there is a supranuclear gaze abnormality|
|MSA||In PSP there is supranuclear gaze palsy, and increased age at symptom onset. MSA prominently 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.
|Niemann-Pick-C||NPC usually starts earlier, has liver enlargement, and has more psychiatric problems.|
|Picks disease (also known as frontotemporal dementia) There are also many variants of frontotemporal dementia.||PSP has more gait instability and less dementia.|
|Diffuse Lewy body disease (DLB)||
PSP has gait instability and supranuclear gaze palsy. Lewy bodies are not increased in PSP (Tsuboi et al, 2001). DLB has a characteristic intolerance of medications.
Patients with PSP all progress and the usual life span after diagnosis is 5 years (Bower et al, 1997). The median time from disease onset to first key motor impairment is 4 years, usually 2 years after initial consultation (Goetz, Leurgans et al. 2003). 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.
Unintelligible speech occurs at a median disease duration of 57 months, or about 5 years. (Goetz, Leurgans et al. 2003)
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.
Older age at onset and classification as probable PSP are factors associated with poorer survival. Early problems with falls, speech, swallowing, diplopia and early insertion of a gastrostomy tube predicts reduced survival (Nath, Ben-Shlomo et al. 2003)
In a word, no. In particular, there is no drug known that will stop or reverse the usual inexorable progression of the disease.
The core problem with treatment of PSP and other neurodegenerative disorders, is that by the time these disorders are detected, the brain damage has already occurred. Thus the "cat is out of the bag". Treatments that reduce ongoing damage, cannot be expected to reverse damage -- "put the cat back into the bag". So far, we do not have methods to regrow dead neurons, or "vacuum" out toxic protein from neural cells. Still, perhaps these drugs might slow down the rate of progression of PSP, which is commonly fatal over 5-10 years. Stopping or slowing progression is presently the main goal of treatment.
Logically, it would seem to us and others (Schneider and Mandelkow, 2008) that as PSP is probably caused by tau, and that symptomatic medication is bound to fail. There simply is no method of regrowing neurons. Thus, prevention of progression should be the goal, and in particular, attention should be directed towards treatments that reduce tau.
Recent studies of specific symptomatic medications (only the ones in bold seem reasonable to us) include:
The situation as of 2018 is that we have loads of unproven treatments. It is unlikely that any of these work, but perhaps we just haven't done enough research yet. For people who are early in the course, they could consider both prevention as well as reversal type treatments (we call these "keep cat in bag", and "put cat back into the bag" type treatments). Once the disease has progressed, it would seem more logical to concentrate on the treatments aimed at reversing the disease (i.e. put cat back into the bag). In as much as there is little or no clinical evidence of these "cats ever getting put back into bags", the likelihood of these drugs working is pretty low. Still, it would seem plausible that perhaps some of these treatments slow things down.
A report from 2013 (Karapetyan et al, 2013) suggested that astemizole (an antihistamine, Hismanil, withdrawn from the market due to fear of cardiac effects) stimulates autophagy -- basically cell garbage disposal -- in mice. If this also works in humans, astemizole might be useful for a variety of disorders where cellular junk accumulates -- PSP, MSA, and Alzheimer's. Astemizole also is reported to have some anti-tumor activity. This is a "put the cat back into the bag" type treatment.
Some neurologists (including the author) occasionally 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. When combined with L-dopa in patients with parkinsonism, this drug is associated with increased mortality (Katzenschlager et al, 2008). It is our view that this drug is worth trying, although not in combination with L-dopa. Some PSP patients on low dose seligiline develop blood pressure instabilities, which limits its use. This is a "keep cat in bag" treatment.
Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Yamamoto, M. and A. H. Schapira (2008). While this is not the same as showing a neuroprotective effect (as the control was levodopa), nevertheless these agents are worth considering. This is a "keep cat in bag" treatment.
Beta agonists (such as asthma medications) may be helpful by turning on cellular machinery that dissolves tau. Peterson et al, 2014. This idea has been proposed for other tau mediated diseases. If true, one would also think that beta-blockers would be detrimental. This is a "put the cat back into the bag" type treatment.
Physical therapy has been reported by several groups to have a positive effect (Suteerawattananon et al, 2002; Zampieri and Di Fabio 2008). 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. This would be a "keep cat from leaving the bag as quickly" treatment.
There is a small literature that documents a positive effect of amitriptyline (Elavil), which is an antidepressant medication. (Engel 1996). This medication is, however, sedating, drys the eyes, and may also have very adverse effects on thinking.This would be a "keep cat in bag" treatment.
Drugs like the calcium channel blockers may be also worth trying as they may prevent apoptosis (programmed cell death) as mentioned above for Seligiline. In Mice, nimodipine has been reported as "efficient" in a model for ALS, a related neurodegenerative disorder (Kriz et al, 2003). This would be a "keep cat in bag" treatment.
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). A "cocktail" of minocycline, riluzole (a glutamate antagonist used in ALS) and nimodipine (a calcium channel blocker) was recently reported as "efficient" in mice in a model of ALS, another degenerative neurological disorder (Kris et al, 2003). Memantine (Namendia) is a newly released glutamate antagonist that may also be worth considering. We know of no studies of these drugs in PSP, however. This is a "keep cat in bag" type treatment.
Flupirtine, an analgesic agent not available in the USA, has several neuroprotective actions including antioxidant, anti-glutamate, and anti-apoptotic actions. It has recently been found helpful in Creutzfeldt-Jakob disease, which is a degenerative neurological disease similar to "mad cow" disease (Otto M, et al). To our knowledge, it has not been tried in PSP. This would be a "keep cat in bag" treatment.
Vitamin E may be slightly helpful. In other degenerative neurological disorders, Vitamin E often has a small effect in reducing the rate of progression. It seems possible that agents that reduce oxidative stress (mainly vitamins) might slow the rate of progression in PSP. This would be a "keep cat in bag" treatment.
The "statin" drugs, used to lower cholesterol also protect against Alzheimer's disease and provide neuroprotection (Chen et al, 2003). These drugs might reduce the speed of progression in PSP. We know of no study of this family of drugs in PSP. Still, they would seem reasonable if only to control cholesterol. This would be a "keep cat in bag" treatment.
L-serine was found helpful in animals by Cox et al (2015) in an animal model for PSP involving cycad nut toxins. So far, this has not been tested in humans. As L-serine is a natural amino acid, it is unlikely to be harmful. On the other hand, it would also seem highly unlikely to reverse any damage already done, so this is a "keep cat in bag" type treatment.