Progressive Supranuclear Palsy (PSP) Information Page Ten Common Questions and Answers for Patients
This guide addresses the 10 most common questions patients have about Progressive Supranuclear Palsy (PSP), providing clarity and support for those navigating this condition.
what is it?
Progressive supranuclear palsy, or PSP, is an atypical parkinsonian syndrome (Parkinson-plus disorder) characterized by progressive, early gait imbalance, frequent unexplained falls (often backwards), impaired eye movements, axial (involving neck or trunk) stiffness or rigidity, speech and swallow difficulty, and cognitive decline.[1] A key feature of PSP—and not seen in Parkinson disease—is progressive supranuclear gaze palsy that is defined by impaired vertical gaze, especially looking down. By contrast, upgaze limitation is common in aging and nonspecific. Supranuclear gaze palsy eventually affects all voluntary eye movements, resulting in the characteristic “stare” in PSP. Other features may include a masked facial expression, decreased blink rate (or involuntary eye closure), double vision, slowed movement (and thought), sloppy eating habits, monotone, slurred speech, lack of spontaneous conversation, grasping or imitative behaviors, and emotional lability (i.e., crying or laughing in unusual situations). Many of these features overlap with those of Parkinson disease, particularly early in the course of disease, and can lead to confusion and misdiagnosis. Additionally, not all PSP patients present in the same way and may have varying features, including language or behavioral changes. Several variants of PSP are now recognized. If PSP is suspected, evaluation by a neurologist or movement disorders specialist familiar with this disorder is strongly recommended to confirm diagnosis and to provide proper care.
Who gets it? Why me?
PSP is one of the most common atypical parkinsonian syndromes, but is still relatively rare and affects about 6 to 10 in 100,000 individuals.[2] PSP is largely a sporadic disease. To date only a few families have been identified with a familial or hereditary form of PSP. However, genetics clearly plays a role in susceptibility and several genes have been identified and associated with PSP risk. These genes are not routinely tested for clinically, but are the subject of active research. In particular several studies have implicated MAPT, the gene that encodes for the microtubular associated protein tau, and its H1 haplotype as a risk factor for PSP (and similarly also Parkinson disease).[3-5] In contrast, the H2 haplotype appears to significantly reduce risk, especially if homozygous (someone who carries two H2 alleles). The MAPT H1 haplotype is common in the general population, though, and reinforces the idea that genetics and environmental factors likely interact to cause disease. Environmental factors include toxins—from proximity or occupational exposure—smoking, infectious agents, level of activity, and even stress. Research is ongoing, but so far no specific environmental factor has been definitively linked to PSP.
What causes it?
Although the exact cause of PSP remains unknown, there is increasing knowledge about its pathology furthering insight into potential mechanisms of the disease. We know that one of the hallmarks of PSP is abnormal deposition of the microtubular associated protein tau (encoded by the MAPT gene) in brain.[6] Tau pathology is implicated in a number of neurodegenerative disorders including Alzheimer’s disease, frontotemporal dementias, corticobasal degeneration (CBD), and PSP. Splice variants of tau result in expression of 6 different versions of the tau protein in the human brain, containing either 3 or 4 repeated microtubule binding domains and referred to as three-repeat (3R) or four-repeat (4R) tau. The 4R tau protein is predominant in PSP (and CBD), whereas the 3R tau is more prevalent in frontotemporal dementia. Normally tau is a protein that associates with microtubules, structures that help support the long processes of neurons. In disease tau becomes hyperphosphorylated (ie, bunch of phosphates molecules get added to it), causing it to dissociate from microtubules, misfold, accumulate, and form abnormal deposits in cells, called neurofibrillary tangles. Abnormal accumulation of tau is toxic to neurons, leading to dysfunction and cell death. Evidence suggests that pathological tau also exits cells and contributes to propagation of pathology and progressive degeneration in the brain.
Understanding the process of how tau goes from a “good” to a “bad” protein and contributes different neurodegenerative diseases is a major area of research. Targeting the “bad” tau in brain has also been the focus of recent therapeutic trials which so far have been unsuccessful (see below). These studies are only the beginning, though, and raise many questions such as when to treat (maybe much earlier), who to treat, and even if targeting tau is best. Other factors such as neuro-inflammation and mitochondrial dysfunction also play a role in the disease and may also be amenable for therapeutics in the future.
How is PSP diagnosed?
There is no one diagnostic test for PSP. The diagnosis remains primarily clinical, meaning that it is based on history, exam, and physician expertise. A diagnosis by a movement disorders-trained neurologist has been shown to match well with the neuropathological diagnosis. Still, PSP is likely both underdiagnosed or misdiagnosed because the symptoms overlap those of other neurological disorders such as Parkinson disease and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). If suspected, referral to a movement disorders neurologist such as those here at UF is highly recommended. PSP can be diagnosed based on typical symptoms of early postural instability, falls, gaze problems, slowed movement, rigidity, speech/swallow problems, and cognitive decline. However, not all patients follow this pattern and variants are seen. Average age of onset is in the early 60’s and ranges from 40 to 80 years. Progression of symptoms is typically more rapid than in Parkinson disease, and poor response to medications such as levodopa can be supportive of the diagnosis but not necessarily diagnostic.
While a thorough history and exam are most important, diagnostic testing can also be useful in supporting diagnosis. One of the most helpful tests is brain MRI (magnetic resonance imaging). Shrinkage or atrophy of the midbrain (top of the brainstem) has been found to be a fairly sensitive indicator of PSP. Looking at the brainstem from a side view image, the midbrain can appear “beaked” and the brainstem suggest a “hummingbird sign.”[7] Measurement of the midbrain size and ratio to other parts (pons) of the brainstem may be helpful in distinguishing PSP from Parkinson disease and another atypical parkinson disorder, multisystem atrophy (MSA).[8] Other tests that can be used include functional brain imaging, such as PET or SPECT, that look at brain activity which can be correlated with known areas of degeneration. However, these tests are not widely available, can be expensive, and are not frequently used. The future may include advanced MRI techniques that look at brain activity and
connectivity. Here at UF, Dr. David Vaillancourt and colleagues are actively studying these imaging techniques to determine whether they can be used to identify PSP and other atypical parkinsonian syndrome from Parkinson disease.
Clinical testing of blood or other tissues (such as cerebral spinal fluid, CSF) for PSP is generally not done. So far the search for useful biomarkers in blood or CSF has not yielded a reliable test for PSP, but is a subject of active research. Genetic testing is currently done only for research.
How is it treated?
Unfortunately, there is no one pill or cure for PSP. Treatment is primarily supportive and may include a combination of medications and supportive therapies. A trial of the Parkinson drug carbidopa-levodopa (commonly known as Sinemet) is warranted in PSP and may require increased dose for effect. Treatment in some patients may improve the Parkinson symptoms including stiffness, rigidity, slowness, walking, balance, and even overall energy. That said, as the disease progresses even increased doses of carbidopa-levodopa may not be helpful and may cause undesirable side effects. There is limited evidence to suggest trial of another, older Parkinson medication called amantadine.[9] Alternative treatments may include use of muscle relaxants for rigidity, or direct muscle injections with botulinum toxin (e.g., Botox), which temporarily may relieve uncomfortable muscle contractions.
Combining these treatments with physical (PT) and occupational therapy (OT) is critical. Falls are a leading cause of injury, disability, functional dependence, and even death. Physical therapy can help with gait, balance, and fall prevention, as well as general mobility. Exercises to stretch muscles can help with mobility and prevent formation of contractures. Occupational therapy addresses activities of daily living, like dressing, grooming, and going to the bathroom, all essential for healthy living and maintaining independence. A comprehensive therapy evaluation is, therefore, crucial and can make a huge difference in quality of life.
Treating speech and swallow impairments is equally important. Speech in PSP can become difficult to produce and understand (i.e., softer, slurred, stuttering, etc.). Cognitive issues also contribute and affect responsiveness, verbal fluency, word-finding, and even comprehension. Speech therapy can address and help with each of these issues.
Swallow difficulty is very common in PSP and another potential hazard. Choking or aspiration of food, liquids, or saliva can result in pneumonia and even death. As such, formal swallow evaluation is strongly recommended and should include regular follow-up exams. To help with swallowing, recommendations may include compensatory strategies, exercises, and thickening agents for liquids. Another option may include considering a feeding or gastric tube if there is significant weight loss, poor nutrition, or difficulty feeding by mouth. However, the choice to undergo a feeding tube placement is complex and not something that all patients desire. Though it can help with feeding, hydration, and medication administration, a feeding tube does not entirely reduce the risk of aspiration, nor does it change prognosis in PSP. We strongly recommend discussing this option with your physician and care team. It is helpful to talk about such care options early in disease in the context of advanced care planning or directives.
Many other features of PSP are also amenable for treatment. Visual disturbance in PSP, such as blurred or double vision, should prompt referral to a neuro-ophthalmologist. Glasses with prisms may help with double vision. Bifocals can be problematic due to the downgaze limitation in PSP forcing one to look through the line separating near and far vision lenses. Separate glasses are sometimes better and needed for reading versus general activity. Involuntary eye closure, or blepharospasm, can reduce vision too and often responds well to botulinum toxin injections. Reduced eye closure or blinking can also lead to dry, irritated eyes, and contribute to poor vision. Regular use of an eye lubricant is recommended to prevent drying and scarring of the cornea. Mood is a big problem in PSP too and may include anxiety, irritability, depression, apathy, and emotional incontinence (called pseudobulbar affect). Without treatment these issues can be quite frustrating, exacerbate symptoms, and complicate therapy. Although a neurologist can start therapy with an antidepressant, proper referral and treatment by a psychiatrist familiar with mood issues in parkinsonism can be very helpful.
Cognitive decline and dementia represent difficult issues to treat in PSP. As with other Parkinson disorders, the primary problem is slowed processing or thinking, rather than memory. A good analogy is “there is film in the camera, but it takes an hour to process.” Although memory medications designed for Alzheimer’s (eg, donepezil, rivastigmine, or memantine) may be tried,[10,11] they often provide only modest benefit and may cause worsening of motor symptoms such as gait. With dementia there may also be behavioral issues such as impulsivity, agitation, irritability, and even aggression. Hallucinations and delusions (fixed, false beliefs), though, are very rare. Safety both for the patient and caregivers is critical. Make sure to discuss any behavioral changes with your provider, who can help develop strategies to address troublesome symptoms.
What about natural therapies and supplements?
Supplements and vitamins are frequently asked about. Surprisingly little is known about these in relation to PSP. Much of what we know is derived from studies on Parkinson disease and may not actually translate to PSP. Coenzyme Q10 (CoQ10) is a supplement that helps with energy production in cells and functions also as an antioxidant. Supplementing the energy of brain cells with CoQ10 is thought to help prevent further loss or degeneration, and thereby might slow disease progression. Unfortuantely, the data on CoQ10 in actual patients is mixed. A large trial in Parkinson disease (NET-PD) with high dose of CoQ10 up to 2400 mg per day showed no benefit. In PSP there have been only two studies to date and the data is mixed with only a trend toward modest improvement.[12]*** CoQ10 is not a regulated drug and comes in many forms (tablet, gel tab, and liquid), resulting in differences in the dose need for effect. Speak to your doctor about recommended doses before taking, but generally 1200 mg/day is needed (can be divided). As for other vitamins there again is limited data. Vitamin E has been touted as an antioxidant, but there is no good evidence for benefit in PSP and increasing data suggests that high doses (above recommended daily allowance; note, similar data for beta carotene and vitamin A) may actually increase risk of death.[13] Therefore, we do not recommend specific vitamin supplementation unless you are determined deficient by your doctor.
What is my prognosis?
So far there is no cure for PSP. Progression of disease is faster than in Parkinson disease, but still over the course of years. Average length of survival from diagnosis ranges from 5-8 years and clearly varies for each patient. In the advanced stages of the disease most patients succumb to complications such as aspiration (swallowing down the windpipe), infection (pneumonia, urinary), and falls, fractures, or head injury. As such, we do all we can to prevent these complications through therapy and supportive care. End of life care, however, is important and we can help with palliative and hospice care decisions that can provide many benefits for the patient and family members. Although often an uncomfortable topic, early discussion with your doctor about end-of-life decisions such as life support, resuscitation, and feeding-tube is equally important and encouraged
What is on the horizon for treatments or a cure?
There is hope! Research on PSP and related disorders has exploded in recent years. We know now more about the pathology of PSP than ever thanks to the generosity of patients. However, the cause of this devastating disease remains unclear. There is active research though in many areas looking at the pathology and role of tau protein in disease, protein processing, genetics, environmental risk factors, biomarkers, brain imaging, and therapeutics for PSP.
Knowledge of tau pathology, in particular, has led to several recent clinical trials aimed at reduction of pathological phosphorylated tau and deposits in brain cells. Glycogen synthesis kinase 3 (GSK-3) inhibitors reduce tau phosphorylation. However, candidate GSK-3 inhibitors such as lithium, valproate, and tideglusib all failed to show any benefit in PSP. Relative recent large phase 2 and 3 clinical trials include drugs like davunetide and antibody therapies such as gosuranemab and tilavonemab that also failed to show benefit. Despite these failures there are ongoing clinical trials in PSP with new drugs aimed at targeting tau or inflammation in brain. With increasing knowledge about the pathologic mechanisms of PSP new targets for therapeutics trials are inevitable.
Other areas that are being explored for potential therapeutics include stem cells, growth hormones, gene therapies (modulating genes or inactivating them, such as with antisense DNA), transcranial magnetic stimulation (TMS), and DBS (deep brain stimulation). For now, none of these are clinically proven and participation is limited to a trial if eligible. DBS in particular is not approved for PSP and largely thought not to be helpful.
What about disease markers?
Biomarkers are also actively being explored to help with diagnosing PSP and distinguish it from other Parkinsonian disorders. Biomarkers can be chemicals, molecules, and genetic information found in tissues such as blood or CSF (cerebrospinal fluid) that need to be both sensitive and specific for whatever disease you are testing. Although so far no one biomarker has been identified for PSP, it may be that set of molecules (molecular “fingerprint”) will be needed to accurately detect or predict disease. Early detection and the ability to correlate a marker with disease progression are both highly desirable. In addition to molecular markers, brain imaging is also being explored as a biomarker for PSP and its progression. Functional MRI and DTI are being used here at UF (Dr. David Vaillancourt) to do just that.
Where do I find more information?
Please feel free to contact me, Dr. Nikolaus McFarland, Director of the PSP/Atypical Parkinson’s Clinic, University of Florida Norman Fixel Institute for Neurological Diseases, email: nikolaus.mcfarland@neurology.ufl.edu for further information.
Some other sites for information include: CurePSP (http://www.psp.org/) National Institutes of Health (http://www.ninds.nih.gov/disorders/psp/psp.htm) PSP Association (in UK) http://www.pspassociation.org.uk/
References
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2. Hoppitt T, Pall H, Calvert M, Gill P, Yao G, et al. (2011) A systematic review of the incidence and prevalence of long-term neurological conditions in the UK. Neuroepidemiology 36: 19-28.
3. Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, et al. (2005) High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 14: 3281-3292.
4. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, et al. (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8: 711-715.
5. Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, et al. (2011) Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 69: 778-792.
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8. Longoni G, Agosta F, Kostic VS, Stojkovic T, Pagani E, et al. (2011) MRI measurements of brainstem structures in patients with Richardson’s syndrome, progressive supranuclear palsy-parkinsonism, and Parkinson’s disease. Mov Disord 26: 247-255.
9. Nieforth KA, Golbe LI (1993) Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharmacol 16: 338-346.
10. Liepelt I, Gaenslen A, Godau J, Di Santo A, Schweitzer KJ, et al. (2010) Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: Clinical observations as a basis for power calculations and safety analysis. Alzheimers Dement 6: 70-74.
11. Karakaya T, Fusser F, Prvulovic D, Hampel H (2012) Treatment options for tauopathies. Curr Treat Options Neurol 14: 126-136.
12. Stamelou M, Reuss A, Pilatus U, Magerkurth J, Niklowitz P, et al. (2008) Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Mov Disord 23: 942-949.
13. Bjelakovic G, Nikolova D, Gluud C (2013) Antioxidant supplements to prevent mortality. JAMA 310: 1178-1179.