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Progressive Supranuclear Palsy

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NORD is very grateful to Rodger J. Elble, MD, PhD, Professor of Neurology, Director, Parkinson Disease and Movement Disorders Center, Neurology Residency Director, Southern Illinois University School of Medicine, for assistance in the preparation of this report.

Synonyms of Progressive Supranuclear Palsy

Disorder Subdivisions

General Discussion

Summary
Progressive supranuclear palsy (PSP) is an uncommon degenerative neurological disorder that causes progressive impairment of balance and walking; impaired eye movement, especially in the downward direction; abnormal muscle tone (rigidity); speech difficulties (dysarthria); and problems related to swallowing and eating (dysphagia). Affected individuals frequently experience personality changes and cognitive impairment. Symptoms typically begin after age 60 but can begin earlier. The exact cause of PSP is unknown. PSP is often misdiagnosed as Parkinson disease, Alzheimer disease, corticobasal degeneration and other neurodegenerative disorders.
Introduction
Drs. John C. Steele, J.C. Richardson and J. Olszewski identified progressive supranuclear palsy as a distinct neurological disorder in 1963.

Symptoms

The signs and symptoms of PSP vary from case to case, but patients generally fall into one of four clinical syndromes (phenotypes): Richardson syndrome, atypical parkinsonism, corticobasal syndrome, and pure akinesia and gait freezing. Less commonly, patients present with cognitive loss and no motor signs.

The most common presentation is the Richardson syndrome, consisting of gait and balance impairment, a wide-eyed staring facial expression, abnormal speech, memory and cognitive impairment and a slowing or loss of voluntary eye movement, particularly in the downward direction (supranuclear ophthalmoplegia). Cognitive symptoms include forgetfulness and personality changes, such as loss of interest in formerly pleasurable activities (apathy), impaired attention and concentration, depression, and increased irritability.
Fewer than half of all PSP patients are initially diagnosed correctly because many patients do not present with the classic Richardson syndrome. Many of these patients are initially slow and have muscle rigidity and occasionally tremor, resembling Parkinson disease, and they may initially respond somewhat to levodopa. Other patients present with bizarre stiffening (rigidity and dystonia) and loss of voluntary function in one upper limb, as is seen in corticobasal degeneration. Rarely, patients exhibit the syndrome of primary akinesia and gait freezing. These patients exhibit hesitant initiation of gait and a tendency to freeze or stop when turning and when crossing thresholds (doorways). Their eye movements and cognition are normal. Small handwriting and low-volume rapid, mumbling speech (tachyphemia or cluttered speech) are typical and are similar to that which occur in Parkinson disease, but in contrast to Parkinson disease, there is no slowness (bradykinesia) or muscle stiffness (rigidity). Finally, some patients with PSP present with cognitive impairment, resembling Alzheimer disease or frontotemporal dementia. Most patients with atypical presentations ultimately develop abnormalities of eye movement, speech, swallowing and gait (Richardson syndrome) in a few years. Thus, the diagnosis of PSP typically becomes more certain as the disease progresses.

Impaired eye movements eventually make reading, driving, and interpersonal eye contact difficult or impossible. Abnormal eyelid control causes the eyes to close involuntarily (blepharospasm) for seconds or more, and some affected individuals may not be able to open their eyes (eye opening apraxia), even when a spasm stops. Other patients have trouble closing their eyes or may blink less than normal, causing the eyes to become dry and red.

Muscles of the body may contract involuntarily, causing the affect body part (e.g., the upper or lower limbs) to assume bizarre postures. This is called dystonia. Blepharospasm is a form of dystonia affecting the muscles around the eyes.

A mild or moderate degree of mental impairment eventually occurs in most patients, and this may be misdiagnosed as Alzheimer disease (AD) when it occurs early in the illness, before significant difficulties with speech, balance and eye movements appear. (For more information on Alzheimer disease, please choose "Alzheimer" as your search term in the Rare Disease Database.)

Some patients experience sleep disturbances such as frequent awakenings and changes in sleeping patterns. Sleep disturbances may be a sign of depression or may be a side effect of a medication. REM (rapid eye movement) sleep behavior disorder is not a characteristic of PSP but is a characteristic of dementia with Lewy bodies, Parkinson disease and multiple system atrophy. In REM sleep behavior disorder, patients talk and move during dream sleep, and the movement can result in personal injury or injury to a bed partner.

Causes

The cause of progressive supranuclear palsy is not known, but it is a form of tauopathy, in which abnormal phosphorylation of the protein tau leads to destruction of vital protein filaments in nerve cells, causing their death. Recent work suggests that the disease is at least partly genetic. Many researchers now believe that various genetic and environmental factors contribute to the development of this disorder.

In the medical literature, the word "tauopathies" is used to refer to several neurodegenerative disorders including PSP, in which tau is mishandled. Other neurodegenerative disorders classified as tauopathies include corticobasal degeneration and Pick's disease.

Patients with a family history of PSP are very rare, and the underlying genetic abnormality is unknown in these families. Some cases of PSP are linked to a mutation or genetic variation in the gene MAPT, which helps to produce (codes for) the tau protein. This gene resides on chromosome 17 (17q21.1). Variants of least three other genes (STX6, EIF2AK3, and MOBP) are associated with an increased the risk of developing PSP. The study of genetic mechanisms should eventually lead to effective medical therapies.

Affected Populations

PSP is under-diagnosed, so it is difficult to know how many people are affected. This disorder is believed to affect approximately 20,000 people in the United States. However, far fewer cases have been diagnosed. According to some reports, PSP is estimated to affect as many as 5 in 100,000 people. The onset of this disorder occurs between 45 and 75 years of age, with the average age of onset at about 63 years. Males are affected more often than females.

Related Disorders

Symptoms of the following disorders can be similar to those of progressive supranuclear palsy. Comparisons may be useful for a differential diagnosis.

Corticobasal degeneration (CBD) is a rare progressive neurological disorder characterized by cell loss and shrinkage (atrophy) in certain areas of the brain (cerebral cortex and basal ganglia). The symptoms and signs of this disease resemble some patients with PSP, and some experts believe that CBD and PSP are variations of the same disease. Both are tauopathies. (For more information, choose "corticobasal degeneration" as your search term in the Rare Disease Database.)

Multiple system atrophy (MSA) is a rare progressive neurological disorder characterized by a varying combination of parkinsonism and cerebellar ataxia (poorly coordinated limb movement, unsteady gait and dysarthria). Many patients with MSA also develop impaired function of the autonomic nervous system, which controls blood pressure, heart rate, sweating, the bowels and the urinary bladder. The exact cause of multiple system atrophy is unknown. (For more information, choose "multiple system atrophy" as your search term in the Rare Disease Database.)

Shy-Drager syndrome is simply multiple system atrophy with autonomic failure. Most experts no longer use this term (For more information on this disorder, choose "Shy-Drager" as your search term in the Rare Disease Database.)

Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (rest tremor), muscular stiffness or inflexibility (rigidity), slowness of movement (bradykinesia) and difficulty carrying out voluntary movements (akinesia). Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal from one nerve cell to another in the brain. Parkinson disease progresses much more slowly than PSP and usually is not incapacitating for a decade or more. (For more information on this disorder, choose "Parkinson's" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
The diagnosis of progressive supranuclear palsy may be suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings.

Treatment
Treatment of progressive supranuclear palsy is symptomatic and supportive. There is no cure at the present time. In some cases, drugs used to treat Parkinson disease (antiparkinsonian agents), such as levodopa, may be of some benefit in relieving symptoms the slowness, but the effect is usually limited and temporary. Antidepressant medications are of some benefit in some cases. The use of these drugs should be monitored carefully by a neurologist experienced in their administration.

Walking aids such as a walker weighted in front and wearing shoes with built-up heels may help in preventing affected individuals from falling backwards. Bifocals or special glasses with prisms may be prescribed for some individuals with PSP to treat certain difficulties in eyesight (i.e., difficulty looking down).

When a patient can no longer swallow, a surgical procedure known as percutaneous gastrostomy can be performed, depending upon the patient’s wishes and quality of life. In this procedure, a tube is placed through the skin of the abdomen into the stomach (intestine) to allow for sufficient feeding.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Progressive Supranuclear Palsy Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

REVIEW ARTICLES
Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA. Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol. 2010;23:394-400.
Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009;8:270-279.

Williams DR, Lees AJ, Wherrett JR, Steele JC. J. Clifford Richardson and 50 years of progressive supranuclear palsy. Neurology 2008;70:566-573.

Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta. 2005;1739:240-50.

Pelak VS, Hall DA. Neuro-ophthalmic manifestations of neurodegenerative disease. Ophthalmol Clin North Am. 2004;17:311-20.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Microtubule-Associated Protein Tau; MAPT. Entry No: 157140. Last Updated 09/10/2013. Available at: http://www.ncbi.nlm.nih.gov/omim/ . Accessed Jan 2, 2014.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Supranuclear Palsy, Progressive; 1; PSNP1. Entry No: 601104. Last Updated 05/31/2012. Available at: http://www.ncbi.nlm.nih.gov/omim/ . Accessed Jan 2, 2014.

Report last updated: 2014/01/27 00:00:00 GMT+0