Progressive supranuclear palsy is a form of atypical parkinsonism (a parkinsonism-plus syndrome), which means that it shares some features with Parkinson's disease such as stiffness of neck and trunk muscles (rigidity), slowness of movement (bradykinesia), and impaired balance. Its most characteristic feature is a specific pattern of abnormal eye movement. PSP was first described in 1964 by Drs. Steele, Richardson, and Olszewski. It occurs more often in men, and the age at onset is typically in the 60's, roughly ten years later than the usual onset of classic Parkinson's disease. Up to 6 in 100,000 people develop PSP.
Symptoms and Signs
Impaired balance is the most disabling symptom of PSP. Instability and falls are caused by a combination of problems: loss of postural (adjustment) reflexes, difficulty lifting one's feet ("freezing") particularly when turning, stiffness of neck and trunk muscles, slowness of movement, and inability to look down at the floor are the major factors that lead to frequent falls and injuries. After an average of 5-8 years, worsening balance usually makes walking (ambulation) very difficult, if not impossible. Patients also have trouble standing from a sitting position and slump forcefully into a chair when sitting down. PSP patients may develop slurred and monotonous speech, trouble swallowing, and episodes of inappropriate laughter and crying, also known as pseudobulbar affect and emotional incontinence of lability. They often acquire a peculiar "worried" or "surprised" facial expression, but despite this appearance, most patients retain relatively normal thinking and memory function until the more advanced stages of the disease. Unlike classic Parkinson's disease, tremor is rarely a prominent part of PSP. PSP affects the brain regions which control vertical gaze (eye movement up and down). Difficulty moving one's eyes in the downward direction is particularly suggestive of the disorder. Patients usually do not complain of abnormal eye movements, although they may notice blurring of vision and problems reading. Many PSP patients become messy eaters because they are unable to look down at their plate, coupled with involuntary eye closure (blepharospasm) and impaired hand coordination. PSP often overlaps in clinical and pathological features with cortico-basal syndrome, and "pure akinesia with gait freezing." PSP with cortico-basal syndrome mimics cortico-basal degeneration (CBD), another atypical parkinsonism disorder, characterized by unilateral or asymmetric limb apraxia, dystonia and rigidity, and a variety of other motor and cognitive/behavioral symptoms.
Most patients with PSP are initially diagnosed with Parkinson's disease, but when the atypical features, particularly early falls and abnormal eye movements emerge, the correct diagnosis becomes apparent. There is no diagnostic test for PSP, but neuroimaging with MRI (a brain scan) often shows characteristic shrinkage (atrophy) of the brain, especially prominent in the midbrain, a rostral segment of the brainstem. Testing may be useful to document sleep disturbances and changes in other physiological parameters, but these are not yet suited to aid in diagnosis.
The cause of PSP is still not fully understood, but pathological changes noted on autopsy examination have provided insights into the mechanisms of brain cell loss (neurodegeneration). Like many other neurodegenerative diseases, patients with PSP accumulate misfolded proteins within specific brain cells. In PSP, cells within the basal ganglia and some brainstem structures are most severely affected. Recent studies have focused on mishandling of tau, a protein that normally acts to stabilize the cellular skeleton of nerve cells. Faulty processing of tau may impair mitochondria, the compartment of cells responsible for energy production, and thus lead to brain cell death. Besides the typical, idiopathic PSP, there are variants of the disease, such as the one found on the island of Guam. Some patients with the typical features of PSP are found at autopsy to have multiple, tiny strokes rather than "tauopathy." Patients with this vascular form of PSP usually have stroke risk factors and evidence of vascular disease on MRI. PSP is usually not an inherited condition.
In the early stages of PSP, levodopa and drugs that act directly on dopamine receptors (dopamine agonists) may partially improve parkinsonian symptoms, such as slowness of movement, but these drugs rarely provide any meaningful improvement in balance, eye, speech and swallowing problems. Davunetide, an experimental neurotrophic factor administered as nasal spray, is currently being investigated at Baylor College of Medicine.
Antidepressant medications and Nuedexta™, dextromethorphan/quinidine (DM/Q) are sometimes useful, particularly in controlling emotional lability (also known as pseudobulbar affect of emotional incontinence). Blepharospasm, which occurs occasionally in PSP, can sometimes be effectively treated with injections of botulinum toxin into the eyebrows and eyelids.
Non-drug treatments of PSP include physical therapy and stretching exercises designed to relieve rigidity and to prevent contractures and deformities as well as to maintain good strength and condition of muscles. Devices which make walking safer, such as a walker that is weighted in the front, can be helpful. Shoes with built-up heels can also help decrease falling backwards. Since patients have difficulty looking down, low objects like coffee tables and throw rugs are best avoided. Because of swallowing problems some patients require placement of a feeding tube directly into the stomach in order to maintain adequate nutrition and prevent aspiration pneumonia. If general health and nutrition can be maintained, some PSP patients can live for 10 years or longer after the onset of symptoms, although their quality of life in the advanced stages of the disease is usually significantly impaired.
At present, there are no therapies that can reverse or even slow the progression of PSP. Furthermore, since PSP is quite rare, clinical drug trials are sometimes not available for affected patients. Nonetheless, there is reason for hope. Because the biology of PSP may be related to other neurodegenerative diseases, it is possible that therapies designed for other conditions will also prove helpful for patients with PSP. Currently, studies on agents targeting tau dysfunction such as tau kinase inhibitors, tau aggregation inhibitors and microtubule stabilizers and agents targeting mitochondrial dysfunction are in preparation or ongoing.
Ashour R, Jankovic J. Joint and skeletal deformities in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Mov Disord. 2006;21:1856-63.
Azher SN, Jankovic J. Clinical aspects of progressive supranuclear palsy. In: Litvan I, Duyckaerts C, eds. Handbook of Clinical Neurology, 3rd ed., Elsevier, Amsterdam, 2008;89:461-73.
Brodsky H, Vuong KD, Thomas M, Jankovic J. Glabellar and palmomental reflexes in parkinsonian disorders. Neurology. 2004;63:1096-8.
Fahn S, Jankovic J, Hallett M. Principles and Practice of Movement Disorders, Churchill Livingstone, Elsevier, Philadelphia, PA, 2011:1-548. (Includes on-line videos and references.)
Golbe LI, Ohman-Strickland PA. A clinical rating scale for progressive supranuclear palsy. Brain. 2007;130:1552-65.
Hasegawa M, Arai T, Akiyama H, et al. TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain. 2007;130:1386-94.
Höglinger GU, Melhem NM, Dickson DW, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011;43:699-705.
Jankovic J, Shannon KM. Movement disorders. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice, 5th ed., Butterworth-Heinemann (Elsevier), Philadelphia, PA, 2008.
Jankovic J, Tolosa E, eds. Parkinson's Disease and Movement Disorders, 5th ed., Lippincott Williams and Wilkins, Philadelphia, PA, 2007:1-720. (Accompanied by a CD video atlas.)
Josephs KA, Dickson DW. Diagnostic accuracy of progressive supranuclear palsy in the Society for Progressive Supranuclear Palsy brain bank. Mov Disord. 2003;18:1018-26.
Kaat LD, Boon AJ, Azmani A, et al. Familial aggregation of parkinsonism in progressive supranuclear palsy. Neurology. 2009;73:98-105.
Levy R. Progressive supranuclear palsy: what's new? Geriatr Psychol Neuropsychiatr Vieil. 2011;9(2):191-201.
Litvan I, Agid Y, Jankovic J, et al. Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology. 1996;46:922-30.
Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural history of progressive supranuclear palsy: A clinical cohort study. Neurology. 2003;60:910-6.
Osaki Y, Ben-Shlomo Y, Lees AJ, et al. Accuracy of clinical diagnosis of progressive supranuclear palsy. Mov Disord. 2004;19:181-9.
Pearce JM. Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): a short historical review. Neurologist. 2007;13:302-4.
Sitburana O, Ondo WG. Brain magnetic resonance imaging (MRI) in Parkinsonian disorders. Parkinsonism Relat Disord. 2009;15:165-74.
Stamelou M, de Silva R, Arias-Carrión O, et al. Rational therapeutic approaches to progressive supranuclear palsy. Brain. 2010 ;133(Pt 6):1578-90.
Wenning GK, Krismer F, Poewe W. New insights into atypical parkinsonism. Curr Opin Neurol. 2011;24:331-8.
Williams DR, Holton JL, Strand C, et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain. 2007;130:1566-76.
Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol. 2009;8:270-9.
Wu LJC, Sitburana O, Davidson A, Jankovic J. Applause sign in parkinsonian disorders and Huntington's disease. Mov Disord. 2008;23:2307-11.