What is progressive supranuclear palsy?
By David R Williams PhD, FRACP
Van Cleef Roet Centre for Nervous Diseases, Monash University, Melbourne
It is perhaps surprising that the clinical syndrome of progressive supranuclear palsy (PSP) was not recognized as a discrete nosological entity prior to J Clifford Richardson's first description in 1963.1 Although patients with the classic quadriad of postural instability, supranuclear gaze palsy, axial rigidity and subcortical cognitive dysfunction had almost certainly been seen by neurologists prior to 1963, they were probably diagnosed with formes frustes Parkinson's disease, post-encephalitic parkinsonism or vascular Parkinsonism.2 Richardson had been trained as a neurologist at the National Hospital for Nervous Diseases, Queen Square where he was strongly influenced by Gordon Holmes and Charles Symonds. Like his British mentors he took time to carefully elucidate the clinical features and the progression of disease in his patients. These traits alerted him to the unique disease that unfolded in seven of his patients, including one close friend, during the second half of the 1950s.3 He observed and described an unusual constellation of signs which included "a vertical supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, dystonic rigidity-in-extension of the neck, and mild dementia."3
By the early 1960s six of these patients had died and a pathological diagnosis of post-encephalitic parkinsonism (PEP) was made in all of them, but Richardson did not agree with this conclusions. He pointed out that none of the patients had a history of preceding encephalitis, the clinical syndrome did not include parkinsonism or oculogyric crises and was relentlessly progressive, quite unlike PEP. The pathological material was reviewed and studied by the neurology resident, John Steele and the Professor of Neuropathology, Jerzy Olszewski. These studies revealed severe brainstem neurofibrillary degeneration and gliosis. In their 1964 manuscript "Progressive supranuclear palsy", Steele and colleagues defined the clinical and pathological hallmarks or PSP and compared it to similar conditions: PEP, Hirano's parkinsonism-dementia complex of Guam and Alzheimer's disease.3 They made clear distinctions between these conditions and PSP however, even today, the pathological boundaries between these diseases remain somewhat blurred and they are all related by the common pathological characteristic of insoluble tau protein accumulation.4
With great foresight Steele, Richardson and Olszewski recognized that "further observations may broaden the clinical spectrum of the disease".3 As defined pathologically, PSP can be reliably associated with at least three different clinical syndromes, which seem to be related to different degrees of pathological severity: 1) Richardson's syndrome (RS), or "classic" PSP, presents as a gradual onset of postural instability and falls within the first two years of disease, along with vertical supranuclear gaze palsy, a frontal dysexecutive syndrome, and rigidity and bradykinesia that is unresponsive to levodopa. Patients who present in this way typically live for a median of six years, and have the most severe pathological abnormalities.5 2) PSP-Parkinsonism (PSP-P) represents a smaller group of patients where Parkinsonism dominates the early clinical picture, and disability appears to progress much more slowly. These patients present with limb bradykinesia, rigidity and in some cases tremor and are commonly mislabelled as Parkinson's disease. Asymmetry of limb signs is seen in some cases. Axial rigidity is often a striking early feature, limb rigidity is more common and severe than in RS where muscle tone may be normal. Some have a jerky postural tremor and even a 4 to 6Hz rest tremor.6-8 A "moderate" or "good" improvement in parkinsonism follows initiation of L-dopa in a proportion of the patients and secondary unresponsiveness occurring over a few years is usual.6 PSP-P can be separated from RS on the grounds of a different clinical picture in the first two years of disease, but clinical overlap occurs and after six years of follow up the clinical phenomenology may become similar.7 In PSP-P the median disease duration is around 10 years. It should be emphasised that few patients classified as PSP-P have the full hand of clinical features, but are classified this way because Parkinsonism is more conspicuous than RS (postural instability, falls, cognitive decline and eye movement abnormalities) in the first two years.7 A number of clinical features may aid in the clinical diagnosis of PSP-P, but in many cases it is difficult to separate these patients from idiopathic Parkinson's disease.(Table) 3) Pure akinesia with gait freezing (PAGF) is a rare presentation of PSP-tau pathology. Patients present with a gradual onset of unsteadiness or slowness of gait initially and hypophonia, which then progresses to gait freezing and start hesitation, but in the absence of limb rigidity and tremor. These patients do not have a sustained response to levodopa. Dementia and ophthalmoplegia are absent in the first five years of disease. In PAGF the median disease duration is around 10 years, and pathological changes is more restricted in its distribution9. 4) Clinicopathological series have shown that some patients with PSP-tau pathology present with a corticobasal syndrome, progressive non-fluent aphasia or apraxia of speech.10, 11
PSP appears to exist amongst a spectrum of primary tauopathies. RS remains readily identifiable but others with similar pathological lesions experience different clinical presentations, presumably due to differences in the distribution of that pathology. PSP-P, pure akinesia with gait freezing, corticobasal syndrome and progressive non-fluent aphasia appear to represent clinical manifestations of PSP-tau pathology that differ clinically and prognostically from RS. By pathological definition these patients have PSP, but in the interests of precision the neurologist should attempt to delineate these patients clinically.
|Richardson's syndrome||PSP-Parkinsonism||Pure akinesia with gait freezing||PSP-CBS||PSP-PNFA||Parkinson's disease|
|Rigidity||Axial>>Limb||Axial< or =Limb||Axial||Yes||Sometimes||Limb>>Axial|
|Tremor||No||Yes/No (Rest or jerky postural)||No||No||No||Yes (Rest)|
|Early postural instability||Yes||No||Yes||No|
|Early cognitive decline||Often||No||No||No||Yes||No|
|Early eye movement abnormalities||Sometimes||No||No||No||Sometimes||No|
|Response to levodopa||No||Often||No||No||No||Usually|
- Williams DR, Lees AJ, Wherrett JR, Steele JC. J. Clifford Richardson and 50 years of progressive supranuclear palsy. Neurology 2008;70(7):566-573.
- Brusa A, Stoehr R, Pramstaller PP. Progressive supranuclear palsy: new disease or variant of postencephalitic parkinsonism? Mov Disord 2004;19(3):247-252.
- Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical supranuclear gaze and pseudobulbar palsy, nuchal dystonia and dementia. ArchNeurol 1964;10:333-359.
- Williams DR. Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. InternMedJ 2006;36(10):652-660.
- Williams DR, Holton J, Strand C, et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain 2007;130(6):1566-1576.
- Birdi S, Rajput AH, Fenton M, et al. Progressive supranuclear palsy diagnosis and confounding features: report on 16 autopsied cases. Mov Disord 2002;17(6):1255-1264.
- Williams DR, de Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 2005;128(Pt 6):1247-1258.
- Kaat LD, Boon AJ, Kamphorst W, Ravid R, Duivenvoorden HJ, van Swieten JC. Frontal presentation in progressive supranuclear palsy. Neurology 2007;69(8):723-729.
- Ahmed Z, Josephs KA, Gonzalez J, DelleDonne A, Dickson DW. Clinical and neuropathologic features of progressive supranuclear palsy with severe pallido-nigro-luysial degeneration and axonal dystrophy. Brain 2008;131(Pt 2):460-472.
- Josephs KA, Boeve BF, Duffy JR, et al. Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia. Neurocase 2005;11(4):283-296.
- Tsuboi Y, Josephs KA, Boeve BF, et al. Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 2005;20(8):982-988.
About Dr. David Williams, PhD
Dr. David Williams graduated from Monash University in 1995. He trained in neurology in Melbourne and as a Research Fellow at the National Hospital for Neurology and Neurosurgery in London from 2003 to 2006. During that time he worked at the Queen Square Brain Bank with Prof. Andrew Lees and completed a PhD at University College London on "Clinical, pathological and biochemical diversity in progressive supranuclear palsy." He has been awarded the American Academy of Neurology Founders Prize (2004), The Movement Disorder Society Junior Award (2004), The Queen Square Prize (2007) and the Leonard Cox award (2007). Dr. Williams works in Melbourne at the Van Cleef Roet Centre for Nervous Diseases, Monash University and is Director of The Movement Disorders Program at The Alfred Hospital. His team's current research interests include functional neurosurgery and deep brain stimulation, atypical Parkinsonism and clinicopathological correlations that involve collaborations with teams in Sydney, London, Italy and North America.