Elsevier

The Lancet Neurology

Volume 1, Issue 6, October 2002, Pages 359-369
The Lancet Neurology

Review
Progressive supranuclear palsy: where are we now?

https://doi.org/10.1016/S1474-4422(02)00161-8Get rights and content

Summary

This review provides an update on progressive supranuclear palsy (PSP, or Steele-Richardson-Olszewski disease), an adult-onset neurodegenerative disorder characterised by early postural instability, which leads to falls, and a vertical supranuclear-gaze palsy. Recent epidemiological studies have shown that the disorder is more common than previously recognised, that it is commonly misdiagnosed, and that it may present to a wide range of hospital specialists. The diagnosis of PSP hinges on clinical acumen. Attempts to identify a suitable biomarker in the CSF or a specific and sensitive imaging or neurophysiological technique have so far failed to have a significant effect on the diagnostic process. Better understanding of the molecular pathology of PSP has highlighted the importance of tau-protein accumulation and tau-genotype susceptibility in its pathogenesis. No drug treatment significantly and consistently benefits patients, and novel therapies are urgently required.

Section snippets

Historical perspective

Larner1 recently made the intriguing suggestion that Charles Dickens was the first to describe a person with classic PSP in 1857 in his novel The Lazy Tour of Two Idle Apprentices: “A chilled, slow, earthy, fixed old man. A cadaverous man of measured speech. An old man who seemed as unable to wink, as if his eyelids had been nailed to his forehead. An old man whose eyes—two spots of fire—had no more motion that [sic] if they had been connected with the back of his skull by screws driven through

Descriptive epidemiological studies

Bower and colleagues3 studied the incidence of PSP over a 14 year period in Olmsted County, MN, USA. 16 incident cases were identified, and none developed before age 50 years. The average annual incidence for ages 50–99 years was 5·3 per 100 000.

Only three studies have directly addressed the prevalence of PSP.4, 5, 6 Table 1 summarises these studies, together with other estimates of the prevalence.7, 8, 9 In the latter, standard diagnostic criteria were not used, and the primary aim of the work

Referral patterns and misdiagnosis of PSP

Age at onset of PSP is characteristically between 60 and 65 years, with no significant difference between the sexes. The median time from disease onset to death is 5·8–5·9 years.11, 12 The mean interval from symptom onset to diagnosis ranges from 3·6 to 4·9 years; thus, many patients with PSP may remain misdiagnosed for much of their disease course.4

Primary-care diagnoses on hospital referral vary widely, and include Parkinson's disease (30%), balance disorders (20%), stroke (10%), and

Diagnostic criteria and clinical heterogeneity

Postural instability, leading to falls (typically backwards) within the first year after disease onset, and a vertical supranuclear-gaze paresis have good discriminatory diagnostic value when PSP is compared with other degenerative parkinsonian syndromes.16 Recently devised diagnostic criteria (National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy [NINDS–SPSP]; panel) rely heavily on these clinical features, together with the fact that no patient

Investigations

The diagnosis of PSP still rests on the clinical history and examination. Attempts have been made, however, to improve diagnostic accuracy through analysis of CSF and protein biomarkers, structural and functional imaging, and neurophysiological techniques.

Pathology

PSP is characterised pathologically by the destruction of several subcortical structures, including the substantia nigra, globus pallidus, subthalamic nucleus, and midbrain and pontine reticular formation.73 Deeper cortical layers, especially around the precentral gyrus, can also be affected to a lesser degree.74 Large numbers of neurofibrillary tangles (made up of ultramicroscopic straight filaments), neuropil threads, and tufted astrocytes are also found within these brain regions (figure 2).

Treatment

Drug treatment for PSP is inadequate, and fundamental breakthroughs in our understanding of the pathogenesis may be needed before real advances are seen. The widespread neuronal loss in the disorder suggests that a neurotransmitter-specific approach, such as replacement or reuptake inhibition, is unlikely to succeed.115 A small review of 12 patients with pathologically proven PSP concluded that use of levodopa, dopamine agonists, amantadine, tricyclic antidepressants, anticholinergic agents,

Conclusion

Despite greater awareness in recent years, many patients with PSP remain undiagnosed or misdiagnosed for much of the duration of their disease. The role of tau protein in the pathophysiological process, and the establishment of a slight genetic predisposition, have stimulated research. Studies on a cluster of a PSP-like disorder in Guadeloupe have produced new clues for potential environmental toxins. If the fundamental pathophysiological process in PSP is overproduction of four-repeat tau, a

Search strategy and selection criteria

Material for this review was found by searches of PubMed in May 2002, with the keywords “progressive supranuclear palsy”. The search was limited to articles published in English entered in the database since mid-1997. Historical references were added where appropriate and not according to any particular search strategy.

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