The following
article is adapted from the last chapter of the book
Progressive Supranuclear Palsy, Clinical and Research
Approaches, edited by Irene Litvan and Yves Agid.
This book, published in 1992 by the Oxford University Press
(ISBN 0-19-507229-4) is meant to be a resource tool for the
medical profession. Thus, the terminology used can be difficult
reading for those lacking this background. The book also has had
limited distribution and since it is a medical reference commands
a premium selling price. It is, however, available from
time-to-time on the web in "used" condition. The copy
we have was purchased that way and arrived in an unblemished
condition at about 50% of the cost of a new copy.
If you are truly looking for a good reference covering PSP and
don't mind making the effort to understand what is presented
here, this book is the best reference I've found. I recommend
it highly! I believe it is honest and will answer many of your
questions and perhaps some of your doctor's questions
too.
Ron Ritch
Of all the neurodegenerative diseases, progressive supranuclear palsy (PSP) is certainly among the most formidable. It is devastating to the basal ganglia much as amyotrophic lateral sclerosis is to the spinal cord or Alzheimer’s disease is to the cerebral cortex. The seriousness of the disease is compounded by the absence of an effective treatment for the symptoms, which advance rapidly and irreversibly. Usually called on for opinions concerning atypical parkinsonian syndromes, the neurologist who diagnose PSP is faced with a heavy responsibility. The clinical picture in these immobile and unstable patients, walled in with silent indifference and gazing hieratically, is singular for four reasons: (1) their limited, often nonexistent reactivity to levodopa; (2) the presence of an axially predominating symmetrical bilateral akinetic-rigid syndrome with no sign of tremor; (3) their postural instability with falls; and (4) the evolution of severe symptoms over short periods of time. It is evidently not idiopathic Parkinson’s disease. Faced with this complex degenerative parkinsonian syndrome, the neurologist can immediately diagnose PSP if supranuclear palsy and a frontal syndrome are present. In the absence of dyspraxia (eliminating the possibility of corticobasal degeneration) and dysautonomia (evoking multisystem atrophy), the diagnosis of PSP becomes highly probable, especially given nuchal dystonia in extension, dysarthria with a pseudobulbar palsy, and eyelid-opening apraxia. None of these symptoms, however, is unique to PSP, and the diagnosis must be supported routinely by two additional procedures: (1) a detailed neuropsychological examination demonstrating the presence of a pure and severe frontal syndrome; and (2) a computed tomography scan or, better, a magnetic resonance imaging scan, essentially to eliminate a nondegenerative etiology. The diagnosis of highly probable PSP resulting from such examinations should suffice in general practice, as other curable disorders have been reasonably excluded. In the neurology department, four complementary examinations permit, in my opinion, an essentially certain diagnosis: (1) electrophysiological demonstration of the dissociation between reflex and voluntary eye movements, if it is not clinically evident; (2) polygraph recordings showing insomnia with significantly reduced paradoxical sleep; (3) recording of evoked cognitive potentials showing increased P300 latency and reduced P300 amplitude; and (4) positron emission tomography scans, unfortunately too expensive for routine use, that show a decrease in the number of dopaminergic D2 receptors in the striatum and hypometabolism in the cortex, particularly the frontal lobes. In short, there is an ensemble of symptoms that are characteristic of the disease, when all the signs are apparent; but because none is pathognomonic, prudence is recommended. The diagnoses of striatonigral and corticobasal degenerations remain the most difficult to exclude. Yet how many cases of PSP escape diagnosis at present? How many false diagnoses are still made?
These errors can be corrected by postmortem examination of the brain, as the pattern of brain lesions is as stereotyped as the clinical picture in most cases. Neuronal loss has been shown, however, to be more diffuse than it was thought to be. Once believed to be limited to the basal ganglia and upper brainstem, lesions are now found, albeit to a lesser degree, in the spinal cord, thalamus, and cerebral cortex. It is difficult, if not impossible, to establish precise anatomoclinical correspondences. At most, one can postulate that: (1) destruction of certain pontomesencephalic nuclei (but which ones?) is implicated in supranuclear palsy and perhaps postural instability and some dystonic phenomena; (2) massive dysfunction of the nigrostriatal dopaminergic pathway probably plays a role in the development of the parkinsonian syndrome, but because the structures that ensure output from the basal ganglia are also severely affected it may be the latter that contribute predominantly to the axial akinetic-rigid syndrome; (3) as far as we know today, the frontal syndrome seems to result from denervation of an essentially intact prefrontal cortex by lesions of sub-cortical structures.
Biochemical studies on PSP brains have contributed at least three elements to our knowledge of the disease: (1) the nigrostriatal dopaminergic system is severely affected, whereas the subcorticocortical dopaminergic, noradrenergic, and serotonergic pathways, lesioned in Parkinson’s disease, are roughly intact; (2) the peculiar degeneration of almost all cholinergic systems in the brain, particularly severe in the basal ganglia and brainstem (although sparing the oculomotor nuclei) makes more than any other central nervous system affection, a veritable "disease of central cholinergic nuclei"; (3) the peptidergic (met and leu-enkephalin, neurotensin, cholecystokinin-8, somatostatin) and GABAergic systems (although there is some doubt in the latter case), which constitute the principal efferent pathways from the basal ganglia, are unexpectedly intact. As for the future, should we engage in the laborious biochemical and immunocytochemical inventory of neuronal lesions in PSP? We must, as it is a prerequisite to better understand the anatomophysiological basis of the symptoms. Furthermore, this approach should contribute to elucidation of the functions of the basal ganglia, for which PSP, with its rich clinical symptomatology and precise neuronal lesions, is an interesting model.
In light of the foregoing, it must be admitted that the pathophysiology of PSP is just beginning to be deciphered. The latter is not surprising when one realizes that the disease was practically unknown 25 years ago — which does not mean that it did not exist. More likely, we did not know how to recognize it. It is therefore not an oversight that this book does not contain a chapter on the pathogenesis of PSP - there would be precious little to put into it. To my knowledge, no research group devotes its energies exclusively to this disease, whereas Alzheimer’s and Parkinson’s diseases have attracted more and more attention. Even if one wanted to approach the question of the origin and mechanism of cell death in a disease such as PSP, where would one begin? There is reason to think that the process is degenerative: selective populations of neurons die progressively, more rapidly than during normal aging or even in idiopathic Parkinson’s disease. The regular and irreversible progress of neuronal loss might be imagined to result from two causes: chronic intoxication by an environmental toxin, although preliminary epidemiological studies do not incriminate any particular factor or an endogenous metabolic disorder in which a toxic substance accumulates or a substance essential for cell survival is deficient. The latter hypothesis, which implies a genetic substrate, is, however, no better substantiated than one proposing an environmental cause. The respective roles of genetic and epigenetic factors in the pathogenesis of the disease remain obscure.
If the disease is not hereditary in the strict sense, it does not seem to be of viral, toxic, or autoimmune origin either. As far as we know, the disease cannot be transmitted to nonhuman primates, and histopathological studies do not substantiate the presence of a slow virus. The fact that neurofibrillary tangles (NFTs) have antigenic properties like those found in Alzheimer’s disease, although their ultrastructural morphology is different, invites research to establish the specificity of these markers in PSP. It is certainly a line of research that should be pursued in collaboration with the numerous researchers who study Alzheimer’s disease. Even if the NFTs are only a consequence of cell degeneration, precise identification of their components should permit analysis of the normal or abnormal metabolites that contribute to the chain of events leading to the death of the cell. The questions can be multiplied in this regard. Why are NFTs different in PSP and Alzheimer’s disease? Why do NFTs form in different cell types in the two diseases? Why are they not associated with senile plaques in PSP, whereas these neuropathological stigmata are as characteristic of Alzheimer’s disease as NFTs?
The fact that certain well-characterized groups of neurons, particularly those using acetylcholine as their neurotransmitter, are selectively affected suggest that maybe a specific trophic factor is deficient. Which one? One that is already known such as nerve growth factor or brain-derived neurotrophic factor? One that will be discovered in the years (or months) ahead? It is evident that others’ hypotheses must be explored as well: abnormal accumulation of metals (but preliminary studies have been disappointing in this sense); defective metabolism of xenobiotics; inefficient DNA repair; excess production of free radicals; dysfunction of the mitochondrial respiratory chain. All these hypotheses are being followed up in the search for the mechanism of cell death in Parkinson’s disease. Which hypothesis should we favor? As we have not yet the means to answer such a difficult issue, we might wait until the answers to these questions have been found for the other neurodegenerative diseases being studied. It could happen with surprising rapidity. On the other hand, it could be a rare affection such as PSP that provides the most informative model of cell death. If so, the means for carrying out the appropriate pathophysiological and pathogenic studies must be assembled. It is here that patients who have formed associations throughout the world have a determining role to play, with a hope of finding a treatment for the symptoms of PSP, even a means to prevent the disease or stop its evolution.
A final consideration: Why "progressive supranuclear palsy"? Should this designation be retained for a disease that is not a paralysis and is not always just supranuclear, although it is truly progressive? Moreover, because there is an Alzheimer’s and a Parkinson’s disease, why should there not be a Steele-Richardson-Olszewsky disease? Is it because it is too long to say? Then why not call it SRO disease?
