PARKINSONISM, described in its entirety over one hundred and fifty years ago,’ rarely presents itself as a diagnostic problem. In consequence, little scrutiny has been directed to the marked variability of this frequently encountered neurological syndrome and to the progression of the disease in large groups of patients. As with most chronic neurological disorders, marked diversity can be expected to exist in age and mode of onset, relative prominence of the cardinal signs and symptoms, rate of progression, and resultant degree of functional impairment. Controversy over the effectiveness of therapeutic measures for parkinsonism is due partially to this wide variability and to the paucity of clinical information about the natural history of the syndrome. It is also re-

https://n.neurology.org/content/neurology/17/5/427.full.pdf

Parkinsonism: Onset, progression, and mortality

Objective: Parkinson’s disease (PD) is a progressive neurological disorder characterised by a large number of motor and non-motor features that can impact on function to a variable degree. This review describes the clinical characteristics of PD with emphasis on those features that differentiate the disease from other parkinsonian disorders. Methods: A MedLine search was performed to identify studies that assess the clinical characteristics of PD. Search terms included “Parkinson’s disease”, “diagnosis” and “signs and symptoms”. Results: Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on clinical criteria. Rest tremor, bradykinesia, rigidity and loss of postural reflexes are generally considered the cardinal signs of PD. The presence and specific presentation of these features are used to differentiate PD from related parkinsonian disorders. Other clinical features include secondary motor symptoms (eg, hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes), non-motor symptoms (eg, autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain). Absence of rest tremor, early occurrence of gait difficulty, postural instability, dementia, hallucinations, and the presence of dysautonomia, ophthalmoparesis, ataxia and other atypical features, coupled with poor or no response to levodopa, suggest diagnoses other than PD. Conclusions: A thorough understanding of the broad spectrum of clinical manifestations of PD is essential to the proper diagnosis of the disease. Genetic mutations or variants, neuroimaging abnormalities and other tests are potential biomarkers that may improve diagnosis and allow the identification of persons at risk.

https://jnnp.bmj.com/content/jnnp/79/4/368.full.pdf

Parkinson’s disease: clinical features and diagnosis

After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mds.21956

The Sydney Multicenter Study of Parkinson's Disease : The Inevitability of Dementia at 20 years

I greatly appreciate the honor you have bestowed by inviting me to give this year’s Robert Wartenberg Lecture, and I would like to take the opportunity to thank my many friends and colleagues in the American Academy of Neurology for their unfailing hospitality and kindness on every occasion that I have visited your continent. Although I never had the pleasure of meeting Robert Wartenberg, curiously, he had a profound influence on my decision to enter neurology. The late Professor Dai Davies, professor of anatomy at St. Thomas’ Hospital Medical School, sensing my interest in the nervous system, lent me his personal copies of Wartenberg’s Examination of Reflexes, Gordon Holmes’ second edition of Introduction to Clinical Neurology, and Wilder Penfield and Theodore Rasmussen’s Cerebral Cortex of Man. At that stage, in the late 1950s, I stepped sideways from the mainstream of medical education into the research laboratory to try to discover why the substantia nigra was black! In my naivete, I thought that this must constitute some clue to the function of this region of the brain, and I even believed, and still do believe, that neuromelanin holds the key to the cause of Parkinson disease. My interest in the basal ganglia was born then and persisted ever after. Naturally I have been led, as many were before, to seek the functions of this mysterious region of the brain. Kinnier Wilson,’ in his Croonian Lectures of 1925, was forced to conclude that “the ganglia situated in the base of the brain still, to a large extent, retain the characteristic of basementsviz., darkness.” What light has been shed over the next 75 years into these dark basements of the brain? Stimulated by the discovery of the importance of dopamine in Parkinson disease, the last decade has witnessed an explosion of research into all aspects of basal ganglia activity. Neuroscientists from many disciplines, all bringing individual skills and philosophies to bear on the problem, have speculated on their function. The classical clinician’s view, based on Kinnier Wilson’s2 discovery of the disease that bears his name and on the careful clinicopathologic correlation that followed, that this region is part of the motor system, has been attacked as narrow-minded. Some physiologists and psychologists, impressed by the wealth of input from virtually all areas of the cerebral cortex into the basal ganglia, have speculated that these regions may exert much wider functions in sensory and “cognitive” domains as well as in the motor sphere. I intend to examine that thesis in the light of clinical evidence. My conclusion is that, as far as that evidence goes, the basal ganglia should still be regarded as organs of motor control. The next question is, what do the basal ganglia contribute to motor organization? Again, I will tackle the problem from the standpoint of clinical evidence to conclude with the hypothesis that the basal ganglia are responsible for the automa= execution of learned motor plans. What clinical material gives the clue t o normal basal ganglia function? Based on present anatomic knowledge, I believe that Parkinson disease comes closest to providing evidence on the consequences

The mysterious motor function of the basal ganglia The Robert Wartenberg Lecture

Parkinsonism is a clinical syndrome comprising combinations of motor problems-namely, bradykinesia, resting tremor, rigidity, flexed posture, "freezing," and loss of postural reflexes. Parkinson's disease (PD) is the major cause of parkinsonism. PD is a slowly progressive parkinsonian syndrome that begins insidiously and usually affects one side of the body before spreading to involve the other side. Pathology shows loss of neuromelanin-containing monoamine neurons, particularly dopamine (DA) neurons in the substantia nigra pars compacta. A pathologic hallmark is the presence of cytoplasmic eosinophilic inclusions (Lewy bodies) in monoamine neurons. The loss of DA content in the nigrostriatal neurons accounts for many of the motor symptoms, which can be ameliorated by DA replacement therapy-that is, levodopa. Most cases are sporadic, of unknown etiology; but rare cases of monogenic mutations (10 genes at present count) show that there are multiple causes for the neuronal degeneration. The pathogenesis of PD remains unknown. Clinical fluctuations and dyskinesias are frequent complications of levodopa therapy; these, as well as some motor features of PD, improve by resetting the abnormal brain physiology towards normal by surgical therapy. Nonmotor symptoms (depression, lack of motivation, passivity, and dementia) are common. As the disease progresses, even motor symptoms become intractable to therapy. No proven means of slowing progression have yet been found.

Description of Parkinson's disease as a clinical syndrome.

PREFACE The advantages which have been derived from the caution with which hypothetical statements are admitted, are in no instance more obvious than in those sciences which more particularly belong to the healing art. It therefore is necessary, that some conciliatory explanation should be offered for the present publication: in which, it is acknowledged, that mere conjecture takes the place of experiment; and, that analogy is the substitute for anatomical examination, the only sure foundation for pathological knowledge. When, however, the nature of the subject, and the circumstances under which it has been here taken up, are considered, it is hoped that the offering of the following pages to the attention of the medical public, will not be severely censured. The disease, respecting which the present inquiry is made, is of a nature highly afflictive. Notwithstanding which, it has not yet obtained a place in the classification of nosologists; some have regarded its characteristic symptoms as distinct and different diseases, and others have given its name to diseases differing essentially from it; whilst the unhappy sufferer has considered it as an evil, from the domination of which he had no prospect of escape. The disease is of long duration: to connect, therefore, the symptoms which occur in its later stages with those which mark its commencement, requires a continuance of observation of the same case, or at least a correct history of its symptoms, even for several years. Of both these advantages the writer has had the opportunities of availing himself, and has hence been led particularly to observe several other cases in which the disease existed in different stages of its progress. By these repeated observations, he hoped that he had been led to a probable conjecture as to the nature of the malady, and that analogy had suggested such means as might be productive of relief, and perhaps even of cure, if employed before the disease had been too long established. He therefore considered it to be a duty to submit his opinions to the examination of others, even in their present state of immaturity and imperfection. To delay their publication did not, indeed, appear to be warrantable. The disease had escaped particular notice; and the task of ascertaining its nature and cause by anatomical investigation, did not seem likely to be taken up by those who, from their abilities and opportunities, were most likely to accomplish it. That these friends to humanity and medical science, who have already unveiled to us many of the morbid processes by which health and life is abridged, might be excited to extend their researches to this malady, was much desired; and it was hoped, that this might be procured by the publication of these remarks. Should the necessary information be thus obtained, the writer will repine at no censurewhich the precipitate publication of mere conjectural suggestions may incur: but shall think himself fully rewarded by having excited the attention of those, who may point out the most appropriate means of relieving a tedious and most distressing malady.

Parkinson James

Papers

An Essay on the Shaking Palsy