Melvin D. Yahr

Parkinsonism onset, progression, and mortality

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-

Parkinsonism: Effects of levodopa treatment on concept formation

Concept formation was compared in 71 parkinsonian patients and 35 controls matched for age and WAIS verbal IQ. It was found that the patients formed significantly fewer concepts, as measured by the Wisconsin Card Sorting Test (WCST). The patients had difficulties in shifting sets and were unable to attend to the completion of a concept. Levodopa-treated patients were able to produce more correct responses, but were still unable to maintain the correct responses to produce more correct concepts than non-levodopa-treated patients. The behavior of the parkinsonian patients on the WCST is similar to that of patients who have undergone frontal lobectomy. In addition, the results indicate that levodopa therapy may improve “vigilance,” without increasing the patients overall cognitive ability.

Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha‐adrenergic agonist (midodrine)

The therapeutic efficacy of midodrine, an alpha-adrenergic agonist that does not cross the blood-brain barrier, was investigated in a double-blind crossover trial in seven patients with orthostatic hypotension due to autonomic failure. We identified two groups of patients: those in whom upright mean arterial pressure significantly increased (group I, n = 3) and those in whom upright mean arterial pressure decreased (group II, n = 4) during midodrine treatment. Body weight changed in a parallel manner with upright blood pressure, increasing in patients of group I and decreasing in patients of group II (p < 0.05). Autonomic cardiovascular reflexes were significantly more impaired in patients of group II than in patients of group I. We conclude that midodrine is effective in the treatment of orthostatic hypotension only in those patients with significant preservation of autonomic reflexes. Conversely, in patients with markedly impaired baroreceptor mechanisms, treatment with midodrine may produce extracellular fluid volume depletion and exacerbate orthostatic hypotension.

Hypotension‐induced vasopressin release distinguishes between pure autonomic failure and multiple system atrophy with autonomic failure

To investigate whether activation of afferent and central baroreceptor pathways could differentiate between pure autonomic failure (PAF) and multiple system atrophy with autonomic failure (MSA), we determined the effect of upright tilt on circulating levels of vasopressin in patients with PAF and patients with MSA. We also studied 14 normal subjects, nine of whom developed acute hypotension due to vasovagal syncope. In patients with PAF and in normal subjects with vasovagal syncope, upright tilt induced marked hypotension and a pronounced increase in the plasma concentration of vasopressin (1.1 ± 0.3 to 38.0 ± 8.0 pmol/l in PAF and 1.0 ± 0.2 to 27.4 ± 7.2 pmol/l in vasovagal syncope, p < 0.005 for both). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin increased little (0.5 ± 0.1 to 1.5 ± 0.3 pmol/l, p < 0.05). During upright tilt, the plasma concentration of norepinephrine significantly increased in normal subjects but did not increase in patients with autonomic failure. Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are normal in patients with PAF but are impaired in patients with MSA. Thus, measurement of baroreceptor-mediated vasopressin release appears to provide a clear marker to differentiate between patients with PAF and patients with MSA.

Overview of present day treatment of Parkinson's disease.

In the light of present day knowledge, augmenting striatal dopaminergic activity is the most effective means for controlling the symptoms of parkinsonism. This is best accomplished by the administration of levodopa with a peripheral decarboxylase inhibitor. However, limitations in its benefits develop after long-term administration in a substantial number of patients. In an attempt to overcome these a number of pharmacological agents acting on striatal dopaminergic mechanisms have undergone clinical trial. Of those tried Deprenyl, an MAO-B inhibitor, given with levodopa and carbidopa has shown the most promise. Preliminary results in 35 patients indicate that it is useful in diminishing the incidence of “on-off” phenomena—one of the most limiting reactions to levodopa—as well as enabling some patients to recoup their loss of therapeutic benefits. Though far from resolving all of the therapeutic difficulties encountered with prolonged use of levodopa, it appears to be a valuable adjunctive agent for the long-term problem patient.

POSTERIOR FOSSA ANEURYSMS.

POSTERIOR FOSSA ANEURYSMS are often said to represent about 15% of intracranial aneurysms. They comprised about 21% of the 1,023 cases collected by McDonald and Korbl in their review of the literature from 1756 to 1939. However, a considerable number of the vertebral and basilar aneurysms referenced in their bibliographic survey are not true aneurysms but diffuse ectasias involving the entire vertebral or basilar artery. Twenty-one or 16% of Dandy’s2 series of 133 intracranial aneurysms were located in the posterior fossa, but 11 were in fact diffuse ectasias which he had encountered in the course of a large number of suboccipital craniectomies performed for the treatment of trigeminal neuralgia or MeniBre’s syndrome.3 An example illustrated in his pioneering monograph shows a dilated vertebral artery which together with a tortuous and dilated basilar artery formed a wide S shaped curve. Whatever the clinical and pathological significance of such ectatic vessels may be, it is certainly quite different from that of saccular or berry aneurysm which by definition represents a dilation of a short segment of a vessel. There would seem to be little justification for confounding the two lesions. Probably the best estimate of the relative incidence of posterior fossa aneurysm may be obtained from the several comprehensive postmortem studies of intracranial aneurysm reported over the past decade (Table 1 ) . These indicate that approximately 8% of intracranial aneurysms occur in the posterior fossa. With improvements in technique, arteriographic study of the vertebral-basilar arterial tree has become an established diagnostic procedure in the past decade.10 Indeed, in many centers, it has become routine to visualize these vessels in cases of subarachnoid hemorrhage particularly when carotid arteriosgraphy does not show a lesion. Consequently, posterior fossa aneurysms, which previously were identified only at autopsy or encountered unexpectedly at operation for suspected tumor, are now regularly recognized during life. An increasing clinical awareness and a growing accumulation of operative cases have recently focused attention on aneurysms in this location. However, infratentorial aneurysms are relatively infrequent, and few clinicians have had experience with more than a random case or two. Moreover, the bulk of the literature is based on autopsy material. The recent review by Hook and associates of 28 cases representing all the posterior fossa aneurysms seen over a period of nearly thirty years in two Swedish clinicsll is the first sizable collection of unselected cases reported to date. With a view to obtaining further data on which to base a general picture of the clinical manifestations and natural history of posterior fossa aneurysms, we collected all the cases of infratentorial saccular aneurysms which had been identified at the Columbia-Presbyterian Medical Center since its opening in 1931. Only true saccular aneurysms or dilations of short segments of the involved artery were reviewed; fusiform enlargements or diffuse ectasias involving long segments or the entire vertebral or basilar artery were excluded. A total of 27 cases were available for study. The first 6 cases were found at autopsy in the ears 1931 to 1953. The first antemortem diagnosis was made by pneumoencephalography in 1955 (case 7) and was confirmed subsequently by autopsy. Subarachnoid hemorrhage in case 8 was ascribed to a supratentorial vascular anomaly; a ruptured basilar artery aneurysm was an unexpected finding at autopsy. Vertebral arteriography has been regularly

Impaired oxidative decarboxylation of pyruvate in fibroblasts from patients with Parkinson's disease

SummaryWhether or not a reported deficiency in brain mitochondrial complex I activity in Parkinsons disease represents a defect encompassing other organs or tissues has been a source of some controversy. We have examined mitochondrial respiration in fibroblasts from patients with Parkinsons disease by measuring the oxidative decarboxylation of [2-14C]pyruvate and [1,4-14C]succinate. We report that oxidation of pyruvate but not succinate was significantly reduced in fibroblasts from Parkinson patients when compared to healthy controls. These observations support the view that a widespread deficit in mitochondrial respiration exists in Parkinsons disease. Fibroblast cultures, moreover, are a source of affected proliferating cells, which can be used for in vitro studies of the nature of the respiratory defect and for testing of pharmacological interventions to correct the deficiency.

A double‐blind, placebo‐controlled trial of TRH in amyotrophic lateral sclerosis

A double-blind, placebo-controlled trial of single doses of thyrotropin releasing hormone (TRH) was performed on 12 patients with amyotrophic lateral sclerosis. Each patient was given subcutaneous injections of TRH 150 mg or placebo, and IV infusions of TRH 500 mg or placebo at 72-to 96-hour intervals. Eight motor and functional ratings were scored at regular intervals after each injection. Side effects were seen in all patients and were obvious to patients and examiners, making true blinding impossible. Nevertheless, statistically significant improvement was seen only in dynametric strength 1 hour after subcutaneous injection (p <0.05). Significant improvement occurred, in one patient only, on subjective speech testing during IV infusion of TRH. In none of six other ratings was there a significant difference between TRH and placebo. Subjective improvement was noted by 11 of 12 patients.

Autopsy findings in parkinsonism following treatment with levodopa

It is one hundred fifty-three years since James Parkinson wrote his now-famous essay’ on the shaking palsy. This short monograph, only 66 pages, is based on 6 cases, 3 of which he had examined in detail and 3 he knew casually, having observed them on the streets or in public places in London. Despite the paucity of the case material, the clarity and detail of this account and the author’s insight into the nature of the disorder are remarkable-probably unsurpassed in the annals of medicine. Parkinson recognized almost all of the major manifestations and much about the natural history of the disorder, including its onset-over 50 years of age-and its progressive disabling nature. Further, in a day when little was known about central nervous system function, he localized the site of the disease in the central nervous system by indicating that it must be due to an “irregularity in the nervous influence rather than the nerves of the parts.” His reasoned suggestion that the pathological site was in the medulla spinalis and that it progressed by extending into the medulla oblongata was not too far off target, but it has taken more than a century to establish this fact. In writing his monograph, James Parkinson indicated that his purpose was not so much to draw attention to it as a nosological entity but rather to stimulate interest in defining its underlying pathology. It was with this in mind, and hoping to draw the pathological anatomist into investigation of this disorder, that he wrote his essay. A s he states in the concluding para-

Visuospatial Orientation in Parkinson's Disease

Visuospatial functioning in patients with Parkinsons disease was investigated using neuropsychological measures of basic visual perception, complex perceptual discrimination, and spatial orientation. Three subgroups of patients were described: (a) those with broadly impaired visuospatial abilities, (b) those with generally intact abilities, and (c) those whose performance on a task of spatial orientation was lower than their performance on a task of complex perceptual discrimination. These subgroup differences were also concordant with three other variables: age, duration of disease, and degree of dementia. It is suggested that decreases in spatial orientation functioning in Parkinsons disease may reflect the speed of progression of this disease.