The natural history of Parkinson's disease in the pre-levodopa and post-levodopa eras.

Since Parkinson's disease was first described by James Parkinson in 1817, the natural history has been confounded by various treatment modalities: the replenishment of deficient dopamine, the addition of the dopamine agonists, and the more recent addition of drugs whose putative action may slow the natural history of the disease. Nevertheless it remains a disease that is slowly and inexorably progressive over several decades. The quality of life during this progression can be improved, and the duration of life before inanition produces life-threatening complications can be extended. New approaches to identifying the disease before the overt symptoms appear and to slowing the progression of the underlying pathophysiology are being explored but to date have not produced significant changes in the prognosis for the individual patient.

An examination of male-female differences in progression and mortality of Parkinson's disease.

We conducted disability and mortality studies to determine if the male preponderance usually found in Parkinson's disease (PD) was reflected in different courses of the diseases in the 2 sexes. We analyzed longitudinal disability score in 47 men and 23 women with PD followed for 6 years at UCLA. We found no significant differences between the sexes in mean disability scores in any of the 6 years. Mean dopa dosage was significantly higher in men, possibly reflecting their generally larger body mass. Choreoathetosis, dementia, or other side effects did not differ between the 2 groups. We obtained observed to expected mortality ratios in 239 men and 132 women followed for 3,831 person-years from records of 4 medical centers. Using the sex-specific US Life Tables to calculate expected mortality, we found the observed to expected ratio for the men was 1.7457 and for the women 2.4740, a significantly greater excess in female mortality. Analyses of mortality using tables which are not sex-specific will fail to uncover the decreased longevity in women with PD. We conclude that, despite the male preponderance in PD, men and women acquire it at the same age, have the same progression and duration of disease, and die at the same age; whereas, in the general population, women have a longer life expectancy than men. It is not known what factors protect women from incurring PD and what lowers their life expectancy to that of men when they do have the disease.

Effect of age at onset on progression and mortality in Parkinson's disease.

We examined longitudinal disability scores in 54 patients with Parkinson's disease followed for 6 years at UCLA. We sorted data into 3 groups based on age at onset of symptoms: group A, onset under 50 years; group B, 50 to 59 years; group C, 60 years or older. There were no significant differences between groups initially. All 3 groups improved dramatically when levodopa was given, but group A showed significantly less disability in years 4, 5, and 6 than did group C. The groups did not differ with respect to side effects. To determine if age at onset affected mortality, we sorted records from 4 geographically diverse centers into the same 3 groups. Results on 359 patients followed for 3,314 person-years, covering a period of 17 years after onset of symptoms, showed that group A had the most favorable observed-to-expected mortality ratio, 1.82, compared with 2.17 and 2.20 for groups B and C respectively, but the difference was not statistically significant. Results from the disability analyses indicate that patients with onset of Parkinson's disease under 50 years of age may have a more favorable prognosis than those whose symptoms begin in later years.

Multi-center study of Parkinson mortality with early versus later dopa treatment.

Four geographically diverse centers provided data on mortality in 359 patients with Parkinson's disease, the majority of whom began dopa treatment during the early experimental trials of 1968 to 1970. Patients were classified into three groups based on the duration of symptoms prior to starting dopa treatment: Group 1, 1 to 3 years; Group 2, 4 to 6 years; Group 3, 7 to 9 years. After 15 years of treatment and 3,689 person-years of observation, Group 1 had an observed-to-expected mortality ratio of 1.43; Group 2, 2.44; and Group 3, 2.95 (p less than 0.05). This result confirmed that increased duration of disease was associated with increased mortality risk. To examine the effect of the time of initiation of dopa treatment, duration of disease was held constant at 17 years for all three groups. Observed-to-expected mortality ratios were 1.43 for Group 1; 2.66 for Group 2; 2.63 for Group 3. This statistically significant advantage for Group 1 (p less than 0.0001) led to the conclusion that early treatment with dopa has a beneficial effect on life expectancy. After 17 years of disease, causes of death in Group 1 were less likely (p = 0.027) to be due to Parkinson's disease than was found in the other groups.

Parkinson's disease: progression and mortality.

Patients with Parkinson's disease were compared during two 15-year periods before and after the introduction of levodopa. With levodopa treatment: The duration of illness at each stage of severity was 3 to 5 years longer; at every duration of illness, death and disability were reduced 1.5- to 3-fold, except in patients whose treatment had been delayed; abnormal involuntary movements that interfered with function occurred in 24% of patients; severe fluctuations that required rescheduling of activities occurred in 29% of patients; severe AIMs and fluctuations were rare during the first 3 years of treatment, but remained constant thereafter, without progressive increase; prevalence of severe fluctuations was related only to age of onset of disease: If under 50, severe fluctuations developed in 66%, if age 50 to 59 at onset, they developed in 30%, if over age 60, in only 6%; average age at death was 6 years older; and observed/expected mortality was 1.2, not significantly different from the unaffected population.

Result of chronic levodopa therapy and its modification by bromocriptine in Parkinson's disease.

15 years' experience with Parkinson's disease treated with levodopa was compared to the 15 years before the advent of levodopa. Progression to severe disability and death was prolonged, at each stage of severity, by 3 to 5 years. At each duration of illness, the percentage of patients with severe disability was reduced significantly. There was some indication that independence was prolonged by early treatment. Life expectancy was increased to approximately that of the unaffected population. However, especially with patients with onset of disease before the age of 50, fluctuations of therapeutic response and severe abnormal involuntary movements interfered with satisfactory therapeutic results. Supplemental bromocriptine produced a smoother therapeutic response and decreased "off" period dystonia and leg pains in over 70% of patients. At dosages below 20 mg daily, it was not particularly effective in severely affected disabled patients. Adverse reactions prevented the use of bromocriptine in less than 20% of patients.

Low dosages of bromocriptine added to levodopa in Parkinson's disease.

Thirty-six patients with Parkinson's disease, on levodopa, were admitted to a double-blind, parallel, 40-week study of adjunct bromocriptine in dosages increased by 2.5 mg every 4 weeks. A 37% improvement of the mean neurologic deficit score was obtained at the maximal daily dosage of 20 mg. Improvement was greatest in patients with mild disease. The wearing-off effect, off-dose abnormal involuntary movements, and leg pains, associated with levodopa, improved in over 70% of patients at an average dosage of 13 mg. Only 15% of patients had adverse reactions severe enough to necessitate discontinuance of the drug. Abnormalities of mental state were less severe than expected, but two patients had exacerbations of angina pectoris.

The discovery, fermentation, isolation, and structure of antibiotic A33853 and its tetraacetyl derivative.

The structure of antibiotic A33853, isolated from the culture broth of Streptomyces sp., NRRL 12068, is reported. The structure was deduced from an X-ray crystallographic study of its tetraacetyl derivative. Tetraacetyl A33853 is unique because it contains an anhydride moiety, an unexpected product from the reaction of A33853 with acetic anhydride and pyridine.

Parkinsonism treated with levodopa: progression and mortality.

Patients with Parkinson's disease treated with levodopa over the past 15 years were compared, by parallel statistical methods, to a group of similar patients followed for 15 years before the levodopa era. The duration of illness at each Stage of disease was longer in the treated group, and, at each duration of illness, there was less disability and death. The prevalence of peak-dose dyskinesias increased with increased duration of treatment, but seldom out-weighed the benefits of treatment. Although extreme fluctuations of therapeutic response were not seen during the first 2 years of treatment, their prevalence was otherwise uninfluenced either by the duration of treatment or by postponing treatment. There is, however, some evidence that the postponement of treatment is accompanied by an increased proportion of patients who become "unresponsive" to levodopa. The age at death was 4.5 years older than in the untreated group, and the mortality rate equal to that of the general population. There is ample evidence that treatment with levodopa improves the quality and length of life, and no real evidence that delaying therapy confers benefits in the future.

Bromocriptine and its use in Parkinsonism.

Bromocriptine is a potent dopamine agonist which directly stimulates dopamine receptors. In the corpus striatum, this action results in alleviation of many of the signs and symptoms of parkinsonism. The effectiveness of bromocriptine may persist for at least one to two years; results of more prolonged treatment are not available. Adverse reactions are common and often severe, but safety in dosages up to 100 mg daily for one to two years has been adequately established. Bromocriptine is qualitatively and quantitatively similar to levodopa in both beneficial and adverse effect. However, because of variations in individual response, bromocriptine sometimes ameliorates the problems of prolonged levodopa therapy, i.e., declining efficacy, fluctuations in therapeutic response, and the development of disabling abnormal involuntary movements, Thus bromocriptine is a valuable adjunct in the treatment of parkinsonism.

Chronic levodopa and renal function.

Renal function studies were performed in seventeen patients, under metabolic ward conditions, before the initiation of therapy with levodopa. These studies were repeated during the first two to three weeks of treatment and, again, after one to two years of chronic therapy. There were no significant differences between the results of pre- and post-therapy studies, except that the blood urea nitrogen was slightly, but significantly, elevated in the nine patients who had been on the drug for one to two years. During the early weeks of treatment, there was an insignificant trend towards hypotension and increased excretion of sodium. This did not persist in those patients followed for one to two years after the initiation of treatment. Glomerular filtration rate, as measured by an endogenous method, was unchanged by chronic therapy with levodopa. These results are in contrast to the acutely increased glomerular filtration rate, as measured by an exogenous method, and the increased sodium excretion following a single dose of levodopa or dopamine.

Increased dosage of carbidopa in patients with Parkinson's disease receiving low doses of levodopa. A pilot study.

Twenty-one patients with Parkinson's disease were studied because their low maintenance dosages of carbidopa-levodopa in the customary ratio of 1:10 provided less than the daily 75 mg of carbidopa believed necessary to achieve full inhibition of extracerebral dopa decarboxylation. The dosage of carbidopa was increased 2.5 times to between 75 and 150 mg daily, while the mean dosage of levodopa essentially was unchanged. The new carbidopa-levodopa ratio was 1:4. During 15 months, this treatment produced a moderate decrease in the severity of parkinsonism and a marked decrease in peripheral adverse reactions, without a significant increase in the central adverse effects of levodopa. It is concluded that increasing the dosage of carbidopa may be beneficial to patients with Parkinson's disease receiving less than 75 mg of carbidopa and 750 mg of levodopa daily.

Neuropsychological impairment with schizophrenia vs. acute and chronic cerebral lesions.

Performed detailed neuropsychological evaluations with 25 recently hospitalized schizophrenics in whom systematic neurologic workups had failed to reveal CNS disease. Efforts were made to minimize possible effects of drug-induced extrapyramidal symptoms on test performance. Although the schizophrenics showed some neuropsychological impairment relative to 25 normals, their deficits were not as severe as those of patients known to have either acute or chronic brain disorders (N = 25). The diagnostic accuracy achieved by the tests supports their use in short-term treatment facilities when the differential diagnosis includes schizophrenia and brain disorder, especially acute brain disorder. Schizophrenics' neuropsychological impairment was more correlated with degree of EEG abnormality than with degree of psychosis, which suggests a possible organic basis for the deficits that they showed on testing.

Hypothalamic atrophy.

A patient, who has been followed for thirteen years, developed the first symptoms of progressive hypothalamic atrophy at the age of 39. The diagnosis was confirmed by pneumoencephalography five years after onset. Hypothalamic dysfunction was manifested clinically by loss of libido, impotence, obesity, polydypsia, somnolence, and rage attacks. Assessment of endocrinologic function demonstrated low serum levels of testosterone, FSH, and LH, a diabetic glucose tolerance curve, decreased basal and hypoglycemic stimulated levels of HGH, and progressively increasing levels of serum prolactin. Repeated pneumoencephalography revealed an initial, and then progressive, enlargement of the third ventricle which was later associated with generalized, but proportionately less severe, atrophy of the cerebellum and cerebral hemispheres. Analysis of the physiologic and endocrinologic mechanisms underlying these abnormalities suggests diffuse hypothalamic damage, especially in the ventromedial area. The decreased somnolence and increased libido and potency which accompanied therapy with levodopa suggest damage to dopaminergic and noradrenergic pathways. Slowly progressive hypothalamic atrophy, confirmed by pneumoencephalography, but without specific etiology, has not been reported previously. This article describes such a patient followed over thirteen years, and the efficacy of therapy with levodopa in ameliorating certain aspects of his disease.

A32390A, a new biologically active metabolite. I. Discovery and fermentation studies.

A32390A is an isonitrile-containing derivative of diacyl D-mannitol. The compound is produced in fermentation as the major component of a metabolic complex known as A32390. A32390A inhibits dopamine-beta-hydroxylase reduces heart and adrenal norepinephrine levels, lowers blood pressure in hypertensive rats, and possesses antibiotic activity vs. Gram-positive bacteria and fungi, including Candida albicans. A32390 is produced in submerged culture by a mold, a species of Pyrenochaeta, NRRL-5786. Glucose and sucrose are among the best carbon sources for the biosynthesis of A32390. Mannitol, although a substituent of the A32390A molecule, supports little or no biosynthesis of the compound when employed as the major carbon source for the fermentation. The addition of crotonic acid derivatives. ethanol, or L-histidine to the fermentation medium enhances the level of A32390 produced.

Dopamine excretion and vulnerability to drug-induced Parkinsonism. Schizophrenic patients.

Before and during a standardized course of trifluoperazine therapy, 18 schizophrenic patients underwent repeated examinations for extrapyramidal motor signs, clinical psychopathology, and urinary excretion of free and conjugated forms of dopamine and its metabolites. Patients excreting more free dopamine and metabolites, or showing less complete conjugation, before drug treatment, were much less likely than others to develop parkinsonian akinesia and rigidity during drug treatment. Neither catatonic rigidity nor akinesia before treatment was predictive of a parkinsonian response to trifluoperazine, but pretreatment tremor may have been. The severity of schizophrenic psychopathology was unrelated to dopamine excretion. This study of schizophrenic patients, and our previous research in Parkinson's disease, suggest that urinary dopamine excretion may reflect dopaminergic function of the extrapyramidal motor system in both conditions.