Biomedical subjects
Publications and source records attributed to C G Goetz.
Dopaminergic agonists are drugs that directly stimulate the dopamine receptors of the striatum and have proved useful in treating Parkinson's disease. In the United States, they are primarily used in conjunction with levodopa. Most have long half-lives and have been particularly useful in controlling and attempting to prevent motor fluctuations.
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Movement disorders have been linked to trauma; however, these cases are uncommon and best substantiated if the movement disorder occurs in close temporal association with the trauma, occurs in context of other clinical signs of neurologic damage, and if evidence of CNS lesions on neuroimaging scans is evident. The pathophysiology of movement disorders relates to basal ganglia dysfunction, and traumatic lesions of peripheral nervous system structures or cortical regions could theoretically alter basal ganglia function indirectly and influence movement disorders. Parkinson's disease, the prototype of movement disorders, does not appear to be caused by trauma.
Jean-Martin Charcot, the world's first chaired professor of neurology, incorporated visual art into his daily practice of neurology. Art served as scientific documentation and was a pivotal tool in the development and dissemination of Charcot's clinicoanatomic method. Although Charcot drew extensively in clinical and laboratory studies, very few of these visual documents have ever been published or are currently available for public study. Charcot was central to the incorporation of medical photographs into the study of neurologic disease and relied heavily on visual material in his capacity as an international teacher. Art also misguided Charcot's career when he relied heavily on artwork in his attempt to convince critics that disorders seen at the Salpêtrière Hospital, Paris, France, were independent of his suggestive influence.
During 1 year we monitored changes in clinical disability scores in 10 patients with Parkinson's disease (PD) who sustained head trauma from motor vehicle accidents. Disability significantly increased immediately after trauma, but returned to baseline levels in subsequent weeks. These patients' signs deteriorated over the subsequent year, but this decline was equivalent to that of a matched control group with PD who did not have a motor vehicle accident or trauma. Based on these data, we conclude that trauma or stress caused by motor vehicle accidents can transiently exacerbate parkinsonian dysfunction without causing persistent increased disability or an alteration in disease course.
We report heretofore undescribed clinical and histological features of a patient with idiopathic Parkinson's disease who showed marked and persistent motoric benefit from an adrenal medulla autograft for 18 months following grafting. The patient returned to the preoperative level of disability prior to his death 30 months after implantation, the longest survival to date for an adrenal transplant. The graft site was primarily necrotic and large numbers of macrophages were still present at the time of death. A few tyrosine hydroxylase-immunoreactive cells were found within the graft, providing the first evidence that adrenal medullary cells may be viable and produce catecholamines following human transplantation. A dense network of tyrosine hydroxylase-immunoreactive terminals and processes was also seen ventral to the implant site and on both of its lateral borders. This response may represent sprouting by residual host dopaminergic neurons mediated by the vigorous response to injury displayed by the host striatum. The relative paucity of surviving chromaffin cells, however, provides further evidence that adrenal medulla grafts survive poorly following intracerebral implantation, and factors other than dopamine replacement may be responsible for most of the functional effects observed following chromaffin cell transplantation.
Rats with unilateral 6-hydroxydopamine lesions (6-OHDA) of the mesencephalon and vehicle controls (SHAM) were chronically treated with carbidopa (CD) or CD plus levodopa (CD/LD) for 18 days. Seventy-two hours following the last treatment, ipsilateral striata, contralateral striata, and cerebellums from each treatment group were homogenized separately and the supernatant extracts were incubated with rostral mesencephalic tegmentum cultures. As indices of growth-promoting activity (GPA), number of viable neurons and their process lengths were measured 40 h later. In all cultures exposed to striatal extracts, the 6-OHDA lesion was associated with greater GPA than the SHAM extracts. CD/LD consumption reduced this GPA in a dose-dependent fashion in both the lesioned and the SHAM animals. These data suggest that denervation of the striatum enhances the production of a striatally derived neurotrophic factor, the production of which is sensitive to levodopa. Chronic levodopa treatment in Parkinson's disease may therefore contribute to disease progression by reducing the compensating effects of this neurotrophic factor on remaining mesencephalic neurons.
Fifteen patients with Parkinson's disease underwent open transplantation of autologous adrenal medulla to the caudate nucleus. Motor function was evaluated before and after surgery and was found to be significantly improved at 5-9 months following surgery. Cerebrospinal fluid was taken from the ventricle adjacent to the implant site at the beginning of the operation and at 1 week, 3 months, and 5-9 months following surgery. The cerebrospinal fluid was assayed for chromogranin A (CgA), the major soluble protein in chromaffin granules, and basic fibroblast growth factor (bFGF), a neurotrophic growth factor found in normal brain and adrenal medulla. CgA levels did not increase following surgery, suggesting that a significant number of chromaffin cells did not survive or that surviving chromaffin cells did not secrete a significant amount of CgA. Basic fibroblast growth factor was undetectable in the ventricular cerebrospinal fluid.
Ninety-four patients with early Parkinson's disease were investigated in a double-blind, placebo-controlled evaluation of MK-458 [hydroxypropyl methylcellulose/lactose matrix (HPMC)], a sustained release formulation of a novel naphthoxazine compound with selective D-2 dopamine receptor agonism. Patients were previously untreated with dopaminergic drugs. Efficacy was assessed by clinical rating scales and by patient self-evaluation. MK-458 (HPMC) caused a significant decrease in most parkinsonian symptoms. Though disability rating scores were lowered by the drug, the scores did not differ significantly from placebo. However, statistically significant improvement occurred with MK-458 (HPMC) on both the physician and the patient global assessments. Adverse reactions such as nausea and vomiting, sedation, confusion, and hallucinations occurred more with MK-458 (HPMC) than with placebo. MK-458 (HPMC) possesses antiparkinsonian efficacy in early Parkinson's disease; however, side-effects are frequently associated with its use. Selective D-2 receptor agonists, such as MK-458 (HPMC), may not be the ideal treatment as monotherapy for Parkinson's disease.
Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinson's disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the "on" and "off" motor and activities of daily living functions from the Unified Parkinson's Disease Rating Scale, occurred in 32% of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily "on" time and the quality of "off" function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as "not improved," only 19% were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in "off" function after neurotransplantation, but a serious level of mortality and morbidity.
The cerebral spinal fluid (CSF) of patients with Parkinson's disease (PD) contains an antibody that immunocytochemically reacts with dopamine (DA) neurons in the substantia nigra (SN). This antibody was found in 78% of the CSF samples taken from patients with clinical PD. In contrast, only 3% of the CSF samples taken from control patients or patients with neurologic symptoms other than PD possessed this antibody. The production of this antibody might contribute to disease progression but does not appear to be the etiologic factor responsible for PD. In other experiments, concentrates of the CSF of patients with PD enhanced growth of mesencephalic cultures relative to control CSF. Both the antibody and the growth-promoting activity found in CSF are associated with degeneration of the SN and might therefore be useful as potential diagnostic markers for PD.
At this point the treatment of dystonias remains highly empirical. Secondary dystonias, especially those related to specific drug treatment, have to be ruled out carefully. A few dystonic subgroups respond well to levodopa medication. In the other syndromes, anticholinergics are the usual first choice. In focal conditions botulinum toxin injections seem to be the most effective regimen, although there are only a few long-term studies. Surgical procedures are an ultimate option.
Eighteen of 19 patients who underwent autologous adrenal medullary transplantation to the right caudate nucleus have been followed up for 18 months. During the course of this study, a statistically significant improvement was noted in percent "on" time, percent "on" time without dyskinesia, activity of daily living (ADL) scores during the "on" stages, and ADL, motor, and Schwab-England scores during the "off" stages. Benefits tended to be maximal at 6 months and to gradually lessen thereafter, although statistically significant improvement in comparison with baseline was still present at 18 months for ADL, motor, and Hoehn-Yahr scores during the "off" stages. Almost all parameters had deteriorated by 18 months compared with 12 months, including those remaining significantly improved in comparison with baseline. These patterns were similar for each of the three participating centers. Complications were largely restricted to the perioperative period.
A pair of identical twins (probability of monozygosity by genetic marking = 99.99%) with Gilles de la Tourette's syndrome (GTS) were studied clinically and neurochemically. The two boys were distinguished within the family by dramatic differences in their behavior and tics. Twin 1 had severe motor tics, loud vocalizations, coprolalia, and school behavior problems, whereas twin 2 was only mildly affected. Neither boy had ever been treated with medication for his tic disorder. Lumbar puncture was performed on each after a night of bed rest. In spite of the marked clinical differences between the two boys, the major indices of dopamine and serotonin turnover in the cerebrospinal fluid were equivalent. Homovanillic acid levels were 65 and 60 ng/ml, respectively, and 5-hydroxyindoleacetic acid levels were 36 and 39 ng/ml. Observation of these twins suggests that the phenotypic expression of GTS relates to more factors than inheritance. Neurochemical metabolites of dopamine and serotonin did not reflect the comparative clinical severity of GTS in these boys.
We evaluated a modified inverted walking stick [visual cue (VC) stick] in Parkinson's disease patients with freezing episodes. Patients underwent baseline trials on a 60-ft track with four walking conditions: unassisted, with a straight walking stick, with the VC stick, and on the track with parallel lines spaced every 12 in. Patients completed three trials of each condition in a randomized order, with total course time and number of freezes recorded. Patients were given the VC stick to use at home until subjective maximum functional benefit was obtained and were then brought back for a follow-up objective evaluation. Eight patients completed the study. The straight stick and VC stick worsened patient performance as a group, while the parallel lines significantly improved group performance. However, two of the eight patients showed benefit from the VC stick. Improvement with parallel lines did not predict improvement with the VC stick. On follow-up trials, the two who initially showed improvement with the VC stick continued to show improvement, while none of the other patients showed additional benefit from a learning effect. We conclude that the VC stick will help a small subpopulation of Parkinson's disease patients with freezing, and this subpopulation can be identified with the initial office visit trial.
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We studied motor and psychomotor changes over 1 year after surgery in 7 patients with severe idiopathic Parkinson's disease (PD) who underwent intrastriatal autologous adrenal medulla transplant. Significant clinical improvements were present 1 year after surgery and primarily involved increased quantity of "on" time and increased quality of "off" time: "on" time increased from a mean 60.7% of the waking day to 82.7%, and "off" function improved. In contrast, although "on" function also improved, statistically significant improvement occurred in only 1 measure, the Unified Parkinson's Disease Rating Scale activities of daily living subscale. Medications did not change, and motor fluctuations persisted. Improvement began several weeks after surgery, was maximal at 4 to 6 months, and was sustained thereafter. There was significant group improvement in quality of life measures of sleep and rest, social isolation, and ambulation. One patient had severe, recurrent depression postoperatively. The efficacy of adrenal transplant surgery is not transient, and specific functional improvements can be prolonged.