Biomedical subjects
R P Newman
Publications and source records attributed to R P Newman.
Pterin abnormalities in dystonia: a metabolic marker with therapeutic implications.
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Dystonia in untreated parkinsonism.
While parkinsonism and dystonia generally are distinct clinical syndromes, both may be prominent features even prior to the use of antiparkinsonian medications. In 10 patients with typical parkinsonism, coincident dystonic features included neck, upper extremity, oromandibular, unilateral upper-lower extremity, and unilateral foot dystonia. Six patients were first affected before the age of 45. For some, dystonia preceded parkinsonism (for 1/2 to 20 years). Limb symptoms tended to be unilateral; in seven patients, parkinsonism also was limited to that side. While levodopa was adequate for improvement of parkinsonism, dystonic symptoms benefited from the combination of levodopa with a dopaminergic ergot. The dystonic features (which also can result from parkinsonian therapy) often add pain and disability to the deficits in parkinsonism. The coexistence of dystonia may constitute a distinctive syndrome of parkinsonism and points to possible etiologic mechanisms shared by these two extrapyramidal disorders.
Tetrahydrobiopterin in dystonia: identification of abnormal metabolism and therapeutic trials.
The pteridine cofactor of tyrosine and tryptophan hydroxylases, tetrahydrobiopterin (BH4), is concentrated in the striatum and other sites of brain monoamine synthesis and is a regulatory factor in the rate-limiting step of catecholamine synthesis. CSF content was decreased in eight patients with dystonic disorders (mean, 13.0 +/- 0.8 pmol/ml CSF compared with 20.6 +/- 1.4 in age-matched normals). We gave several trials of synthetic BH4 intravenously to 10 dystonic patients with benefit for 2 subjects with diurnally fluctuating dystonia, 1 with hemidystonia and parkinsonism, and 1 with generalized torsion dystonia. The findings of biopterin abnormality and the observed clinical improvements may point to a role for the cofactor in the pathogenesis and, possibly, the treatment of some forms of primary dystonia.
EMD 23,448: effects of a putative dopamine autoreceptor agonist in chorea.
A novel dopamine agonist, which stimulates presynaptic dopamine receptors in the experimental animal, was administered acutely to four patients with chorea. Abnormal involuntary movements worsened, plasma prolactin levels fell, and plasma growth hormone concentrations increased in all patients tested. These effects resemble those associated with a postsynaptic rather than presynaptic dopamine agonist, and thus raise some question about the ability of conventional dopaminomimetic screens to predict clinical activity.
Selective paralysis of downward gaze caused by bilateral lesions of the mesencephalic periaqueductal gray matter.
A patient who had selective paralysis of downward gaze caused by bilateral lesions of the dorsolateral mesencephalic periaqueductal gray (PAG) matter is reported. Her necropsy findings differed from all previous reports of the syndrome, in that regions of the mesencephalon that have been considered as critical for executing downward gaze (dorsomedial to red nuclei, rostral interstitial nuclei of the medial longitudinal fasciculus [ri MLF]) were normal. These lesions may have produced the syndrome by involving the caudal portions of the nuclei of the posterior commissure (subcommissural), from which one of the commissural systems used by the ri MLF originates. It is also possible that the syndrome was produced by selective destruction of PAG neurons that generate downward impulses or by interruption of posterior commissure fibers containing downward impulses that travel through the dorsolateral PAG before terminating in the more ventral mesencephalon.
Motor function in the normal aging population: treatment with levodopa.
In normal elderly humans there is progressive motor dysfunction and loss of nigrostriatal neurons and brain dopamine similar to, although of a milder degree than, that seen in Parkinson's disease. Ten healthy elderly volunteers were given carbidopa/levodopa or placebo in a double-blind crossover study. We measured movement velocity, reaction time, tremor, visual evoked response (VER), and electroretinography (ERG). Significant changes were seen only in ERG. Motor functions and VER were unchanged. Although there appeared to be pharmacologic activity (ie, changes in ERG), levodopa, in adequate antiparkinson dosage, had no impact on the mild extrapyramidal impairment of normal elderly subjects.
Dystonia: treatment with bromocriptine.
As with parkinsonism, certain dystonias may involve disturbances in dopaminergic neurotransmission. The effects of bromocriptine, 18-150 mg/day (mean, 72.5), were studied in 15 patients with a variety of dystonic disorders, using a double-blind, crossover format. Of the 13 patients completing several weeks of medication, seven improved more than 10% and two worsened, on clinical ratings, while five recognized improvement in disability. Dopaminomimetic agents such as bromocriptine, used in the dose range effective for treating parkinsonism, may yield symptomatic improvement with several patterns of dystonia.
Paroxysmal choreoathetosis due to hypoglycemia.
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Altitudinal hemianopia caused by occipital infarctions. Clinical and computerized tomographic correlations.
Two patients with altitudinal homonymous hemianopia caused by bilateral occipital infarctions were studied. Their clinical-computerized tomographic correlations showed the anatomic representation of the superior and inferior visual fields in the lower and upper banks of the calcarine fissure, respectively. The patient with the superior-field defect was unusual because he retained normal color vision and facial recognition abilities, despite having bilateral lesions that have classically produced central achromatopsia and prosopagnosia.
Abetalipoproteinemia and metastatic spinal cord glioblastoma.
Abetalipoproteinemia (ABL [Bassen-Kornzweig syndrome]) is characterized by marked hypolipidemia with absence of low-density lipoproteins, fat-soluble vitamin deficiency, spinocerebellar ataxia, and retinitis pigmentosa. Our patient had ABL, severe neurologic disease, and spinal cord malignancy, as well as disseminated CNS and extraneural metastases. It is possible that patients with this disorder and long-standing fat-soluble vitamin deficiency may have increased risk for CNS malignancy.
Peripheral beta-adrenergic blockade treatment of parkinsonian tremor.
The effect of nadolol, a peripherally acting beta-adrenergic blocker, on resting, postural, and intention tremor was examined in 8 patients with idiopathic Parkinson's disease whose motor symptoms, other than tremor, were well controlled with conventional medications. In a double-blind, placebo-controlled, crossover design, patients received 80 to 320 mg of nadolol for six weeks while continuing their previous therapeutic regimen. Accelerometer readings showed a 34% reduction (p less than 0.025) in tremor distance, but no change in tremor frequency, during nadolol therapy. Maximum benefit was achieved with a dose of 240 mg, when resting tremor improved 54%, postural tremor 32%, and intention tremor 54%. Physician ratings and patient reports supported the accelerometer results. Nadolol appears to be a safe, effective adjunct to current dopaminergic and anticholinergic therapy for severe tremor in Parkinson's disease.
Treatment of resting tremor by beta-adrenergic blockade.
The effect of nadolol, a peripherally acting beta-adrenergic blocker, on resting tremor was examined in eight patients with idiopathic Parkinson's disease. With the use of a double-blind, placebo-controlled study of crossover design, patients received 80 to 320 mg of nadolol for 6 weeks while continuing their previous treatment regimen. Accelerometer readings showed a progressive reduction in tremor amplitude, but no change in tremor frequency, with increasing nadolol dosage. Maximum benefit was achieved at 240 mg, when resting tremor improved 50% (p less than 0.01). Physician ratings confirmed these findings. The results suggest that response to beta-adrenergic blockade may not be limited to postural or intention tremor and that such agents may not reliably differentiate between the tremor of Parkinson's disease and essential tremor.
Blink rates and disorders of movement.
Blink rate, a putative noninvasive marker of central dopamine activity, was assessed in medication-free patients with Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dystonia. The normal control rate of 24 blinks per minute was significantly higher than the rate of 12 and 4 blinks per minute recorded for patients with Parkinson's disease and progressive supranuclear palsy, respectively. The rates for patients with Huntington's disease and dystonia did not differ significantly from those of controls (36 and 26 blinks per minute, respectively).
Effortful and automatic memory: effects of dopamine.
With advancing age, there are changes in both cognitive functions and neurotransmitter metabolism. Dopamine plays a role in learning, memory, and related cognitive processes. We evaluated the effects of supplemental dopamine in precursor form (levodopa) on various aspects of memory in elderly normal volunteers in a controlled, double-blind study. Access to semantic memory and automatic processes were unaffected, but levodopa reliably facilitated effortful memory processing. Levodopa may be useful clinically in attenuating impairments in effortful cognitive tasks. Different neural systems probably mediate different forms of cognition.
Tyrosine hydroxylase cofactor (tetrahydrobiopterin) in parkinsonism.
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Diagnosis and management of Parkinson's disease.
Advances in the understanding of parkinsonism have done much to ensure correct diagnosis and more rational management. The authors offers an updated approach to the difficult-to-diagnose early stages, as well as management strategies for the duration of the disease.
Treatment of dystonia with tetrahydrobiopterin.
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