Search

Many in vitro studies have shown that levodopa is a potent toxin which is lethal to various cultured neuronal and non-neuronal cells. The in vitro toxicity of levodopa is linked mainly to its auto-oxidation, which generates a variety of harmful free radical species including superoxide, hydrogen peroxide, and hydroxyl radicals, and also semiquinones and quinones produced via the dopa-melanin metabolic route. Such toxic effects of levodopa can be blocked by co-treatment with antioxidants, particularly thiol-containing compounds. Several studies have shown that levodopa kills cells by triggering apoptosis, an active, intrinsic cell suicide program. Exposure of cultured neurons to levodopa induced the characteristic apoptotic cascade, including cell shrinkage, membrane blebbing, and nuclear and DNA fragmentation. Although levodopa is extremely toxic in vitro, there is no evidence that it damages nigrostriatal dopaminergic neurons in vivo in experimental animals and in patients with Parkinson's disease (PD). Likewise, although there is some evidence for the occurrence of apoptosis in the parkinsonian substantia nigra, it is not known whether levodopa administration is capable of inducing or accelerating programmed cell death of residual pigmented nigral neurons in PD.

In Parkinson's disease (PD), response fluctuations may be due, in part, to pharmacokinetic problems including poor solubility of levodopa and difficulties in its absorption. We administered levodopa ethylester (LDEE), a new highly soluble prodrug of levodopa, by subcutaneous and intramuscular injections to PD patients with response fluctuations, in an open trial to examine its safety and efficacy. Various doses of LDEE (150-400 mg) turned patients "on" with a high success rate (43 of 45 injections). Latencies to "turning on" decreased and duration of on responses increased in a dose-dependent manner. LDEE, given either subcutaneously or intramuscularly, produced similar beneficial effects and induced rapid and sustained elevations in plasma levodopa levels. The drug was well tolerated with only minor and negligible side effects. Study suggests that subcutaneous and intramuscular administration of LDEE may be advantageous as a novel therapeutic strategy for response fluctuations. It may be particularly useful to rapidly and predictably res-cue patients from a variety of disabling "off" situations.

The Mashhadi-Jewish community originating in Iran is a closed and ethnically segregated population with a unique history and a high rate of intrafamilial marriage among its members. A high risk of infection by human T-lymphotropic virus type I (HTLV-I) and of adult T-cell leukemia associated with such infection was found in this population. HTLV-I is also associated with a syndrome of progressive spastic paraparesis. We therefore evaluated the occurrence of HTLV-I infection and spastic paraparesis in Mashhadi-born Iranian Jews who immigrated to Israel. We examined 83 Mashhadi-born subjects (52 women, 31 men; mean age, 61 +/- 15.5 years) and 73 age-matched non-Mashhadi Iranian-born Jews. Blood samples were tested for HTLV-I antibodies by particle agglutination test. The polymerase chain reaction (PCR) was used to detect HTLV-I proviral DNA sequences from peripheral blood mononuclear cells. Fifteen Mashhadi-born Jews (18%) were both seropositive and PCR-positive for HTLV-I. Four HTLV-I-seronegative subjects were found to be positive for HTLV-I proviral DNA by PCR. Of the 19 HTLV-I-infected subjects (11 women, 8 men; mean age, 59 +/- 16 years), 13 (68%) had spastic paraparesis of varying severity. There were no signs of myelopathy in the Mashhadi-born subjects who were negative for HTLV-I proviral DNA by PCR. None of the non-Mashhadi Iranian Jews was seropositive or PCR-positive for HTLV-I proviral DNA, or had clinical signs of spastic paraparesis.(ABSTRACT TRUNCATED AT 250 WORDS)

In 42 patients with acute unilateral ischemic or hemorrhagic hemispheric stroke, conjugate eye deviation toward the lesioned side was usually of brief duration. It subsided within 48 hours in 24 patients (57%) and lasted no longer than 5 days in 38 patients (90%). Early disappearance of conjugate eye deviation was an isolated phenomenon and preceded any improvement in the other focal neurological deficits, which persisted in their initial severity. In 6 additional patients with stroke, conjugate eye deviation was remarkably prolonged, lasting from 13 to more than 43 days. In all 6 there was evidence for preexisting damage to the contralateral frontal region. Our study suggests that early recovery of conjugate eye deviation in patients with acute hemispheric stroke may be mediated by the contralateral unaffected frontal eye field.

Regional cerebral blood flow (rCBF) was measured in human subjects during saccadic eye movements by a 254-channel dynamic gamma camera. Focal rCBF increases were repeatedly observed in an area within the middle precentral and premotor regions which corresponds to the frontal eye field in humans. Our findings suggest that this region is localized between the "face" and "hand" areas in the precentral gyrus and extends anteriorly out of the primary motor strip into the adjacent premotor zone. In addition, saccades were associated with focal blood flow increases in regions corresponding to the frontal supplementary motor area and to the posterior temporooccipital visual association cortex. Similar changes in patterns of rCBF occurred during contralateral and ipsilateral horizontal saccades and also during vertical saccades, and did not differ between the right and left hemispheres. Focal rCBF increases were observed in the frontal eye field during several additional test procedures including ocular fixation and visual perception of a nonmoving target, auditory stimulation with closed eyes, and reading. It is presumed that these focal flow increases reflect increased localized neuronal activity and metabolic rate and therefore permit visualization of the cortical activation pattern associated with saccadic eye movements in humans.

Regional cerebral blood flow was measured in 14 patients with Down's syndrome, in 46 patients with Alzheimer's disease and senile dementia of the Alzheimer type, and in 114 age-matched controls, using the xenon 133 inhalation technique. Cerebral blood flow was reduced in 13 of 14 Down's patients by a mean of 16.8 ± 2.5% from expected age-matched normal values. Degrees of regional cerebral blood flow reduction did not differ among the frontal, temporal, parietal, and occipital regions in both cerebral hemispheres. The regional cerebral blood flow Decemberreases were similar in magnitude and pattern to those in Alzheimer patients. These findings constitute an additional similarity between the two disorders.

In intact striatum, the enzyme dopa decarboxylase is localized predominantly in dopaminergic nerve terminals. In Parkinson disease, loss of dopaminergic neurons is associated with massive depletion of striatal decarboxylase activity. Nevertheless, efficacy of exogenous L-dopa in parkinsonism is generally believed to result from its enzymatic decarboxylation to dopamine in the corpus striatum. It has previously been suggested that, after degeneration of nigrostriatal pathways, decarboxylation of administered L-dopa may occur mainly at such striatal sites as surviving dopaminergic terminals, serotonergic neurons, or capillaries; but currently available data do not favor these hypotheses. Recent experimental studies indicate that a substantial amount of decarboxylase activity is localized in striatal interneurons or efferent neurons that may not normally synthesize monoamines. We propose that after depletion of dopaminergic terminals, these nonaminergic striatal neurons may contain a large fraction of residual dopa decarboxylase activity and may represent an important locus for conversion of administered dopa to functional dopamine in the parkinsonian corpus striatum.

Regional cerebral blood flow (rCBF) was measured by the xenon 133 inhalation method in 20 patients with senile and presenile dementia, and values were compared with flow data obtained in a series of 44 age-matched normal controls. The rCBF was reduced in patients with both presenile and senile dementia, and the degree of decrease exceeded the age-related rCBF decline in normal subjects. Similar rCBF reductions were observed in the left and right cerebral hemispheres and in general were homogeneously distributed in the various areas. The rCBF reductions in normal aging and in dementia may be associated with similar underlying cerebral morphological changes. Our findings suggest that the greater rCBF decreases in dementia compared with the values in age-matched controls may quantitatively reflect more severe pathological alterations in the brains of patients with intellectual deterioration.

A 20-year-old woman with psychomotor seizures developed prolonged unilateral status epilepticus followed by coma, right hemiparesis, fever, liver failure, and eventually death. Neuropathological findings included severe neuronal ischemic cell change and massive brain edema, essentially restricted to the left cerebral hemisphere. Massive destruction of the hemisphere involved in epileptic activity with sparing of the contralateral hemisphere provides supportive evidence that in humans prolonged seizure activity can cause permanent brain damage.

Twenty-six patients with recently diagnosed leptomeningeal metastases underwent multiple diagnostic procedures in order to assess possible cerebral parenchymal involvement. Pretreatment studies included detailed neurological examination, computed tomographic scan, electroencephalogram, neuropsychological assessment, psychiatric evaluation, and measurement of regional cerebral blood flow (rCBF) using the xenon 133 inhalation technique. At diagnosis 50% of the patients had symptoms and signs of cerebral dysfunction. Computed tomographic scanning and electroencephalography detected abnormalities in 42% and 58%, respectively. Scoring was abnormally low on at least three neuropsychological tests in 93% of the patients. The mean rCBF was reduced in 88% of patients by 16.1 +/- 2.5% (mean +/- SEM; range, 8 to 45%) compared with age-matched controls (p less than 0.001). rCBF was reduced and cognition was impaired in patients with or without overt cerebral manifestations. Neuropsychological testing and rCBF measurement may be helpful in early detection of cerebral dysfunction in patients with leptomeningeal metastases.