Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson's disease with N-0923 TDS: a double-blind, placebo-controlled study.

N-0923 is a non-ergot, dopaminergic D(2) agonist designed to be transdermally available. It has anti-parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated.

N-0923, a novel soluble dopamine D2 agonist in the treatment of parkinsonism.

N-0923, a novel aminotetralin dopamine D2 agonist, was shown to effectively reverse parkinsonian symptoms in nine dopa/agonist-responsive Parkinson's disease patients. The drug was given up to 4.5 hours by continuous intravenous (i.v.) infusion using an i.v. pump. The onset of anti-parkinsonian effect was seen within minutes of the initiation of the infusion and was absent within 90 minutes of cessation of the infusion. The short elimination half-life of N-0923 (90 min) would allow for the rapid initiation of drug effect when necessary and at the same time permit the effect to be terminated quickly if necessary. The drug would be useful in situations where oral medication is not feasible or is associated with erratic absorption. The patients tolerated the drug well. Dose escalation load was limited by nausea and vomiting. It should be noted that the doses were increased until these symptoms occurred, but therapeutic effects were noted well before the side effects occurred. Using a modified Columbia scale, maximum improvement consisted of a 27-95% drop in score. Maximum response was obtained at infusion rates varying from 2-16 microg/kg per hour and at blood levels of 0.11-1.49 microg/mL.

A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Vigilance performance in Parkinson's disease and depression.

Patients with Parkinson's disease (PD), patients with Major Depression (MD) and normal control (NC) subjects were administered a continuous performance test (CPT) under neutral and incentive conditions. Patients made more errors than NC subjects with the MD group making a disproportionately large number of omission errors and the PD group tending to make commission errors. Incentive reduced errors across groups. Reaction times were slowest in the MD group. The pattern of findings in patients with MD is consistent with a failure of effort-demanding cognitive processes. In contrast, nondemented patients with PD appeared to have deficiencies in executive control. A previously reported paradoxical effect of incentive on recognition memory performance in depressed patients did not generalize to a vigilance task.

Antibodies to the axolemma-enriched fraction in the cerebrospinal fluid and serum of patients with multiple sclerosis and other neurological diseases.

Antibodies to an axolemma-enriched fraction (AEF) antigen have been detected in the cerebrospinal fluid (CSF) and serum of patients with Multiple Sclerosis (MS) using an enzyme-linked immunosorbent assay (ELISA). A marginal elevation (P < 0.08) of anti-AEF IgG was found in MS CSF when compared with OND samples. When CSF was diluted to a standardized IgG concentration, the anti-AEF IgG level in MS CSF was significantly elevated (P=0.007) when compared to OND CSF. MS serum was also found to contain a significantly higher level (P < 0.001) of anti-AEF IgG when compared to OND serum using the ELISA technique.

Brain structure changes in schizophrenics with high serum titers of antibodies to herpes virus.

We compared five indices of brain structure between two groups of schizophrenics, namely, those with high and normal levels of antibody in the serum to herpes virus. Eleven 'immuno-positive' and 21 'immuno-normal' subjects obtained from a concomitant study of serum IgG antibody to viruses underwent magnetic resonance imaging (MRI) utilizing a 1 Tesla magnet and 8 mm thick slices. We measured ventricle-brain ratio (VBR), 3rd ventricle width, cortical atrophy, area of corpus callosum, and frontal lobe area. The differences between groups were assessed by t-test and chi-square analysis. Eight of 11 immuno-positives compared to 7 of 21 immuno-normals showed evidence of cortical atrophy (chi 2 = 4.49, p < 0.03). The immuno-positives had smaller left frontal area (mean + s.d = 125.69 + 21.30 versus 143.76 + 19.84, t = 2.07, p < 0.05) and larger 2nd quadrant of the corpus callosum (mean + s.d. = 1.58 + 0.39 versus 1.27 + 0.52, t = 2.68, p < 0.01). The right frontal area also was smaller in immuno-positives but not significant. VBR, 3rd ventricle and the 1st, 3rd and 4th callosal quadrants did not differ between the groups. We conclude that high antibody titers to herpes found in the sera of some schizophrenics might reflect an earlier pathogenetic process that affected brain development. Further studies of antibodies in CSF and brain structure in these or similar subjects and those suspected to be exposed to viral infections in utero should be vigorously pursued to obtain definitive evidence for this hypothesis.

Serum cortisol and cerebrospinal fluid beta-endorphins in status epilepticus. Their possible relation to prognosis.

OBJECTIVE: To determine if blood cortisol and cerebrospinal fluid beta-endorphin levels correlate with prognosis following status epilepticus. DESIGN: Twenty-seven adult patients with status epilepticus had blood cortisol and cerebrospinal fluid beta-endorphin levels measured within 12 hours after the cessation of clinical seizures. SETTING: Patients with status epilepticus as well as patients with non-status epilepticus seizures came from the Comprehensive Epilepsy Program at the Medical College of Virginia, Richmond. PATIENTS: Twenty-seven patients with status epilepticus. Control patients for the cortisol study were patients who had acute seizures who did not meet the criteria for status epilepticus. The cerebrospinal fluid control subjects were patients without neurologic symptoms undergoing spinal anesthesia. OUTCOME MEASURES: The clinical status of the patients 1 week after status epilepticus as well as the Glascow Outcome Score and the Glascow Coma Score 1 week after status epilepticus. RESULTS: The difference in blood cortisol levels in patients with status epilepticus with poor prognosis was significantly different from both patients with non-status epilepticus seizures (P < .001) and patients with status epilepticus with good prognosis (P < .01). Cerebrospinal fluid beta-endorphin levels were elevated in patients with status epilepticus patients vs control subjects (P < .05), but no significant difference was noted between the patients with status epilepticus with good and poor prognosis. CONCLUSIONS: Serum cortisol levels may provide a useful predictive indicator of prognosis in status epilepticus and cortisol level elevation may play a role in the pathophysiologic condition of status epilepticus.

Cerebrospinal fluid lactate levels and prognosis in status epilepticus.

Despite recent advances in the treatment of status epilepticus (SE), the mortality and morbidity associated with this condition remains high. Although the reasons for this excessive mortality are not known, several factors are suspected, including cerebral ischemia, cardiovascular collapse, toxic stimulation by neurotransmitters and hormones, or toxic products of intermediary metabolism. Cerebral lactic acidosis can cause cortical injury and has been shown to occur with seizures in experimental animals and in a limited number of human studies. We determined cerebrospinal fluid (CSF) and plasma lactate in 29 patients with generalized SE of diverse etiology. CSF was obtained within 12 h of termination of clinical seizure activity. The mean CSF lactate for all SE patients was elevated (3.74 +/- 0.31 mM) as compared with that of normal controls (1.60 +/- 0.10 mM) from non-neurologic patients undergoing spinal anesthesia. In patients who died or had a poor neurologic recovery, CSF lactate level was 5.36 +/- 0.58 mM (9 patients), whereas in 20 patients who showed good recovery CSF lactate level was 3.01 +/- 0.22 mM (p less than 0.005). The results demonstrate that SE causes a significant increase in CSF lactate and suggest that the magnitude of lactate elevation may serve as a predictive indicator of morbidity and mortality.

Cerebellar degeneration and Meige's syndrome.

We have reported a case of Meige's syndrome in a middle-aged man who eventually had a cerebellar degeneration syndrome. The extrapyramidal symptoms preceded cerebellar signs and symptoms by 5 years. Most patients with idiopathic Meige's syndrome show some improvement with high-dose anticholinergic therapy. Our patient's lack of response to such agents and his subsequent cerebellar symptoms are reminiscent of the situation seen with parkinsonian patients who do not respond to medications, indicating a more widespread degenerative disease. The association of extrapyramidal symptoms with some spinocerebellar disorders, and the pathologic changes seen in the one reported autopsy case, should place the group of spinocerebellar disorders high on the differential list.

Parkinsonism and extraocular motor abnormalities with unusual neuropathological findings.

Parkinsonian patients with ocular motility abnormalities are usually considered to have progressive supranuclear palsy. However, a number of other conditions have been noted to have the combination of parkinsonism and ocular problems. We report a case of rigid akinetic parkinsonism, oculomotor palsy, and eyelid apraxia with postmortem examination. Our findings are unusual in that there was marked gliosis of the substantia nigra with a large amount of free extracellular neuromelanin despite a 3-year clinical course. Only rare hyaline inclusion bodies and no neurofibrillary tangles were seen in the brainstem. Excessive calcification of the vessels of the globus pallidus were also noted. This case represents another example of the diversity of conditions producing parkinsonism with extraocular motor abnormalities.

Serum IgG antibody to herpes viruses in schizophrenia.

Immunoglobulin measurements have provided indirect evidence to suggest that viruses may play an etiologic role in schizophrenia. The authors review the conflicting studies and report their own measurements of serum antibody absorbance to five viral antigens using an ELISA technique in 38 schizophrenic patients and 22 matched controls. For herpes simplex virus, 12 subjects (32%) had antibody levels more than 2 SD above the control mean.

Autoantibodies to brain lipids in schizophrenia.

Serum IgG antibody to brain lipids was measured with an ELISA technique in 38 schizophrenic patients and 22 normal subjects. There were no significant differences between groups. The authors discuss methodological differences between this study and studies with positive findings.

A fatal case of sun exposure in a multiple sclerosis patient.

A 35-year-old woman with a long standing history of relapsing-remitting multiple sclerosis became physically incapacitated by heat-induced muscle weakness while sunbathing and suffered fatal sun exposure. These deleterious effects of increased core temperature on the neurological symptoms have been documented for a half century. Elevation of the patient's core temperature may lead to either transient or permanent neurologic symptoms and signs that predispose to considerable morbidity and mortality.

Characterization of an antiserum against an axolemma-enriched fraction.

An antiserum was raised to rat central nervous system (CNS) axolemma-enriched fractions (AEF), which showed no cross-reactivity with myelin proteins or liver microsomes yet gave an endpoint titer of 1:51 200 to CNS AEF by the enzyme-linked immunosorbent assay (ELISA). Immunochemical staining of electroblotted proteins from rat CNS and peripheral nervous system (PNS) AEFs separated by gel electrophoresis identified a major reactive band at 38.5 kD. CNS AEF also showed major immunoreactivity at 91 kD (+/- 3 kD) and a broad band from 110 kD to 130 kD. By immunoperoxidase staining the antiserum specifically recognized the axolemma of peripheral nerve and synaptic terminals in the CNS. The significance of the specificity is discussed with respect to anti-synaptosome antisera.

A micromethod for absorption of specific antibody using an enzyme-linked immunosorbent assay (ELISA).

A procedure for absorbing specific antibodies using an enzyme-linked immunosorbent assay system (ELISA) has been developed. This is accomplished by serial absorption of the serum using less than 20 micrograms antigen. The sera can then be used in an ELISA system to test reactivity with other antigens. The system was tested by absorbing anti-myelin or anti-cerebroside antibodies and comparing these results with bulk absorption.

Micromethod for detection of oligoclonal IgG in unconcentrated CSF by polyacrylamide gel electrophoresis.

A micromethod to detect oligoclonal IgG from 50 microL of unconcentrated CSF was developed by using polyacrylamide gel electrophoresis in sodium dodecyl sulfate (SDS-PAGE). Of 17 patients with multiple sclerosis, oligoclonal bands were demonstrated in 16 instances (94%) by micro-SDS-PAGE and in 13 (76%) by agarose gel electrophoresis. The corresponding figures among 30 patients with optic neuritis were 16 (54%) and five (17%), respectively, and among ten patients with other neurological disease the figures were two (20%) and none, respectively. Thus, micro-SDS-PAGE is more sensitive than agarose gel electrophoresis for detection of oligoclonal IgG. The small volume of unconcentrated CSF that is required enhances the usefulness of this test.

Suppressor cell activity in multiple sclerosis.

Patients with multiple sclerosis and matched controls were tested for lymphocyte stimulation response and induction of suppressor cell activity in response to concanavalin A (Con A) and antigens from axolemma or myelin. Of 17 stable patients, 6 failed to have a suppressor cell response activated by one of these brain cell antigens. Among the patients who lacked these suppressor responses, five had lymphocyte stimulation responses to the same antigens. All matched controls except for one had suppressor cell responses to these antigens and none responded with a positive cellular immune reaction. We found no difference in lymphoproliferative responses to Con A in patients and controls. The level of suppressor cell activity induced by Con A in the stable MS patients varied but did not differ significantly from that of controls.

Lipid composition of axolemma-enriched fractions from human brains.

The lipid composition was determined for axolemma-enriched fractions and myelin which were isolated via a preparation of purified myelinated axons. The myelin had a lipid composition which was compatible with that previously reported for myelin isolated by alternative procedures. The most dense axolemma-enriched fraction contained 25.3% cholesterol, 25.8% galactolipid (21.3% cerebrosides and 4.8% sulfatides), and 48.9% phospholipid. The major phospholipids were the ethanolamine phospholipid (19.8% of total lipid weight; 49.0% in the plasmalogen form) and choline phospholipids (18.7% of total lipid weight; 16.0% in the plasmalogen form) with lesser amounts of sphingomyelin, phosphatidylserine, and phosphatidylinositol also present; the ganglioside content was 13.9 micrograms of acetylneuraminic acid per mg protein. The less dense axolemma-enriched fraction had a lipid composition which was intermediate between that of myelin and the more dense axolemma-enriched fraction. On the average, less than 2.3% of the total protein in the axolemma-enriched fraction was myelin basic protein. Both axolemma-enriched fractions stained uniformly with Luxol fast blue and demonstrated specific saxitoxin-binding which was enriched 2- to 7-fold over that of the whole white matter homogenate from which the fractions were isolated. The choline and ethanolamine phospholipids in that most dense axolemma-enriched fractions contained a greater percentage of unsaturated fatty acids compared with the comparable phospholipids in myelin. The content of unsaturated fatty acids in these phospholipids of the axolemma-enriched fraction was not as great as that of human CNS synaptic plasma membranes. However, the chain length distribution of these phospholipid fatty acids was similar in myelin, synaptic plasma membrane, and the axolemma-enriched fraction. The distribution of aldehydes derived from the ethanolamine phospholipids of the more dense axolemma-enriched fraction closely resemble the distribution of the comparable aldehydes in the myelin fraction. The possible origin and function of the lipids in the axolemma-enriched fractions are discussed.

Enzyme-linked immunosorbent assay (ELISA) for antibodies to human myelin and axolemma-enriched fractions.

The Enzyme-Linked Immunosorbent Assay (ELISA) is a well established procedure for antibody determination which has gained wide acceptance, particularly in diagnostic virology. We have adapted the method for use with the lipid rich antigens of human myelin and axolemma enriched fractions. Adsorption of the antigen onto the assay plates was rapid and relatively independent of pH. Antibodies to myelin and axolemma cross-reacted extensively. Little antibody reaction was noted using human liver microsomes, indicating the antibodies were specific but that myelin and axolemma shared at least one strong common antigen. With further purification of the antigen, this method should be useful in evaluating immunogenicity and antigenic purity of these membrane fractions.

Psuedotumor cerebri and insecticide intoxication.

Three patients with headache and increased intracranial pressure had elevated blood, serum, and adipose levels of the organochlorine insecticide chlordecone (Kepone). These patients were among 23 employees who suffered from chronic chlordecone intoxication resulting from industrial exposure. In our three patients, investigations eliminated an intracranial mass or other known causes of psuedotumor cerebri. In all three patients, the capacity for cerebrospinal fluid (CSF) absorption was assessed by graded infusions into the subarachnoid space, and was found to be impaired even when papilledema was minimal.