Flunarizine blocks elevation of free cytosolic calcium in synaptosomes following sustained depolarization.

Gerbil cerebral cortical synaptosomes loaded with the fluorescent calcium probe FURA-2 were used to study depolarization-induced presynaptic cytosolic free calcium concentration, as an in vitro model of cerebral ischemia. The depolarization-induced increase in intrasynaptosomal cytosolic free calcium concentration is not sodium-dependent or sodium channel-dependent and may be due to an influx of extrasynaptosomal calcium resulting from a cadmium- and omega-conotoxin-sensitive, nickel-, nifedipine-, and nimodipine-insensitive voltage-regulated channel. The depolarization-induced increase in intrasynaptosomal free cytosolic calcium concentration is also inhibited by flunarizine, a calcium antagonist that has protective effects in animal models of cerebral anoxia and ischemia. Our results suggest that presynaptic calcium uptake following depolarization may be mediated in part by an N-type channel. Flunarizine may block presynaptic calcium accumulation, in part, by blocking this N-type channel; this blockade may be just one of several mechanisms by which flunarizine exerts protective effects following cerebral ischemia.

Phenytoin and chlorpromazine in the treatment of spasticity.

The efficacy of phenytoin sodium and chlorpromazine hydrochloride in the reduction of spasticity was evaluated in both open and controlled studies. In each study, the majority of patients exhibited both objective and subjective signs of improvement. Reduction of motor tone in spastic muscles, as well as improvement in functiional status, was observed. Most patients experienced greater benefit from the combination of phenytoin and chlorpromazine than from either drug alone. The use of the drugs in combination permitted decreased chlorpromazine doses and reduced unwanted side effects such as lethargy and somnolence. These drugs may exert their action by suppressing fusimotor efferent as well as afferent discharged from muscle spindles. The results suggest that the fusimotor system is an important pharmacologic target in the treatment of spasticity.

Familial tapetoretinal degeneration and epilepsy.

Tapetoretinal degeneration is described in two siblings in association with generalized major motor seizures and intellectual impairment. Neither of these patients have the characteristic dysmorphic features or biochemical abnormalities seen in previously described cases, which are reviewed. Inheritance was probably autosomal recessive.

Malabsorption of pyridostigmine in patients with myasthenia gravis.

Four patients with myasthenia gravis were under unsatisfactory control while receiving oral pyridostigmine. In each of these patients, the serum levels of this drug were below those observed in patients with myasthenia gravis who are well controlled. The strength of each of these patients improved when the serum pyridostigmine level was increased by intravenous administration of this agent. Furthermore, the rate of disappearance of pyridostigmine from the serum following intravenous administration was the same as that for control subjects and patients under good control. This demonstrates that failure to achieve adequate serum pyridostigmine levels following oral administration is due to malabsorption rather than to increased rates of tissue uptake, degradation, or excretion of the drug.

The pharmacokinetics of pyridostigmine.

A simplified gas chromatographic method for measuring quaternary ammonium compounds has been developed and used to measure the serum concentration of pyridostigmine in human beings. Pyridostigmine is present in the serum within 1 hour after oral administration and reaches a peak at 2 hours. Results in several patients suggest that the serum concentration achieved is related to the size of the dose and that there is a relationship between serum concentration and clinical response.

Cytomegalovirus encephalitis associated with episodic neurologic deficits and OKT-8+ pleocytosis.

After 3 days of symptoms suggesting a viral illness, a 35-year-old man experienced three episodes of aphasia, right-sided sensory symptoms, and bifrontal headache. Each lasted several hours. CSF examination revealed a moderate lymphocytosis consisting of 80% OKT-8+ cells. Serum anti-cytomegalovirus (anti-CMV) antibody titer was elevated at 1:1,024 and subsequently fell to 1:64. Episodic symptoms recurred 5 months later, at which time the anti-CMV titer peaked at 1:8,192. A trial of inhaled oxygen aborted two episodes after several minutes each.

Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).

BACKGROUND AND OBJECTIVE: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-1a (IFN beta-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. METHODS: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. RESULTS: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFN beta-1a was observed when > or = 2.0 point worsening from baseline EDSS was required or when worsening was required to persist for > or = 1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN beta-1a recipients who reached the primary study outcome. (3) Significantly fewer IFN beta-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0 (unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFN beta-1a treatment. CONCLUSIONS: The primary clinical outcome for the IFN beta-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFN beta-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group.

BACKGROUND AND OBJECTIVE: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS: The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

The role of duplex carotid sonography, digital subtraction angiography, and arteriography in the evaluation of transient ischemic attack and the asymptomatic carotid bruit.

This article reviews the uses of arteriography, venous digital subtraction angiography, and duplex carotid sonography in the evaluation of patients with an asymptomatic carotid bruit or carotid system transient ischemic attack. It concludes with a description of the authors' guidelines for their use.

Antiepileptic therapeutic drug monitoring.

The effort to employ therapeutic drug monitoring in the management of patients with convulsive disorders has been extremely successful. Fortunately, the drugs used by the majority of these patients are readily measured in plasma, and in most cases the plasma concentration is a valid measure of the appropriateness of the dosage of drug administered. Monitoring also helps to ensure patient compliance to drug schedules and allows appropriate adjustment of dosage in patients who are taking concomitant drugs that influence anticonvulsant drug levels. Accurate and reliable quantitative methodology is available to all laboratories, with the method of analysis selected reflecting the technical capabilities of the laboratory personnel.

Pharmacology of calcium antagonists: clinical relevance in neurology.

Calcium antagonists are of potential value in preventing neuronal death following cerebral ischemia or anoxia. Prevention of calcium influx into neurons, not just preservation of cerebral blood flow, is necessary if these agents are to be protective. To be of value clinically in humans, these agents must be effective even if administered after the ischemic insult has occurred. Experimental studies suggest that flunarizine, which inhibits calcium influx following brain anoxia, prolongs clinical survival and prevents neuronal death even when administered after the ischemic event, has no known significant toxic effects in humans following acute administration, has important potential value in the treatment of stroke, and should be evaluated in controlled clinical trials of patients with acute stroke.

Simplified detection of quaternary ammonium compounds by gas chromatography.

An analytical method for the measurement of quaternary ammonium compounds in biological fluids has been developed. Samples are prepared by forming the corresponding iodides, which are extracted and isolated. The residue is taken into n-hexane or into water and part of the solution obtained is injected onto the gas chromatograph where thermal degradation takes place. The methyl iodide released is measured by a 63Ni electron capture detector. This method is quite sensitive and detects with good reliability and reproducibility as little as 10(-14) mole quaternary ammonium compound.

Abnormal brain scans in multiple sclerosis.

A 25 year old man, with a family history of multiple sclerosis in two preceding generations, developed transient sensory changes and incoordination, initially on the left side, and then several months later on the right side in association with an elevated CSF gamma globulin. This was followed by an acute optic neuritis. During the latter episode he developed a positive brain scan which was unaccompanied by any clinical findings explained by a lesion in that area. Cerebral arteriography was normal and the brain scan returned to normal four weeks later, possibly as a result of blood brain barrier restoration. Abnormal brain scans appear to occur only during acute exacerbations of demyelinating disease, and multiple sclerosis should be part of the differential diagnosis of a positive brain scan in a person in the appropriate age range.

Comprehensive toxicology screening in the emergency department: an aid to clinical diagnosis.

An audit of 2,641 toxicology requests from the Georgetown University Hospital Emergency Department from 1981 through 1984 was conducted to assess the contribution of toxicology laboratory results to the clinical evaluation of the intoxicated patient. Positive findings were obtained in 80% of the patients tested. Ethanol was the most common intoxicant, accounting for 48% of all positive results and an average serum concentration of 250 mg/dl. Multiple drug use was documented in 28% of the patients with positive results; some ingested as many as six substances. Women were more likely than men to be polydrug users. A comparison of laboratory findings with diagnosis based on history and examination for 76 patients revealed that the laboratory provided additional information on the nature of the intoxication two-thirds of the time. Our conclusion is that the toxicology laboratory offering a broadly based screening service when properly utilized by the emergency department staff can aid in establishing an accurate diagnosis and provide a guide to therapy in the intoxicated patient.

Effect of flunarizine on electroencephalogram recovery and brain temperature in gerbils after brain ischemia.

BACKGROUND AND PURPOSE: This study was designed to determine whether flunarizine enhances the rate of brain recovery as measured by electroencephalography after cerebral ischemia and whether these effects are attributable to changes in brain temperature. METHODS: Male gerbils (n = 81) were treated with either 10 mg/kg flunarizine or its vehicle, beta-cyclodextrin, intraperitoneally, 60 minutes before bilateral carotid occlusion of either 4 or 6 minutes' duration. The electroencephalogram was continuously recorded in the preischemic, ischemic, and postischemic stages of the experiment and rated for the time necessary for the return of 4-6, 7-10, and 11-15 Hz activity. In a second set of experiments, intracerebral temperature was monitored for 60 minutes before ischemia, during 10 minutes of carotid occlusion, and for 60 minutes after ischemia. RESULTS: Flunarizine pretreatment resulted in significantly more rapid return of electroencephalographic activity in each of the three frequency categories monitored when compared with those animals pretreated with vehicle alone (p less than 0.001). Flunarizine had no effect on brain temperature before, during, or up to 60 minutes after termination of ischemia. CONCLUSIONS: Flunarizine, which has been of efficacy in reducing neuronal death, mortality, and functional impairment when administered after ischemic insults, may have prophylactic value in accelerating brain recovery from ischemia, but does not have this effect as a result of altered brain temperature.

Monocular rotary nystagmus.

A patient with transient monocular rotary-vertical nystagmus demonstrated decreased gain of vertical pursuit and normal vestibulo-ocular reflex on electrooculogram. A supranuclear brain stem lesion, resulting in lack of monocular inhibition of oculomotor neurons, is postulated on the basis of these findings.