The role of interferon in the protective effect of a synthetic double-stranded polyribonucleotide against intranasal vesicular stomatitis virus challenge in mice.

Intravenous injection of polyinosinic acid/polycytidylic acid [(poly rI).(poly rC)] offered significant protection against intranasal challenge of young mice with vesicular stomatitis virus (VSV). Optimal protection was obtained when a single dose was administered 2 hr before virus challenge, but repeated doses were effective when started as late as 3 days after virus challenge. The therapeutic ratio or ratio of maximum tolerated dose to minimum effective dose for a single intravenous injection of (poly rI).(poly rC) 2 hr before virus inoculation was >/=8 mg/kg:0.004 mg/kg or >/=200.Dose-response curves for interferon production and antiviral protection by (poly rI).(poly rC) were closely parallel. Equivalent doses of poly rI or poly rC alone did not exert any interferon-inducing capacity or protective effect on intranasal VSV challenge. Several factors, which are known to potentiate or antagonize interferon production, increased or decreased the interferon-inducing capacity and antiviral protection of either (poly rI).(poly rC) or maleic acid/divinyl ether copolymer (MA/DVE) in parallel. Interferon production and antiviral protection by MA/DVE were enhanced by arginine but abolished by prior treatment with MA/DVE; DEAE-dextran (intraperitoneally), kinetin riboside and isopentenyladenosine, and prior injection of endotoxin reduced both interferon production and antiviral protection by (poly rI).(poly rC). Treatment with exogenous interferon in amounts which closely mimicked the levels of circulating interferon produced endogenously by an effective dose of (poly rI).(poly rC) gave protection against intranasal VSV which was identical with that dose of (poly rI).(poly rC). This strongly suggests that interferon production accounts for the whole protective effect of (poly rI).(poly rC) in the intranasal VSV assay.

The Health Care Financing Administration's new examination documentation criteria: minimum auditing standards for the neurologic examination to be used by Medicare and other payors. Report from the American Academy of Neurology Medical Economics and Management Subcommittee.

Medicare recently announced the adoption of minimum documentation criteria for the neurologic examination. These criteria are added to existing standards for the history and medical decision-making. These criteria will be used in compliance audits by Medicare and other payors. Given the current federal initiative to eliminate fraud in the Medicare program, all neurologists need to comply with these standards. These criteria are for documentation only. Neurologic standards of care require a more complex and diverse examination pertinent to the problem(s) under consideration. Further guidance as to the content of a neurologic evaluation is outlined in the article "Practice guidelines: Neurologic evaluation" (Neurology 1990; 40: 871). The level of history and examination required for specific services is defined in the American Medical Association current procedural terminology book. Documentation standards for examination of children are not yet defined.

A profile of neurology practice based on Medicare services: an AAN Medical Economics and Management Committee report. American Academy of Neurology.

OBJECTIVE: This report uses Medicare data to provide insight into the patient care services most often provided by neurologists. METHODS: The 1998 Medicare data set for physician services was obtained from the Health Care Financing Administration. Neurologists' services were tabulated and compared to the 1998 American Academy of Neurology Member Demographic and Practice Characteristics Report. A profile was derived of neurologists' typical services. RESULTS: Patient visits represent 70% of neurologists' services when evaluated by income. Office was the site of service for 62% of patient visit income. Established patients were 29% of patient visit income. Neurologists frequently code patient visits at levels of service higher than used by other physicians. EMG and nerve conduction velocity together represent 55% of neurodiagnostic services when evaluated by income. CONCLUSIONS: Patient care continues to be the main service of neurologists, with office care more than hospital care. Established patient care is an important part of patient services, confirming the role of the neurologist in principal care. Neurologists' patient care levels of service are higher than for other physicians.

Evaluation of stroke using EEG frequency analysis and topographic mapping.

Frequency analysis and topographic mapping of EEG were studied in 20 consecutive patients with mild stroke and in 20 age-matched normal subjects. Abnormally large increases in delta and decreases in alpha activity were seen over the scalp in 17 of 20 patients and in no normal subjects. Theta was unreliable by itself. The scalp area so localized appeared correct in each case compared with signs, symptoms, and neuroimaging studies. These computerized EEG analysis techniques were abnormal significantly more often than routine EEGs. The results obtained here with simple techniques agree with past studies done with more complex types of EEG analysis.

Evoked potentials predict the clinical changes in a multiple sclerosis drug study.

Visual, brainstem auditory, and median nerve somatosensory evoked potential (EP) tests were performed annually during a 3-year, double-blind, placebo-controlled study of azathioprine with or without steroids in chronic progressive MS. Treatment-related visual and somatosensory EP changes became statistically different 1 year before corresponding differences were seen in the Standard Neurological Examination scores. The statistical significance of EP changes was substantially greater than seen for changes in other clinical scales. The degree of significance was increased by using EP latency values, rather than simple criteria for change. EPs are sensitive, objective measurements useful in MS therapeutic trials.

Asymptomatic HIV infection does not cause EEG abnormalities: results from the Multicenter AIDS Cohort Study (MACS)

We conducted EEG testing in 200 asymptomatic homosexual men, half of whom were HIV seropositive. We chose to include half of the subjects because they were rated as impaired on a neuropsychological screening test. We used both traditional visual EEG interpretation and quantitative EEG analysis. Abnormal EEGs and borderline degrees of EEG slowing occurred in 32% of these men. These EEG changes were not related to HIV serostatus. EEG changes did correlate with the impaired neuropsychological test performance. Clinicians faced with abnormal EEG results or borderline EEG slowing in an asymptomatic HIV-seropositive patient should not attribute the EEG change to effects of the serostatus itself but should look for other causes.

Clinical experience with azathioprine: the pros.

We performed a randomized, placebo-controlled, double-blind, comparative clinical trial of 36 weeks of methylprednisolone and 3 years of azathioprine in 98 patients in the chronic progression phase of multiple sclerosis (MS). We demonstrated a trend in favor of the combination therapy for limiting progression. The relapse rate in the azathioprine recipients was half that of the control group, and visual evoked potential latencies were stabilized in those who received the combination. We think that a therapeutic trial of continuous use of the combination of adrenal steroids with azathioprine would be worthwhile if administered early in the course of the disease.

Pentoxifylline is not a promising treatment for multiple sclerosis in progression phase.

Fourteen MS patients took pentoxifylline at varying doses for up to 24 months. In vitro production of tumor necrosis factor alpha was reduced in patients taking 2,400 to 3,200 mg/day of pentoxifylline for 12 weeks or more. Twelve of the 14 patients experienced worsening of the disease during the study according to clinical, MRI, or visual evoked potential criteria. These results provide no hint of efficacy for pentoxifylline as a treatment for MS in progression phase.

Ocular motility anomalies in developmental misdirection of the optic chiasm.

A 35-year-old normally pigmented man underwent monocular hemifield visual-evoked potential examinations that indicated a lack of normal decussation of nasal paramacular retinogeniculate fibers in the optic chiasm. We studied effects of this anomaly on ocular motility using electro-oculography and the magnetic search-coil technique. The patient exhibited horizontal congenital nystagmus with a predominantly positive exponential waveform. Horizontal smooth pursuit and optokinetic nystagmus were consistently reversed, independent of eye position in the orbit. Vertical tracking was uniformly normal. Horizontal vestibulo-ocular reflexes recorded in the dark during passive rotation exhibited normal gain and phase, whereas rotation recorded in the light reduced gain. Although active head movements reversed horizontal vestibulo-ocular reflexes, vertical vestibulo-ocular reflexes in light and darkness were normal. Our study suggested an association between a lack of normal decussation of retinal fibers in the optic chiasm, and reversed visual tracking and congenital nystagmus.

Quantitative EEG: I. Techniques and problems of frequency analysis and topographic mapping.

Quantitative EEG techniques include frequency analysis (spectral analysis), significance probability mapping, and other analytic techniques. Each can be done on spontaneous EEG in various states or in conjunction with sensory stimulation. Several types of displays are available, including topographic mapping of scalp electrical activity. Assessment of normality in these records must take into account age, gender, state of alertness, medications, and other factors. Substantial statistical issues are critical in these assessments and must be thoroughly understood by all users. Other problems can easily mislead the interpretations of these tests, sometimes in subtle ways. References are often active. Traditional EEG artifacts can appear in surprising ways, and new artifacts can be caused by computer processing and display format. Important technical choices must be made in recording quantitative EEG, and the correct choices are not clearly known. These choices include references, number of channels, epoch length, number of epochs acquired, and artifact rejection criteria. This review summarizes a variety of the techniques commonly used. Advantages of particular methods are contrasted. Problems with these techniques are discussed at length, with emphasis on the difficulties and choices facing users of typical commercial quantitative EEG machines. As quantitative EEG techniques come into some clinical use, issues of nomenclature, technique, normality, and problems will become widely understood. For now, clinicians should respect the problems inherent in these techniques. Quantitative EEG tests should only be interpreted along with the traditional paper EEG tracing that represents the raw data on which the quantitative analysis was performed. A thorough familiarity with traditional EEG is a prerequisite to understanding the meaning of the quantitative EEG results.

Quantitative EEG: II. Frequency analysis and topographic mapping in clinical settings.

The results of many studies using quantitative EEG techniques in clinical settings have been published. Those reports are reviewed here, with emphasis on those that used EEG frequency analysis and topographic mapping. In cerebrovascular disease, these methods can confirm the existence of lesions that are too mild to show up on routine EEG or too mild or too early to show up on computed tomography. The results correlate well with cerebral blood flow studies. These EEG tests can be done continuously in an intensive care unit or operating room. However, exact localization ability is inferior to that seen using traditional neuroimaging tests. In epilepsy, quantitative EEG techniques have found subtle degrees of background EEG changes near epileptic foci. Other methods can quantify epileptic spikes in useful ways and can indicate which region is driving other regions during seizures. Quantification is also useful for measuring drug effects when drugs (such as thiopental) are given deliberately to provoke acute EEG changes. Other measurements of drug effects may become useful in the future. In patients with mass lesions and metabolic encephalopathies, quantitative EEG changes do occur, and some of these correlate with the clinical state. However, in the latter settings, the clinical advantages for patient care are not yet clear, especially in comparison to available neuro-imaging studies and other routine medical tests. For dementia, quantitative EEG techniques are being developed. Some of these tests are accurate in moderately or severely demented patients, but there is still poor accuracy for early or borderline cases. For dyslexia, schizophrenia, and depression, there is a considerable volume of research reports but still no consensus about how to use quantitative EEG tests for care of individual patients. These tests require substantial user expertise in EEG. At present, these tests should be viewed as adjunctive to traditional EEG testing: such routine EEG testing should serve as the foundation for any clinical use of quantitative EEG tools.

Intraoperative electroencephalography.

EEG is useful in several operating room procedures. It has come to be a standard part of monitoring patients during carotid endarterectomy. Monitoring for cerebral hypoperfusion or emboli can also be done in cardiac surgery or other similar settings. For carotid endarterectomy, studies in humans suggest that the risk of stroke can be reduced 10-fold by selective vascular shunting based on major EEG changes compared to no shunting. EEG can be recorded from exposed cerebral cortex, a technique referred to as electrocorticography. Such recordings can help identify damaged cortex, separating it from normal functioning cortex. This can influence the extent of neurosurgical cortical resections. Although much of the technology in the operating room is based on that common in routine EEG testing, some differences exist and are discussed here. The well-trained electroencephalographer should find recording and interpreting EEG in the surgical setting to be a natural extension of routine EEG.

The development of EEG brain mapping.

The field of EEG brain mapping is a collection of many separate techniques for quantified EEG analysis. The most popular technique is the color-coded topographic mapping of frequency content, usually taken in the alert eyes-closed state. This field has developed progressively over 60 years and now is gradually entering use in clinical situations. Accepted clinical uses are still rather limited. A variety of substantial problems exists regarding artifacts, confounding clinical issues, the diversity of available techniques, and statistical interpretation. Clinically, the tests may demonstrate an abnormality but are generally nonspecific regarding the type of responsible pathology. They localize impairment far less well than neuroimaging tests. These digital EEG techniques should not be used separately from the polygraph EEG at this time and should be only used by persons who have sufficient skills, knowledge, and abilities in traditional polygraph EEG interpretation along with additional knowledge and experience in statistical and EEG computer-processing techniques.

Recording electrode site nomenclature.

Several additions and extensions to the 10-20 System have been proposed. The major sets of proposals are reviewed here. The principal uses of these additional scalp recording sites are for clinical evoked potential testing and for acquisition of EEGs from very large numbers of scalp sites. Three separate systematic nomenclatures have arisen for filling in the half-step gaps in the 10-20 placements. These are compared and contrasted here.

Assessing digital and quantitative EEG in clinical settings.

Assessment of clinical utility involves a series of steps based primarily on published peer-reviewed medical literature. Relevant publications usually use the scientific method, appropriate control groups, blinded reading, prospective design, and other study elements. Assessments are more credible when conducted by those who do not have a conflict of interest in the technique. A detailed assessment of digital and quantitative EEG was conducted recently by the American Academy of Neurology. The American Clinical Neurophysiology Society was a joint sponsor. This assessment concluded that digital EEG is an excellent substitute for paper EEG. It also found quantitative techniques helpful in epilepsy monitoring, seizure detections, and in operating room/intensive care unit trend monitors. Several other applications were considered promising, whereas some applications were considered not ready for clinical use. Substantial problems still plague the field, predisposing to false-positive results.

The centrifugal effect and other spatial artifacts of topographic EEG mapping.

Topographic maps of EEG can contain artifacts that are foreign to clinical electroencephalographers trained to read traditional EEG records. Several spatial artifacts are described and discussed here, including the centrifugal effect, ring enhancement, spatial aliasing, electrode hills and holes, color-step effects, and restriction of minima/maxima to electrode sites. Users of quantitated EEG with topographic maps should be aware of these artifacts and should have a high suspicion for other analogous artifactual spatial phenomena when interpreting individual patient records.

Continuous EEG monitoring in the intensive care unit: early findings and clinical efficacy.

The assessment of the neurocritical care patient involves serial assessment of neurologic status using bedside clinical examination and a variety of periodic neurophysiologic testing. Continuous electroencephalographic (CEEG) monitoring in the intensive care unit offers a unique means to track neurologic function directly and regionally. CEEG is becoming more widespread with a growing but small body of literature. The purpose of this paper is to outline the current experience with intensive care unit CEEG monitoring. The basic methods and caveats are discussed. We review the underlying rationale for using CEEG which is that secondary neurologic injury commonly occurs in the intensive care unit and at times is hard to detect. CEEG has a proven role in detecting secondary injuries, namely seizures and brain ischemia. The basic tenets of establishing clinical effectiveness for CEEG in the ICU are discussed while acknowledging a need for further study of clinical effectiveness. We review our initial clinical experience of CEEG in 300 patients and outline the clinical efficacy in terms of cost reduction and improvement in outcome (P < 0.01) using CEEG. Finally, several controversial aspects of CEEG are enumerated, and the need for additional study to answer these pressing questions is presented.

Monitoring carotid test occlusions with continuous EEG and clinical examination.

We routinely monitor invasive neuroradiologic carotid balloon test occlusions with continuous polygraph and quantitative EEG along with repeated detailed clinical examinations. Four of 17 consecutive cases showed changes during carotid occlusion. In one instance, an immediate delta increase was accompanied by slurred speech and aphasia. Another showed alpha attenuation without clinical change. A third patient had significant clinical change without EEG change. Nine of the 17 cases underwent permanent therapeutic carotid occlusion as treatment of an intracerebral vascular abnormality. Seven of these nine had no EEG or clinical changes during monitoring and have had no functional abnormalities on follow-up. The patient with focal alpha attenuation had an accidental balloon detachment but has had no functional or structural neurologic abnormalities. The patient with minor regional increased delta received a permanent carotid occlusion and went on to develop clinical signs 24 h later. We believe that continuous EEG monitoring and repeated clinical examinations provide useful ways of evaluating cerebral circulation during carotid test occlusions.

Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring.

OBJECT: The early pathophysiological features of traumatic brain injury observed in the intensive care unit (ICU) have been described in terms of altered cerebral blood flow, altered brain metabolism, and neurochemical excitotoxicity. Seizures occur in animal models of brain injury and in human brain injury. Previous studies of posttraumatic seizures in humans have been based principally on clinical observations without a systematic approach to electroencephalographic (EEG) recording of seizures. The purpose of this study was to determine prospectively the incidence of convulsive and nonconvulsive seizures by using continuous EEG monitoring in patients in the ICU during the initial 14 days post-injury. METHODS: Ninety-four patients with moderate-to-severe brain injuries underwent continuous EEG monitoring begin-ning at admission to the ICU (mean delay 9.6+/-5.4 hours) and extending up to 14 days postinjury. Convulsive and nonconvulsive seizures occurred in 21 (22%) of the 94 patients, with six of them displaying status epilepticus. In more than half of the patients (52%) the seizures were nonconvulsive and were diagnosed on the basis of EEG studies alone. All six patients with status epilepticus died, compared with a mortality rate of 24% (18 of 73) in the nonseizure group (p<0.001). The patients with status epilepticus had a shorter mean length of stay (9.14+/-5.9 days compared with 14+/-9 days [t-test, p<0.031). Seizures occurred despite initiation of prophylactic phenytoin on admission to the emergency room, with maintenance at mean levels of 16.6+/-2.8 mg/dl. No differences in key prognostic factors (such as the Glasgow Coma Scale score, early hypoxemia, early hypotension, or 1-month Glasgow Outcome Scale score) were found between the patients with seizures and those without. CONCLUSIONS: Seizures occur in more than one in five patients during the 1st week after moderate-to-severe brain injury and may play a role in the pathobiological conditions associated with brain injury.

Magnetoencephalographic localization of a language processing cortical area adjacent to a cerebral arteriovenous malformation. Case report.

In order to accurately estimate the risk of surgery for dominant perisylvian arteriovenous malformations, the topographical relationship of the lesion to language cortex must be determined. A case is presented in which a magnetoencephalographic (MEG) study was used to map preoperatively and noninvasively an intracortical source of speech-receptive cortex in a 25-year-old right-handed man with a dominant left temporal lobe arteriovenous malformation. The speech-evoked magnetic field was analyzed at 36 positions over the left hemisphere in response to presentations of the consonant-vowel syllables "da" and "ga." A topographical map of the magnetic component evoked at 110 msec after stimulus onset, which was negative going to the vertex in concurrent electrical recordings, was congruent with a superficial cortical neuronal current source. This source was displaced from that usually observed in normal individuals to tonal or click stimuli, being superior to the probable location of auditory cortex, and superior and anterior to the probable location of Wernicke's area as conventionally described. The MEG results were in accord with the determination of position of a language-processing cortical area as assessed by direct electrical stimulation of the cortex during surgery under local anesthesia, and by superselective Amytal (amobarbital) injection during angiography. The MEG recordings and exposed brain stimulation sites were coordinated by cranial measurements, skull x-ray landmarks, and angiographic anatomy. Investigations such as this, which compare MEG findings with those from established clinical procedures, are an essential step in determining the physiological and anatomical utility of magnetoencephalography for noninvasive clinical functional localization.