An Empirical Method of Detecting Time-Dependent Confounding: An Observational Study of Next Day Delirium in a Medical ICU.

Longitudinal research on older persons in the medical intensive care unit (MICU) is often complicated by the time-dependent confounding of concurrently administered interventions such as medications and intubation. Such temporal confounding can bias the respective longitudinal associations between concurrently administered treatments and a longitudinal outcome such as delirium. Although marginal structural models address time-dependent confounding, their application is non-trivial and preferably justified by empirical evidence. Using data from a longitudinal study of older persons in the MICU, we constructed a plausibility score from 0 - 10 where higher values indicate higher plausibility of time-dependent confounding of the association between a time-varying explanatory variable and an outcome. Based on longitudinal plots, measures of correlation, and longitudinal regression, the plausibility scores were compared to the differences in estimates obtained with non-weighted and marginal structural models of next day delirium. The plausibility scores of the three possible pairings of daily doses of fentanyl, haloperidol, and intubation indicated the following: low plausibility for haloperidol and intubation, moderate plausibility for fentanyl and haloperidol, and high plausibility for fentanyl and intubation. Comparing multivariable models of next day delirium with and without adjustment for time-dependent confounding, only intubation's association changed substantively. In our observational study of older persons in the MICU, the plausibility scores were generally reflective of the observed differences between coefficients estimated from non-weighted and marginal structural models.

Quality improvement in neurology: AAN epilepsy quality measures: Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology.

OBJECTIVE: Epilepsy is a common neurologic condition with significant personal, societal, medical, and economic burdens. There are considerable gaps in the quality of care delivered. Measuring the quality of care delivered is the first step to its improvement. Performance measures are easily identified and quantitated ways to assess whether specific activities were carried out during a patient encounter. Therefore, epilepsy performance measures were derived through a standardized systematic process and may be the basis for pay-for-performance initiatives and maintenance of certification requirements. METHODS: Epilepsy measures were developed through the American Medical Association-convened Physician Consortium for Performance Improvement (PCPI) independent measure development process, which marked the first time a medical specialty society followed this process. Guidelines, measures, and consensus papers reviewed for the period 1998 to 2008 using the National Guidelines Clearinghouse, the National Quality Measures Clearinghouse, PubMed, MEDLINE, and the Cochrane Library were evaluated using a framework to determine the acceptability of each guideline or other evidence review document for measures development. Recommendation statements based on level of evidence, importance, validity, and gap in care were developed into candidate measures. A panel of experts from representative organizations vetted the measures. A period of public comment was followed by approval from the American Academy of Neurology and the PCPI. RESULTS: Literature search identified 160 relevant recommendation statements from 19 guidelines and 2 consensus papers. Systematic assessment resulted in 20 recommendation statements that were refined to 8 candidate measures by the expert panel. The measures are relevant to seizure type and frequency, etiology or epilepsy syndrome, EEG, neuroimaging, antiepileptic drug side effects, safety issues, referral for refractory epilepsy, and issues for women of childbearing potential. CONCLUSION: There is a reasonable evidence base, and consensus for, deriving performance measures for quality of epilepsy care. It is anticipated that implementation of these performance measures will improve care for patients with epilepsy if adopted by providers.

Detecting differential memory performance among Spanish-speaking patients with temporal lobe epilepsy.

There is relatively little research pertaining to neuropsychological assessment of Spanish-speaking individuals with intractable temporal lobe epilepsy (TLE). The current study examined verbal and visual memory performances in 38 primarily Spanish-speaking patients with TLE (Right = 15, Left = 23) of similar epilepsy duration to determine if lateralizing differences can be found using verbal and nonverbal memory tests. On a test specifically designed to assess auditory learning and memory among Spanish-speaking individuals, the Spanish Verbal Learning Test (SVLT), patients with left TLE performed significantly worse than patients with right TLE. In contrast, no significant differences in story or visual memory were seen using common memory tests translated into Spanish. Similar to what has been found in English speakers, these results show that verbal memory differences can be seen between left and right sided TLE patients who are Spanish-speaking to aid in providing lateralizing information; however, these differences may be best detected using tests developed for and standardized on Spanish-speaking patients.

Qualitative analysis of WMS-III Logical Memory and Visual Reproduction in temporal lobe epilepsy.

Clinical observation of performance on the Logical Memory (LM) and Visual Reproduction (VR) subtests from the WMS-III has revealed some variability in retention rates across stories and figures. This paper examined the degree to which this variability occurs in lateralized temporal lobe epilepsy (TLE) in comparison to a matched group from the WMS-III standardization sample, and explored whether analysis of qualitative aspects of LM and VR performance yield additional lateralizing information in TLE. Analysis of LM and VR scaled scores revealed differences between the TLE groups for LM, but not VR scores. All subjects benefited from repetition of LM Story B, with greater improvement in story retention in the Left versus Right TLE group. Variability in VR recall across figures was seen in all groups, with a bimodal distribution of retention rates for each figure and a sizable percentage of each group completely forgetting two or more figures. These results suggest that more careful analysis of individual LM story performance may be useful in some patients with TLE, whereas variability in VR retention across figures is common and should not be over interpreted.

The concept of risk in biomedical research involving human subjects.

An established ethical principle of biomedical research involving human subjects stipulates that risk to subjects should be proportionate to an experiment's potential benefits. Sometimes this principle is imprecisely stated as a requirement that 'risks and benefits' be balanced. First, it is noted why this language is imprecise. Second, the persistence of such language is attributed to how it functions as a rhetorical trope. Finally, an argument is made that such a trope is infelicitous because it may not achieve its intended persuasive purposes. More importantly, it should be avoided because it masks the important role that chance plays in clinical research. Risk is the possibility of harm. As a precondition of harm it is unintended and undesirable in projects of biomedical research. It requires ethical vigilance. As a vehicle of chance, however, it is both intended and desirable. It requires methodological appreciation.

Neurophysiologic and neuroradiologic features of intractable epilepsy after traumatic brain injury in adults.

BACKGROUND: There is controversy regarding the precise mechanism by which epilepsy results after traumatic brain injury (TBI). Previous reports have suggested that mesial temporal lobe epilepsy may result from TBI only in young children, while neocortical epilepsy arises from TBI in later life. These conclusions were based on surgical series and may be biased because of patient selection. OBJECTIVE: To determine the frequency of mesial temporal lobe as opposed to neocortical epilepsy in patients with intractable epilepsy resulting from TBI after the age of 10 years. PATIENTS AND METHODS: We identified 23 patients with intractable epilepsy who had TBI after the age of 10 years, preceding the onset of epilepsy. Patients were studied by simultaneous videotape and scalp electroencephalographic recording of typical seizures; magnetic resonance imaging; neuropsychologic studies; and, when appropriate, intracarotid amobarbital testing. Two patients underwent anterior temporal lobectomies. RESULTS: Of the 23 patients, 8 (35%) had mesial temporal lobe epilepsy, based on the finding of hippocampal sclerosis on a magnetic resonance imaging scan, consistent interictal and ictal electroencephalographic recordings, evidence of temporal lobe dysfunction on neuropsychologic testing, and characteristic seizure semiology. Two of these patients underwent anterior temporal lobectomies with clinical benefit, and hippocampal sclerosis was confirmed pathologically. In 2 cases, patients were not treated surgically because of bilateral temporal lobe dysfunction noted on intracarotid amobarbital testing. Eleven patients had neocortical epilepsy; 1 had primary generalized epilepsy; and, in 3, the site of seizure onset was not localized. CONCLUSIONS: Mesial temporal lobe epilepsy can result from TBI in adolescents and adults as well as in children, and can often be bilateral and associated with multifocal injury. This information may be useful in developing prophylactic therapy for posttraumatic epilepsy.

Nonconvulsive status epilepticus resulting from Jarisch-Herxheimer reaction in a patient with neurosyphilis.

We report a case of Jarisch-Herxheimer reaction in a patient with neurosyphilis, which was complicated by nonconvulsive status epilepticus. The EEG features suggested a focal seizure onset, although the patient's MRI was normal. JHR is common in the treatment of neurosyphilis, but usually produces only transient systemic constitutional symptoms. Neurologic deterioration is rare, but can be dramatic, as in our patient. NCSE should be considered as an explanation for persistent obtundation and transient focal neurologic findings in this setting.

St Louis encephalitis: a review of 11 cases in a 1995 Dallas, Tex, epidemic.

OBJECTIVE: To update some of the clinical features of St Louis encephalitis (SLE), a common arboviral infection that occurs in epidemic patterns in the south-central and midwestern United States. METHODS: Eleven patients with SLE from a 1995 epidemic in Dallas, Tex, were studied clinically, radiologically, neurophysiologically, and neuropathologically (in 1 case). RESULTS: The electroencephalograms and magnetic resonance imaging (MRI) scans of our patients revealed features that have received little attention in previous studies. Of the 9 patients who were examined with electroencephalography, all 9 had seizures or other abnormalities, and 1 had nonconvulsive status epilepticus. Two of 6 patients who had MRIs showed substantia nigra edema. Finally, 2 (18%) of our patients had coinfection with the human immunodeficiency virus. CONCLUSIONS: The MRI findings of substantia nigra edema in patients with SLE have not been previously reported. Nonconvulsive status epilepticus can occur in patients with SLE and should be considered in patients with prolonged encephalopathy. Finally, human immunodeficiency virus coinfection may be a risk factor for symptomatic SLE infection.

Angelman syndrome: correlations between epilepsy phenotypes and genotypes.

We compared epilepsy phenotypes with genotypes of Angelman syndrome (AS), including chromosome 15q11-13 deletions (class I), uniparental disomy (class II), methylation imprinting abnormalities (class III), and mutation in the UBE3A gene (class IV). Twenty patients were prospectively selected based on clinical cytogenetic and molecular diagnosis of AS. All patients had 6 to 72 hours of closed-circuit television videotaping and digitized electroencephalogrpahic (EEG) telemetry. Patients from all genotypic classes had characteristic EEGs with diffuse bifrontally dominant high-amplitude 1- to 3-Hz notched or triphasic or polyphasic slow waves, or slow and sharp waves. Class I patients had severe intractable epilepsy, most frequently with atypical absences and myoclonias and less frequently with generalized extensor tonic seizures or flexor spasms. Epileptic spasms were recorded in AS patients as old as 41 years. Aged-matched class II, III, and IV patients had either no epilepsy or drug-responsive mild epilepsy with relatively infrequent atypical absences, myoclonias, or atonic seizures. In conclusion, maternally inherited chromosome 15q11-13 deletions produce severe epilepsy. Loss-of-function UBE3A mutations, uniparental disomy, or methylation imprint abnormalities in AS are associated with relatively mild epilepsy. Involvement of other genes in the chromosome 15q11-13 deletion, such as GABRB3, may explain severe epilepsy in AS.

Evaluation of neurologic function in Gulf War veterans. A blinded case-control study.

OBJECTIVE: To determine whether Gulf War-related illnesses are associated with central or peripheral nervous system dysfunction. DESIGN: Nested case-control study. PARTICIPANTS: Twenty-three veterans with factor analysis-derived syndromes (the cases), 10 well veterans deployed to the Gulf War (the deployed controls), and 10 well veterans not deployed to the Gulf War (the nondeployed controls). METHOD: With investigators blinded to group identities, participants underwent objective neurophysiological, audiovestibular, neuroradiological, neuropsychological, and blood tests. MAIN OUTCOME MEASURES: Evidence of neurologic dysfunction. RESULTS: Compared with the 20 controls, the 23 cases had significantly more neuropsychological evidence of brain dysfunction on the Halstead Impairment Index (P=.01), greater interside asymmetry of the wave I to wave III interpeak latency of brain stem auditory evoked potentials (P=.02), greater interocular asymmetry of nystagmic velocity on rotational testing, increased asymmetry of saccadic velocity (P=.04), more prolonged interpeak latency of the lumbar-to-cerebral peaks on posterior tibial somatosensory evoked potentials (on right side, P=.03, and on the left side, P=.005), and diminished nystagmic velocity after caloric stimulation bilaterally (P values range from .02 to .04). Cases (n=5) with syndrome 1 ("impaired cognition") were the most impaired on brain stem auditory evoked potentials (P=.005); those (n=13) with syndrome 2 ("confusion-ataxia") were the most impaired on the Halstead Impairment Index (P=.006), rotational testing (P=.01), asymmetry of saccadic velocity (P=.03), and somatosensory evoked potentials (P< or =.01); and those (n=5) with syndrome 3 ("arthro-myo-neuropathy") were the most impaired on caloric stimulation (P< or =.01). CONCLUSIONS: The 3 factor-derived syndromes identified among Gulf War veterans appear to represent variants of a generalized injury to the nervous system.

Supplementary motor area seizures: propagation pathways as studied with invasive recordings.

We studied propagation of epileptic discharges in five patients with supplementary motor area (SMA) seizures with subdural grid electrodes implanted over the dorsolateral frontal neocortex and in the interhemispheric fissure. We found that both interictal and ictal epileptic discharges occurred synchronously in the SMA and the primary cortex. The actively involved electrodes were separated by silent electrodes. The time lag between the SMA and the primary motor cortex averaged 25 msec for interictal and 100 msec for ictal discharges. Cortical stimulations of the affected electrodes showed motor effects in corresponding body parts. All patients underwent resections of the EEG onset zone within the SMA while sparing the primary motor cortex and experienced a significant (>90%) reduction of seizure frequency. We conclude that epileptic activity is propagated between the SMA and the primary motor cortex by a somatotopically organized monosynaptic pathway.

Endangered bliss: Reflections on joy and religion.

This essay begins with the observation that experiences of intense joy are increasingly absent from the religious lives of many Americans. Examination of the linguistic history of the words "bliss" and "bless" suggests the origins and implications of this loss of joy. A case is made that bliss is crucial to vital Christian life, so long as it occurs in the context of disciplined behavior productive of moral and aesthetic value.

Presence of Bereitschaftspotential preceding psychogenic myoclonus: clinical application of jerk-locked back averaging.

The method of jerk-locked back averaging was applied to six patients with clinically diagnosed psychogenic myoclonus. Five patients had a slow negative EEG shift corresponding to Bereitschaftspotential at the central region starting 0.7 to 2.1 seconds before the onset of the myoclonic jerk. One patient had no potential preceding the myoclonic jerk, whereas a small negative potential preceded the voluntary movement mimicking the jerk. The demonstration of Bereitschaftspotential before an apparently involuntary myoclonic jerk helps the clinical diagnosis of psychogenic myoclonus, although the absence of Bereitschaftspotential does not necessarily indicate that the movement is involuntary. Jerk-locked back averaging is clinically useful as a specific laboratory examination in this condition.

Modulation of GABAA receptor binding in human brain by neuroactive steroids: species and brain regional differences.

Allosteric modulation by neuroactive steroids of radioligand binding sites on the GABAA receptor complex was demonstrated by autoradiography in vitro in several regions of human brain and the effects compared to those in rat brain. Comparing human and rat, two steroids known to be active in enhancing GABA-mediated postsynaptic inhibition, 5 alpha-pregnane-3 alpha,21-diol-20-one (tetrahydro-deoxycorticosterone, THDOC) and alphaxalone (5 alpha-pregnane-3 alpha-hydroxy-11,20-dione), allosterically inhibited [35S]T-BPS binding to the picrotoxin/convulsant site in both species in several regions including the hippocampus. Unlike rat, human brain binding of [3H]flunitrazepam to the benzodiazepine site was not enhanced by alphaxalone (at any concentration), but was unaffected in many regions and inhibited in others. Binding of [3H]muscimol to high and low affinity GABA sites were enhanced by both steroids in all tested regions of rat brain, although to varying degrees. However, several lobes of human cortex showed no modulation of muscimol binding by either steroid, and THDOC, but not alphaxalone, inhibited in some areas. Comparing regions, THDOC at high concentrations (10 microM) enhanced in human frontal lobe and primary sensory and motor cortex, with greater effect in deep layers than superficial. This steroid had no effect in other parts of parietal lobe and inhibited muscimol binding in temporal lobe, primary visual cortex, and other parts of occipital lobe. Concentration-dependence curves for THDOC showed regional variation, e.g., in the hippocampal formation and surrounding neocortex. These regional and species differences are consistent with the existence of multiple GABAA receptor subtypes that differ in pharmacology. This heterogeneity provides both the opportunity and the difficulty of targeting clinically useful medications such as antiepileptic drugs to the appropriate human brain regions, and the species differences in regional subtype expression suggest caution in use of animal models.

Frontal lobe seizures: electroclinical syndromes.

To define further the electroclinical manifestations of frontal lobe epilepsy (FLE), we studied 150 seizures manifested by 24 patients; 18 patients had subdural electrode arrays (SEA). The findings in these patients clearly overlapped presumably reflecting the interconnections between functionally related frontal zones; yet the manner in which the symptoms clustered and the sequence in which they occurred generally indicated the anatomic site of the epileptogenic zone. We divided the patients into three major groups: (a) those with supplementary motor seizures, (b) those with focal motor seizures, and (c) those with complex partial seizures (CPS, psychomotor seizures). Supplementary motor seizures began with tonic posturing of the extremities. Focal motor seizures generally began with conscious contralateral version or unilateral clonic focal motor activity; tonic posturing was noted only late in the seizure. CPS (psychomotor) began with unresponsiveness at onset, followed by staring or unconscious contraversion. We compared frontal lobe seizures with temporal lobe seizures reported previously; oral-alimentary automatisms, repetitive hand movements, or looking around, were more common in temporal lobe seizures, whereas tonic posturing and bicycling movements were more common in frontal lobe psychomotor seizures.

Mirror focus: function of seizure frequency and influence on outcome after surgery.

The concept of the mirror focus (MF) implies that an actively discharging epileptiform region may induce similar paroxysmal behavior in a homologous site. In a group of patients with complex partial seizures (CPS) we investigated whether occurrence of a MF was influenced by certain clinical factors and whether surgical outcome was influenced by the presence of an MF. Factors studied included age at onset, duration, and total number of seizures. Patients had had CPS for > 3 years and had pathologically proven temporal lobe neoplasms. Seizure frequency was estimated by the history-taking physician. We estimated total seizure number by multiplying frequency by duration. Seven patients had MF, and 15 did not. Mean age at onset of seizures, duration of seizure disorder, and total seizure number did not vary statistically between the two groups of patients. All patients with an MF except 1 were seizure-free at follow-up. Ten of the 15 patients without MF were seizure-free. Three patients who were not seizure-free had had subtotal resection owing to tumor overlap with eloquent cortex. We conclude that an MF is not a contraindication to operation even when the preponderance of interictal spike activity is contralateral to the tumor or when seizures appear to arise from the MF on scalp EEG.

The effect of propofol on the electroencephalogram of patients with epilepsy.

The effect of propofol on the electroencephalogram (EEG) in patients with epilepsy is still unclear. Case reports with electroencephalographic documentation highlight pro- and anticonvulsant effects and beta activation of the EEG. This prospective study sought to determine the effect of propofol in 17 patients undergoing cortical resection for intractable epilepsy. Each patient received 2 mg/kg of propofol intravenously and the EEG was recorded from chronically implanted subdural electrodes placed during a previous craniotomy. Frequency of interictal spikes, time to burst suppression, and appearance of beta activation were recorded. The median frequency of interictal spikes decreased significantly from 2 spikes/min before to 0 spikes/min after propofol (P = 0.001). Seizure activity did not increase after propofol. Profound burst suppression and an increase in beta activity were noted consistently. The use of propofol in patients with epilepsy seems to be safe but may interfere with the recording of EEG spikes.

Lateralizing signs in intractable partial epilepsy: blinded multiple-observer analysis.

We evaluated the accuracy and interobserver variability of selected ictal and postictal behavioral changes. Three observers, blinded to clinical history, EEG, and side of surgical resection, analyzed videotapes of 166 seizures in 38 patients, looking for lateralizing signs. Twenty-seven patients with temporal lobe resections were seizure-free for > or = 1 year postoperatively, and 11 with extratemporal resections had at least 90% reduction in seizures > or = 1 year postsurgery. The epileptogenic region (ER) was lateralized by analyzing lateralizing signs in 78% of patients; positive predictive value (PPV) was 94% (90% CI = 87% to 100%). Overall kappa was 0.68. Signs were considered present if seen by two or more observers. Forty-five percent had version, ie, forced and sustained head deviation (kappa = 0.76, PPV = 94%); 37% had dystonic posturing of the upper extremity (kappa = 0.47, PPV = 93%); and 34% had unilateral mouth deviation (kappa = 0.83, PPV = 92%). These signs indicated a contralateral ER. Twenty-one percent had unilateral upper extremity automatisms, all ipsilateral to the ER (kappa = 0.65, PPV = 100%); 21% had postictal dysnomia, indicating a dominant-hemisphere ER (kappa = 0.89, PPV = 100%); and 16% had ictal speech, usually indicating a nondominant-hemisphere ER (kappa = 0.75, PPV = 83%). Dystonic posturing, postictal dysnomia, ictal speech, and unilateral upper extremity automatisms may indicate a higher probability of temporal lobe epilepsy. Analysis of lateralizing signs shows good interobserver agreement and provides useful clinical information.