Reversible and irreversible cranial MRI findings associated with status epilepticus.

OBJECTIVE: There is limited information on neuroimaging changes in status epilepticus (SE). The objective of this study was to characterize the abnormalities associated with SE in cranial MRI of patients with SE. METHODS: A retrospective review of our records from 2001 to 2010 identified 203 patients with SE. Magnetic resonance imaging (MRI) changes considered were not attributable to any neurological disorder. RESULTS: Ten patients who met the inclusion criteria were found to have significant abnormalities. Magnetic resonance imaging findings included increased T2 signal changes in the gray and/or white matter with corresponding diffusion-weighted imaging (DWI) abnormalities (n=9). Apparent diffusion coefficient (ADC) values were both reduced (n=3) and increased (n=3). Other findings included changes affecting one hemisphere, a perilesional and homologous region, hippocampal changes, and findings in the thalamus, basal ganglia, brain stem, and cerebellum. CONCLUSIONS: Magnetic resonance imaging changes were diffuse. Notably, MRI changes were found to involve the brain stem, cerebellum, basal ganglia, and thalamus. Magnetic resonance imaging changes in the latter areas have not been previously well described. In addition, MRI changes tended to evolve after 1week; therefore, serial MRI is recommended in order to follow and highlight the MRI changes related to the neuroanatomic involvement seen in status epilepticus.

Involuntary craniofacial lingual movements in intensive care-acquired quadriplegia.

BACKGROUND: The syndrome of involuntary craniofacial lingual movements in the setting of acute intensive care-acquired quadriplegia (critical illness neuromyopathy) following sepsis-associated encephalopathy has not been previously described. We suggest a localization and treatment for this disabling condition. METHODS: Three patients (2 female) from our center were quadriplegic from critical illness neuromyopathy when they developed involuntary craniofacial lingual movements following sepsis-associated encephalopathy. RESULTS: Extensive investigations failed to identify an etiology for the abnormal movements. Movements were of large amplitude, of moderate speed, and semi-rhythmic in the jaw, tongue, and palate, persistent and extremely bothersome to all patients. Injection with Botulinum toxin type A was very beneficial. CONCLUSIONS: Involuntary craniofacial lingual movements in the setting of flaccid quadriplegia following sepsis-associated encephalopathy are consistent with focal craniofacial brainstem myoclonus and constitutes a new syndrome. Botulinum toxin type A treatment maybe helpful in treatment.

Recovery of awareness after hyperacute hepatic encephalopathy with "flat" EEG, severe brain edema and deep coma.

BACKGROUND: Hyperacute hepatic failure (HHF) has a high mortality rate that is most commonly due to severe cerebral edema. However, brain swelling and marked clinical and EEG suppression are potentially reversible, even though the same findings are associated with a very poor neurological outcome in anoxic-ischemic encephalopathy. METHODS: We present three cases that illustrate neurological recovery despite severe brain swelling and loss of EEG activity. RESULTS: All patients recovered conscious awareness, including one who transiently lost cranial nerve reflexes. CONCLUSIONS: Despite deep coma, markedly suppressed EEG and brain edema, aggressive control of ICP may lead to good recovery in acute hepatic failure.

Continuous EEG monitoring in the intensive care unit.

The purpose and indications for continuous electroencephalography monitoring (CEEG) in intensive care unit (ICU) patients include seizure detection, monitoring the effects of treatment (including depth of sedation), grading and classification of EEG abnormalities, ischemia detection and prognostication. Practical considerations of ICU CEEG include: choice of montages (patterns of electrode placement and connections), EEG electrodes, recognition of artifacts, and the use of automated or computerized analysis. These aspects are reviewed, along with an identifcation of current advances and challenges for the future of CEEG in the ICU.

The amino acid/auxin:proton symport permease family.

Amino acids and their derivatives are transported into and out of cells by a variety of permease types which comprise several distinct protein families. We here present a systematic analysis of a group of homologous transport proteins which together comprise the eukaryotic-specific amino acid/auxin permease (AAAP) family (TC #2. 18). In characterizing this family, we have (1) identified all sequenced members of the family, (2) aligned their sequences, (3) identified regions of striking conservation, (4) derived a family-specific signature sequence, and (5) proposed a topological model that appears to be applicable to all members of the family. We have also constructed AAAP family phylogenetic trees and dendrograms using six different programs that allow us to trace the evolutionary history of the family, estimate the relatedness of proteins from dissimilar organismal phyla, and evaluate the reliability of the different programs available for phylogenetic studies. The TREE and neighbor-joining programs gave fully consistent results while CLUSTAL W gave similar but non-identical results. Other programs gave less consistent results. The phylogenetic analyses reveal (1) that many plant AAAP family proteins arose recently by multiple gene duplication events that occurred within a single organism, (2) that some plant members of the family with strikingly different specificities diverged early in evolutionary history, and (3) that AAAP family proteins from fungi and animals diverged from the plant proteins long ago, possibly when animals, plants and fungi diverged from each other. The Neurospora protein nevertheless exhibits overlapping specificity with those found in plants. Preliminary evidence is presented suggesting that proteins of the AAAP family are distantly related to proteins of the large ubiquitous amino acid/polyamine/choline family (TC #2.3) as well as to those of two small bacterial amino acid transporter families, the ArAAP family (TC #2.42) and the STP family (TC #2.43).

Phylogenetic characterization of novel transport protein families revealed by genome analyses.

As a result of recent genome sequencing projects as well as detailed biochemical, molecular genetic and physiological experimentation on representative transport proteins, we have come to realize that all organisms possess an extensive but limited array of transport protein types that allow the uptake of nutrients and excretion of toxic substances. These proteins fall into phylogenetic families that presumably reflect their evolutionary histories. Some of these families are restricted to a single phylogenetic group of organisms and may have arisen recently in evolutionary time while others are found ubiquitously and may be ancient. In this study we conduct systematic phylogenetic analyses of 26 families of transport systems that either had not been characterized previously or were in need of updating. Among the families analyzed are some that are bacterial-specific, others that are eukaryotic-specific, and others that are ubiquitous. They can function by either a channel-type or a carrier-type mechanism, and in the latter case, they are frequently energized by coupling solute transport to the flux of an ion down its electrochemical gradient. We tabulate the currently sequenced members of the 26 families analyzed, describe the properties of these families, and present partial multiple alignments, signature sequences and phylogenetic trees for them all.

Solvent-induced collapse of alpha-synuclein and acid-denatured cytochrome c.

The effects of solution conditions on protein collapse were studied by measuring the hydrodynamic radii of two unfolded proteins, alpha-synuclein and acid-denatured ferricytochrome c, in dilute solution and in 1 M glucose. The radius of alpha-synuclein in dilute solution is less than that predicted for a highly denatured state, and adding 1 M glucose causes further collapse. Circular dichroic data show that alpha-synuclein lacks organized structure in both dilute solution and 1 M glucose. On the other hand, the radius of acid-denatured cytochrome c in dilute solution is consistent with that of a highly denatured state, and 1 M glucose induces collapse to the size and structure of native cytochrome c. Taken together, these data show that alpha-synuclein, a natively unfolded protein, is collapsed even in dilute solution, but lacks structure.

Probing weakly polar interactions in cytochrome c.

Theoretical, statistical, and model studies suggest that proteins are stabilized by weakly polar attractions between sulfur atoms and properly oriented aromatic rings. The two sulfur-containing amino acids, methionine and cysteine, occur frequently among functional alleles in random mutant libraries of Saccharomyces cerevisiae iso-1-cytochrome c genes at positions that form a weakly polar aromatic-aromatic interaction, the wild-type protein. To determine if a weakly polar sulfur-aromatic interaction replaced the aromatic-aromatic interaction, the structure and stability of two variants were examined. Phenylalanine 10, which interacts with tyrosine 97, was replaced by methionine and cysteine. The cysteine was modified to form the methionine and cysteine analog, S-methyl cysteine (CysSMe). Proton NMR studies indicate that changing Phe 10 to Met or CysSMe affects only local structure and that the structures of sulfur-containing variants are nearly identical. Analysis of chemical shifts and nuclear Overhauser effect data indicates that both sulfur-containing side chains are in position to form a weakly polar interaction with Tyr 97. The F10M and F10CSMe variants are 2-3 kcal mol-1 less stable than iso-1-cytochrome c at 300 K. Comparison of the stabilities of the F10M and F10CSMe variants allows evaluation of the potential weakly polar interaction between the additional sulfur atom of F10CSMe and the aromatic moiety of Tyr 97. The F10CSMe;C102T variant is 0.7 +/- 0.3 kcal mol-1 more stable than the F10M;C102T protein. The increased stability is explained by the difference in hydrophobicity of the sulfur-containing side chains. We conclude that any weakly polar interaction between the additional sulfur and the aromatic ring is too weak to detect or is masked by destabilizing contributions to the free energy of denaturation.

Amide proton exchange rates of oxidized and reduced Saccharomyces cerevisiae iso-1-cytochrome c.

Proton NMR spectroscopy was used to determine the rate constant, kobs, for exchange of labile protons in both oxidized (Fe(III)) and reduced (Fe(II)) iso-1-cytochrome c. We find that slowly exchanging backbone amide protons tend to lack solvent-accessible surface area, possess backbone hydrogen bonds, and are present in regions of regular secondary structure as well as in omega-loops. Furthermore, there is no correlation between kobs and the distance from a backbone amide nitrogen to the nearest solvent-accessible atom. These observations are consistent with the local unfolding model. Comparisons of the free energy change for denaturation, delta Gd, at 298 K to the free energy change for local unfolding, delta Gop, at 298 K for the oxidized protein suggest that certain conformations possessing higher free energy than the denatured state are detected at equilibrium. Reduction of the protein results in a general increase in delta Gop. Comparisons of delta Gd to delta Gop for the reduced protein show that the most open states of the reduced protein possess more structure than its chemically denatured form. This persistent structure in high-energy conformations of the reduced form appears to involve the axially coordinated heme.

An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality.

Of 49 patients with nonconvulsive seizures studied with continuous EEG monitoring, the overall mortality was 33% (16/49). Of the 23 patients with nonconvulsive status epilepticus (NCSE), 13 died (mortality 57%). Individual variables significantly associated with mortality were age, presence of NCSE, seizure duration, hospital and NICU length of stay, and delay to diagnosis and etiology (acute illness versus remote symptomatic). With multivariate logistic regression, only seizure duration (p = 0.0057, OR = 1.131/hour) and delay to diagnosis (p = 0.0351, OR = 1.039/hour) were associated with increased mortality. Acute symptomatic cases could not be adequately classified as either absence, simple, or complex partial status epilepticus when the impairment of consciousness arose form the initial illness. Current classifications of status epilepticus are inadequate for such cases.

The significance of myoclonic status epilepticus in postanoxic coma.

We report 11 adults who exhibited myoclonic status epilepticus (MSE) after cardiac arrest. Based on pathologic, electroencephalographic, and clinical evidence, we conclude that our patients died from the initial anoxic-ischemic insult rather than as a result of MSE. We suggest that the seizures in these nonsurvivors were self-limited events arising from lethal damage to neurons. Thus, in patients with bilaterally synchronous facial myoclonus, bilateral loss of pupillary or oculovestibular reflexes, and suppression and burst-suppression on EEG, it is not warranted to use anesthetic barbiturates to treat MSE.

Creutzfeldt-Jakob disease without periodic sharp wave complexes: a clinical, electroencephalographic, and pathologic study.

A comparison of clinical, EEG, and pathologic features was carried out on all cases of autopsy-proven Creutzfeldt-Jakob disease (CJD) studied over the last 10 years. Periodic sharp wave complexes (PSWCs) were present in three but absent in seven patients. Myoclonus was documented in two of the three with and in only one of the seven without PSWCs. The three with PSWCs had severe neocortical and at least mild thalamic involvement; those without PSWCs had more variable disease topography. The diagnosis of CJD should not be rejected if PSWCs are absent.

Peripheral nerve function in sepsis and multiple organ failure.

Forty-three patients who had sepsis and multiple organ failure (critical illness) were studied prospectively to determine the incidence and severity of peripheral nerve function and to correlate such function with a number of variables. Electrophysiologic studies indicated a primary axonal degeneration of motor and sensory fibers in 30 (70 percent). Fifteen (30 percent) had the clinical signs of difficulty in weaning from assisted ventilation, weakness of limb muscles, and reduced or absent deep tendon reflexes. Full recovery from the polyneuropathy occurred among the 23 (53 percent) who survived, except three who had a very severe polyneuropathy. A peripheral nerve function index, computed from electrophysiologic measurements, showed statistically significant (p less than 0.01) negative correlations with the time in the critical care unit, and the serum glucose value; the serum albumin level showed a positive correlation. Multiple regression analyses indicated all three factors accounted for 47 percent (r2 = 0.4678) of all potential variables. In a separate analysis, the nerve function index correlated with the amplitude of the diaphragm compound muscle action potential (p less than 0.01). The results were consistent with the polyneuropathy being due to the same mechanisms that are currently postulated to cause dysfunction in this syndrome of other organ systems (including the neuromuscular respiratory system).

Sleep in critically ill patients requiring mechanical ventilation.

STUDY OBJECTIVES: To objectively measure sleep in critically ill patients requiring mechanical ventilation and to define selection criteria for future studies of sleep continuity in this population. DESIGN: Prospective cohort analysis. SETTING: University teaching hospital medical-surgical ICU. PATIENTS: Twenty critically ill (APACHE II [acute physiology and chronic health evaluation II] acute physiology score [APS], 10 +/- 5), mechanically ventilated adults (male 12, female 8, age 62 +/- 15 years) with mild to moderate acute lung injury (lung injury score, 1.8 +/- 0.9) 10 +/- 7 days after admission to the ICU. MEASUREMENTS AND RESULTS: Patients were divided into three groups based on 24-h polysomnography (PSG) findings. No patient demonstrated normal sleep. In the "disrupted sleep" group (n = 8), electrophysiologic sleep was identified and was distributed throughout the day (6:00 AM to 10:00 PM; 4.0 +/- 2.9 h) and night (10:00 PM to 6:00 AM; 3.0 +/- 1.9 h) with equivalent proportions of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Nocturnal sleep efficiency was severely reduced (38 +/- 24%) with an increased proportion of stage 1 NREM sleep (40 +/- 28% total sleep time [TST]) and a reduced proportion of REM sleep (10 +/- 14% TST). Severe sleep fragmentation was reflected by a high frequency of arousals (20 +/- 17/h) and awakenings (22 +/- 25/h). Electrophysiologic sleep was not identifiable in the PSG recordings of the remaining patients. These were classified either as "atypical sleep" (n = 5), characterized by transitions from stage 1 NREM to slow wave sleep with a virtual absence of stage 2 NREM and reduced stage REM sleep, or "coma" (n = 7), characterized by > 50% delta or theta EEG activity with (n = 5) and without (n = 2) evidence of EEG activation either spontaneously or in response to deep painful stimuli. The combined atypical sleep and coma groups had a higher APS (13 +/- 4 vs 6 +/- 4) and higher doses of sedative medications than the disrupted sleep group. CONCLUSION: Sleep, as it is conventionally measured, was identified only in a subgroup of critically ill patients requiring mechanical ventilation and was severely disrupted. We have proposed specific criteria to select patients for future studies to evaluate potential causes of sleep disruption in this population.

Effects of morphine on the electroencephalograms of neonates: a prospective, observational study.

OBJECTIVES: Although opiates have been reported to profoundly alter the EEG and cause seizures in full-term and premature newborn babies, no prospective study has systematically studied the effects of morphine on the EEG of normal neonates. METHODS: A prospective observational study was conducted on 20 neurologically and metabolically normal newborn babies of > or =26 weeks post-conceptional age, with EEG recordings performed while on and off morphine infusions. RESULTS: The recordings performed while the babies were on morphine were all abnormal; the principal abnormalities consisted of prolonged periods of electrical quiescence (PPEQs) and excessive interictal epileptiform activity. After the morphine was discontinued, the PPEQs resolved and the EEG background rhythms were normal for age, but 5 continued to have excessive sharp transients. All babies did well clinically and did not require anti-epileptic drug therapy. CONCLUSIONS: Morphine produces a profound, largely reversible alteration of all neonatal EEGs at various post-conceptional ages. The study has implications for caution in formulating conclusions regarding the clinical significance of EEGs of critically ill neonates on morphine infusions.

The cortical representation of somatosensory evoked potentials of the phrenic nerve.

Respiratory electrophysiological studies are of essential value in diagnosing and managing patients with respiratory failure, but assessment of the sensory phrenic nerve fibres has been neglected. We recorded phrenic nerve somatosensory evoked potentials (SSEPs) by combining neurophysiological and neuroimaging techniques in three healthy subjects. Evoked potentials of the phrenic nerve showed the highest amplitude at CP3, determined by the modified 10-20 EEG system, and occurred at a constant latency, PI at 12.0 +/- 0.6 ms, and NI at 17.3 +/- 0.8 ms. Single photon emission computer tomography (SPECT) performed during phrenic nerve stimulation revealed focal neuronal activation in the somatosensory pathways. Intravenously administered Tc-99m Ethyl Cysteinate Dimer (ECD) was used as a blood flow tracer to obtain baseline and activated images. After image registration, baseline images were compared voxel-by-voxel with the activation images. The mean inter-subject summation image of the activated state was compared with that of the baseline state using ten normal subjects. The extent of the total voxel volume increase on the mean images of the 3 activated SPECT images was 0.7%, and a mean signal increase of 22%. For further anatomic localization of regional increases in signal, the magnetic resonance image (MRI) scan of each subject was registered and superimposed on the activated stage SPECT image. This method may be used clinically to study the pathophysiology of impaired central respiratory drive.

Ethics in the intensive care unit with emphasis on medical futility in comatose survivors of cardiac arrest.

Medical futility refers to situations or cases in which treatment offers no meaningful benefit to the patient. Brain death does not pose a management problem because patients are considered to be dead. Management of other cases requires sequential considerations. First, the prognosis must be established with certainty. Then, if it is determined that there is no possibility of the patient regaining conscious awareness, a level of care should be decided through discussions involving the physician and significant others. Usually there is a consensus that high-level intensive care is not justified to maintain such a low quality of life. When the patient's advance directives or the substitute decision maker's request differs from the physician's recommendations, there are methods of resolving the issues that respect ethical and legal principles.

The EEG in coma.

The EEG allows insight into thalamocortical function in comatose patients when this is inaccessible clinically. A single EEG can help with broad diagnostic categorization whereas continuous or serial EEG provides monitoring for unstable and potentially treatable conditions and for monitoring the effects of therapy. The EEG plays a supplemental role in establishing the prognosis in disease states that are capable of causing neuronal death. The most prevalent and problematic of these conditions involves survivors of cardiac arrest who are initially in coma with intact brainstem reflexes. In such patients single EEGs are of 100% specificity for no possibility of recovery of consciousness only for essentially complete generalized suppression (<10 microV) after the first day of the arrest. Several other generalized patterns, including less marked suppression, burst-suppression, epileptiform activity, periodic complexes, and alpha-theta coma patterns, usually but not invariably indicate a poor outcome. Serial EEGs, continuous raw and automated "trending," testing of reactivity, and the inclusion of multiple variables hold promise for an improved role in the prognostic determination in these patients.