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Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

Although there are many biochemical methods to measure amyloid-β (Aβ)42 concentration, one of the critical issues in the study of the effects of Aβ42 on the nervous system is a simple physiological measurement. The in vitro rat sciatic nerve model is employed and the nerve action potential (NAP) is quantified with different stimuli while exposed to different concentrations of Aβ42. Aβ42 predominantly reduces the NAP amplitude with minimal effects on other parameters except at low stimulus currents and short inter-stimulus intervals. The effects of Aβ42 are significantly concentration-dependent, with a maximum reduction in NAP amplitude at a concentration of 70 nM and smaller effects on the NAP amplitude at higher and lower concentrations. However, even physiologic concentrations in the range of 70 pM did reduce the NAP amplitude. The effects of Aβ42 became maximal 5-8 h after exposure and did not reverse during a 30 min washout period. The in vitro rat sciatic nerve model is sensitive to the effects of physiologic concentrations of Aβ42. These experiments suggest that the effect of Aβ42 is a very complex function of concentration that may be the result of amyloid-related changes in membrane properties or sodium channels.

Quickly and efficiently extracting evoked potential information from noise is critical to the clinical practice of intraoperative neurophysiologic monitoring (IONM). Currently this is primarily done using trained professionals to interpret averaged waveforms. The purpose of this paper is to evaluate and compare multiple means of electronically extracting simple to understand evoked potential characteristics with minimum averaging. A number of evoked potential models are studied and their performance evaluated as a function of the signal to noise level in simulations., Methods: which extract the least number of parameters from the data are least sensitive to the effects of noise and are easiest to interpret. The simplest model uses the baseline evoked potential and the correlation receiver to provide an amplitude measure. Amplitude measures extracted using the correlation receiver show superior performance to those based on peak to peak amplitude measures. In addition, measures of change in latency or shape of the evoked potential can be extracted using the derivative of the baseline evoked response or other methods. This methodology allows real-time access to amplitude measures that can be understood by the entire OR staff as they are small, dimensionless numbers of order unity which are simple to interpret. The IONM team can then adjust averaging and other parameters to allow for visual interpretation of waveforms as appropriate., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:M.S. is president of the Fresno Institute of NeuroscienceJ.S. is a consultant with Inomed and is on the board of directors of NervioJ.W. has nothing to declare., (© 2023 The Authors.)

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms. Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies. This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored.

As the search for modalities to cure Alzheimer's disease (AD) has made slow progress, research has now turned to innovative pathways involving neural and peripheral inflammation and neuro-regeneration. Widely used AD treatments provide only symptomatic relief without changing the disease course. The recently FDA-approved anti-amyloid drugs, aducanumab and lecanemab, have demonstrated unclear real-world efficacy with a substantial side effect profile. Interest is growing in targeting the early stages of AD before irreversible pathologic changes so that cognitive function and neuronal viability can be preserved. Neuroinflammation is a fundamental feature of AD that involves complex relationships among cerebral immune cells and pro-inflammatory cytokines, which could be altered pharmacologically by AD therapy. Here, we provide an overview of the manipulations attempted in pre-clinical experiments. These include inhibition of microglial receptors, attenuation of inflammation and enhancement of toxin-clearing autophagy. In addition, modulation of the microbiome-brain-gut axis, dietary changes, and increased mental and physical exercise are under evaluation as ways to optimize brain health. As the scientific and medical communities work together, new solutions may be on the horizon to slow or halt AD progression.

Despite intensive research, effective treatments for many common and devastating diseases are lacking. For example, huge efforts and billions of dollars have been invested in Alzheimer's disease (AD), which affects over 50 million people worldwide. However, there is still no effective drug that can slow or cure AD. This relates, in part, to the absence of an animal model or cellular system that incorporates all the relevant features of the disease. Therefore, large scale studies on human populations and tissues will be key to better understanding dementia and developing methods to prevent or treat it. This is especially difficult because the dementia phenotype can result from many different processes and is likely to be affected by multiple personal and environmental variables. We hypothesize that analyzing massive volumes of demographic data that are currently available and combining this with genomic, proteomic, and metabolomic profiles of AD patients and their families, new insights into pathophysiology and treatment of AD may arise. While this requires much coordination and cooperation among large institutions, the potential for advancement would be life-changing for millions of people. In many ways this represents the next step in the information revolution started by the Human Genome Project., Competing Interests: Conflict of interest: All authors declare no conflicts of interest in this paper., (© 2022 the Author(s), licensee AIMS Press.)

Objective: To determine the prevalence of electrographic seizure (ES) and electrographic status epilepticus (ESE) in dogs and cats that underwent electroencephalography (EEG) because of suspected seizure activity and to characterize the clinical characteristics, risk factors, and in-hospital mortality rates for dogs and cats with ES or ESE., Design: Retrospective case series., Animals: 89 dogs and 15 cats., Procedures: Medical records of dogs and cats that underwent EEG at a veterinary neurology service between May 2009 and April 2015 were reviewed. Electrographic seizure was defined as ictal discharges that evolved in frequency, duration, or morphology and lasted at least 10 seconds, and ESE was defined as ES that lasted ≥ 10 minutes. Patient signalment and history, physical and neurologic examination findings, diagnostic test results, and outcome were compared between patients with and without ES or ESE., Results: Among the 104 patients, ES and ESE were diagnosed in 21 (20%) and 12 (12%), respectively. Seventeen (81%) patients with ES had no or only subtle signs of seizure activity. The in-hospital mortality rate was 48% and 50% for patients with ES and ESE, respectively, compared with 19% for patients without ES or ESE. Risk factors for ES and ESE included young age, overt seizure activity within 8 hours before EEG, and history of cluster seizures., Conclusions and Clinical Revelance: Results indicated that ES and ESE were fairly common in dogs and cats with suspected seizure activity and affected patients often had only subtle clinical signs. Therefore, EEG is necessary to detect patients with ES and ESE.

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Minimally invasive biomarkers of MS are required for disease diagnosis and treatment. Differentially methylated circulating-free DNA (cfDNA) is a useful biomarker for disease diagnosis and prognosis, and may offer to be a viable approach for understanding MS. Here, methylation-specific primers and quantitative real-time PCR were used to study methylation patterns of the myelin oligodendrocyte glycoprotein (MOG) gene, which is expressed primarily in myelin-producing oligodendrocytes (ODCs). MOG-DNA was demethylated in O4(+) ODCs in mice and in DNA from human oligodendrocyte precursor cells (OPCs) when compared with other cell types. In the cuprizone-fed mouse model of demyelination, ODC derived demethylated MOG cfDNA was increased in serum and was associated with tissue-wide demyelination, demonstrating the utility of demethylated MOG cfDNA as a biomarker of ODC death. Collected sera from patients with active (symptomatic) relapsing-remitting MS (RRMS) demonstrated a higher signature of demethylated MOG cfDNA when compared with patients with inactive disease and healthy controls. Taken together, these results offer a minimally invasive approach to measuring ODC death in the blood of MS patients that may be used to monitor disease progression., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The response of the peripheral nerve to anoxia is modulated by many factors including glucose and temperature. The purposes of this article are to demonstrate the effects of these factors on the pathological changes induced by anoxia and to compare the electrophysiologic changes and pathological changes in the same nerves., Methods: Sciatic nerves were harvested from rats and placed in a perfusion apparatus where neurophysiologic responses could be recorded continuously during a 16 h experiment. After the experiment, light microscopy and electron microscopy were performed., Results: Light microscopic images showed mild changes from anoxia at normoglycemia. Hypoglycemic anoxia produced massive axonal swelling while hyperglycemic anoxia produced apparent changes in the myelin. Anoxic changes were not uniform in all axons. Electron microscopy showed only minor disruptions of the cytoskeleton with anoxia during normoglycemia. At the extremes of glucose concentration especially with hyperglycemia, there was a more severe disruption of intermediate filaments and loss of axonal structure with anoxia. Hypothermia protected axons from the effect of anoxia and produced peak axonal swelling in the 17-30°C range., Conclusions: The combination of hyperglycemia or hypoglycemia and anoxia produces extremely severe axonal disruption. Changes in axonal diameter are complex and are influenced by many factors.

Background: The organized stroke alert is critical in quickly evaluating and treating patients with acute stroke. The purpose of this paper was to further understand how this process functions in a moderate sized general hospital by exploring the effects of patient location and time of day on the pace of evaluation and the eventual outcome of evaluation., Methods: Retrospective chart review., Results: The rate of stroke alerts depended on the time of day and patient location. There was a low probability (41%) that the eventual diagnosis was stroke after a stroke alert, but there was no effect of diagnosis on the pace of evaluation. The time between stroke alert and a computed tomography (CT) scan being read was shortest for patients in the emergency room (ER) and longer for patients in the intensive care unit (ICU) or medical/surgical floors. Patients evaluated on medical/surgical floors were less likely to receive tissue plasminogen activator (tPA) than those evaluated in the ER, even though the comorbidities were similar. This may be due to the greater severity of the comorbidities in patients who were already admitted to the hospital., Conclusion: The rate of tPA administration was lower for stroke alerts called from medical/surgical floors than from the ER. Stroke alerts were most frequent in late afternoon.

Background: The majority of spinal surgeons now utilize intraoperative neurophysiological monitoring (IONM) during spinal procedures to limit the risk of inadvertent injury. Nevertheless, probably the most frequent error is the failure of the surgeon and IONM to obtain adequate preoperative baselines (e.g. before intubation or positioning)., Methods: Intraoperative neural monitoring should begin with the spinal surgeon, anesthesiologist, and monitoring technician/neurologist reviewing the patient's neurological deficits, the operative approach, the most anticipated risks and complications as well as the type of monitoring to be used (e.g. somatosensory evoked responses [SEP], motor evoked potential [MEP] monitoring, and electromyography [EMGs]). Baseline data should accurately reflect the preoperative status of the patient, and provide the appropriate data to be monitored and maintained throughout surgery., Results: Significant but transient changes from the established preoperative baseline SEP and MEP often reflect alterations in the anesthetic technique (e.g. hypotension/hypoperfusion). However, when these changes persist, and resuscitative maneuvers have been exhausted (e.g. removing an oversized graft to avoid ischemia, utilizing total intravenous anesthesia [TIVA] correctly, reversing hypotension, changing the patient's cervical position, checking the electrode placement, checking the position of the limbs, and other factors), significant MEP/SEP changes may signal a major impending neural injury., Conclusion: IONM is only as good as how competently it is implemented by the technologist/neurologist, and understood by the surgeon and anesthesiologist. If any team member does not understand what and how the monitoring should be performed, then it becomes a useless adjunct to spinal surgery.

Case Description: A 10-year-old domestic shorthair cat was evaluated because of presumed seizures., Clinical Findings: The cat had intermittent mydriasis, hyperthermia, and facial twitching. Findings of MRI and CSF sample analysis were unremarkable, and results of infectious disease testing were negative. Treatment was initiated with phenobarbital, zonisamide, and levetiracetam; however, the presumed seizure activity continued. Results of analysis of continuous electroencephalographic recording indicated the cat had nonconvulsive status epilepticus., Treatment and Outcome: The cat was treated with phenobarbital IV (6 mg/kg [2.7 mg/lb] q 30 min during a 9-hour period; total dose, 108 mg/kg [49.1 mg/lb]); treatment was stopped when a burst-suppression electroencephalographic pattern was detected. During this high-dose phenobarbital treatment period, an endotracheal tube was placed and the cat was monitored and received fluids, hetastarch, and dopamine IV. Continuous mechanical ventilation was not required. After treatment, the cat developed unclassified cardiomyopathy, azotemia, anemia, and pneumonia. These problems resolved during a 9-month period., Clinical Relevance: Findings for the cat of this report indicated electroencephalographic evidence of nonconvulsive status epilepticus. Administration of a high total dose of phenobarbital and monitoring of treatment by use of electroencephalography were successful for resolution of the problem, and treatment sequelae resolved.

Background: Patient safety is a top priority of healthcare organizations. The Joint Commission (TJC) is now requiring that healthcare organizations promulgate polices to investigate and resolve disruptive behavior among employees., Methods: OUR AIMS IN THIS INVESTIGATION UTILIZING THE PROVIDER CONFLICT QUESTIONNAIRE (PCQ: Appendix A) included; determining what conflicts exist among a large sample of healthcare providers, how to assess the extent and frequency of disruptive behaviors, and what types of consequences result from these conflicts. The PCQ was distributed utilizing electronic postings, and predetermined e-mail lists to nurses and physicians across the US., Results: The convenience sample included 617 respondents to the questionnaire. All incomplete responses (failure to answer all 17 items on the questionnaire) were excluded from data analysis. Our major finding was that disruptive behavior was the greatest problem observed in 82% of organizations; 74% personally witnessed these behaviors, while 5% personally experienced these behaviors. Friedman analysis of variance (ANOVA) analyses demonstrated that the difference between these three estimates were significant (χ(2) = 207.8 df = 2, P < 0.0001)., Conclusion: Healthcare organizations in the US are bound by TJC regulations to develop leadership standards that address disruptive behavior. These organizations can no longer stand by and ignore behaviors that threaten not only the bottom line of the institution, but also most critically, patient safety. As more attention is being paid to recommendations and mandates from the TJC and the Institute of Medicine (IOM), we will need more data, like those provided from this study, to better document how to address, resolve, and prevent future "misbehaviors".

The functions of different G-protein αβγ subunit combinations are traditionally ascribed to their various α components. However, the discovery of similarly diverse γ subtypes raises the possibility that they may also contribute to specificity. To test this possibility, we used a gene targeting approach to determine whether the closely related γ(3) and γ(7) subunits can perform functionally interchangeable roles in mice. In contrast to single knock-out mice that show normal survival, Gng3(-/-)Gng7(-/-) double knock-out mice display a progressive seizure disorder that dramatically reduces their median life span to only 75 days. Biochemical analyses reveal that the severe phenotype is not due to redundant roles for the two γ subunits in the same signaling pathway but rather is attributed to their unique actions in different signaling pathways. The results suggest that the γ(3) subunit is a component of a G(i/o) protein that is required for γ-aminobutyric acid, type B, receptor-regulated neuronal excitability, whereas the γ(7) subunit is a component of a G(olf) protein that is responsible for A(2A) adenosine or D(1) dopamine receptor-induced neuro-protective response. The development of this mouse model offers a novel experimental framework for exploring how signaling pathways integrate to produce normal brain function and how their combined dysfunction leads to spontaneous seizures and premature death. The results underscore the critical role of the γ subunit in this process.

Background: Intraoperative neurophysiologic monitoring (IONM) is a technique that is helpful for assessing the nervous system during spine surgery., Methods: This is a review of the field describing the basic mechanisms behind the techniques of IONM. These include the most often utilized trancranial motor evoked potentials (Tc-MEPs), somatosensory evoked potentials (SSEPs), and stimulated and spontaneous EMG activity. It also describes some of the issues regarding practices and qualifications of practitioners., Results: Although the anatomic pathways responsible for the Tc-MEP and SSEP are well known and these clinical techniques have a high sensitivity and specificity, there is little published data showing that monitoring actually leads to improved patient outcomes. It is evident that IONM has high utility when the risk of injury is high, but may be only marginally helpful when the risk of injury is very low. The monitoring team must be well trained, be able to provide the surgeon feedback in real time, and coordinate activities with those of the surgical and anesthesia teams., Conclusions: Although IONM is a valuable technique that provides sensitive and specific indications of neurologic injury, it does have limitations that must be understood. Maintaining a high quality of practice with appropriately trained personnel is critical.

Background: Although the neurologic status of patients undergoing cardiac operations has been well studied at other times, there are few studies of neurologic status in the immediate postoperative state. This study used standardized nursing neurologic evaluations to describe the sequence of neurologic changes during the first few hours after cardiac operations and the factors that influence them., Methods: In this prospective study, patients arriving in the intensive care unit after cardiac operations were serially assessed using the using the Neurologic Intensive Care Evaluation (NICE) for up to 24 hours postoperatively. The study evaluated the effects on outcome of various preoperative and intraoperative variables, as well as the NICE scores., Results: Recovery of brainstem reflexes occurred at 1.4 +/- 1.4 hours, and the fully alert state occurred at a mean of 5.1 +/- 3.8 hours after admission to the intensive care unit in patients without a new neurologic deficit. Patients with new neurologic deficits or patients discharged to supervised care settings took longer to reach each neurologic milestone. Older patients, patients with more complex surgical procedures, and patients with higher cardiovascular risk factors took longer to become fully alert. The time to reach the highest NICE score was a strong predictor of the duration of intubation but only weakly predicted other outcome variables in a multivariable analysis., Conclusions: Standardized, serial nursing neurologic assessments of postoperative cardiac patients provide insight into the immediate postoperative period and may be a useful tool for early identification of patients at risk for adverse outcomes.

Detecting acute nerve compression using neurophysiologic studies is an important part of the practice of clinical intra-operative neurophysiology. The goal of this paper was to study the changes in the compound muscle action potential (CMAP) during acute mechanical compression. This is the type of injury most likely to occur during surgery. Thus, understanding the changes in the CMAP during this type of injury will be useful in the detection and prevention using intra-operative neurophysiologic monitoring. The model involved compression of the hamster sciatic nerve over a region of 1.3 mm with pressures up to 2000 mmHg for times on the order of 3 minutes. In this model CMAP amplitude dropped to 50% of its baseline value when a pressure of roughly 1000 mmHg is applied while, at the same time, nerve conduction velocities decline by only 5%. The ability to detect statistically significant changes in the CMAP at low force levels using other descriptors of the CMAP including duration, latency variation, etc alone or in conjunction with amplitude and velocity measures was investigated. However, these other parameters did not allow for earlier detection of significant changes. This study focused on a model in which nerve injury on a short time scale is purely mechanical in origin. It demonstrated that a pure compression injury produced large changes in CMAP amplitude prior to large changes in conduction velocity. On the other hand, ischemic and stretch injuries are associated with larger changes in conduction velocity for a given value of CMAP amplitude reduction.

Background: Measurements of auto and cross covariance functions are frequently used to investigate neural systems. In interpreting this data, it is commonly assumed that the largest contribution to the recordings comes from sources near the electrode. However, the potential recorded at an electrode represents the superimposition of the potentials generated by large numbers of active neural structures. This creates situations under which the measured auto and cross covariance functions are dominated by the activity in structures far from the electrode and in which the distance dependence of the cross-covariance function differs significantly from that describing the activity in the actual neural structures., Methods: Direct application of electrostatics to calculate the theoretical auto and cross covariance functions that would be recorded from electrodes immersed in a large volume filled with active neural structures with specific statistical properties., Results: It is demonstrated that the potentials recorded from a monopolar electrode surrounded by dipole sources in a uniform medium are predominantly due to activity in neural structures far from the electrode when neuronal correlations drop more slowly than 1/r3 or when the size of the neural system is much smaller than a known correlation distance. Recordings from quadrupolar sources are strongly dependent on distant neurons when correlations drop more slowly than 1/r or the size of the system is much smaller than the correlation distance. Differences between bipolar and monopolar recordings are discussed. It is also demonstrated that the cross covariance of the recorded in two spatially separated electrodes declines as a power-law function of the distance between them even when the electrical activity from different neuronal structures is uncorrelated., Conclusion: When extracellular electrophysiologic recordings are made from systems containing large numbers of neural structures, it is important to interpret measured auto and cross covariance functions cautiously in light of the long range nature of the electric fields. Using recording electrodes that are bipolar or quadrupolar minimizes or eliminates these effects and hence these electrodes are preferred when electrical recordings are made for the purpose of auto and cross correlation analysis of local electrical activity.

Background: Classifying the types of extracellular potentials recorded when neural structures are activated is an important component in understanding nerve pathophysiology. Varying definitions and approaches to understanding the factors that influence the potentials recorded during neural activity have made this issue complex., Methods: In this article, many of the factors which influence the distribution of electric potential produced by a traveling action potential are discussed from a theoretical standpoint with illustrative simulations., Results: For an axon of arbitrary shape, it is shown that a quadrupolar potential is generated by action potentials traveling along a straight axon. However, a dipole moment is generated at any point where an axon bends or its diameter changes. Next, it is shown how asymmetric disturbances in the conductivity of the medium surrounding an axon produce dipolar potentials, even during propagation along a straight axon. Next, by studying the electric fields generated by a dipole source in an insulating cylinder, it is shown that in finite volume conductors, the extracellular potentials can be very different from those in infinite volume conductors. Finally, the effects of impulses propagating along axons with inhomogeneous cable properties are analyzed., Conclusion: Because of the well-defined factors affecting extracellular potentials, the vague terms far-field and near-field potentials should be abandoned in favor of more accurate descriptions of the potentials.

The potential recorded by a set of electrodes as an action potential traverses a small axonal segment is proportional to the transmembrane potential produced during stimulation of that axon segment by the same set of recording electrodes, under certain circumstances. First, the membrane must have a constant thickness which is so small that the difference between the surface area of the inner and outer surfaces is minimal. Second, all media must be linear. Third, there must be a monotonically increasing relation between the mean transmembrane potential induced by a stimulus and the maximum transmembrane potential. Fourth, as each axon segment depolarizes, the transmembrane current and change in membrane potential during this time are same. This principle remains true for magnetic stimulation and recording as long as currents generated at the boundaries between regions of differing conductivity outside the axon contribute minimally to the field at the axon. This allows the identification of the point at which an action potential generates a maximal extracellular potential as the point that is stimulated with the lowest threshold.

Background: Neurocognitive changes are common after cardiac operations. The acute post-operative period is a critical time when significant neurologic changes may be detected and appropriate therapy initiated promptly. Formal neuropsychologic testing in this situation however is impractical so other means of early detection are required. The goal of this preliminary study was to determine whether simple, standardized, serial nursing neurologic evaluations using the Neurologic Intensive Care Evaluation (NICE) could be helpful in screening patients for neurologic injury in the immediate post-operative period., Material/methods: Details of the intra-operative and post-operative anesthetic management were obtained during report and nurses subsequently scored acute post-operative patients in the CTSICU using the NICE every half hour for the first five hours. Finally, a chart review was performed to determine the neurologic outcome of the patients., Results: The time to achieve the lower NICE scores which reflect mainly brainstem function was the same whereas the time to achieve NICE scores>4 was prolonged in patients with neurocognitive dysfunction. The effect of intra-operative factors on the times to achieve NICE scores was different for the higher and lower scores. The times to reach NICE scores correlated with outcome variables including the time in ICU and time of intubation., Conclusions: Standardized, serial nursing neurologic assessments of post-operative cardiac patients may be a useful tool for early identification of patients with neurologic injury. They may also provide useful information complementing the data obtained from detailed neuropsychologic testing on the neurologic effects of cardiac operations.

Background: Delayed postoperative paraplegia is a recognized complication of thoracic (TAA) or thoracoabdominal aortic aneurysm (TAAA) repair. The purpose of this study was to evaluate the effectiveness of interventions to treat delayed-onset paraplegia., Methods: Between January 1, 2000 and August 31, 2001, 99 patients underwent surgical repair of TAA, Crawford type I, II, or III TAAA. Standard intraoperative management included distal aortic perfusion and cerebrospinal fluid (CSF) drainage unless contraindicated. Therapeutic interventions to treat delayed paraplegia included lumbar CSF drainage and vasopressor therapy., Results: Three of the 99 patients had paraplegia upon awakening. Delayed-onset paraplegia occurred in 8 patients, 2 of whom had recurrent episodes. In those 8 patients, the initial episode occurred at a median of 21.6 hours (range 6.4 to 110.0 hours) after surgery and the second episode averaged 176 hours after surgery. At the onset of paraplegia, the average mean arterial pressure was 74 mm Hg and CSF pressure was 14 mm Hg. Three of the 8 patients had a functioning CSF catheter at the onset and the other 5 patients had catheters subsequently placed. Therapeutic interventions increased blood pressure to a mean arterial pressure of 95 mm Hg and decreased CSF pressure to 10 mm Hg. Five of the 8 patients with delayed-onset paraplegia made a full neurologic recovery and 3 had partial recovery., Conclusions: Patients with delayed-onset paraplegia had an increased chance of recovery as compared with those patients in whom paraplegia was diagnosed upon emergence from anesthesia. Acute interventions directed to increase spinal cord perfusion by increasing systemic blood pressure and decreasing CSF pressure were effective for the reversal of delayed onset of paraplegia after TAA or TAAA repair, resulting in an overall 3% incidence of permanent paraplegia and 3% incidence of residual paraparesis.

Background: The available techniques for intravascular gene delivery to the heart are inefficient and not organ-specific. Yet, effective treatment of heart failure will likely require transgene expression by the majority of cardiac myocytes. To address this problem, we developed a novel cannulation technique that achieves efficient isolation of the heart in situ using separate cardiopulmonary bypass (CPB) circuits for the heart and body in dogs., Methods: The arterial inflow and venous effluent from the two circuits were physically isolated. The efficiency of separation was 98% to 99% in three preliminary experiments using Evans Blue dye-labeled albumin. In 6 dogs, the cardiac circuit was perfused with oxygenated crystalloid cardioplegia at 37 degrees C containing approximately 4 x 10(11) particles of an adenovirus encoding LacZ (AdCMVLacZ) with a perfusion pressure of 170 to 200 mm Hg for 15 minutes allowing virus to recirculate through the heart approximately 15 times. Cross-clamp time was 26 +/- 2 minutes and CPB time was 90 +/- 3 minutes., Results: Five animals survived and were euthanized at 7 days. Beta-galactosidase activities measured using a chemiluminescent assay were three orders of magnitude higher in all areas of the heart than in the liver. Histological analyses revealed heterogeneous X-Gal staining of myocytes in all areas of the myocardium., Conclusions: Despite using a constitutive promoter, this technique yields relatively cardiac-specific transgene expression and is potentially translatable to clinical applications. Future studies will allow for further optimization of the conditions necessary for vector-mediated gene delivery to the heart.

Background: Hypothermia is used clinically to prevent neurologic injury but the degree of protection which it affords at various levels of the nervous system in humans is difficult to establish., Material/methods: The temporal changes in EEG amplitude and somatosensory evoked potential (SEP) amplitudes in a patient experiencing acute normothermic hypoxemia, a patient experiencing acute circulatory arrest at moderate hypothermia and a collection of patients undergoing deep hypothermic circulatory arrest were analyzed to determine the rate at which changes occur during acute lack of oxygen delivery at various temperatures., Results: In each case, it was found that more rostrally generated potentials disappeared more quickly than more peripheral potentials. All potentials decayed more slowly during acute normothermic hypoxemia than during circulatory arrest. During circulatory arrest at 14.4 degrees C, the amplitude of the Erb's point, N13 and N18 potentials in the SEP took 5 times longer to drop to 50% of their value at the onset of ischemia than with circulatory arrest at 30.9 degrees C., Conclusions: The longer times to disappearance of the SEP potentials during deep hypothermia compared to moderate hypothermia was consistent with the predicted 3.5-6.5 fold reduction in metabolic activity at deep hypothermia compared to moderate hypothermia. The prolonged time to disappearance of the SEP during normothermic hypoxemia demonstrates that even with reduced oxygen delivery the continued delivery of metabolic substrate can be critical to neural function.

Background: Electrophysiologic studies during rewarming after deep hypothermic circulatory arrest probe the state of the brain during this critical period and may provide insight into the neurological effects of circulatory arrest and the neurologic outcome., Methods: Electroencephalogram (EEG) and evoked potentials were monitored during rewarming in 109 patients undergoing aortic surgery with hypothermic circulatory arrest., Results: The sequence of neurophysiologic events during rewarming did not mirror the events during cooling. The evoked potentials recovered first followed by EEG burst-suppression and then continuous EEG. The time to recovery of the evoked potentials N20-P22 complex was significantly correlated with the time of circulatory arrest even in patients without postoperative neurologic deficits (r = 0.37, (p = 0.002). The nasopharyngeal temperatures at which continuous EEG activity and the N20-P22 complex returned were strongly correlated (r = 0.44, p = 0.0002; r = 0.41, p = 0.00003) with postoperative neurologic impairment. Specifically, the relative risk for postoperative neurologic impairment increased by a factor of 1.56 (95% CI 1.1 to 2.2) for every degree increase in temperature at which the EEG first became continuous., Conclusions: No trend toward shortened recovery times or improved neurologic outcome was noted with lower temperatures at circulatory arrest, indicating that the process of cooling to electrocerebral silence produced a relatively uniform degree of cerebral protection, independent of the actual nasopharyngeal temperature.

Background: Deep hypothermia is an important cerebral protectant and is critical in procedures requiring circulatory arrest. The purpose of this study was to determine the factors that influence the neurophysiologic changes during cooling before circulatory arrest, in particular the occurrence of electrocerebral silence., Methods: In 109 patients undergoing hypothermic circulatory arrest with neurophysiologic monitoring, five electrophysiologic events were selected for detailed study., Results: The mean nasopharyngeal temperature when periodic complexes appeared in the electroencephalogram after cooling was 29.6 degrees C +/- 3 degrees C, electroencephalogram burst-suppression appeared at 24.4 degrees C +/- 4 degrees C, and electrocerebral silence appeared at 17.8 degrees C +/- 4 degrees C. The N20-P22 complex of the somatosensory evoked response disappeared at 21.4 degrees C +/- 4 degrees C, and the somatosensory evoked response N13 wave disappeared at 17.3 degrees C +/- 4 degrees C. The temperatures of these various events were not significantly affected by any patient-specific or surgical variables, although the time to cool to electrocerebral silence was prolonged by high hemoglobin concentrations, low arterial partial pressure of carbon dioxide, and by slow cooling rates. Only 60% of patients demonstrated electrocerebral silence by either a nasopharyngeal temperature of 18 degrees C or a cooling time of 30 minutes., Conclusions: With the high degree of interpatient variability in these neurophysiologic measures, the only absolute predictors of electrocerebral silence were nasopharyngeal temperature below 12.5 degrees C and cooling longer than 50 minutes.

Retrograde cerebral perfusion with hypothermic circulatory arrest confers additional cerebral protection during repair of type A aortic dissection. We present a 42-year-old man with acute type A aortic dissection and a persistent, left superior vena cava. Cannulation of the right and left superior vena cava is used for retrograde perfusion of both hemispheres with bilateral monitoring of electroencephalogram and somatosensory-evoked potentials during and after the hypothermic circulatory arrest interval.

Unlabelled: Retrograde cerebral perfusion (RCP) potentially delivers metabolic substrate to the brain during surgery using hypothermic circulatory arrest (HCA). Serial measurements of O2 extraction ratio (OER), PCO2, and pH from the RCP inflow and outflow were used to determine the time course for O2 delivery in 28 adults undergoing aortic reconstruction using HCA with RCP. HCA was instituted after systemic cooling on cardiopulmonary bypass for 3 min after the electroencephalogram became isoelectric. RCP with oxygenated blood at 10 degrees C was administered at an internal jugular venous pressure of 20-25 mm Hg. Serial analyses of blood oxygen, carbon dioxide, pH, and hemoglobin concentration were made in samples from the RCP inflow (superior vena cava) and outflow (innominate and left carotid arteries) at different times after institution of RCP. Nineteen patients had no strokes, five patients had preoperative strokes, and four patients had intraoperative strokes. In the group of patients without strokes, HCA with RCP was initiated at a mean nasopharyngeal temperature of 14.3 degrees C with mean RCP flow rate of 220 mL/min, which lasted 19-70 min. OER increased over time to a maximal detected value of 0.66 and increased to 0.5 of its maximal detected value 15 min after initiation of HCA. The RCP inflow-outflow gradient for PCO2 (slope 0.73 mm Hg/min; P < 0.001) and pH (slope 0.007 U/min; P < 0.001) changed linearly over time after initiation of HCA. In the group of patients with preoperative or intraoperative strokes, the OER and the RCP inflow-outflow gradient for PCO2 changed significantly more slowly over time after HCA compared with the group of patients without strokes. During RCP, continued CO2 production and increased O2 extraction over time across the cerebral vascular bed suggest the presence of viable, but possibly ischemic tissue. Reduced cerebral metabolism in infarcted brain regions may explain the decreased rate of O2 extraction during RCP in patients with strokes., Implications: Examining the time course of oxygen extraction, carbon dioxide production, and pH changes from the retrograde cerebral perfusate provided a means to assess metabolic activity during hypothermic circulatory arrest.

Purpose: We compared propofol with high-dose barbiturates in the treatment of refractory status epilepticus (RSE) and propose a protocol for the administration of propofol in RSE in adults, correlating propofol's effect with plasma levels., Methods: Sixteen patients with RSE were included; 8 were treated primarily with high-dose barbiturates and 8 were treated primarily with propofol., Results: Both groups of patients had multiple medical problems and a subsequent high mortality. A smaller but not statistically significant fraction of patients had their seizures controlled with propofol (63%) than with high-dose barbiturate therapy (82%). The time from initiation of high-dose barbiturate therapy to attainment of control of RSE was longer (123 min) than the time to attainment of seizure control in the group receiving propofol (2.6 min, p = 0.002). Plasma concentrations of propofol associated with control of SE were 14 microM +/- 4 (2.5 microg/ml). Recurrent seizures were common when propofol infusions were suddenly discontinued but not when the infusions were gradually tapered., Conclusions: If used appropriately, propofol infusions can effectively and quickly terminate many but not all episodes of RSE. Propofol is a promising agent for use in treating RSE, but more studies are required to determine its true value in comparison with other agents.

Objectives: The objectives of this study were to determine if monitoring of intraoperative somatosensory evoked potentials could be used to detect stroke during cardiac operations and to establish indicators of cerebral ischemia based on changes in these potentials., Methods: Twenty-five patients undergoing cardiac operations underwent preoperative and postoperative neurologic examinations as well as intraoperative recording of somatosensory evoked potentials. Detailed analysis of the waveforms of these potentials was performed., Results: Two of the 25 patients had intraoperative strokes. These patients and only these patients had changes in their somatosensory evoked potentials during the operation suggesting cerebral ischemia. The unilateral disappearance of the cortical somatosensory evoked potential waves correlated significantly with the clinical outcome of stroke (p < 0.004). Ischemic changes were detected in real time and were related to the removal of the aortic crossclamp in one patient and to the initiation of cardiopulmonary bypass in the other., Conclusions: Somatosensory evoked potentials can detect intraoperative stroke during cardiac operations. Acute, unilateral decreases in amplitude of the cortical potential are more useful than changes in latency in detecting intraoperative stroke.

Unlabelled: In this paper we correlate the findings on 99mTc-HMPAO brain SPECT with the results of clinical examinations and electroencephalography to determine the utility of SPECT in the evaluation of patients with suspected status epilepticus., Methods: Thirteen patients with suspected status epilepticus underwent serial neurologic examinations, serial electroencephalograms, CT/MRI scanning and 99mTc-HMPAO SPECT. Seven patients were diagnosed with status epilepticus and six patients received other neurological diagnoses., Results: All patients with status epilepticus at the time of the brain SPECT scan demonstrated focal hyperperfusion on SPECT in an area concordant with that suggested by EEG. One patient with status epilepticus demonstrated a persistent area of hyperperfusion on SPECT 24 hr after the cessation of status with no evidence of breakdown in the blood-brain barrier demonstrated by 99mTc-DTPA SPECT. No patient in this study without a diagnosis of status epilepticus had focal areas of hyperperfusion on SPECT., Conclusion: We suggest that a 99mTc-HMPAO SPECT scan demonstrating focal hyperperfusion in a patient being evaluated for partial status epilepticus is nonspecific. Even in the absence of a structural lesion causing local breakdown in the blood-brain barrier, it may indicate either ongoing status epilepticus or recently terminated status. However, a SPECT scan demonstrating no area of focal hyperperfusion argues against the diagnosis of partial status.