EEG dynamics induced by zolpidem forecast consciousness evolution in prolonged disorders of consciousness.

OBJECTIVE: To explore whether the EEG dynamics induced by zolpidem can predict consciousness evolution in patients with prolonged disorders of consciousness (PDOC). METHODS: We conducted a prospective explorative analysis on thirty-six patients with PDOC and eleven healthy controls. The EEG power spectrum was analyzed and categorized into 'ABCD' patterns at baseline and one hour after zolpidem administration at 10 mg. The clinical outcome was defined as consciousness improvement and no improvement six months after enrollment using the Coma Recovery Scale-Revised (CRS-R) score. RESULTS: Zolpidem administration significantly increased the EEG power in the delta & theta bands and decreased EEG power in the beta bands in healthy controls. Further follow-up studies indicated that the increased EEG beta-band power induced by zolpidem can predict an improved consciousness six months after enrollment with an area under the receiver operating characteristic curve (AUC) of 0.829, the sensitivity of 94.38% and an accuracy of 81.48%. CONCLUSIONS: Our work revealed that the specific EEG responses to zolpidem can predict consciousness recovery in PDOC patients. SIGNIFICANCE: The zolpidem-induced specific EEG responses could potentially predict the recovery of PDOC patients, which may help clinicians and patients' families in their decision-making process.

A decreasing plasma concentration of a toxicologically active metabolite 9-carboxymethoxymethylguanine after dialysis - A potential new clinical biomarker for improving encephalopathy in patients treated with acyclovir.

Although acyclovir is a key drug for the treatment of herpes infections, a consciousness disorder known as "acyclovir encephalopathy" is among its side effects. We encountered a patient with encephalopathy and measured the plasma and cerebrospinal fluid concentrations of acyclovir and its toxicologically active metabolite 9-carboxymethoxymethylguanine (CMMG). Before dialysis, cerebrospinal fluid concentrations of acyclovir and CMMG in this patient with a consciousness disorder were approximately 10% and 1%, respectively, of their plasma concentrations. After 3 days of dialysis, plasma CMMG levels decreased to detectable but below quantitative levels (<0.1 µg/mL), resulting in normal consciousness. These results suggest that decreasing plasma CMMG concentration could be one of clinical biomarkers for improving consciousness in patients with encephalopathy associated with acyclovir.

Aperiodic brain activity and response to anesthesia vary in disorders of consciousness.

In the human electroencephalogram (EEG), oscillatory power co-exist with non-oscillatory, aperiodic activity. Although EEG analysis has traditionally focused exclusively on oscillatory power, recent investigations have shown that the aperiodic EEG component can distinguish conscious wakefulness from sleep and anesthetic-induced unconsciousness. This study investigates the aperiodic EEG component of individuals in a disorder of consciousness (DOC); how it changes in response to exposure to anesthesia; and how it relates to the brain's information richness and criticality. High-density EEG was recorded from 43 individuals in a DOC, with 16 of these individuals undergoing a protocol of propofol anesthesia. The aperiodic component was defined by the spectral slope of the power spectral density. Our results demonstrate that the EEG aperiodic component is more informative about the participants' level of consciousness than the oscillatory component, especially for patients that suffered from a stroke. Importantly, the pharmacologically induced change in the spectral slope from 30 to 45 Hz positively correlated with individual's pre-anesthetic level of consciousness. The pharmacologically induced loss of information-richness and criticality was associated with individual's pre-anesthetic aperiodic component. During exposure to anesthesia, the aperiodic component distinguished individuals with DOC, according to their 3-month recovery status. The aperiodic EEG component has been historically neglected; this research highlights the necessity of considering this measure for the assessment of individuals in DOC and future research that seeks to understand the neurophysiological underpinnings of consciousness.

[A Case of Esophageal Cancer with Consciousness Disorder Due to Hyperammonemia during FP Treatment].

Hyperammonemia induced by 5-fluorouracil(5-FU)is known as a rare adverse event, but there are few reports of hyperammonemia occurring during FP(5-FU plus CDDP)treatment for esophageal cancer. We report a case of esophageal cancer with consciousness disorder due to hyperammonemia during FP treatment with an examination of some of the relevant literature. The patient was a man of approximately 70 years of age who was received FP treatment. He showed consciousness disorder on day 4. A blood test showed hyperammonemia(427µg/dL), which was considered to be the cause of his consciousness disorder. He was treated with branched chain amino acid infusion, lactulose and kanamycin and made a full recovery. An operation for esophageal cancer was performed after 3 months and he is currently followed up without recurrence. Hyperammonemia should be considered as a differential diagnosis of consciousness disorder during chemotherapy including 5-FU.

Dextromethorphan-Induced Altered Level of Consciousness in Children: A Case Series.

BACKGROUND: Dextromethorphan, an N-methyl-d-aspartate receptor antagonist, has been used as cold and cough medication. Serious adverse events with therapeutic doses of dextromethorphan are rarely observed. Here, we report three cases of altered levels of consciousness in children with a therapeutic dose of dextromethorphan. CASE PRESENTATION: In all three cases, children developed an altered level of consciousness after taking the first dose of syrup dextromethorphan. Children were unresponsive to any verbal command and pain stimuli. Medical history revealed no pre-existing comorbidities. Other systemic, cardiovascular, abdominal, respiratory and nervous system examinations were normal. All patients were hospitalised and managed with symptomatic and supportive care. Dextromethorphan was stopped. After adequate treatment, all of them recovered satisfactorily. The causality assessment was done based on the World Health Organization Uppsala Monitoring Centre causality scale, and it was probable/likely in all three cases. CONCLUSION: In children, an altered level of consciousness could occur with therapeutic doses of dextromethorphan; hence, health care professionals should prescribe dextromethorphan with extreme caution.

Brain Responses to Propofol in Advance of Recovery from Coma and Disorders of Consciousness: A Preliminary Study.

Rationale: Predicting recovery of consciousness in unresponsive, brain-injured individuals has crucial implications for clinical decision-making. Propofol induces distinctive brain network reconfiguration in the healthy brain as it loses consciousness. In patients with disorders of consciousness, the brain network's reconfiguration to propofol may reveal the patient's underlying capacity for consciousness. Objectives: To design and test a new metric for the prognostication of consciousness recovery in disorders of consciousness. Methods: Using a within-subject design, we conducted an anesthetic protocol with concomitant high-density EEG in 12 patients with a disorder of consciousness after a brain injury. We quantified the reconfiguration of EEG network hubs and directed functional connectivity before, during, and after propofol exposure and obtained an index of propofol-induced network reconfiguration: the adaptive reconfiguration index. We compared the index of patients who recovered consciousness 3 months after EEG (n = 3) to that of patients who did not recover or remained in a chronic disorder of consciousness (n = 7) and conducted a logistic regression to assess prognostic accuracy. Measurements and Main Results: The adaptive reconfiguration index was significantly higher in patients who later recovered full consciousness (U value = 21, P = 0.008) and able to discriminate with 100% accuracy whether the patient recovered consciousness. Conclusions: The adaptive reconfiguration index of patients who recovered from a disorder of consciousness at 3-month follow-up was linearly separable from that of patients who did not recover or remained in a chronic disorder of consciousness on the single-subject level. EEG and propofol can be administered at the bedside with few contraindications, affording the adaptive reconfiguration index tremendous translational potential as a prognostic measure of consciousness recovery in acute clinical settings.

[Overdose from a patch]. / Überdosis durch ein Pflaster.

HISTORY AND CLINICAL FINDINGS: We present the case of an 89-year-old patient with impaired consciousness for whom the emergency services were called. She was soporose and showed a pronounced generalized muscle rigidity. Due to a third-party history the incorrect use of a fentanyl patch was found out to be at cause. TREATMENT AND CLINICAL COURSE: The antidote administration of naloxone led to restoration. The need for repetitive administration confirmed the clinical hypothesis. CONCLUSION: The application of fentanyl via the skin in the form of transdermal therapeutic systems (TTS) has become more popular over the years. Incorrect administration causes intoxication with the leading symptoms of loss of consciousness and respiratory depression. This case report extends the spectrum of symptoms to include skeletal muscle rigidity otherwise only described in connection with intravenous administration, especially in anaesthetic settings.

Cholinergic crisis caused by ingesting topical carpronium chloride solution: A case report.

A cholinergic crisiss is a state characterized by excess acetylcholine owing to the ingestion of cholinesterase inhibitors or cholinergic agonists. We report the first case of a cholinergic crisis after the ingestion of a carpronium chloride solution, a topical solution used to treat alopecia, seborrhea sicca, and vitiligo. An 81-year-old woman with no prior medical history was transported to our emergency department because the patient had disturbance of consciousness after ingesting three bottles of FUROZIN® solution (90 mL, 4500 mg as carpronium chloride). A family member who found the patient called for emergency medical services (EMS) personnel, who contacted the patient ten minutes after ingestion. The patient's Glasgow Coma Scale score was 12 (E4V3M5), and vital signs were as follows: blood pressure, 80/40 mmHg; heart rate, 40 beats/min. The patient vomited repeatedly in the ambulance. On arrival to the ED, the patient's systolic blood pressure and heart rate temporarily decreased to 80 mmHg and 40 beats/min, respectively. Seventy-eight minutes after ingestion, gastric lavage was performed. The patient's symptoms, which included excess salivation, sweating, and hot flush, improved 24 h after ingestion, and the patient's vital signs stabilized without atropine or vasopressors. On the second day of admission, the patient was examined by a psychiatrist and discharged without suicidal ideation. Carpronium chloride has a chemical structure similar to that of acetylcholine; therefore, it exhibits both cholinergic and local vasodilatory activities. There is limited information on the pharmacokinetics of ingested carpronium chloride; therefore, physicians should be made aware that ingesting a carpronium chloride solution may cause a cholinergic crisis.

Acute subjective effects in LSD- and MDMA-assisted psychotherapy.

BACKGROUND: Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s-1980s, and are currently being re-investigated as treatments for several psychiatric disorders. In Switzerland, limited medical use of these substances is possible in patients not responding to other treatments (compassionate use). METHODS: This study aimed to describe patient characteristics, treatment indications and acute alterations of mind in patients receiving LSD (100-200 µg) and/or MDMA (100-175 mg) within the Swiss compassionate use programme from 2014-2018. Acute effects were assessed using the 5 Dimensions of Altered States of Consciousness scale and the Mystical Experience Questionnaire, and compared with those in healthy volunteers administered with LSD or MDMA and patients treated alone with LSD in clinical trials. RESULTS: Eighteen patients (including 12 women and six men, aged 29-77 years) were treated in group settings. Indications mostly included posttraumatic stress disorder and major depression. Generally, a drug-assisted session was conducted every 3.5 months after 3-10 psychotherapy sessions. LSD induced pronounced alterations of consciousness on the 5 Dimensions of Altered States of Consciousness scale, and mystical-type experiences with increases in all scales on the Mystical Experience Questionnaire. Effects were largely comparable between patients in the compassionate use programme and patients or healthy subjects treated alone in a research setting. CONCLUSION: LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects. The data may serve as a basis for further controlled studies of substance-assisted psychotherapy.

Toxic transdermal absorption of isopropyl alcohol with falsely elevated creatinine.

Transdermal absorption of isopropyl alcohol (IPA) can cause toxicity at high doses, but case reports of this phenomenon are limited. This is a single patient encounter and chart review describing a 33-year-old previously healthy female who presented obtunded, wrapped in IPA soaked round cotton pads with overlying shrink wrap, her family's home remedy for a mild persistent rash. This case highlights several interesting aspects of IPA toxicity, including evidence that toxic doses of IPA are possible through transdermal absorption and creatinine may be falsely elevated due to acetone's interference with the measurement of creatinine on some assays.

Asymmetric neural dynamics characterize loss and recovery of consciousness.

Anesthetics are known to disrupt neural interactions in cortical and subcortical brain circuits. While the effect of anesthetic drugs on consciousness is reversible, the neural mechanism mediating induction and recovery may be different. Insight into these distinct mechanisms can be gained from a systematic comparison of neural dynamics during slow induction of and emergence from anesthesia. To this end, we used functional magnetic resonance imaging (fMRI) data obtained in healthy volunteers before, during, and after the administration of propofol at incrementally adjusted target concentrations. We analyzed functional connectivity of corticocortical and subcorticocortical networks and the temporal autocorrelation of fMRI signal as an index of neural processing timescales. We found that en route to unconsciousness, temporal autocorrelation across the entire brain gradually increased, whereas functional connectivity gradually decreased. In contrast, regaining consciousness was associated with an abrupt restoration of cortical but not subcortical temporal autocorrelation and an abrupt boost of subcorticocortical functional connectivity. Pharmacokinetic effects could not account for the difference in neural dynamics between induction and emergence. We conclude that the induction and recovery phases of anesthesia follow asymmetric neural dynamics. A rapid increase in the speed of cortical neural processing and subcorticocortical neural interactions may be a mechanism that reboots consciousness.

Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice.

BACKGROUND: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. METHODS: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose-response effects of cumulative LSD doses (5-160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex. RESULTS: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose-response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex. CONCLUSION: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Dose-response relationships of psilocybin-induced subjective experiences in humans.

BACKGROUND: Psilocybin is the psychoactive component in Psilocybe mushrooms ('magic mushrooms'). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies. AIM: Establishing dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups. METHOD: We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose-response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale. RESULTS: Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose. CONCLUSION: Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences.

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings.

BACKGROUND: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings. AIMS: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. "set" and "setting"), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings. METHODS: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants. RESULTS: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band. CONCLUSIONS: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.

Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.

Electrocardiographic findings of methanol toxicity: a cross-sectional study of 356 cases in Iran.

BACKGROUND: Methanol is widely used in industry; however, methanol poisoning is not common. In this regard, a number of outbreaks have been recently reported due to inappropriate processing of alcoholic beverages. Shiraz, a city located in the southern part of Iran, faced one of such outbreaks in 2020 during COVID-19 pandemic. There is no sufficient literature on the electrocardiographic findings in methanol toxicity. This study aimed to address this gap in the literature. METHOD: A total of 356 cases with methanol toxicity referred to Shiraz University of Medical Science Tertiary Hospitals (Faghihi and Namazi) in March and April, 2020. The clinical findings of blindness and impaired level of consciousness, lab data such as arterial blood gas, electrolytes, and creatinine, and the most common findings from ECGs were collected. RESULTS: The most common ECG findings were J point elevation (68.8%), presence of U wave (59.2%), QTc prolongation (53.2% in males and 28.6% in females), and fragmented QRS (33.7%). An outstanding finding in this study was the presence of myocardial infarction in 5.3% of the cases. This finding, to the best of our knowledge, has only been reported in a few case reports. Brugada pattern (8.1%) and Osborn wave (3.7%) were the other interesting findings. In multivariate analysis, when confounding factors were adjusted, myocardial infarction, atrioventricular conduction disturbances, sinus tachycardia, and the prolonged QTC > 500 msecond were four independent factors correlated with methanol toxicity severity measured with arterial blood PH on arterial blood gas measurements, with odds ratios of 12.82, 4.46, 2.32 and 3.15 (P < 0.05 for all), respectively. CONCLUSION: Electrocardiographic variations during methanol intoxication are remarkable and well-correlated with poisoning severity. Myocardial infarction was an egregious and yet a common concerning finding in this sample, which need to be ruled out in methanol toxicity.

Level of Consciousness Is Dissociable from Electroencephalographic Measures of Cortical Connectivity, Slow Oscillations, and Complexity.

Leading neuroscientific theories posit a central role for the functional integration of cortical areas in conscious states. Considerable evidence supporting this hypothesis is based on network changes during anesthesia, but it is unclear whether these changes represent state-related (conscious vs unconscious) or drug-related (anesthetic vs no anesthetic) effects. We recently demonstrated that carbachol delivery to prefrontal cortex (PFC) restored wakefulness despite continuous administration of the general anesthetic sevoflurane. By contrast, carbachol delivery to parietal cortex, or noradrenaline delivery to either prefrontal or parietal cortices, failed to restore wakefulness. Thus, carbachol-induced reversal of sevoflurane anesthesia represents a unique state that combines wakefulness with clinically relevant anesthetic concentrations in the brain. To differentiate the state-related and drug-related associations of cortical connectivity and dynamics, we analyzed the electroencephalographic data gathered from adult male Sprague Dawley rats during the aforementioned experiments for changes in functional cortical gamma connectivity (25-155 Hz), slow oscillations (0.5-1 Hz), and complexity (<175 Hz). We show that higher gamma (85-155 Hz) connectivity is decreased (p ≤ 0.02) during sevoflurane anesthesia, an expected finding, but was not restored during wakefulness induced by carbachol delivery to PFC. Conversely, for rats in which wakefulness was not restored, the functional gamma connectivity remained reduced, but there was a significant decrease (p < 0.001) in the power of slow oscillations and increase (p < 0.001) in cortical complexity, which was similar to that observed during wakefulness induced after carbachol delivery to PFC. We conclude that the level of consciousness can be dissociated from cortical connectivity, oscillations, and dynamics.SIGNIFICANCE STATEMENT Numerous theories of consciousness suggest that functional connectivity across the cortex is characteristic of the conscious state and is reduced during anesthesia. However, it is unknown whether the observed changes are state-related (conscious vs unconscious) or drug-related (drug vs no drug). We used a novel rat model in which cholinergic stimulation of PFC produced wakefulness despite continuous exposure to a general anesthetic. We demonstrate that, as expected, general anesthesia reduces connectivity. Surprisingly, the connectivity remains suppressed despite pharmacologically induced wakefulness in the presence of anesthetic, with restoration occurring only after the anesthetic is discontinued. Thus, whether an animal exhibits wakefulness or not can be dissociated from cortical connectivity, prompting a reevaluation of the role of connectivity in level of consciousness.

Impaired consciousness, hypokalaemia and renal tubular acidosis in sustained Nurofen Plus abuse.

Ibuprofen-induced renal tubular acidosis is a rare but important diagnosis which should be considered in patients presenting with hypokalaemia and metabolic acidosis. This case report details the case of a 33-year-old woman presenting with reduced conscious state, metabolic acidosis and profound hypokalaemia without an obvious cause. With correction of the patient's electrolyte and acid-base disturbance, her conscious state improved allowing disclosure of her use of Nurofen Plus for its euphoric opiate effects. The diagnosis of renal tubular acidosis had been considered and subsequent disclosure of excessive chronic ingestion of ibuprofen suggested this to be the underlying cause. The striking feature of our patient was the insidious development of the problem and delayed accurate drug history. An important safety message arising from our case is the composite risk of dependence on the opiate component of over the counter analgesics, such as Nurofen Plus, and adverse events related to the ibuprofen component.