Induced Coma, Death, and Organ Transplantation: A Physiologic, Genetic, and Theological Perspective.

In the clinic, the death certificate is issued if brain electrical activity is no longer detectable. However, recent research has shown that in model organisms and humans, gene activity continues for at least 96 h postmortem. The discovery that many genes are still working up to 48 h after death questions our definition of death and has implications for organ transplants and forensics. If genes can be active up to 48 h after death, is the person technically still alive at that point? We discovered a very interesting parallel between genes that were upregulated in the brain after death and genes upregulated in the brains that were subjected to medically-induced coma, including transcripts involved in neurotransmission, proteasomal degradation, apoptosis, inflammation, and most interestingly, cancer. Since these genes are involved in cellular proliferation, their activation after death could represent the cellular reaction to escape mortality and raises the question of organ viability and genetics used for transplantation after death. One factor limiting the organ availability for transplantation is religious belief. However, more recently, organ donation for the benefit of humans in need has been seen as "posthumous giving of organs and tissues can be a manifestation of love spreading also to the other side of death".

MicroRNA-9-3p: a novel predictor of neurological outcome after cardiac arrest.

AIMS: Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose after hospital arrival are at high risk of mortality due to anoxic brain injury. MicroRNA are small-non-coding RNA molecules ultimately involved in gene-silencing. They show promise as biomarkers, as they are stable in body fluids. The microRNA 9-3p (miR-9-3p) is associated with neurological injury in trauma and subarachnoid haemorrhage. METHODS AND RESULTS: This post hoc analysis considered all 171 comatose OHCA patients from a single centre in the target temperature management (TTM) trial. Patients were randomized to TTM at either 33°C or 36°C for 24 h. MicroRNA-9-3p (miR-9-3p) was measured in plasma sampled at admission and at 28, 48, and 72 h. There were no significant differences in age, gender, and pre-hospital data, including lactate level at admission, between miR-9-3p level quartiles. miR-9-3p levels changed markedly following OHCA with a peak at 48 h. Median miR-9-3p levels between TTM 33°C vs. 36°C were not different at any of the four time points. Elevated miR-9-3p levels at 48 h were strongly associated with an unfavourable neurological outcome [OR: 2.21, 95% confidence interval (CI): 1.64-3.15, P < 0.0001). MiR-9-3p was inferior to neuron-specific enolase in predicting functional neurological outcome [area under the curve: 0.79 (95% CI: 0.71-0.87) vs. 0.91 (95% CI: 0.85-0.97)]. CONCLUSION: MiR-9-3p is strongly associated with neurological outcome following OHCA, and the levels of miR-9-3p are peaking 48 hours following cardiac arrest.

Effects of Xingnaojing Injection on Adenosinergic Transmission and Orexin Signaling in Lateral Hypothalamus of Ethanol-Induced Coma Rats.

Acute alcohol exposure induces unconscious condition such as coma whose main physical manifestation is the loss of righting reflex (LORR). Xingnaojing Injection (XNJI), which came from Chinese classic formula An Gong Niu Huang Pill, is widely used for consciousness disorders in China, such as coma. Although XNJI efficiently shortened the duration of LORR induced by acute ethanol, it remains unknown how XNJI acts on ethanol-induced coma (EIC). We performed experiments to examine the effects of XNJI on orexin and adenosine (AD) signaling in the lateral hypothalamic area (LHA) in EIC rats. Results showed that XNJI reduced the duration of LORR, which implied that XNJI promotes recovery form coma. Microdialysis data indicated that acute ethanol significantly increased AD release in the LHA but had no effect on orexin A levels. The qPCR results displayed a significant reduction in the Orexin-1 receptors (OX1R) expression with a concomitant increase in the A1 receptor (A1R) and equilibrative nucleoside transporter type 1 (ENT1) expression in EIC rats. In contrast, XNJI reduced the extracellular AD levels but orexin A levels remained unaffected. XNJI also counteracted the downregulation of the OX1R expression and upregulation of A1R and ENT1 expression caused by EIC. As for ADK expression, XNJI but not ethanol, displayed an upregulation in the LHA in EIC rats. Based on these results, we suggest that XNJI promotes arousal by inhibiting adenosine neurotransmission via reducing AD level and the expression of A1R and ENT1.

Identification of novel biomarkers for prediction of neurological prognosis following cardiac arrest.

BACKGROUND: Early prognostication of neurological outcome in comatose patients after cardiac arrest (CA) is important for devising patient treatment strategies. However, there is still a lack of sensitive and specific biomarkers for easy identification of these patients. We evaluated whether molecular signatures from blood of CA patients might help to improve the prediction of neurological outcome. METHODS: We examined 22 comatose patients resuscitated after CA and obtained peripheral blood samples 48 hours after CA. To identify novel blood biomarkers, we aimed to measure neurological outcomes according to the Cerebral Performance Category (CPC) score at 6 months after CA and to determine blood transcriptome-based molecular signature of poor neurological outcome group. RESULTS: According to the CPC score, 10 patients exhibited a CPC score of one and 12 patients, a CPC score four to five. Blood transcriptomics revealed differently expressed profiles between the good outcome group and poor outcome group. A total of 150 genes were down-regulated and 237 genes were up-regulated in the poor neurological outcome group compared with good outcome group. From the blood transcriptome-based signatures, we identified that MAPK3, BCL2 and AKT1 were more specific and sensitive diagnostic biomarkers in poor neurological outcome with an area under the curve of 0.867 (p<0.0001), 0.800 (p=0.003), and 0.767 (p=0.016) respectively. CONCLUSIONS: We identify three biomarkers as potential predictors of neurological outcome following CA. Further assessment of the prognostic value of transcriptomic analysis in larger cohorts of CA patients is needed.

Recurrent coma and fever in familial hemiplegic migraine type 2. A prospective 15-year follow-up of a large family with a novel ATP1A2 mutation.

Background Familial hemiplegic migraine (FHM) is a rare monogenic migraine subtype characterised by attacks associated with transient motor weakness. Clinical information is mainly based on reports of small families with only short follow-up. Here, we document a prospective 15-year follow-up of an extended family with FHM type 2. Patients and methods After diagnosing FHM in a patient with severe attacks associated with coma and fever, we identified eight more family members with FHM and one with possible FHM. All family members were prospectively followed for 15 years. In total 13 clinically affected and 21 clinically non-affected family members were genetically tested and repeatedly investigated. Results A novel p.Arg348Pro ATP1A2 mutation was found in 14 family members: 12 with clinical FHM, one with psychomotor retardation and possible FHM, and one without FHM features. In 9/12 (75%) family members with genetically confirmed FHM, attacks were severe, long-lasting, and often associated with impaired consciousness and fever. Such attacks were frequently misdiagnosed and treated as viral meningitis or stroke. Epilepsy was reported in three family members with FHM and in the one with psychomotor retardation and possible FHM. Ataxia was not observed. Conclusion FHM should be considered in patients with recurrent coma and fever.

Fatal hyperammonaemia due to late-onset ornithine transcarbamylase deficiency.

In this case report we describe a 67-year-old male, admitted to the ICU with pneumonia who unexpectedly developed a fatal coma due to hyperammonaemia. At postmortem the diagnosis late-onset ornithine transcarbamylase deficiency was made. The non-specific clinical presentation, the rapid deterioration and incidentally the fatal outcome all underline the importance of recognition and knowledge of this genetic disorder. Several measures to treat and prevent potentially fatal episodes of hyperammonaemia are available, if only the disorder is recognised in time. In retrospect, several clues to the diagnosis were available in this fatal case, such as voluntary protein avoidance, as well as several male family members who died at a young age of an unknown cause. After his death, two daughters were discovered to be carriers of an OTC gene mutation, as well as his infant grandson. We emphasise the importance of obtaining ammonia levels in all patients with unexplained coma, seizures or cerebral oedema, irrespective of their age, especially in patients in the ICU or in an otherwise catabolic state.

Phenotypic variability in a four generation family with a p.Thr666Met CACNA1A gene mutation.

BACKGROUND: Familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6 are distinct neurological disorders associated with mutations in the CACNA1A gene. Phenotypic variability and clinical overlap are recognized. PATIENTS: We describe a 2-year-old child with transiently decreased consciousness and clinical and radiological signs of early-onset cerebellar atrophy. The family history was significant, and 11 affected members across four generations indicated an unusually wide clinical spectrum including migraine, hemiplegia, coma, and progressive cerebellar ataxia. RESULTS: The p.Thr666Met mutation of the CACNA1A gene was identified in the index patient and in five of his affected relatives who were analyzed. Our patient is the youngest one of this entity diagnosed to date. CONCLUSIONS: Taking into account such a wide clinical expression of these gene mutations, it could be more accurate to speak about "channel-related diseases" to characterize the clinical expression according to the genetic analysis and to the phenotypes associated with each CACNA1A gene mutation.

Interleukin 6 and apolipoprotein E as predictors of acute brain dysfunction and survival in critical care patients.

BACKGROUND: Delirium occurs in up to 80% of intensive care patients and is associated with poor outcomes. The biological cause of delirium remains elusive. OBJECTIVES: To determine if delirium and recovery are associated with serum levels of interleukins and apolipoprotein E over time and with apolipoprotein E genotype. METHODS: The sample consisted of 77 patients with no previous cognitive deficits who required mechanical ventilation for 24 to 96 hours. Daily serum samples were obtained for enzyme-linked immunosorbent assay measurements of interleukins 6, 8, and 10 and apolipoprotein E. DNA extracted from blood was analyzed for apolipoprotein E genotyping. The Confusion Assessment Method for the Intensive Care Unit was administered daily on days 2 through 9. RESULTS: Among the 77 patients, 23% had no delirium, 46% experienced delirium, and 31% experienced coma. Additionally, 77% had delirium or coma (acute brain dysfunction), and compared with other patients, had fewer ventilator-free days (P = .03), longer stay (P = .04), higher care needs at discharge (P = .001), higher mortality (P = .02), and higher levels of interleukin 6 (P = .03), and the APOE*3/*3 apolipoprotein E genotype (P = .05). Serum levels of apolipoprotein E correlated with levels of interleukins 8 and 10. Patients with the E4 allele of apolipoprotein E had shorter duration of delirium (P = .02) and lower mortality (P = .03) than did patients without this allele. CONCLUSIONS: Apolipoprotein E plays a complex role in illness response and recovery in critically ill patients. The relationship between apolipoprotein E genotype and brain dysfunction and survival is unclear.

[Circadian clock genes expression in peripheral blood mononuclear cells of comatose patients]. / Expression des genes de l'horloge circadienne dans les cellules sanguines mononuclées chez des comateux.

BACKGROUND: Recently circadian clock genes have been identified in humans but information regarding their expression has remained very limited. The evaluation of circadian variations in the expression of clock genes in humans seems to be a major importance both from a fundamental point of view as a diagnostic and therapeutic perspective. In this context, several works including ours have described the fluctuation of clock genes. AIMS: describing rhythmic expression of clock genes in intensive care units patients during 24h and we tried to determine the effect of the absence of synchronizers such as light/ dark cycle on these rhythms. METHODS: 15 patients received care in private room in intensive care units in the hospital Sahloul (5 comatous and 10 non comatous patients). For RNA isolation we used peripheral blood mononuclear cells which represent an ideal material to investigate non-invasively the human clock at the molecular level. RESULTS: In the present study, we noticed that clock genes mRNA exhibit a circadian expression in comatose patients, while the rhythmicity of some studied genes disappeared in non-comatose patients. CONCLUSION: The disturbance of the rhythmic fluctuation of the clock genes could be the result of the effect of surgery on some biological rhythms as it could be explained by the lack of synchronizers in intensive care units such as light/dark cycle.

Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.

BACKGROUND: Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier. OBJECTIVES: To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU. PATIENTS AND MEASUREMENTS: In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1ß, and monocyte chemotactic protein-1. RESULTS: Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05). CONCLUSIONS: Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.

Hemiplegic migraine, seizures, progressive spastic paraparesis, mood disorder, and coma in siblings with low systemic serotonin.

BACKGROUND: Serotonin has an important role in vascular resistance and blood pressure control, and a functional serotonin transporter polymorphism has been associated with migraine. Disturbances in serotonin metabolism have been associated with autism, depression, and myoclonus related conditions, but serotonin has far more functions in the body. Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura in which attacks are associated with hemiparesis. CASES: We present two siblings with hemiplegic migraine, depression, progressive spastic paraparesis, myelopathy, and spinal cord atrophy. One of the sisters presented with prolonged coma after a migraine episode. Both sisters were found to have low cerebrospinal fluid serotonin metabolite (5-hydroxyindoleacetic acid), low platelet serotonin levels, and diminished serotonin transport capacity. Their clinical symptoms improved on 5-hydroxytryptophan replacement therapy. Mutational analysis of the CACNA1A and ATP1A2 genes was negative. CONCLUSION: This is the first time that systemic serotonin deficiency has been described in familial hemiplegic migraine. We hypothesize that the deficiency of serotonin transport may be part of a complex cellular membrane trafficking dysfunction involving not only the serotonin transporter but also other transporters and ion channels.

A new genetic model of activity-induced Ras signaling dependent pre-synaptic plasticity in Drosophila.

Techniques to induce activity-dependent neuronal plasticity in vivo allow the underlying signaling pathways to be studied in their biological context. Here, we demonstrate activity-induced plasticity at neuromuscular synapses of Drosophila double mutant for comatose (an NSF mutant) and Kum (a SERCA mutant), and present an analysis of the underlying signaling pathways. comt; Kum (CK) double mutants exhibit increased locomotor activity under normal culture conditions, concomitant with a larger neuromuscular junction synapse and stably elevated evoked transmitter release. The observed enhancements of synaptic size and transmitter release in CK mutants are completely abrogated by: a) reduced activity of motor neurons; b) attenuation of the Ras/ERK signaling cascade; or c) inhibition of the transcription factors Fos and CREB. All of which restrict synaptic properties to near wild type levels. Together, these results document neural activity-dependent plasticity of motor synapses in CK animals that requires Ras/ERK signaling and normal transcriptional activity of Fos and CREB. Further, novel in vivo reporters of neuronal Ras activation and Fos transcription also confirm increased signaling through a Ras/AP-1 pathway in motor neurons of CK animals, consistent with results from our genetic experiments. Thus, this study: a) provides a robust system in which to study activity-induced synaptic plasticity in vivo; b) establishes a causal link between neural activity, Ras signaling, transcriptional regulation and pre-synaptic plasticity in glutamatergic motor neurons of Drosophila larvae; and c) presents novel, genetically encoded reporters for Ras and AP-1 dependent signaling pathways in Drosophila.

Congenital ataxia, mental retardation, and dyskinesia associated with a novel CACNA1A mutation.

The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependent P/Q-type Ca( 2+) channels. Mutations in this gene result in clinical heterogeneity, and present with either chronic progressive symptoms, paroxysmal events, or both, with clinical overlap among the different phenotypes. The authors describe a seven year-old boy with mental retardation and congenital cerebellar ataxia that developed dyskinesia at the age of a few months, and recurrent episodes of coma following mild head trauma associated with motor and autonomic signs, from the second year of life. An extensive metabolic evaluation, interictal electroencephalography (EEG), and muscle biopsy were normal. Brain magnetic resonance imaging (MRI) during one of these episodes revealed edema of the right hemisphere and cerebellar atrophy. Genetic testing revealed a R1350Q mutation in the CACNA1A gene. This is a novel de novo mutation.Congenital cerebellar ataxia can be a result of CACNA1A mutations, especially when associated with recurrent unexplained coma.

Life-threatening dextromethorphan intoxication associated with interaction with amitriptyline in a poor CYP2D6 metabolizer: a single case re-exposure study.

We report a case of life-threatening intoxication and a controlled re-exposure study to dextromethorphan. A 60-year-old man developed postsurgical neuropathic cervical pain treated by hydromorphone, gabapentin, clonazepam, and amitriptyline. He received a dextromethorphan preparation for a catarrhal syndrome. Two days later, he was admitted into an emergency department in a profound coma. Thirty-six hours later, after withdrawal of all drugs, the situation normalized. A genotyping for UDP-glucuronyltransferase 1A1 and CYP2D6 was followed by a re-exposure study. During the three days, vital parameters and side effects of drugs were prospectively recorded. The second day, dextromethorphan was introduced. No significant impairment in parameters nor influence on analgesic efficacy were noted. Dextromethorphan concentrations suggested an accumulation without reaching any steady state. Somnolence was noted for plasma concentrations around 100ng/mL. The CYP2D6*4 variant leading to a poor metabolizer phenotype was found. Moreover, this phenotype was potentially aggravated by amitriptyline intake. This study allowed the identification and the confirmation of the cause of the coma. In conclusion, it is probably wise to recommend avoiding dextromethorphan in patients taking tricyclic antidepressants or another inhibitor of CYP2D6. Drug-drug interactions are probably underdiagnosed and underreported, and drugs considered as safe may induce serious complications.

Acute hyperammonemic coma with chronic valproic acid therapy.

OBJECTIVE: To report a case of dose-related hyperammonemic coma without liver failure in a patient receiving chronic valproate therapy. CASE SUMMARY: A 56-year-old woman with poorly controlled epilepsy, receiving valproate at subtherapeutic levels for 6 years, developed a life-threatening hyperammonemic coma following a moderate dosage increase. DISCUSSION: Hyperammonemic coma without associated liver failure is an extremely rare complication of valproate therapy, described primarily in patients with inborn errors of metabolism and occurring idiosyncratically during initial stages of therapy. In our case, family history was suggestive of an X-linked disorder, raising the possibility that our patient may have been an asymptomatic carrier of a urea cycle enzyme deficiency unmasked by valproate therapy. To our knowledge, as of October 24, 2005, only one prior case of hyperammonemic coma in the context of chronic valproate monotherapy has been described. Application of the Naranjo probability scale score suggests that a causal relationship between valproic acid and hyperammonemic coma was probable. CONCLUSIONS: The widespread use of valproic acid emphasizes the need to maintain a high degree of suspicion with respect to this rare but potentially fatal adverse effect at all times, regardless of therapy duration.

Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II.

The authors report a patient with familial hemiplegic migraine type II who developed a long-lasting attack including fever, right-sided hemiplegia, aphasia, and coma. Quantitative analysis of early gadolinium-enhanced MRI revealed a mild but significant left-hemispheric blood-brain barrier (BBB) opening limited to the cortex and preceding cortical edema. The findings suggest that the delayed cortical edema was vasogenic in the severe migraine aura variant of this ATP1A2 mutation carrier.