- Email: [email protected]
Traumatic brain injury research highlights in 2015
2015 Round-up
proteins. This mechanism of proteome widening has enormous biological influence and a very high level of complexity. However, to what extent single nucleotide variants (SNVs) can influence RNA alternative splicing is only partly known. Xiong and colleagues,4 using an original machine-learning bioinformatic approach, discovered that more than 20 000 SNVs, including missense, nonsense, and even synonymous SNVs, could regulate the number of exons in cell-specific mRNAs. The authors successfully validated their novel computational model in spinal muscle atrophy, the second most frequent autosomal-recessive disease of childhood and one of the leading causes of death in infancy. Their reliable prediction model expands the potentialities of genome-wide association studies through the identification of new disease-causing RNA splicing alterations that could represent putative therapeutic targets. Altered balance between protein synthesis and degradation leading to intracellular accumulation of misfolded protein aggregates and failure of clearance mechanisms are emerging mechanisms in ALS and Charcot-Marie-Tooth neuropathy. Endoplasmic reticulum stress has a key role in regulating proteostasis through the activation of the unfolded protein response. A first-line adaptive response against misfolded protein accumulation is the phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) that leads to decreased protein synthesis. The enhancement of this self-limiting response seems crucial to rescue cells from misfolded protein accumulation. Das and colleagues5 demonstrated that
sephin 1 selectively binds and inhibits the regulatory subunit of eIF2α phosphatase and safely prevents molecular, morphological, and motor impairment in transgenic mouse models of superoxide dismutase 1-associated amyotrophic lateral sclerosis and myelin protein zero-associated Charcot-Marie-Tooth (CMT1B). These findings, while providing a specific basis for disease-modifying treatment of amyotrophic lateral sclerosis and CMT1B, open new scenarios on therapies for a broader range of diseases associated with misfolded protein accumulation. Adriano Chiò, Giuseppe Lauria “Rita Levi Montalcini” Department of Neuroscience, University of Turin (AC); Neuroscience Institute of Turin (AC); Institute of Cognitive Sciences and Technologies, Consiglio Nazionale delle Ricerche, Rome, Italy (AC); Department of Clinical Neurosciences, IRCCS Foundation, “Carlo Besta” Neurological Institute, Milan, Italy (GL) [email protected] AC serves on the editorial advisory board of Amyotrophic Lateral Sclerosis; he declares grants from the Italian Ministry of Health and the European Commission; he serves on scientific advisory boards for Biogen Idec, Cytokinetics, Neuraltus, and Italfarmaco. GL declares no competing interests. 1
2 3
4
5
Cirulli ET, Lasseigne BN, Petrovski S, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 2015; 347: 1436–41. Zhang K, Donnelly CJ, Haeusler AR, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 2015; 525: 56–61. Freibaum BD, Lu Y, Lopez-Gonzalez R, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 2015; 525: 129–33. Xiong HY, Alipanahi B, Lee LJ, et al. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science 2015; 347: 1254806. Das I, Krzyzosiak A, Schneider K, et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 2015; 348: 239–42.
Traumatic brain injury research highlights in 2015 Traumatic brain injury (TBI) research is in the midst of a golden age in both preclinical and clinical arenas, emphasised by large comparative effectiveness trials targeting the need for stronger evidence-based care. These trials include the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) trial in adults and the Approaches and Decisions for Acute Pediatric TBI (ADAPT) trial in children,1,2 along with the development of clinical and preclinical common data elements.3,4 Other factors fueling this golden age are funding from the US Department of Defense for www.thelancet.com/neurology Vol 15 January 2016
research on blast-induced TBI and its links to posttraumatic stress disorder, and the media storm that has accompanied both the identification of chronic traumatic encephalopathy (CTE) resulting from mild repetitive TBI in elite athletes and the possibility that TBI is linked to the development of many neurodegenerative diseases.5 The range of publications on TBI in 2015 (more than 2800) includes notable clinical and preclinical reports. Two clinical trials were noteworthy. Nichol and colleagues6 published the results of a multicentre 13
2015 Round-up
Amelie-Benoist/BSIP/Science Photo Library
randomised controlled trial (RCT) of the use of erythropoietin (40000 units given within 24 h) to treat moderate or severe TBI (NCT00987454). Disappointingly, erythropoietin failed to improve 6-month Extended Glasgow Outcome Scale Extended (GOS-E) score (the primary outcome) compared with placebo. This report follows another high-quality negative clinical trial of erythropoietin in severe TBI (NCT00313716).7 Erythropoietin also did not increase the occurrence of deep venous thrombosis, which has been suggested to contribute to its failure in stroke trials. Surprisingly, despite more than 20 preclinical studies showing benefit of erythropoietin in TBI, clinical trials failed to replicate this finding. Because clinical trial design in TBI offers unique challenges, (eg, patient heterogeneity) it might be necessary in preclinical research for treatments to show highly robust benefit across several heterogeneous models. Such an approach is underway in work being done by the multicentre preclinical drug-screening consortium, Operation Brain Trauma Therapy.8 Advances in both clinical trial design and rigorous multicentre preclinical therapeutic screening seem important to successful translation of effective treatments for TBI. In another important clinical trial, Andrews and colleagues9 studied 387 patients in a multicentre RCT that compared the use of mild-to-moderate hypothermia (35–32°C) with the initiation of hyperosmolar treatment (guidelines-based standard care) for patients with refractory intracranial
14
hypertension (intracranial pressure >20 mm Hg). Remarkably, a favourable outcome (based on 6-month GOS-E) was more often seen in the control group (37%) than the hypothermia group (26%, p=0·03). This report adds to the list of studies failing to show the use of hypothermia in treatment of severe TBI, which have moved clinical care of TBI to an era of targeted temperature management (controlled normothermia or ultra-mild hypothermia [36°C]) rather than conventional hypothermia. Three preclinical reports stand out in 2015. In a series of seminal investigations, the laboratory of Malik Nedergaard has defined a brain-wide network of paravascular channels, termed the glymphatic pathway, which helps clearance of solutes and proteins from the brain via CSF flow through the parenchyma. The investigators’ preclinical research also reveals an enduring impairment of glymphatic pathway function (by about 60%) after TBI.10 The glymphatic pathway could have broad implications for patient management and outcome in TBI, including an effect on mechanisms ranging from acute intracranial hypertension to CTE. An active area of research in TBI is in the development of serum biomarkers such as glial fibrillary acidic protein for diagnostic applications and therapeutic monitoring. This year, Plog and colleagues11 showed in a murine TBI model that CSF movement in the glymphatic pathway transports biomarkers from the brain into the blood via the cervical lymphatics, rather than biomarker transit being reliant solely on a disrupted blood–brain barrier. The researchers showed that many clinically relevant factors influence glymphatic flux, such as CSF drainage and sleep. These findings could affect serum biomarker development and data interpretation after TBI and also help explain how brain injury biomarkers can be detected in serum after CNS insults that are not accompanied by blood–brain barrier disruption, such as cardiac arrest. The effect of this pathway on TBI is only beginning to be understood, but might ultimately change patient management. In a provocative study, Kondo and colleagues12 reported on the acute accumulation and spread of cisphosphorylated tau protein (cis P-tau) in injured murine brain after TBI. Accumulation of this toxic tau isomer disrupts axonal microtubule networks and leads to apoptosis. The authors coined the term cistauosis for www.thelancet.com/neurology Vol 15 January 2016
2015 Round-up
this process after TBI and showed that treatment with a monoclonal antibody specifically targeting cis P-tau prevented its spread and improved several outcomes. The possibility that blocking this pathway could have therapeutic implications for both acute and chronic sequelae of TBI is appealing, and merits additional exploration. Finally, consistent with the emerging use of targeted temperature management in neurocritical care of TBI, it is well known that hyperthermia and fever are deleterious. Titus and colleagues13 in the laboratory of Dalton Dietrich reported that brief periods of hyperthermia (39°C) at the time of extremely mild fluid percussion TBI in rats produced cognitive deficits after 1 week despite an injury level that was otherwise devoid of behavioural deficits. Cooling the rats back to normothermia at 15 min after TBI prevented development of the deficits. In view of the well descried prevalence of concussions during the summer months in training camps for youth sports such as football, this finding, if translated to humans, could be important. Thus, despite the fact that clinical trials of new treatments in TBI have been unsuccessful so far, optimism remains that the present surge in TBI investigations will lead to breakthroughs for the field.
PMK is funded by US Army grants W81XWH-10-1-0623 and W81XWH-14-2-0018. RSBC declares no competing interests. 1
2
3
4
5
6
7
8
9
10
11
12
*Patrick M Kochanek, Robert S B Clark Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260 USA (PMK, RSBC) [email protected]
13
Maas A, Menon DK, Steyerberg EW, et al. Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): a prospective longitudinal observational study. Neurosurgery 2015; 76: 67–80. Bell MJ, Adelson PD, Hutchison JS, et al. Differences in medical therapy goals for children with severe traumatic brain injury—an international study. Pediatr Crit Care Med 2013; 14: 811–18. Yue JK, Vassar MJ, Lingsma HF, et al. Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. J Neurotrauma 2013; 30: 1831–44. Smith DH, Hicks RR, Johnson VE, et al. Pre-clinical traumatic brain injury common data elements: Toward a common language across laboratories. J Neurotrauma 2015; 32: 1725–. DeKosky ST, Blennow K, Ikonomovic MD, et al. Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol 2013; 9: 192–200. Nichol A, French C, Little L, et al. Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomized controlled trial. Lancet 2015; published online October 6. http://dx.doi.org/10.1016/S01406736(15)00386-4. Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 2014; 312: 36–47. Kochanek PM, Bramlett HM, Dixon CE, et al. Operation brain trauma therapy: approach to modeling, therapy evaluation, drug selection, and biomarker assessments, for a multi-center pre-clinical drug screening consortium for acute therapies in severe traumatic brain injury. J Neurotrauma 2015; published online Oct 6. DOI:10.1089/neu.2015.4113. Andrews PJD, Sinclair HL, Rodriguez A, et al. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med 2015; published online Oct 7. DOI: 10.1056/NEJMoa1507581 . Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes Tau pathology after traumatic brain injury. J Neurosci 2014; 34: 16180–93. Plog BA, Dashnaw ML, HItomi E, et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci 2015; 35: 518–26. Kondo A, Shahpasand K, Mannix R, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 2015; 523: 431–36. Titus DJ, Furones C, Atkins CM, et al. Emergence of cognitive deficits after mild traumatic brain injury due to hyperthermia. Exp Neurol 2015; 263: 254–62.
Waking up to sleep research in 2015 Developments in sleep medicine during 2015 have advanced the understanding of the risks associated with disordered sleep, shed new light on treatment, and brought recommendations on sleep duration to the public. Excessive daytime sleepiness can substantially impair quality of life and safety. The central disorders of hypersomnolence result in excessive sleepiness despite adequate sleep duration and in the absence of an identifiable disorder that would otherwise explain non-restorative sleep. Idiopathic hypersomnia and narcolepsy fall into this category. Stimulant www.thelancet.com/neurology Vol 15 January 2016
drugs have been used to treat central disorders of hypersomnolence but these are not always adequately effective, particularly in idiopathic hypersomnia. Patients with both idiopathic hypersomnia and narcolepsy show enhanced γ-aminobutyric acid (GABA) A receptor signalling. The antibiotic clarithromycin is a negative allosteric modulator of the GABA-A receptor; therefore, it was investigated as a candidate treatment for CNS hypersomnia.1 Trotti and colleagues1 did a randomised, placebo-controlled, double-blind, crossover trial in 20 patients with narcolepsy, idiopathic hypersomnia, and subjective 15
proteins. This mechanism of proteome widening has enormous biological influence and a very high level of complexity. However, to what extent single nucleotide variants (SNVs) can influence RNA alternative splicing is only partly known. Xiong and colleagues,4 using an original machine-learning bioinformatic approach, discovered that more than 20 000 SNVs, including missense, nonsense, and even synonymous SNVs, could regulate the number of exons in cell-specific mRNAs. The authors successfully validated their novel computational model in spinal muscle atrophy, the second most frequent autosomal-recessive disease of childhood and one of the leading causes of death in infancy. Their reliable prediction model expands the potentialities of genome-wide association studies through the identification of new disease-causing RNA splicing alterations that could represent putative therapeutic targets. Altered balance between protein synthesis and degradation leading to intracellular accumulation of misfolded protein aggregates and failure of clearance mechanisms are emerging mechanisms in ALS and Charcot-Marie-Tooth neuropathy. Endoplasmic reticulum stress has a key role in regulating proteostasis through the activation of the unfolded protein response. A first-line adaptive response against misfolded protein accumulation is the phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) that leads to decreased protein synthesis. The enhancement of this self-limiting response seems crucial to rescue cells from misfolded protein accumulation. Das and colleagues5 demonstrated that
sephin 1 selectively binds and inhibits the regulatory subunit of eIF2α phosphatase and safely prevents molecular, morphological, and motor impairment in transgenic mouse models of superoxide dismutase 1-associated amyotrophic lateral sclerosis and myelin protein zero-associated Charcot-Marie-Tooth (CMT1B). These findings, while providing a specific basis for disease-modifying treatment of amyotrophic lateral sclerosis and CMT1B, open new scenarios on therapies for a broader range of diseases associated with misfolded protein accumulation. Adriano Chiò, Giuseppe Lauria “Rita Levi Montalcini” Department of Neuroscience, University of Turin (AC); Neuroscience Institute of Turin (AC); Institute of Cognitive Sciences and Technologies, Consiglio Nazionale delle Ricerche, Rome, Italy (AC); Department of Clinical Neurosciences, IRCCS Foundation, “Carlo Besta” Neurological Institute, Milan, Italy (GL) [email protected] AC serves on the editorial advisory board of Amyotrophic Lateral Sclerosis; he declares grants from the Italian Ministry of Health and the European Commission; he serves on scientific advisory boards for Biogen Idec, Cytokinetics, Neuraltus, and Italfarmaco. GL declares no competing interests. 1
2 3
4
5
Cirulli ET, Lasseigne BN, Petrovski S, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 2015; 347: 1436–41. Zhang K, Donnelly CJ, Haeusler AR, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 2015; 525: 56–61. Freibaum BD, Lu Y, Lopez-Gonzalez R, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 2015; 525: 129–33. Xiong HY, Alipanahi B, Lee LJ, et al. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science 2015; 347: 1254806. Das I, Krzyzosiak A, Schneider K, et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 2015; 348: 239–42.
Traumatic brain injury research highlights in 2015 Traumatic brain injury (TBI) research is in the midst of a golden age in both preclinical and clinical arenas, emphasised by large comparative effectiveness trials targeting the need for stronger evidence-based care. These trials include the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) trial in adults and the Approaches and Decisions for Acute Pediatric TBI (ADAPT) trial in children,1,2 along with the development of clinical and preclinical common data elements.3,4 Other factors fueling this golden age are funding from the US Department of Defense for www.thelancet.com/neurology Vol 15 January 2016
research on blast-induced TBI and its links to posttraumatic stress disorder, and the media storm that has accompanied both the identification of chronic traumatic encephalopathy (CTE) resulting from mild repetitive TBI in elite athletes and the possibility that TBI is linked to the development of many neurodegenerative diseases.5 The range of publications on TBI in 2015 (more than 2800) includes notable clinical and preclinical reports. Two clinical trials were noteworthy. Nichol and colleagues6 published the results of a multicentre 13
2015 Round-up
Amelie-Benoist/BSIP/Science Photo Library
randomised controlled trial (RCT) of the use of erythropoietin (40000 units given within 24 h) to treat moderate or severe TBI (NCT00987454). Disappointingly, erythropoietin failed to improve 6-month Extended Glasgow Outcome Scale Extended (GOS-E) score (the primary outcome) compared with placebo. This report follows another high-quality negative clinical trial of erythropoietin in severe TBI (NCT00313716).7 Erythropoietin also did not increase the occurrence of deep venous thrombosis, which has been suggested to contribute to its failure in stroke trials. Surprisingly, despite more than 20 preclinical studies showing benefit of erythropoietin in TBI, clinical trials failed to replicate this finding. Because clinical trial design in TBI offers unique challenges, (eg, patient heterogeneity) it might be necessary in preclinical research for treatments to show highly robust benefit across several heterogeneous models. Such an approach is underway in work being done by the multicentre preclinical drug-screening consortium, Operation Brain Trauma Therapy.8 Advances in both clinical trial design and rigorous multicentre preclinical therapeutic screening seem important to successful translation of effective treatments for TBI. In another important clinical trial, Andrews and colleagues9 studied 387 patients in a multicentre RCT that compared the use of mild-to-moderate hypothermia (35–32°C) with the initiation of hyperosmolar treatment (guidelines-based standard care) for patients with refractory intracranial
14
hypertension (intracranial pressure >20 mm Hg). Remarkably, a favourable outcome (based on 6-month GOS-E) was more often seen in the control group (37%) than the hypothermia group (26%, p=0·03). This report adds to the list of studies failing to show the use of hypothermia in treatment of severe TBI, which have moved clinical care of TBI to an era of targeted temperature management (controlled normothermia or ultra-mild hypothermia [36°C]) rather than conventional hypothermia. Three preclinical reports stand out in 2015. In a series of seminal investigations, the laboratory of Malik Nedergaard has defined a brain-wide network of paravascular channels, termed the glymphatic pathway, which helps clearance of solutes and proteins from the brain via CSF flow through the parenchyma. The investigators’ preclinical research also reveals an enduring impairment of glymphatic pathway function (by about 60%) after TBI.10 The glymphatic pathway could have broad implications for patient management and outcome in TBI, including an effect on mechanisms ranging from acute intracranial hypertension to CTE. An active area of research in TBI is in the development of serum biomarkers such as glial fibrillary acidic protein for diagnostic applications and therapeutic monitoring. This year, Plog and colleagues11 showed in a murine TBI model that CSF movement in the glymphatic pathway transports biomarkers from the brain into the blood via the cervical lymphatics, rather than biomarker transit being reliant solely on a disrupted blood–brain barrier. The researchers showed that many clinically relevant factors influence glymphatic flux, such as CSF drainage and sleep. These findings could affect serum biomarker development and data interpretation after TBI and also help explain how brain injury biomarkers can be detected in serum after CNS insults that are not accompanied by blood–brain barrier disruption, such as cardiac arrest. The effect of this pathway on TBI is only beginning to be understood, but might ultimately change patient management. In a provocative study, Kondo and colleagues12 reported on the acute accumulation and spread of cisphosphorylated tau protein (cis P-tau) in injured murine brain after TBI. Accumulation of this toxic tau isomer disrupts axonal microtubule networks and leads to apoptosis. The authors coined the term cistauosis for www.thelancet.com/neurology Vol 15 January 2016
2015 Round-up
this process after TBI and showed that treatment with a monoclonal antibody specifically targeting cis P-tau prevented its spread and improved several outcomes. The possibility that blocking this pathway could have therapeutic implications for both acute and chronic sequelae of TBI is appealing, and merits additional exploration. Finally, consistent with the emerging use of targeted temperature management in neurocritical care of TBI, it is well known that hyperthermia and fever are deleterious. Titus and colleagues13 in the laboratory of Dalton Dietrich reported that brief periods of hyperthermia (39°C) at the time of extremely mild fluid percussion TBI in rats produced cognitive deficits after 1 week despite an injury level that was otherwise devoid of behavioural deficits. Cooling the rats back to normothermia at 15 min after TBI prevented development of the deficits. In view of the well descried prevalence of concussions during the summer months in training camps for youth sports such as football, this finding, if translated to humans, could be important. Thus, despite the fact that clinical trials of new treatments in TBI have been unsuccessful so far, optimism remains that the present surge in TBI investigations will lead to breakthroughs for the field.
PMK is funded by US Army grants W81XWH-10-1-0623 and W81XWH-14-2-0018. RSBC declares no competing interests. 1
2
3
4
5
6
7
8
9
10
11
12
*Patrick M Kochanek, Robert S B Clark Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260 USA (PMK, RSBC) [email protected]
13
Maas A, Menon DK, Steyerberg EW, et al. Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): a prospective longitudinal observational study. Neurosurgery 2015; 76: 67–80. Bell MJ, Adelson PD, Hutchison JS, et al. Differences in medical therapy goals for children with severe traumatic brain injury—an international study. Pediatr Crit Care Med 2013; 14: 811–18. Yue JK, Vassar MJ, Lingsma HF, et al. Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. J Neurotrauma 2013; 30: 1831–44. Smith DH, Hicks RR, Johnson VE, et al. Pre-clinical traumatic brain injury common data elements: Toward a common language across laboratories. J Neurotrauma 2015; 32: 1725–. DeKosky ST, Blennow K, Ikonomovic MD, et al. Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol 2013; 9: 192–200. Nichol A, French C, Little L, et al. Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomized controlled trial. Lancet 2015; published online October 6. http://dx.doi.org/10.1016/S01406736(15)00386-4. Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 2014; 312: 36–47. Kochanek PM, Bramlett HM, Dixon CE, et al. Operation brain trauma therapy: approach to modeling, therapy evaluation, drug selection, and biomarker assessments, for a multi-center pre-clinical drug screening consortium for acute therapies in severe traumatic brain injury. J Neurotrauma 2015; published online Oct 6. DOI:10.1089/neu.2015.4113. Andrews PJD, Sinclair HL, Rodriguez A, et al. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med 2015; published online Oct 7. DOI: 10.1056/NEJMoa1507581 . Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes Tau pathology after traumatic brain injury. J Neurosci 2014; 34: 16180–93. Plog BA, Dashnaw ML, HItomi E, et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci 2015; 35: 518–26. Kondo A, Shahpasand K, Mannix R, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 2015; 523: 431–36. Titus DJ, Furones C, Atkins CM, et al. Emergence of cognitive deficits after mild traumatic brain injury due to hyperthermia. Exp Neurol 2015; 263: 254–62.
Waking up to sleep research in 2015 Developments in sleep medicine during 2015 have advanced the understanding of the risks associated with disordered sleep, shed new light on treatment, and brought recommendations on sleep duration to the public. Excessive daytime sleepiness can substantially impair quality of life and safety. The central disorders of hypersomnolence result in excessive sleepiness despite adequate sleep duration and in the absence of an identifiable disorder that would otherwise explain non-restorative sleep. Idiopathic hypersomnia and narcolepsy fall into this category. Stimulant www.thelancet.com/neurology Vol 15 January 2016
drugs have been used to treat central disorders of hypersomnolence but these are not always adequately effective, particularly in idiopathic hypersomnia. Patients with both idiopathic hypersomnia and narcolepsy show enhanced γ-aminobutyric acid (GABA) A receptor signalling. The antibiotic clarithromycin is a negative allosteric modulator of the GABA-A receptor; therefore, it was investigated as a candidate treatment for CNS hypersomnia.1 Trotti and colleagues1 did a randomised, placebo-controlled, double-blind, crossover trial in 20 patients with narcolepsy, idiopathic hypersomnia, and subjective 15