2014 Round-up
of cases of amyotrophic lateral sclerosis in Europe. Importantly, molecular data show a toxic mechanism for C9orf72 through dipeptide repeats derived from the unconventional translation of the hexanucleotide repeat.3 Although other mechanisms, including RNA toxicity, might also have a role, these findings support progress to planned trials for antisense oligonucleotides in C9orf72 amyotrophic lateral sclerosis. Small-molecule approaches have also been used to correct splicing events in spinal muscular atrophy, a progressive motor neuron disorder in infants. Spinal muscular atrophy is most commonly caused by mutations in the survival motor neuron SMN1 gene that results in decreased levels of the SMN protein. Another closely related gene, SMN2, normally produces only small amounts of full transcript of a virtually identical gene due to a single nucleotide polymorphism that alters its splicing pattern. Restoration of SMN1-like splicing in SMN2 could be beneficial in patients with spinal muscular atrophy. A 2014 study used patient-derived cells to screen more than 200 000 small molecules to identify compounds that restore splicing of SMN2.4 Cell lines and two mouse models showed the preclinical efficacy of this approach and confirmed specificity of the molecular effect.4 There were also important preclinical and clinical developments in stem-cell therapies in 2014. An interesting proof-of-principle study in mice showed how optogenetically modified embryonic-stem-cell-derived motor neurons can be transplanted into a peripheral nerve that had previously undergone constriction to denervate the muscles it supplied. The transplanted cells survived and extended axons to reinnervate the denervated muscle.5 Optical stimulation of these grafted neurons resulted in physiological activation of motor units leading to muscle contraction. This technique could lead to developing beneficial applications such as
diaphragmatic pacing in amyotrophic lateral sclerosis. A phase 1/2A cell therapy trial was done in patients with the late-onset autosomal-dominant genetic muscle disease oculopharyngeal muscular dystrophy. The investigators injected patient-derived autologous muscle cells from an unaffected quadriceps muscle into the affected pharyngeal muscles. Tolerability and safety of the procedure were established, along with encouraging effects on swallowing that will need to be confirmed in larger trials.6 However, the role that intraspinal injections of neural stem cells might have in the treatment for amyotrophic lateral sclerosis needs further study. Multistakeholder coordination and data integration through experimental therapy centres that drive trial networks will accelerate progress towards treatments. The increasing numbers of experimental therapy interventions indicate that a genuine transition from gene discovery to experimental therapeutics is starting to occur for patients with neuromuscular diseases. Pietro Fratta, *Michael G Hanna MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK [email protected] We have no competing interests. 1
2 3
4
5
6
Voit T, Topaloglu H, Straub V, et al. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 2014; 13: 987–96. Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerv. 2014; 5: 47–87. Rohrer J, Isaacs A, Mizlienska S, Mead S, Lashley T, Wray S. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol (in press). Naryshkin NA, Weetall M, Dakka A, et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 2014; 345: 688–93. Bryson JB, Machado CB, Crossley M, et al. Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice. Science 2014; 344: 94–97. Périé S, Trollet C, Mouly V, et al. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study. Mol Ther J Am Soc Gene Ther 2014; 22: 219–25.
Concussion research: new horizons With a growing number of youth and adolescents participating in sports worldwide, understanding the acute assessment and treatment of sport-related concussion and the possible long-term consequences is imperative. Our knowledge of concussion has advanced substantially over the past two decades, but many questions remain unanswered. 14
During the early 2000s, most research was focused on the validation of concussion assessment tools, and the effectiveness of a multimodal assessment battery (symptom checklists, cognitive tests, and balance tests) was subsequently established. Attention is now turning towards education, acute diagnostic biomarkers, and treatment. In 2014, innovative investigations that www.thelancet.com/neurology Vol 14 January 2015
2014 Round-up
www.thelancet.com/neurology Vol 14 January 2015
highest concentrations of S-100β and total tau were noted within 1 h of injury, and decreased during recovery from concussion. Although these findings must be verified in future studies, this investigation is an important step in the identification of blood biomarkers that could help to detect many concussions that currently go undiagnosed. Few evidence-based studies exist on the best treatment for concussion. Physical and cognitive rest continues to be the gold standard, but mostly in the absence of empirical data to support this notion. In 2014, a randomised, controlled clinical trial investigated a novel rehabilitative approach to reduce persistent symptoms resulting from concussion.4 All patients received a standard of care that included: postural education; range- of- motion exercises; cognitive and physical rest until asymptomatic; and a graded exertion protocol. The intervention group also received cervical spine and vestibular rehabilitation. The cervical rehabilitation consisted of manual therapy of the cervical and thoracic spine (joint mobilisation techniques), cervical neuromotor retraining exercises, and sensorimotor retraining exercises. The vestibular rehabilitation protocol included an individualised programme of habituation, gaze stabilisation, adaptation exercises, standing and dynamic balance exercises, and canalith repositioning manoeuvres. A sports medicine physician masked to the treatment groups assessed the primary outcome: time to full medical clearance for return to sport. The data showed that almost 75% of patients with persistent symptoms
Jason Cohn/Reuters/Corbis
seek to challenge and improve the currently accepted assessment battery have been reported. Emerging evidence has shed light on the brain’s acute and longer-term response to trauma. As an update to their 2001 review1 of the scientific literature on concussion pathophysiology, Christopher Giza and David Hovda2 have re-examined the basic cellular and biochemical mechanics of concussive injury. 10 years of original research into mild traumatic brain injury, derived from several disciplines, including molecular biology, neuroimaging, and clinical field research, is reviewed in this article. The hypotheses set out in this review provide foundations for future translational and interventional investigations of the pathophysiological bases of acute and long-term symptoms resulting from concussion. The proposed associations include disrupted ion flux and migraine-like symptoms, energy crisis and increased vulnerability to repeat concussion, axonal dysfunction and slowed cognition, and altered neurotransmission resulting in slowed cognition and reaction time. If validated in future studies, this novel way to link laboratory and clinic will have far-reaching implications for understanding the consequences of concussion and identifying the best course of treatment after injury. Despite advances in assessment, most diagnostic procedures for concussion remain reliant on self-report of symptoms. Sometimes described as a hidden injury or hidden epidemic, many concussions go unreported and, therefore, undetected. This has led researchers to investigate the efficacy of advanced technologies, such as brain imaging and blood biomarker analysis, to diagnose concussion. These objective measures could be more definitive than existing diagnostic measures and reduce reliance on self-reported symptoms. Several CSF biomarkers, including total tau, have been implicated in other neurological disorders, such as stroke. Tau deposition has also been at the forefront of investigations into chronic traumatic encephalopathy, a condition thought to be caused by repetitive brain trauma over the course of a lifetime. In an investigation of professional hockey players in Sweden, total tau and S-100 calcium-binding protein β (S-100β) concentrations were increased at 1 h after concussion compared with preseason measures.3 Total tau concentration remained increased at 144 h post-concussion compared with preseason values. The
15
2014 Round-up
in the intervention group were cleared within 8 weeks of starting treatment compared with less than 10% of patients in the non-intervention group. Intervention patients were 3·91 (95% CI 1·34–11·34) times more likely to be cleared by 8 weeks than the non-intervention group. Despite the relatively small sample size (n=29), this study is an important step to challenge the current wait-and-see approach to concussion management. In addition to diagnosis and treatment, improvement in knowledge and awareness about concussion remains a challenge. Concussion education targeted to athletes, parents, and coaches is the key to increased concussion symptom reporting, and ultimately reduction of the potential for undiagnosed and untreated brain injuries. Many governing bodies, both at the youth and elite level, have instituted policies to ensure that athletes, parents, and coaches are educated about the signs, symptoms, and appropriate return-to-play criteria following concussion. Although these policies are essential to raise awareness of concussion injury, educational intervention methods and materials must also be properly assessed to ensure the message is communicated correctly. The effectiveness of various educational materials and policies introduced by the governing bodies has been investigated at individual sport and national levels. In a troubling finding, perceived under-reporting norms among adolescent male athletes increased 1 month after the release of educational materials, suggesting that late-season under-reporting might be perceived as normal.5 Additionally, evidence suggests that legislation alone is not enough to improve concussion knowledge and attitudes about symptom reporting.6 Instead, a cultural shift within individual teams, including the
athletes, their parents, and the coaching staff, is needed. Continued efforts to refine educational intervention methods and materials will drive this culture shift, leading to safer sport participation for athletes of all ages and skill levels. Together, these investigations represent an attempt to move concussion research into new territory, and to challenge accepted clinical practice to improve overall patient outcomes. More work is needed, but concussion research took a leap forward in 2014. New technologies, improved research methods, and improved understanding of concussive mechanisms and pathophysiology have the potential to push concussion research to the next frontier in the coming years. Robert C Lynall, Kevin M Guskiewicz Matthew Gfeller Sport-Related TBI Research Center, Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA [email protected] We declare no competing interests. 1 2 3 4
5
6
Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train 2001; 36: 228–35. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery 2014; 75 (suppl 4): S24–33. Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol 2014; 71: 684–92. Schneider KJ, Meeuwisse WH, Nettel-Aguirre A, et al. Cervicovestibular rehabilitation in sport-related concussion: a randomised controlled trial. Br J Sports Med 2014; 48: 1294–98. Kroshus E, Baugh CM, Hawrilenko M, Daneshvar DH. Pilot randomized evaluation of publically available concussion education materials: evidence of a possible negative effect. Health Educ Behav 2014; published online Aug 15. DOI:10.1177/1090198114543011. Rivara FP, Schiff MA, Chrisman SP, Chung SK, Ellenbogen RG, Herring SA. The effect of coach education on reporting of concussions among high school athletes after passage of a concussion law. Am J Sports Med 2014; 42: 1197–1203.
Paediatric neurology: from molecular mechanisms to targeted treatments Notable advances continue to be made in understanding of the molecular basis of important paediatric neurological disorders, with new insights into the clinical spectrum linked to specific genetic defects and unexpected overlaps between disorders with distinct genetic causes. These advances are leading to important breakthroughs in translational research and new possibilities for effective treatments. 16
The new generation of sequencing techniques is providing insight into complex disorders associated with brain malformations and, in particular, the role of somatic mosaicism in such disorders. In a large collaborative study of 158 people with a range of brain malformations—including subcortical band heterotopia, polymicrogyria with megalencephaly, periventricular nodular heterotopia, and pachygyria— www.thelancet.com/neurology Vol 14 January 2015
of cases of amyotrophic lateral sclerosis in Europe. Importantly, molecular data show a toxic mechanism for C9orf72 through dipeptide repeats derived from the unconventional translation of the hexanucleotide repeat.3 Although other mechanisms, including RNA toxicity, might also have a role, these findings support progress to planned trials for antisense oligonucleotides in C9orf72 amyotrophic lateral sclerosis. Small-molecule approaches have also been used to correct splicing events in spinal muscular atrophy, a progressive motor neuron disorder in infants. Spinal muscular atrophy is most commonly caused by mutations in the survival motor neuron SMN1 gene that results in decreased levels of the SMN protein. Another closely related gene, SMN2, normally produces only small amounts of full transcript of a virtually identical gene due to a single nucleotide polymorphism that alters its splicing pattern. Restoration of SMN1-like splicing in SMN2 could be beneficial in patients with spinal muscular atrophy. A 2014 study used patient-derived cells to screen more than 200 000 small molecules to identify compounds that restore splicing of SMN2.4 Cell lines and two mouse models showed the preclinical efficacy of this approach and confirmed specificity of the molecular effect.4 There were also important preclinical and clinical developments in stem-cell therapies in 2014. An interesting proof-of-principle study in mice showed how optogenetically modified embryonic-stem-cell-derived motor neurons can be transplanted into a peripheral nerve that had previously undergone constriction to denervate the muscles it supplied. The transplanted cells survived and extended axons to reinnervate the denervated muscle.5 Optical stimulation of these grafted neurons resulted in physiological activation of motor units leading to muscle contraction. This technique could lead to developing beneficial applications such as
diaphragmatic pacing in amyotrophic lateral sclerosis. A phase 1/2A cell therapy trial was done in patients with the late-onset autosomal-dominant genetic muscle disease oculopharyngeal muscular dystrophy. The investigators injected patient-derived autologous muscle cells from an unaffected quadriceps muscle into the affected pharyngeal muscles. Tolerability and safety of the procedure were established, along with encouraging effects on swallowing that will need to be confirmed in larger trials.6 However, the role that intraspinal injections of neural stem cells might have in the treatment for amyotrophic lateral sclerosis needs further study. Multistakeholder coordination and data integration through experimental therapy centres that drive trial networks will accelerate progress towards treatments. The increasing numbers of experimental therapy interventions indicate that a genuine transition from gene discovery to experimental therapeutics is starting to occur for patients with neuromuscular diseases. Pietro Fratta, *Michael G Hanna MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK [email protected] We have no competing interests. 1
2 3
4
5
6
Voit T, Topaloglu H, Straub V, et al. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 2014; 13: 987–96. Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerv. 2014; 5: 47–87. Rohrer J, Isaacs A, Mizlienska S, Mead S, Lashley T, Wray S. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol (in press). Naryshkin NA, Weetall M, Dakka A, et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 2014; 345: 688–93. Bryson JB, Machado CB, Crossley M, et al. Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice. Science 2014; 344: 94–97. Périé S, Trollet C, Mouly V, et al. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study. Mol Ther J Am Soc Gene Ther 2014; 22: 219–25.
Concussion research: new horizons With a growing number of youth and adolescents participating in sports worldwide, understanding the acute assessment and treatment of sport-related concussion and the possible long-term consequences is imperative. Our knowledge of concussion has advanced substantially over the past two decades, but many questions remain unanswered. 14
During the early 2000s, most research was focused on the validation of concussion assessment tools, and the effectiveness of a multimodal assessment battery (symptom checklists, cognitive tests, and balance tests) was subsequently established. Attention is now turning towards education, acute diagnostic biomarkers, and treatment. In 2014, innovative investigations that www.thelancet.com/neurology Vol 14 January 2015
2014 Round-up
www.thelancet.com/neurology Vol 14 January 2015
highest concentrations of S-100β and total tau were noted within 1 h of injury, and decreased during recovery from concussion. Although these findings must be verified in future studies, this investigation is an important step in the identification of blood biomarkers that could help to detect many concussions that currently go undiagnosed. Few evidence-based studies exist on the best treatment for concussion. Physical and cognitive rest continues to be the gold standard, but mostly in the absence of empirical data to support this notion. In 2014, a randomised, controlled clinical trial investigated a novel rehabilitative approach to reduce persistent symptoms resulting from concussion.4 All patients received a standard of care that included: postural education; range- of- motion exercises; cognitive and physical rest until asymptomatic; and a graded exertion protocol. The intervention group also received cervical spine and vestibular rehabilitation. The cervical rehabilitation consisted of manual therapy of the cervical and thoracic spine (joint mobilisation techniques), cervical neuromotor retraining exercises, and sensorimotor retraining exercises. The vestibular rehabilitation protocol included an individualised programme of habituation, gaze stabilisation, adaptation exercises, standing and dynamic balance exercises, and canalith repositioning manoeuvres. A sports medicine physician masked to the treatment groups assessed the primary outcome: time to full medical clearance for return to sport. The data showed that almost 75% of patients with persistent symptoms
Jason Cohn/Reuters/Corbis
seek to challenge and improve the currently accepted assessment battery have been reported. Emerging evidence has shed light on the brain’s acute and longer-term response to trauma. As an update to their 2001 review1 of the scientific literature on concussion pathophysiology, Christopher Giza and David Hovda2 have re-examined the basic cellular and biochemical mechanics of concussive injury. 10 years of original research into mild traumatic brain injury, derived from several disciplines, including molecular biology, neuroimaging, and clinical field research, is reviewed in this article. The hypotheses set out in this review provide foundations for future translational and interventional investigations of the pathophysiological bases of acute and long-term symptoms resulting from concussion. The proposed associations include disrupted ion flux and migraine-like symptoms, energy crisis and increased vulnerability to repeat concussion, axonal dysfunction and slowed cognition, and altered neurotransmission resulting in slowed cognition and reaction time. If validated in future studies, this novel way to link laboratory and clinic will have far-reaching implications for understanding the consequences of concussion and identifying the best course of treatment after injury. Despite advances in assessment, most diagnostic procedures for concussion remain reliant on self-report of symptoms. Sometimes described as a hidden injury or hidden epidemic, many concussions go unreported and, therefore, undetected. This has led researchers to investigate the efficacy of advanced technologies, such as brain imaging and blood biomarker analysis, to diagnose concussion. These objective measures could be more definitive than existing diagnostic measures and reduce reliance on self-reported symptoms. Several CSF biomarkers, including total tau, have been implicated in other neurological disorders, such as stroke. Tau deposition has also been at the forefront of investigations into chronic traumatic encephalopathy, a condition thought to be caused by repetitive brain trauma over the course of a lifetime. In an investigation of professional hockey players in Sweden, total tau and S-100 calcium-binding protein β (S-100β) concentrations were increased at 1 h after concussion compared with preseason measures.3 Total tau concentration remained increased at 144 h post-concussion compared with preseason values. The
15
2014 Round-up
in the intervention group were cleared within 8 weeks of starting treatment compared with less than 10% of patients in the non-intervention group. Intervention patients were 3·91 (95% CI 1·34–11·34) times more likely to be cleared by 8 weeks than the non-intervention group. Despite the relatively small sample size (n=29), this study is an important step to challenge the current wait-and-see approach to concussion management. In addition to diagnosis and treatment, improvement in knowledge and awareness about concussion remains a challenge. Concussion education targeted to athletes, parents, and coaches is the key to increased concussion symptom reporting, and ultimately reduction of the potential for undiagnosed and untreated brain injuries. Many governing bodies, both at the youth and elite level, have instituted policies to ensure that athletes, parents, and coaches are educated about the signs, symptoms, and appropriate return-to-play criteria following concussion. Although these policies are essential to raise awareness of concussion injury, educational intervention methods and materials must also be properly assessed to ensure the message is communicated correctly. The effectiveness of various educational materials and policies introduced by the governing bodies has been investigated at individual sport and national levels. In a troubling finding, perceived under-reporting norms among adolescent male athletes increased 1 month after the release of educational materials, suggesting that late-season under-reporting might be perceived as normal.5 Additionally, evidence suggests that legislation alone is not enough to improve concussion knowledge and attitudes about symptom reporting.6 Instead, a cultural shift within individual teams, including the
athletes, their parents, and the coaching staff, is needed. Continued efforts to refine educational intervention methods and materials will drive this culture shift, leading to safer sport participation for athletes of all ages and skill levels. Together, these investigations represent an attempt to move concussion research into new territory, and to challenge accepted clinical practice to improve overall patient outcomes. More work is needed, but concussion research took a leap forward in 2014. New technologies, improved research methods, and improved understanding of concussive mechanisms and pathophysiology have the potential to push concussion research to the next frontier in the coming years. Robert C Lynall, Kevin M Guskiewicz Matthew Gfeller Sport-Related TBI Research Center, Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA [email protected] We declare no competing interests. 1 2 3 4
5
6
Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train 2001; 36: 228–35. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery 2014; 75 (suppl 4): S24–33. Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol 2014; 71: 684–92. Schneider KJ, Meeuwisse WH, Nettel-Aguirre A, et al. Cervicovestibular rehabilitation in sport-related concussion: a randomised controlled trial. Br J Sports Med 2014; 48: 1294–98. Kroshus E, Baugh CM, Hawrilenko M, Daneshvar DH. Pilot randomized evaluation of publically available concussion education materials: evidence of a possible negative effect. Health Educ Behav 2014; published online Aug 15. DOI:10.1177/1090198114543011. Rivara FP, Schiff MA, Chrisman SP, Chung SK, Ellenbogen RG, Herring SA. The effect of coach education on reporting of concussions among high school athletes after passage of a concussion law. Am J Sports Med 2014; 42: 1197–1203.
Paediatric neurology: from molecular mechanisms to targeted treatments Notable advances continue to be made in understanding of the molecular basis of important paediatric neurological disorders, with new insights into the clinical spectrum linked to specific genetic defects and unexpected overlaps between disorders with distinct genetic causes. These advances are leading to important breakthroughs in translational research and new possibilities for effective treatments. 16
The new generation of sequencing techniques is providing insight into complex disorders associated with brain malformations and, in particular, the role of somatic mosaicism in such disorders. In a large collaborative study of 158 people with a range of brain malformations—including subcortical band heterotopia, polymicrogyria with megalencephaly, periventricular nodular heterotopia, and pachygyria— www.thelancet.com/neurology Vol 14 January 2015
