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
Saumya Jamuar and colleagues1 identified causative mutations in 27 affected individuals. In 8 (30%) of 27 of these cases, the mutations were somatic, most frequently in the genes DCX and LIS1 (subcortical band heterotopia), FLNA (periventricular nodular heterotopia), and TUBB2B (pachygyria). Furthermore, the researchers identified several novel germline mutations in DYNC1H1 and KIF5C, and KIF7, KIF1A, and KIF26A. Mutations in DYNC1H1 have previously been implicated in cortical malformations, most often in polymicrogyria, although several of the affected individuals in this study had posterior-predominant pachygyria. Because DYNC1H1 forms a complex with the LIS1 protein, this might explain why there are clinical similarities between individuals with mutations in DYNC1H1 and those with mutations in LIS1. Notably, mutations in DYNC1H1 have previously been associated with lower-limb spinal muscular atrophy; overlapping phenotypes of neurogenic weakness with cortical dysplasia have now been described,2 including severe generalised neurogenic arthrogryposis,3 reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. Increasingly, researchers are identifying genetic abnormalities associated with early-onset epileptic encephalopathies, and mutations in the same gene have been shown to cause epilepsies of varying severity and age of onset. One such example is KCNT1, which encodes a sodium-gated potassium channel and has been implicated in both autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). EIMFS is a complex disorder with an extremely poor prognosis for long-term seizure control and neurodevelopment, and a high rate of morbidity and mortality. By contrast, ADNFLE presents in mid-to-late childhood, and has a range of severity.4,5 With use of a Xenopus laevis oocyte-based automated two-electrode voltageclamp assay, Carol Milligan and colleagues6 showed that KCNT1 mutations implicated in epilepsy cause a marked increase in channel function and, perhaps more importantly, that there was a significant group difference in gain of function between mutations associated with ADNFLE and those associated with EIMFS. The researchers also showed that quinidine, a drug approved for the treatment of cardiac arrhythmias, significantly reduced this gain of function www.thelancet.com/neurology Vol 14 January 2015
Zero Creatives/Cultura/Science Photo Library
2014 Round-up
in all mutations studied. The need for targeted, controlled clinical trials to extend these observations— which will be challenging because of the rarity of these disorders—was underscored by a positive case report of quinidine use in EIMFS from David Bearden and colleagues.7 The discovery of further genetic causes of early onset epileptic encephalopathies and more targeted treatments might open doors to the optimisation of treatment in other severe complex epilepsies. Genetics is also leading the way in a move towards translational research in movement disorders. Dopamine transporter deficiency syndrome due to mutations in SLC6A3 typically presents with early infantile-onset progressive parkinsonism dystonia. Joanne Ng and colleagues8 described eight patients from five new families, widening the clinical phenotype. In-vitro studies of mutant dopamine transporter showed multifaceted loss of dopamine. Impaired dopamine uptake was universally present, and more severely affected in dopamine transporter mutants that cause infantile-onset rather than juvenile-onset disease. Genotype–phenotype analysis in the cohort suggested that higher residual dopamine 17
2014 Round-up
transporter activity probably contributes to postponed disease presentation in later-onset adult cases. The findings suggest that the disease can mimic many movement disorders, including dystonic, dyskinetic, or spastic cerebral palsy, and early-onset parkinsonism in adults. Elucidation of cause and mechanisms opens prospects of more effective diagnosis and treatment. In translational research for neuromuscular disorders, the results of two studies that aimed to partially restore the ability to produce dystrophin in boys affected by Duchenne muscular dystrophy were published: a randomised, double-blind, placebocontrolled study of repeated administration of antisense oligonucleotides (drisapersen) designed to partially correct specific intragenic DMD deletions in 53 boys with Duchenne muscular dystrophy;9 and a large (174 patients), randomised, double-blind, placebo-controlled trial of ataluren, a drug designed to allow read-through of DMD in affected boys with nonsense mutations.10 In both studies, the primary outcome was the change in 6 minute walk distance at week 259 or week 48,10 a relevant endpoint for a disorder in which walking ability is severely and progressively reduced. The results of these studies are remarkable: for the first time, drugs targeted at the primary molecular defect in the disorder seem to have provided a clinical benefit. Both studies also identified challenges for clinical trial design and execution in Duchenne muscular dystrophy. For example, in both studies, the efficacy was detectable in only one of two dose treatment groups, such that a post-hoc analysis was needed to show significant change in one of these studies.10 Nevertheless, the coherence of other secondary outcome measures meant that conditional approval was obtained for ataluren from the European Medicines Agency, and a further global phase 3 confirmatory study is underway. The US Food and Drug Administration has outlined a regulatory path in 2014, under an accelerated approval pathway, for both drisapersen and eteplirsen, a related antisense oligonucleotide also for boys with Duchenne muscular dystrophy. A notable and unexpected finding is that somatic DMD mutations are commonly present in human mesenchymal tumours such as gastrointestinal stromal tumour, rhabdomyosarcoma,
18
and leiomyosarcoma, all characterised by myogenic differentiation.11 Although the mechanism for this occurrence is unclear, and might be related to transcription-associated recombination, this is yet another example of the complex role of many of the proteins we commonly associate with single-gene diseases. In conclusion, these selected highlights from 2014 emphasise how insight into the genetic bases of neurological disorders is not only rapidly advancing, but also resulting in knowledge that is being used for development of personalised therapeutic approaches, some now close to final market approval. *Francesco Muntoni, J Helen Cross Developmental Neuroscience Programme, UCL Institute of Child Health and Great Ormond Street Hospital for Children, London WC1N 1EH, UK [email protected] FM declares grants from Sarepta therapeutics, PTC Therapeutics, Prosensa, Muscular Dystrophy Campaign, Wellcome Trust, Medical Research Council, and Association Francaise Myopathies, during the conduct of the study and declares personal fees from Pfizer, PTC, and Sarepta, outside the submitted work. JHC declares advisory board fees to her department from Viropharma and Brabant, advisory board fees and honoraria to her department from Eisai and Nutricia, and grants from Vitaflo and GW Pharma, all outside the submitted work. 1 2
3
4
5
6
7
8
9
10
11
Jamuar SS, Lam AT, Kircher M, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med 2014; 371: 733–43. Fiorillo C, Moro F, Yi J, et al. Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development. Hum Mutat 2014; 35: 298–302. Scoto M, Rossor A, Harms M, et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology (in press). McTague A, Appleton R, Avula S, et al. Migrating partial seizures of infancy (MPSI): expansion of the electroclinical, radiological and pathological disease spectrum. Brain 2013; 136: 1578–79. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder Brain 1995; 118: 61–73. Milligan CJ, Li M, Gazina EV, Heron SE, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014; 75: 581–90. Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014; 76: 457–61. Ng J, Zhen J, Meyer E, et al. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain 2014; 137: 1107–19. 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, for the PTC124-GD-007-DMD STUDY GROUP. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 2014; 50: 477–87. Wang Y, Marino-Enriquez A, Bennett RR, et al. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat Genet 2014; 46: 601–06.
www.thelancet.com/neurology Vol 14 January 2015
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
Saumya Jamuar and colleagues1 identified causative mutations in 27 affected individuals. In 8 (30%) of 27 of these cases, the mutations were somatic, most frequently in the genes DCX and LIS1 (subcortical band heterotopia), FLNA (periventricular nodular heterotopia), and TUBB2B (pachygyria). Furthermore, the researchers identified several novel germline mutations in DYNC1H1 and KIF5C, and KIF7, KIF1A, and KIF26A. Mutations in DYNC1H1 have previously been implicated in cortical malformations, most often in polymicrogyria, although several of the affected individuals in this study had posterior-predominant pachygyria. Because DYNC1H1 forms a complex with the LIS1 protein, this might explain why there are clinical similarities between individuals with mutations in DYNC1H1 and those with mutations in LIS1. Notably, mutations in DYNC1H1 have previously been associated with lower-limb spinal muscular atrophy; overlapping phenotypes of neurogenic weakness with cortical dysplasia have now been described,2 including severe generalised neurogenic arthrogryposis,3 reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. Increasingly, researchers are identifying genetic abnormalities associated with early-onset epileptic encephalopathies, and mutations in the same gene have been shown to cause epilepsies of varying severity and age of onset. One such example is KCNT1, which encodes a sodium-gated potassium channel and has been implicated in both autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). EIMFS is a complex disorder with an extremely poor prognosis for long-term seizure control and neurodevelopment, and a high rate of morbidity and mortality. By contrast, ADNFLE presents in mid-to-late childhood, and has a range of severity.4,5 With use of a Xenopus laevis oocyte-based automated two-electrode voltageclamp assay, Carol Milligan and colleagues6 showed that KCNT1 mutations implicated in epilepsy cause a marked increase in channel function and, perhaps more importantly, that there was a significant group difference in gain of function between mutations associated with ADNFLE and those associated with EIMFS. The researchers also showed that quinidine, a drug approved for the treatment of cardiac arrhythmias, significantly reduced this gain of function www.thelancet.com/neurology Vol 14 January 2015
Zero Creatives/Cultura/Science Photo Library
2014 Round-up
in all mutations studied. The need for targeted, controlled clinical trials to extend these observations— which will be challenging because of the rarity of these disorders—was underscored by a positive case report of quinidine use in EIMFS from David Bearden and colleagues.7 The discovery of further genetic causes of early onset epileptic encephalopathies and more targeted treatments might open doors to the optimisation of treatment in other severe complex epilepsies. Genetics is also leading the way in a move towards translational research in movement disorders. Dopamine transporter deficiency syndrome due to mutations in SLC6A3 typically presents with early infantile-onset progressive parkinsonism dystonia. Joanne Ng and colleagues8 described eight patients from five new families, widening the clinical phenotype. In-vitro studies of mutant dopamine transporter showed multifaceted loss of dopamine. Impaired dopamine uptake was universally present, and more severely affected in dopamine transporter mutants that cause infantile-onset rather than juvenile-onset disease. Genotype–phenotype analysis in the cohort suggested that higher residual dopamine 17
2014 Round-up
transporter activity probably contributes to postponed disease presentation in later-onset adult cases. The findings suggest that the disease can mimic many movement disorders, including dystonic, dyskinetic, or spastic cerebral palsy, and early-onset parkinsonism in adults. Elucidation of cause and mechanisms opens prospects of more effective diagnosis and treatment. In translational research for neuromuscular disorders, the results of two studies that aimed to partially restore the ability to produce dystrophin in boys affected by Duchenne muscular dystrophy were published: a randomised, double-blind, placebocontrolled study of repeated administration of antisense oligonucleotides (drisapersen) designed to partially correct specific intragenic DMD deletions in 53 boys with Duchenne muscular dystrophy;9 and a large (174 patients), randomised, double-blind, placebo-controlled trial of ataluren, a drug designed to allow read-through of DMD in affected boys with nonsense mutations.10 In both studies, the primary outcome was the change in 6 minute walk distance at week 259 or week 48,10 a relevant endpoint for a disorder in which walking ability is severely and progressively reduced. The results of these studies are remarkable: for the first time, drugs targeted at the primary molecular defect in the disorder seem to have provided a clinical benefit. Both studies also identified challenges for clinical trial design and execution in Duchenne muscular dystrophy. For example, in both studies, the efficacy was detectable in only one of two dose treatment groups, such that a post-hoc analysis was needed to show significant change in one of these studies.10 Nevertheless, the coherence of other secondary outcome measures meant that conditional approval was obtained for ataluren from the European Medicines Agency, and a further global phase 3 confirmatory study is underway. The US Food and Drug Administration has outlined a regulatory path in 2014, under an accelerated approval pathway, for both drisapersen and eteplirsen, a related antisense oligonucleotide also for boys with Duchenne muscular dystrophy. A notable and unexpected finding is that somatic DMD mutations are commonly present in human mesenchymal tumours such as gastrointestinal stromal tumour, rhabdomyosarcoma,
18
and leiomyosarcoma, all characterised by myogenic differentiation.11 Although the mechanism for this occurrence is unclear, and might be related to transcription-associated recombination, this is yet another example of the complex role of many of the proteins we commonly associate with single-gene diseases. In conclusion, these selected highlights from 2014 emphasise how insight into the genetic bases of neurological disorders is not only rapidly advancing, but also resulting in knowledge that is being used for development of personalised therapeutic approaches, some now close to final market approval. *Francesco Muntoni, J Helen Cross Developmental Neuroscience Programme, UCL Institute of Child Health and Great Ormond Street Hospital for Children, London WC1N 1EH, UK [email protected] FM declares grants from Sarepta therapeutics, PTC Therapeutics, Prosensa, Muscular Dystrophy Campaign, Wellcome Trust, Medical Research Council, and Association Francaise Myopathies, during the conduct of the study and declares personal fees from Pfizer, PTC, and Sarepta, outside the submitted work. JHC declares advisory board fees to her department from Viropharma and Brabant, advisory board fees and honoraria to her department from Eisai and Nutricia, and grants from Vitaflo and GW Pharma, all outside the submitted work. 1 2
3
4
5
6
7
8
9
10
11
Jamuar SS, Lam AT, Kircher M, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med 2014; 371: 733–43. Fiorillo C, Moro F, Yi J, et al. Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development. Hum Mutat 2014; 35: 298–302. Scoto M, Rossor A, Harms M, et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology (in press). McTague A, Appleton R, Avula S, et al. Migrating partial seizures of infancy (MPSI): expansion of the electroclinical, radiological and pathological disease spectrum. Brain 2013; 136: 1578–79. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder Brain 1995; 118: 61–73. Milligan CJ, Li M, Gazina EV, Heron SE, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014; 75: 581–90. Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014; 76: 457–61. Ng J, Zhen J, Meyer E, et al. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain 2014; 137: 1107–19. 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, for the PTC124-GD-007-DMD STUDY GROUP. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 2014; 50: 477–87. Wang Y, Marino-Enriquez A, Bennett RR, et al. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat Genet 2014; 46: 601–06.
www.thelancet.com/neurology Vol 14 January 2015
