2014 Round-up
measurable biomarkers that correlate with an illness, at least in part because of shared underlying genetic factors. One study5 detected abnormal brain network properties in the 6–9 Hz band of scalp electroencephalography in patients with IGE and in their unaffected first–degree relatives. The authors propose that abnormal brain network topology might be an endophenotype of IGE, although not sufficient to cause epilepsy.5 Juvenile myoclonic epilepsy is a heritable IGE syndrome with myoclonic jerks that can be provoked by cognitive activity, and functional MRI showed that increases in cognitive load in patients and unaffected siblings caused abnormal activation of primary motor cortex and the supplementary motor area.6 This study provides evidence for familial endophenotypes in patients with IGE and unaffected relatives and suggests that their epilepsy should no longer be classified as idiopathic. 7 What are the implications of the changing criteria and categories of epilepsy? As with all good research, they reveal new horizons and prompt new questions. The
next steps will be to define better when epilepsy begins and when it ends, at least for most patients. Dieter Schmidt Epilepsy Research Group, Berlin D-14163, Germany [email protected] I declare no competing interests. 1 2 3
4
5
6
7
Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55: 475–82. Hauser A. Commentary: ILAE Definition of Epilepsy. Epilepsia. 2014; 55: 488–90. Berg AT, Rychlik K, Levy SR, Testa FM. Complete remission of childhoodonset epilepsy: stability and prediction over two decades. Brain 2014; published online Oct 22. DOI:10.1093/brain/awu294. Sillanpää M, Schmidt D. Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy. Epilepsy Behav 2006; 8: 713–19. Chowdhury FA, Woldman W, FitzGerald TH, et al. Revealing a brain network endophenotype in families with idiopathic generalized epilepsy. PLoS One 2014; 9: e110136. Wandschneider B, Centeno M, Vollmar C, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain 2014; 137: 2469–79. Berkovic SF, Jackson GD. ‘Idiopathic’ no more! Abnormal interaction of large-scale brain networks in generalized epilepsy. Brain 2014; 137: 2400–02.
Movement disorders: discoveries in pathophysiology and therapy Movement disorders are common and are frequently treated by neurologists. Clinical phenotype and pathophysiology are heterogenous. In 2014, research in the specialty of movement disorders advanced our understanding of pathogenesis, translational aspects, and therapy. Our understanding of disease mechanisms of rare movement disorders such as hereditary spastic paraplegia, with its hallmark feature of lower limb spasticity caused mainly by axonal degeneration in the cortical tract, has been hampered by low disease prevalence and genotypic and phenotypic heterogeneity. Whole-exome sequencing analysis identified mutations in no less than 18 new putative genes, and consecutive network analysis showed that many of these genes converge in key biological processes, including axon and synapse development, cellular transport, and nucleotide metabolism.1 Moreover, a significant association of these genes with other neurodegenerative movement disorders was also identified. www.thelancet.com/neurology Vol 14 January 2015
Another exciting pathophysiological similarity between movement disorders was discovered for the spreading of pathology. Parkinson’s disease was the first neurodegenerative movement disorder for which a prion-like spreading of pathology was shown to affect allografted ventral mesencephalic tissue. Several in-vitro and in-vivo models have subsequently shown that neurons release and uptake α-synuclein. Research in 2014 showed that aggregation of α-synuclein in neurons might be triggered by exogenously preformed α-synuclein fibrils or Lewy body extracts.2,3 This prionlike protein spread has now for the first time been shown for mutant huntingtin in genetically normal and unrelated allografted neural tissue transplanted into the brain of patients with Huntington’s disease. Astonishingly, the mechanisms of spreading in Huntington’s disease, which is a monogenetic disease, are similar to those of Parkinson’s disease, and this indicates that non–cell-autonomous mechanisms can drive monogenetic neurodegenerative disorders. This study could have implications for future clinical 9
Amelie-Benoist/BSIP/Science Photo Library
2014 Round-up
and therapeutic studies of patients with Huntington’s disease and possibly other neurodegenerative diseases that are characterised by the formation of mutant protein oligomers and aggregates. Taking a translational approach, a new opportunity for therapy was opened when monoclonal α-synuclein antibodies were shown to reduce the formation of Lewy bodies and Lewy neurites by preventing uptake of preformed fibrils and cell-to-cell transmission of α-synuclein, and thereby stall neurodegeneration.5 Additionally, a next-generation active vaccination technology with short peptides was developed,6 from which a peptide that elicited a specific response against α-synuclein was identified. Immunisation of transgenic mice (PDGF-α-syn transgenic mice and mThy1-α-syn transgenic mice) resulted in high antibody titres in cerebrospinal fluid, plasma, and CNS. The ability of this antibody to recognise α-synuclein aggregates and reduce their accumulation in the brain enabled the first phase 1 clinical study7 of immunisation in Parkinson’s disease. Although the results of this small phase 1 safety trial are unpublished, the endpoints were seemingly met, which sets the stage for a larger phase 2 trial. Epigenetic therapy has been used in an attempt to influence the expression of specific disease-causing genes and control the accumulation of diseasemediating proteins. Two studies have pioneered the application of epigenetic therapy for Friedreich’s ataxia: one with an orally delivered histone deacetylase inhibitor8, and the other with orally delivered 10
nicotinamide.9 Both studies tested the compounds in cell culture models and in patients with Friedreich’s ataxia, with frataxin expression as a main outcome parameter in patients. In both studies, an increase of frataxin expression was noted after therapy. However, clinical changes were not reported and might only occur when patients are treated for longer periods. Early therapy of Parkinson’s disease was the subject of the PD MED trial,10 one of the largest trials (1620 patients) to compare initial levodopa therapy with two levodopasparing therapies (dopamine agonists or monoamine oxidase inhibitors). This study was based on subjective evaluation with the Parkinson’s disease Questionnaire 39 (PDQ-39) as the main outcome parameter. At 3 years, levodopa treatment was associated with a 1·8 points better mobility score on the PDQ-39 compared with the levodopa-sparing therapies, which—although significant—was not regarded as clinically meaningful by the investigators. Although methodological constraints limit the interpretation of these findings, mobility in patients receiving initial levodopa over a long period was equal to or even better than mobility in patients in other groups. This argues against avoiding levodopa, particularly in the treatment of elderly people. Optimising and strengthening of the brain’s compensatory mechanisms is increasingly recognised as an important therapeutic approach to movement disorders. This approach has been convincingly shown for various forms of physical therapy, Lee-Silvermanvoice training, and even multiprofessional training. A large controlled trial of home-based occupational therapy for patients with Parkinson’s disease showed mild but significant improvements to hand function.11 This study also showed that patients can be integrated effectively in the therapeutic concept of home-based therapies that are free of side-effects. Deep brain stimulation (DBS) of the internal pallidum is used for generalised dystonia that is resistant to medical treatment, but DBS has not been extended to other forms of dystonia. The first controlled trial of neurostimulation in patients with cervical dystonia otherwise unresponsive to botulinum toxin injections showed significant improvement in those treated with DBS.12 These improvements were about 25%, with a mean score of 20 on the Toronto Western Spasmodic Torticollis Rating Scale (from 0 to 35) at 3 months and 6 months, and were thus clinically relevant. Of 16 severe www.thelancet.com/neurology Vol 14 January 2015
2014 Round-up
adverse events, only five remained after 6 months. Hence, DBS might become an option for those patients who do not respond to any existing treatment.
3
Daniela Berg, *Günther Deuschl
5
Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany (DB); German Center of Neurodegenerative Diseases, Tübingen, Germany (DB); Department of Neurology, UKSH, Kiel Campus, Christian-Albrechts University Kiel, Kiel, Germany (GD) [email protected] DB declares grants from Michael J Fox Foundation, Janssen Pharmaceutica, dPV (German Parkinson’s Disease Association), German Federal Ministry of Education and Research, International Parkinson Fonds, Boehringer Ingelheim Pharma GmbH, TEVA Pharma GmbH, and UCB Pharma GmbH; personal fees from UCB Pharma GmbH, Novartis Pharma GmbH, Lundbeck, UCB Pharma GmbH, TEVA Pharma GmbH, University of Tübingen, Centre for Neurology, Hertie-Institute for Clinical Brain Research, and German Center for Neurodegenerative Diseases (DZNE) Tübingen; all outside the submitted work. GD declares grants from German Research Council, German Ministery of Education and Health, and Medtronic; personal fees from UCB, Desitin, Medtronic, Sapiens, Boston Scientific, and Britannica; all outside the submitted work. 1
2
Novarino G, Fenstermaker AG, Zaki MS, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 2014; 343: 506–11. Recasens A, Dehay B, Bove J, et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014; 75: 351–62.
4
6
7
8 9
10
11
12
Volpicelli-Daley LA, Luk KC, Lee VM. Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat Protoc 2014; 9: 2135–46. Cicchetti F, Lacroix S, Cisbani G, et al. Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Ann Neurol 2014; 76: 31–42. Tran HT, Chung CH, Iba M, et al. Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Rep 2014; 7: 2054–65. Mandler M, Valera E, Rockenstein E, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol 2014; 127: 861–79. Brachmann S. Successful Phase 1 Trial for Parkinson’s Vaccine. 2014. http:// www.ipwatchdog.com/2014/08/07/successful-phase-1-trial-forparkinsons-vaccine/id=50717/ (accessed Nov 25, 2014). Soragni E, Miao W, Iudicello M, et al. Epigenetic therapy for Friedreich ataxia. Ann Neurol 2014; 76: 489–508. Libri V, Yandim C, Athanasopoulos S, et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet 2014; 384: 504–13. PD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 2014; 384: 1196–205. Sturkenboom IH, Graff MJ, Hendriks JC, et al. Efficacy of occupational therapy for patients with Parkinson’s disease: a randomised controlled trial. Lancet Neurol 2014; 13: 557–66. Volkmann J, Mueller J, Deuschl G, et al. Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial. Lancet Neurol 2014; 13: 875–84.
MS and related disorders: looking for markers of phenotypes Multiple sclerosis (MS) research addressed several challenges in 2014, including progressive MS. Despite advances in other forms of MS, there are no approved treatments for progressive MS because of the scarcity of reliable methods to test when, how, and why MS progresses. Nonetheless, post-hoc analyses of placebocontrolled trials1,2 suggest that a subset of patients with progressive MS might benefit from immunedirected therapies, which are usually effective in the management of relapsing–remitting MS. The first step towards identifying subsets of patients with progressive MS is a more precise characterisation of the different progressive MS disease courses. The MS Phenotype Group reviewed the 1996 progressive MS phenotype classification (primary progressive, secondary progressive, and progressive relapsing) and updated the framework for patients’ inclusion in clinical and basic research studies on the basis of integrated assessment of clinical and validated MRI data.3 Two important changes that would modify the old classification were proposed: a yearly clinical and MRI-based www.thelancet.com/neurology Vol 14 January 2015
assessment of disease activity (occurrence of relapse, MRI gadolinium-enhancing lesions, or unequivocally enlarged lesions) and a yearly determination of disability progression (increase in neurological dysfunction confirmed throughout a defined time interval). According to the new classification, the progressive relapsing course is eliminated and primary progressive and secondary progressive courses are merged in one group named progressive MS. Progressive MS is subclassified according to the presence or absence of activity (ie, active or inactive) and according to the presence or absence of confirmed progression (ie, with progression or without progression). A regular tracking of symptoms and signs of inflammatory and neurodegenerative processes might help to select subsets of patients with progressive MS who might benefit from specific treatments. The MS Phenotype Group emphasises that further research is needed to define better the role of biological markers and non-conventional MRI in assessment, confirmation, or revision of MS phenotype descriptions. 11
measurable biomarkers that correlate with an illness, at least in part because of shared underlying genetic factors. One study5 detected abnormal brain network properties in the 6–9 Hz band of scalp electroencephalography in patients with IGE and in their unaffected first–degree relatives. The authors propose that abnormal brain network topology might be an endophenotype of IGE, although not sufficient to cause epilepsy.5 Juvenile myoclonic epilepsy is a heritable IGE syndrome with myoclonic jerks that can be provoked by cognitive activity, and functional MRI showed that increases in cognitive load in patients and unaffected siblings caused abnormal activation of primary motor cortex and the supplementary motor area.6 This study provides evidence for familial endophenotypes in patients with IGE and unaffected relatives and suggests that their epilepsy should no longer be classified as idiopathic. 7 What are the implications of the changing criteria and categories of epilepsy? As with all good research, they reveal new horizons and prompt new questions. The
next steps will be to define better when epilepsy begins and when it ends, at least for most patients. Dieter Schmidt Epilepsy Research Group, Berlin D-14163, Germany [email protected] I declare no competing interests. 1 2 3
4
5
6
7
Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55: 475–82. Hauser A. Commentary: ILAE Definition of Epilepsy. Epilepsia. 2014; 55: 488–90. Berg AT, Rychlik K, Levy SR, Testa FM. Complete remission of childhoodonset epilepsy: stability and prediction over two decades. Brain 2014; published online Oct 22. DOI:10.1093/brain/awu294. Sillanpää M, Schmidt D. Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy. Epilepsy Behav 2006; 8: 713–19. Chowdhury FA, Woldman W, FitzGerald TH, et al. Revealing a brain network endophenotype in families with idiopathic generalized epilepsy. PLoS One 2014; 9: e110136. Wandschneider B, Centeno M, Vollmar C, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain 2014; 137: 2469–79. Berkovic SF, Jackson GD. ‘Idiopathic’ no more! Abnormal interaction of large-scale brain networks in generalized epilepsy. Brain 2014; 137: 2400–02.
Movement disorders: discoveries in pathophysiology and therapy Movement disorders are common and are frequently treated by neurologists. Clinical phenotype and pathophysiology are heterogenous. In 2014, research in the specialty of movement disorders advanced our understanding of pathogenesis, translational aspects, and therapy. Our understanding of disease mechanisms of rare movement disorders such as hereditary spastic paraplegia, with its hallmark feature of lower limb spasticity caused mainly by axonal degeneration in the cortical tract, has been hampered by low disease prevalence and genotypic and phenotypic heterogeneity. Whole-exome sequencing analysis identified mutations in no less than 18 new putative genes, and consecutive network analysis showed that many of these genes converge in key biological processes, including axon and synapse development, cellular transport, and nucleotide metabolism.1 Moreover, a significant association of these genes with other neurodegenerative movement disorders was also identified. www.thelancet.com/neurology Vol 14 January 2015
Another exciting pathophysiological similarity between movement disorders was discovered for the spreading of pathology. Parkinson’s disease was the first neurodegenerative movement disorder for which a prion-like spreading of pathology was shown to affect allografted ventral mesencephalic tissue. Several in-vitro and in-vivo models have subsequently shown that neurons release and uptake α-synuclein. Research in 2014 showed that aggregation of α-synuclein in neurons might be triggered by exogenously preformed α-synuclein fibrils or Lewy body extracts.2,3 This prionlike protein spread has now for the first time been shown for mutant huntingtin in genetically normal and unrelated allografted neural tissue transplanted into the brain of patients with Huntington’s disease. Astonishingly, the mechanisms of spreading in Huntington’s disease, which is a monogenetic disease, are similar to those of Parkinson’s disease, and this indicates that non–cell-autonomous mechanisms can drive monogenetic neurodegenerative disorders. This study could have implications for future clinical 9
Amelie-Benoist/BSIP/Science Photo Library
2014 Round-up
and therapeutic studies of patients with Huntington’s disease and possibly other neurodegenerative diseases that are characterised by the formation of mutant protein oligomers and aggregates. Taking a translational approach, a new opportunity for therapy was opened when monoclonal α-synuclein antibodies were shown to reduce the formation of Lewy bodies and Lewy neurites by preventing uptake of preformed fibrils and cell-to-cell transmission of α-synuclein, and thereby stall neurodegeneration.5 Additionally, a next-generation active vaccination technology with short peptides was developed,6 from which a peptide that elicited a specific response against α-synuclein was identified. Immunisation of transgenic mice (PDGF-α-syn transgenic mice and mThy1-α-syn transgenic mice) resulted in high antibody titres in cerebrospinal fluid, plasma, and CNS. The ability of this antibody to recognise α-synuclein aggregates and reduce their accumulation in the brain enabled the first phase 1 clinical study7 of immunisation in Parkinson’s disease. Although the results of this small phase 1 safety trial are unpublished, the endpoints were seemingly met, which sets the stage for a larger phase 2 trial. Epigenetic therapy has been used in an attempt to influence the expression of specific disease-causing genes and control the accumulation of diseasemediating proteins. Two studies have pioneered the application of epigenetic therapy for Friedreich’s ataxia: one with an orally delivered histone deacetylase inhibitor8, and the other with orally delivered 10
nicotinamide.9 Both studies tested the compounds in cell culture models and in patients with Friedreich’s ataxia, with frataxin expression as a main outcome parameter in patients. In both studies, an increase of frataxin expression was noted after therapy. However, clinical changes were not reported and might only occur when patients are treated for longer periods. Early therapy of Parkinson’s disease was the subject of the PD MED trial,10 one of the largest trials (1620 patients) to compare initial levodopa therapy with two levodopasparing therapies (dopamine agonists or monoamine oxidase inhibitors). This study was based on subjective evaluation with the Parkinson’s disease Questionnaire 39 (PDQ-39) as the main outcome parameter. At 3 years, levodopa treatment was associated with a 1·8 points better mobility score on the PDQ-39 compared with the levodopa-sparing therapies, which—although significant—was not regarded as clinically meaningful by the investigators. Although methodological constraints limit the interpretation of these findings, mobility in patients receiving initial levodopa over a long period was equal to or even better than mobility in patients in other groups. This argues against avoiding levodopa, particularly in the treatment of elderly people. Optimising and strengthening of the brain’s compensatory mechanisms is increasingly recognised as an important therapeutic approach to movement disorders. This approach has been convincingly shown for various forms of physical therapy, Lee-Silvermanvoice training, and even multiprofessional training. A large controlled trial of home-based occupational therapy for patients with Parkinson’s disease showed mild but significant improvements to hand function.11 This study also showed that patients can be integrated effectively in the therapeutic concept of home-based therapies that are free of side-effects. Deep brain stimulation (DBS) of the internal pallidum is used for generalised dystonia that is resistant to medical treatment, but DBS has not been extended to other forms of dystonia. The first controlled trial of neurostimulation in patients with cervical dystonia otherwise unresponsive to botulinum toxin injections showed significant improvement in those treated with DBS.12 These improvements were about 25%, with a mean score of 20 on the Toronto Western Spasmodic Torticollis Rating Scale (from 0 to 35) at 3 months and 6 months, and were thus clinically relevant. Of 16 severe www.thelancet.com/neurology Vol 14 January 2015
2014 Round-up
adverse events, only five remained after 6 months. Hence, DBS might become an option for those patients who do not respond to any existing treatment.
3
Daniela Berg, *Günther Deuschl
5
Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany (DB); German Center of Neurodegenerative Diseases, Tübingen, Germany (DB); Department of Neurology, UKSH, Kiel Campus, Christian-Albrechts University Kiel, Kiel, Germany (GD) [email protected] DB declares grants from Michael J Fox Foundation, Janssen Pharmaceutica, dPV (German Parkinson’s Disease Association), German Federal Ministry of Education and Research, International Parkinson Fonds, Boehringer Ingelheim Pharma GmbH, TEVA Pharma GmbH, and UCB Pharma GmbH; personal fees from UCB Pharma GmbH, Novartis Pharma GmbH, Lundbeck, UCB Pharma GmbH, TEVA Pharma GmbH, University of Tübingen, Centre for Neurology, Hertie-Institute for Clinical Brain Research, and German Center for Neurodegenerative Diseases (DZNE) Tübingen; all outside the submitted work. GD declares grants from German Research Council, German Ministery of Education and Health, and Medtronic; personal fees from UCB, Desitin, Medtronic, Sapiens, Boston Scientific, and Britannica; all outside the submitted work. 1
2
Novarino G, Fenstermaker AG, Zaki MS, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 2014; 343: 506–11. Recasens A, Dehay B, Bove J, et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014; 75: 351–62.
4
6
7
8 9
10
11
12
Volpicelli-Daley LA, Luk KC, Lee VM. Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat Protoc 2014; 9: 2135–46. Cicchetti F, Lacroix S, Cisbani G, et al. Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Ann Neurol 2014; 76: 31–42. Tran HT, Chung CH, Iba M, et al. Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Rep 2014; 7: 2054–65. Mandler M, Valera E, Rockenstein E, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol 2014; 127: 861–79. Brachmann S. Successful Phase 1 Trial for Parkinson’s Vaccine. 2014. http:// www.ipwatchdog.com/2014/08/07/successful-phase-1-trial-forparkinsons-vaccine/id=50717/ (accessed Nov 25, 2014). Soragni E, Miao W, Iudicello M, et al. Epigenetic therapy for Friedreich ataxia. Ann Neurol 2014; 76: 489–508. Libri V, Yandim C, Athanasopoulos S, et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet 2014; 384: 504–13. PD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 2014; 384: 1196–205. Sturkenboom IH, Graff MJ, Hendriks JC, et al. Efficacy of occupational therapy for patients with Parkinson’s disease: a randomised controlled trial. Lancet Neurol 2014; 13: 557–66. Volkmann J, Mueller J, Deuschl G, et al. Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial. Lancet Neurol 2014; 13: 875–84.
MS and related disorders: looking for markers of phenotypes Multiple sclerosis (MS) research addressed several challenges in 2014, including progressive MS. Despite advances in other forms of MS, there are no approved treatments for progressive MS because of the scarcity of reliable methods to test when, how, and why MS progresses. Nonetheless, post-hoc analyses of placebocontrolled trials1,2 suggest that a subset of patients with progressive MS might benefit from immunedirected therapies, which are usually effective in the management of relapsing–remitting MS. The first step towards identifying subsets of patients with progressive MS is a more precise characterisation of the different progressive MS disease courses. The MS Phenotype Group reviewed the 1996 progressive MS phenotype classification (primary progressive, secondary progressive, and progressive relapsing) and updated the framework for patients’ inclusion in clinical and basic research studies on the basis of integrated assessment of clinical and validated MRI data.3 Two important changes that would modify the old classification were proposed: a yearly clinical and MRI-based www.thelancet.com/neurology Vol 14 January 2015
assessment of disease activity (occurrence of relapse, MRI gadolinium-enhancing lesions, or unequivocally enlarged lesions) and a yearly determination of disability progression (increase in neurological dysfunction confirmed throughout a defined time interval). According to the new classification, the progressive relapsing course is eliminated and primary progressive and secondary progressive courses are merged in one group named progressive MS. Progressive MS is subclassified according to the presence or absence of activity (ie, active or inactive) and according to the presence or absence of confirmed progression (ie, with progression or without progression). A regular tracking of symptoms and signs of inflammatory and neurodegenerative processes might help to select subsets of patients with progressive MS who might benefit from specific treatments. The MS Phenotype Group emphasises that further research is needed to define better the role of biological markers and non-conventional MRI in assessment, confirmation, or revision of MS phenotype descriptions. 11
![[Proliferative vitreoretinopathy: new discoveries in pathophysiology and therapy].](/assets/img/hold.png)
