YEAR IN REVIEW effects of a compound by disentangling disease course modification from sympto matic effects of a drug. Ironically, a negative trial that explored putative disease- modifying effects of parmipexole—a dopamine agonist with known symptomatic action—provided support for the use of the delayed-start design in early PD.7 Patients in the early start group (n = 210, 6–9 months before delayed start) did not do better at 15 months than those in the delayed start group (n = 200)—an observation that could not be explained by a floor effect or insufficient washout period. Of note, DAT imaging in a subgroup of patients showed similar results. The only pitfall of this trial was a higher dropout rate in the delayed-start group (22%) than in the early-start group (15%), which was attributable to worsening of PD in 10% and 2% of cases, respectively. Deep brain stimulation (DBS) is the major therapeutic breakthrough of the past 25 years for the management of PD. DBS is usually offered patients who have severe motor fluctuations or debilitating tremor despite optimal medical treatment. A large randomized controlled trial (EARLYSTIM) involving multiple centres in Germany and France assessed the efficacy of DBS of the subthalamic nucleus combined with best available medical treatment in 251 patients who were younger and had less advanced disease than those currently selected for DBS.8 The mean age of enrolled patients was 52 years, with mean disease duration of 7.5 years and mean duration of motor complications of 1.7 years. The study reached its primary end point: quality of life as assessed by the 39-Item PD Questionnaire was considerably improved after 24 months in patients receiving DBS compared with the group receiving medical treatment alone. Several secondary outcomes also favoured DBS. Whether these results will change current clinical practice and substantially increase the number of patients with PD who receive DBS is, however, uncertain, at least in the short term. A retrospective analysis of a cohort of patients with PD from a tertiary centre showed that only 2.5% of the cohort met the EARLYSTIM criteria, possibly because patients in tertiary centres usually have more advanced PD.9 Convincing general neurologists to refer their patients early enough for DBS to yield the maximum benefit could be a challenge. Finally, current DBS protocols were developed empirically and do not take account of the latest discoveries in PD pathophysiology—that is, abnormal synchronization of 66 | FEBRUARY 2014 | VOLUME 10
neuronal activity in basal ganglia and cortical networks. In an elegant clinical proof-ofconcept study, targeting of the subthalamic nucleus with adaptive DBS—which delivers electrical stimulation only when abnormal local field potential activity is detected— was more effective in improving motor symptoms than standard DBS, even though the overall stimulation time was reduced by 50%.10 Findings in 2013 continue to shift the definition of PD towards earlier, premotor phases, which could facilitate administration of putative disease-modifying therapies before most nigrostriatal dopamine neurons have undergone irreversible damage. An earlier diagnosis might also increase the chance to attenuate or stop the prion-like propagation of α‑synuclein toxicity. The results of the EARLYSTIM trial suggest that standard DBS could also be beneficial in early PD. Finally, pathophysiology-driven adaptive DBS techniques are challenging the traditional DBS designs and might become a reality in clinical practice in the near future. Institut des Maladies Neurodégénératives, CHU de Bordeaux, CNRS UMR5293, Université Bordeaux, place Amélie Raba-Léon, 33076 Bordeaux cedex, France (F. Tison, W. G. Meissner). Correspondence to: F. Tison [email protected] Competing interests The authors declare associations with the following companies/organizations: Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva/Lundbeck, UCB. F. Tison declares associations with the following
companies: Abbot and Addex. W. G. Meissner declares associations with the following companies/ organizations: Adaptive Neuromodulation, APTES, PSP-France. See the article online for full details of the relationships. 1.
Cui, G. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238–242 (2013). 2. Lévesque, M. & Parent, A. The striatofugal fiber system in primates: a reevaluation of its organization based on single-axon tracing studies. Proc. Natl Acad. Sci. USA 102, 11888–11893 (2005). 3. Recasens, A. et al. Lewy body extracts from Parkinson’s disease brains trigger α‑synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. http://dx.doi.org/ 10.1002/ana.24066. 4. Berg, D. et al. Changing the research criteria for the diagnosis of Parkinson’s disease: obstacles and opportunities. Lancet Neurol. 12, 514–524 (2013). 5. Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136, 2419–2431 (2013). 6. Iranzo, A. et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid‑eye‑movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12, 443–453 (2013). 7. Schapira, A. H. et al. Pramipexole in patients with early Parkinson’s disease (PROUD): a randomised delayed-start trial. Lancet Neurol. 12, 747–755 (2013). 8. Schuepbach, W. M. et al. Neurostimulation for Parkinson’s disease with early motor complications. N. Engl. J. Med. 368, 610–622 (2013). 9. Sprenger, F., Seppi, K., Wolf, E. & Poewe, W. Relevance of EARLYSTIM in a tertiary movement disorder center. Mov. Disord. http:// dx.doi.org/10.1002/mds.25631. 10. Little, S. et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann. Neurol. 74, 449–457 (2013).
STROKE IN 2013
Disappointments and advances in acute stroke intervention Michael Tymianski
Clinical trials in stroke intervention during the past year have yielded contrasting results. Endovascular therapies and procedures to reduce stroke risk caused by patent foramen ovale have failed to demonstrate superiority over standard medical treatments. By contrast, a trial of neuroprotection— traditionally thought to be ineffective in humans—offers hope. Tymianski, M. Nat. Rev. Neurol. 10, 66–68 (2014); published online 7 January 2014; doi:10.1038/nrneurol.2013.271
Stroke affects 15 million individuals annually worldwide, incurring enormous socioeconomic costs. Accordingly, stroke interventions have the potential to make
a substantial impact on world health. During the past year, the completion of much-anticipated randomized controlled trials has turned the tables on preconceived www.nature.com/nrneurol
© 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Figure 1 | Evolution of the ischaemic core over time in cynomolgus macaques with AIS caused by middle cerebral artery occlusion. The ischaemic core was defined as the brain volume that caused increased signal intensity on DWI MRI. The data shown are from three macaques. The solid line represents the best-fit curve. Each dot represents a single volume measurement. The DWI signal reaches a plateau ~3 h after ischaemia onset (0 h). Adapted, with permission from Nature Publishing Group © Cook, D. J. et al. Nature 483, 213–217 (2012).8 Abbreviations: AIS, acute ischaemic stroke; DWI, diffusion-weighted imaging.
Although recanalization indicates better outcomes after AIS, and endovascular treatment achieves high recanalization rates, the IMS III and SYNTHESIS Expansion trials attest that even effective recanalization is futile if it occurs too late. A stroke inter vention can only be effective if given while salvageable brain tissue is still present. Insights regarding the t herapeutic window in the average AIS could be obtained from existing tPA trials, which suggest that the strongest benefit is gained when thrombolysis is initiated within 3 h of stroke onset. This ~3 h window is also suggested by recent studies in gyren cephalic primates, which indicated that the ischaemic penumbra—t he target of stroke therapy—shrinks rapidly over 3 h so that tissue salvage past this timeframe might not be clinically effective (Figure 1).8 The MR RESCUE trial3 evaluated whether penu mbra imaging could be used to select patients who would benefit from endovascular therapy. Patients were randomly assigned within 8 h of stroke onset to endovascular embolectomy or standard care (which included tPA for patients who qualified for this treatment according to the standard criteria), and were stratified according to whether imaging demonstrated a favourable penumbral pattern (substantial salvageable tissue and small infarct core) or a non-penumbral pattern (large core or small or absent pen umbra). The primary outcome was based on the 3‑month mRS score. Unfortunately, embolectomy was not superior to standard care in patients with either a favourable or a non-favourable penumbral pattern. Thus, although the penumbra is an important target for stroke treatment, it should not be confused with a selection criterion for embolectomy. The IMS III, SYNTHESIS Expansion and MR RESCUE trials provide the impetus to
NATURE REVIEWS | NEUROLOGY
▶
100 DWI volume (% of perfusion deficit volume)
notions about stroke treatment. Most of the trials tested endovascular interventions that the medical community anticipated to be validated. Disappointingly, three trials of endovascular recanalization of occluded intracranial arteries during acute ischaemic stroke (AIS),1,2,3 and two trials of percutaneous closure of patent foramen ovale (PFO) to prevent embolic strokes,4,5 have failed to demonstrate superiority over existing medical therapy. By contrast, a trial of neuroprotection—a strategy that had previously failed to demonstrate benefits in patients with stroke—provided evidence of efficacy, 6 suggesting a way forward that might positively affect the prospects of both n europrotection and endovascular treatments. Arterial recanalization is a strong surrogate measure for clinical outcome in AIS. Presently, tissue plasminogen activator (tPA) is the only widely approved recanal ization therapy, but early tPA administration achieves recanalization rates of only 40–50% within 6 h of stroke onset,7 and the rates are even worse if the occlusion affects the internal carotid or proximal middle cerebral artery. Endovascular therapies, which achieve high recanalization rates, were thus hypothesized to improve clinical outcomes in AIS. The IMS III trial1 examined the benefits of endovascular recanalization in 656 patients to whom intravenous tPA was given within 3 h of stroke onset. Patients received either intravenous tPA alone or intravenous tPA followed by endovascular treatment. The primary outcome was 90-day modified Rankin Scale (mRS) score of ≤2, indicating functional independence. The study planned to enrol up to 900 participants, but was discontinued early due to futility. Although endovascular therapy yielded higher recanalization rates, clinical outcomes after assignment of 656 participants were similar in the two groups. The authors propose that the delays in initiating endovascular therapy might have c ontributed to the negative study result. In the SYNTHESIS Expansion trial2, 362 patients with AIS were randomly allocated to endovascular therapy or to intravenous tPA within 4.5 h of symptom onset. The primary outcome was an mRS score of 0–1 at 3-month follow-up. The groups differed in that the median time from stroke onset to the start of treatment was 1 h greater (3.75 h) for endovascular therapy than for intravenous tPA (2.75 h). Unfortunately, endovascular intervention did not prove superior to intravenous tPA.
80
60
40
20
0
0
2
4 Time (h)
6
8
re-examine the indications for endovascular stroke therapy. At the very least, they have restored equipoise to the treatment paradigm and could facilitate the success of future trials. By using new devices that yield improved recanalization rates, and an optimized workflow that minimizes the interval between symptom onset and reperfusion, the efficacy of endovascular therapy might be validated in a more reliable manner. PFO is found in ~25% of people, increasing to ~50% in patients who sustain crypto genic ischaemic strokes.4 Many patients with stroke who are found to have PFO undergo percutaneous closure procedures to prevent further strokes, even though the PFO could be incidental. In 2013, two eagerly awaited studies compared the benefits of PFO closure with standard medical treatment. The RESPECT trial4 and the PC Trial5 were multinational randomized controlled trials. Patients were enrolled if they had PFO plus ischaemic stroke, transient ischaemic attack (TIA), a peripheral thromboembolic event (RESPECT trial only), or prior cryptogenic Key advances ■■ The IMS III1 and SYNTHESIS Expansion2 trials re-enforced the idea that recanalization of blocked arteries, no matter how effective, cannot be of benefit if it occurs too late ■■ Furthermore, IMS III and SYNTHESIS Expansion trials corroborated the notion that the targeting window for acute stroke therapies is likely to be in the order of 3 h1,2 ■■ The RESPECT trial4 and the PC Trial5 failed to resolve the controversies surrounding the efficacy of patent foramen ovale closure to prevent cryptogenic strokes ■■ The ENACT trial provided the first evidence that neuroprotection in the adult human brain is possible after the onset of ischaemic brain injury6
VOLUME 10 | FEBRUARY 2014 | 67 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW ischaemic stroke (PC Trial only). Patients were randomly assigned to PFO closure or to medical therapy. The trial end points included death, nonfatal stroke, TIA or peripheral embolism. Both trials followed the 909-patient CLOSURE I trial, 9 which suggested no benefit of PFO closure over medical therapy for stroke or TIA prevention. The PC Trial (414 patients) also failed to show a benefit of PFO closure. 5 In the RESPECT trial (980 patients), no significant benefit of PFO closure was observed in the primary intention-to-treat analysis, but closure was superior to medical therapy in the perprotocol and as-treated analyses. 4 Taken together, the CLOSURE I, RESPECT and PC Trials are unlikely to convince sceptics of the benefits of PFO closure in patients with cryptogenic stroke, although RESPECT provides a potential positive signal that could be investigated further given the equipoise between percutaneous intervention and medical treatment. Neuroprotection for AIS is defined as a therapy aimed at enhancing the brain’s resilience to ischaemia to improve clinical outcome. Half a century of neuroprotection research has failed to translate over 1,000 experimental treatments to clinical utility,10 but the ENACT trial6 might have finally provided a positive signal. ENACT explored whether administration of the PSD95 inhibitor NA‑1 (also known as TatNR2B9c)8 after stroke onset could reduce ischaemic brain damage in patients undergoing endovascular brain aneurysm repair. Such individuals have a high incidence of small procedurally induced ischaemic strokes. 185 participants were enrolled in a multicentre, randomized, double-blinded trial, and received a single intravenous infusion of NA‑1 or saline (as a control) after the endovascular procedure. Patients who received NA‑1 sustained markedly fewer ischaemic infarcts, as gauged by MRI. Among those patients with ruptured aneurysms, NA‑1 reduced the number and volume of strokes and improved neuro logical outcome at 30 days. This trial provides the first evidence that neuro protection in the ischaemic human brain is feasible and measurable, and sets the stage for future trials to improve AIS outcomes via monotherapy or in combination with recanalization strategies. The past year has provided a sobering reminder of the challenge of subjecting stroke interventions to rigorous scientific scrutiny, even when they are intuitively 68 | FEBRUARY 2014 | VOLUME 10
accepted in common medical practice. Nonetheless, each advance discussed above contributes to future studies in stroke research, and aids improvement of outcomes for patients with stroke. Toronto Western Hospital, Division of Neurosurgery, 4W‑435, 399 Bathurst Street, Toronto, ON M5T-2S8, Canada. [email protected] Competing interests M. Tymianski declares an association with the following company: NoNO. See the article online for full details of this relationship. 1.
2.
3.
Broderick, J. P. et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N. Engl. J. Med. 368, 893–903 (2013). Ciccone, A. et al. Endovascular treatment for acute ischemic stroke. N. Engl. J. Med. 368, 904–913 (2013). Kidwell, C. S. et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N. Engl. J. Med. 368, 914–923 (2013).
4.
Carroll, J. D. et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N. Engl. J. Med. 368, 1092–1100 (2013). 5. Meier, B. et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N. Engl. J. Med. 368, 1083–1091 (2013). 6. Hill, M. D. et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebocontrolled trial. Lancet Neurol. 11, 942–950 (2012). 7. Rha, J. H. & Saver, J. L. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 3, 967–973 (2007). 8. Cook, D. J., Teves, L. & Tymianski, M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483, 213–217 (2012). 9. Furlan, A. J. et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N. Engl. J. Med. 366, 991–999 (2012). 10. O’Collins, V. E. et al. 1,026 experimental treatments in acute stroke. Ann. Neurol. 59, 467–477 (2006).
NEURO-ONCOLOGY IN 2013
Improving outcome in newly diagnosed malignant glioma Michael Weller and Wolfgang Wick
In 2013, two discoveries—that alkylating agent chemotherapy prolongs survival when added to radiotherapy for patients with anaplastic oligodendroglial tumours with 1p19q codeletion, and that bevacizumab prolongs progression-free survival in patients with newly diagnosed glioblastoma—have dominated debate in neuro-oncology. These findings could help to define new standards of care in malignant glioma. Weller, M. & Wick, W. Nat. Rev. Neurol. 10, 68–70 (2014); published online 14 January 2014; doi:10.1038/nrneurol.2013.268
Anaplastic gliomas (WHO grade III) and glioblastomas (WHO grade IV) are collectively termed malignant gliomas. Morphological subclassification of anaplastic gliomas into astrocytic, oligodendroglial and oligoastrocytic (mixed) types is challenging and requires molecular guidance, but has major prognostic significance. By contrast, morphological subtyping of glioblastoma has no impact on clinical decision-making. Major advances in the diagnosis and management of malignant gliomas came with the clarification of the prognostic versus predictive role of three molecular markers: 1p19q c odeletion, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase (IDH) 1 or 2
mutation. 1 High-t hroughput studies have further refined the molecular classification and somatic genomic landscape of glioblastoma.2,3 Maximal safe surgery, as feasible, followed by radiotherapy of the involved brain region, remained the standard of care for malignant gliomas for decades until the introduction of temozolomide (TMZ) chemoradiotherapy (TMZ/RT→TMZ) for newly diagnosed glioblastoma in 2005. The latest results of four major clinical trials, as reported in 2013, suggest further options for the treatment of malignant glioma. Long-term follow-up of patients from two randomized clinical trials—European Organization for Research and Treatment of Cancer (EORTC) 26951 and Radiation www.nature.com/nrneurol
© 2014 Macmillan Publishers Limited. All rights reserved
neuronal activity in basal ganglia and cortical networks. In an elegant clinical proof-ofconcept study, targeting of the subthalamic nucleus with adaptive DBS—which delivers electrical stimulation only when abnormal local field potential activity is detected— was more effective in improving motor symptoms than standard DBS, even though the overall stimulation time was reduced by 50%.10 Findings in 2013 continue to shift the definition of PD towards earlier, premotor phases, which could facilitate administration of putative disease-modifying therapies before most nigrostriatal dopamine neurons have undergone irreversible damage. An earlier diagnosis might also increase the chance to attenuate or stop the prion-like propagation of α‑synuclein toxicity. The results of the EARLYSTIM trial suggest that standard DBS could also be beneficial in early PD. Finally, pathophysiology-driven adaptive DBS techniques are challenging the traditional DBS designs and might become a reality in clinical practice in the near future. Institut des Maladies Neurodégénératives, CHU de Bordeaux, CNRS UMR5293, Université Bordeaux, place Amélie Raba-Léon, 33076 Bordeaux cedex, France (F. Tison, W. G. Meissner). Correspondence to: F. Tison [email protected] Competing interests The authors declare associations with the following companies/organizations: Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva/Lundbeck, UCB. F. Tison declares associations with the following
companies: Abbot and Addex. W. G. Meissner declares associations with the following companies/ organizations: Adaptive Neuromodulation, APTES, PSP-France. See the article online for full details of the relationships. 1.
Cui, G. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238–242 (2013). 2. Lévesque, M. & Parent, A. The striatofugal fiber system in primates: a reevaluation of its organization based on single-axon tracing studies. Proc. Natl Acad. Sci. USA 102, 11888–11893 (2005). 3. Recasens, A. et al. Lewy body extracts from Parkinson’s disease brains trigger α‑synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. http://dx.doi.org/ 10.1002/ana.24066. 4. Berg, D. et al. Changing the research criteria for the diagnosis of Parkinson’s disease: obstacles and opportunities. Lancet Neurol. 12, 514–524 (2013). 5. Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136, 2419–2431 (2013). 6. Iranzo, A. et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid‑eye‑movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12, 443–453 (2013). 7. Schapira, A. H. et al. Pramipexole in patients with early Parkinson’s disease (PROUD): a randomised delayed-start trial. Lancet Neurol. 12, 747–755 (2013). 8. Schuepbach, W. M. et al. Neurostimulation for Parkinson’s disease with early motor complications. N. Engl. J. Med. 368, 610–622 (2013). 9. Sprenger, F., Seppi, K., Wolf, E. & Poewe, W. Relevance of EARLYSTIM in a tertiary movement disorder center. Mov. Disord. http:// dx.doi.org/10.1002/mds.25631. 10. Little, S. et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann. Neurol. 74, 449–457 (2013).
STROKE IN 2013
Disappointments and advances in acute stroke intervention Michael Tymianski
Clinical trials in stroke intervention during the past year have yielded contrasting results. Endovascular therapies and procedures to reduce stroke risk caused by patent foramen ovale have failed to demonstrate superiority over standard medical treatments. By contrast, a trial of neuroprotection— traditionally thought to be ineffective in humans—offers hope. Tymianski, M. Nat. Rev. Neurol. 10, 66–68 (2014); published online 7 January 2014; doi:10.1038/nrneurol.2013.271
Stroke affects 15 million individuals annually worldwide, incurring enormous socioeconomic costs. Accordingly, stroke interventions have the potential to make
a substantial impact on world health. During the past year, the completion of much-anticipated randomized controlled trials has turned the tables on preconceived www.nature.com/nrneurol
© 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Figure 1 | Evolution of the ischaemic core over time in cynomolgus macaques with AIS caused by middle cerebral artery occlusion. The ischaemic core was defined as the brain volume that caused increased signal intensity on DWI MRI. The data shown are from three macaques. The solid line represents the best-fit curve. Each dot represents a single volume measurement. The DWI signal reaches a plateau ~3 h after ischaemia onset (0 h). Adapted, with permission from Nature Publishing Group © Cook, D. J. et al. Nature 483, 213–217 (2012).8 Abbreviations: AIS, acute ischaemic stroke; DWI, diffusion-weighted imaging.
Although recanalization indicates better outcomes after AIS, and endovascular treatment achieves high recanalization rates, the IMS III and SYNTHESIS Expansion trials attest that even effective recanalization is futile if it occurs too late. A stroke inter vention can only be effective if given while salvageable brain tissue is still present. Insights regarding the t herapeutic window in the average AIS could be obtained from existing tPA trials, which suggest that the strongest benefit is gained when thrombolysis is initiated within 3 h of stroke onset. This ~3 h window is also suggested by recent studies in gyren cephalic primates, which indicated that the ischaemic penumbra—t he target of stroke therapy—shrinks rapidly over 3 h so that tissue salvage past this timeframe might not be clinically effective (Figure 1).8 The MR RESCUE trial3 evaluated whether penu mbra imaging could be used to select patients who would benefit from endovascular therapy. Patients were randomly assigned within 8 h of stroke onset to endovascular embolectomy or standard care (which included tPA for patients who qualified for this treatment according to the standard criteria), and were stratified according to whether imaging demonstrated a favourable penumbral pattern (substantial salvageable tissue and small infarct core) or a non-penumbral pattern (large core or small or absent pen umbra). The primary outcome was based on the 3‑month mRS score. Unfortunately, embolectomy was not superior to standard care in patients with either a favourable or a non-favourable penumbral pattern. Thus, although the penumbra is an important target for stroke treatment, it should not be confused with a selection criterion for embolectomy. The IMS III, SYNTHESIS Expansion and MR RESCUE trials provide the impetus to
NATURE REVIEWS | NEUROLOGY
▶
100 DWI volume (% of perfusion deficit volume)
notions about stroke treatment. Most of the trials tested endovascular interventions that the medical community anticipated to be validated. Disappointingly, three trials of endovascular recanalization of occluded intracranial arteries during acute ischaemic stroke (AIS),1,2,3 and two trials of percutaneous closure of patent foramen ovale (PFO) to prevent embolic strokes,4,5 have failed to demonstrate superiority over existing medical therapy. By contrast, a trial of neuroprotection—a strategy that had previously failed to demonstrate benefits in patients with stroke—provided evidence of efficacy, 6 suggesting a way forward that might positively affect the prospects of both n europrotection and endovascular treatments. Arterial recanalization is a strong surrogate measure for clinical outcome in AIS. Presently, tissue plasminogen activator (tPA) is the only widely approved recanal ization therapy, but early tPA administration achieves recanalization rates of only 40–50% within 6 h of stroke onset,7 and the rates are even worse if the occlusion affects the internal carotid or proximal middle cerebral artery. Endovascular therapies, which achieve high recanalization rates, were thus hypothesized to improve clinical outcomes in AIS. The IMS III trial1 examined the benefits of endovascular recanalization in 656 patients to whom intravenous tPA was given within 3 h of stroke onset. Patients received either intravenous tPA alone or intravenous tPA followed by endovascular treatment. The primary outcome was 90-day modified Rankin Scale (mRS) score of ≤2, indicating functional independence. The study planned to enrol up to 900 participants, but was discontinued early due to futility. Although endovascular therapy yielded higher recanalization rates, clinical outcomes after assignment of 656 participants were similar in the two groups. The authors propose that the delays in initiating endovascular therapy might have c ontributed to the negative study result. In the SYNTHESIS Expansion trial2, 362 patients with AIS were randomly allocated to endovascular therapy or to intravenous tPA within 4.5 h of symptom onset. The primary outcome was an mRS score of 0–1 at 3-month follow-up. The groups differed in that the median time from stroke onset to the start of treatment was 1 h greater (3.75 h) for endovascular therapy than for intravenous tPA (2.75 h). Unfortunately, endovascular intervention did not prove superior to intravenous tPA.
80
60
40
20
0
0
2
4 Time (h)
6
8
re-examine the indications for endovascular stroke therapy. At the very least, they have restored equipoise to the treatment paradigm and could facilitate the success of future trials. By using new devices that yield improved recanalization rates, and an optimized workflow that minimizes the interval between symptom onset and reperfusion, the efficacy of endovascular therapy might be validated in a more reliable manner. PFO is found in ~25% of people, increasing to ~50% in patients who sustain crypto genic ischaemic strokes.4 Many patients with stroke who are found to have PFO undergo percutaneous closure procedures to prevent further strokes, even though the PFO could be incidental. In 2013, two eagerly awaited studies compared the benefits of PFO closure with standard medical treatment. The RESPECT trial4 and the PC Trial5 were multinational randomized controlled trials. Patients were enrolled if they had PFO plus ischaemic stroke, transient ischaemic attack (TIA), a peripheral thromboembolic event (RESPECT trial only), or prior cryptogenic Key advances ■■ The IMS III1 and SYNTHESIS Expansion2 trials re-enforced the idea that recanalization of blocked arteries, no matter how effective, cannot be of benefit if it occurs too late ■■ Furthermore, IMS III and SYNTHESIS Expansion trials corroborated the notion that the targeting window for acute stroke therapies is likely to be in the order of 3 h1,2 ■■ The RESPECT trial4 and the PC Trial5 failed to resolve the controversies surrounding the efficacy of patent foramen ovale closure to prevent cryptogenic strokes ■■ The ENACT trial provided the first evidence that neuroprotection in the adult human brain is possible after the onset of ischaemic brain injury6
VOLUME 10 | FEBRUARY 2014 | 67 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW ischaemic stroke (PC Trial only). Patients were randomly assigned to PFO closure or to medical therapy. The trial end points included death, nonfatal stroke, TIA or peripheral embolism. Both trials followed the 909-patient CLOSURE I trial, 9 which suggested no benefit of PFO closure over medical therapy for stroke or TIA prevention. The PC Trial (414 patients) also failed to show a benefit of PFO closure. 5 In the RESPECT trial (980 patients), no significant benefit of PFO closure was observed in the primary intention-to-treat analysis, but closure was superior to medical therapy in the perprotocol and as-treated analyses. 4 Taken together, the CLOSURE I, RESPECT and PC Trials are unlikely to convince sceptics of the benefits of PFO closure in patients with cryptogenic stroke, although RESPECT provides a potential positive signal that could be investigated further given the equipoise between percutaneous intervention and medical treatment. Neuroprotection for AIS is defined as a therapy aimed at enhancing the brain’s resilience to ischaemia to improve clinical outcome. Half a century of neuroprotection research has failed to translate over 1,000 experimental treatments to clinical utility,10 but the ENACT trial6 might have finally provided a positive signal. ENACT explored whether administration of the PSD95 inhibitor NA‑1 (also known as TatNR2B9c)8 after stroke onset could reduce ischaemic brain damage in patients undergoing endovascular brain aneurysm repair. Such individuals have a high incidence of small procedurally induced ischaemic strokes. 185 participants were enrolled in a multicentre, randomized, double-blinded trial, and received a single intravenous infusion of NA‑1 or saline (as a control) after the endovascular procedure. Patients who received NA‑1 sustained markedly fewer ischaemic infarcts, as gauged by MRI. Among those patients with ruptured aneurysms, NA‑1 reduced the number and volume of strokes and improved neuro logical outcome at 30 days. This trial provides the first evidence that neuro protection in the ischaemic human brain is feasible and measurable, and sets the stage for future trials to improve AIS outcomes via monotherapy or in combination with recanalization strategies. The past year has provided a sobering reminder of the challenge of subjecting stroke interventions to rigorous scientific scrutiny, even when they are intuitively 68 | FEBRUARY 2014 | VOLUME 10
accepted in common medical practice. Nonetheless, each advance discussed above contributes to future studies in stroke research, and aids improvement of outcomes for patients with stroke. Toronto Western Hospital, Division of Neurosurgery, 4W‑435, 399 Bathurst Street, Toronto, ON M5T-2S8, Canada. [email protected] Competing interests M. Tymianski declares an association with the following company: NoNO. See the article online for full details of this relationship. 1.
2.
3.
Broderick, J. P. et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N. Engl. J. Med. 368, 893–903 (2013). Ciccone, A. et al. Endovascular treatment for acute ischemic stroke. N. Engl. J. Med. 368, 904–913 (2013). Kidwell, C. S. et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N. Engl. J. Med. 368, 914–923 (2013).
4.
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NEURO-ONCOLOGY IN 2013
Improving outcome in newly diagnosed malignant glioma Michael Weller and Wolfgang Wick
In 2013, two discoveries—that alkylating agent chemotherapy prolongs survival when added to radiotherapy for patients with anaplastic oligodendroglial tumours with 1p19q codeletion, and that bevacizumab prolongs progression-free survival in patients with newly diagnosed glioblastoma—have dominated debate in neuro-oncology. These findings could help to define new standards of care in malignant glioma. Weller, M. & Wick, W. Nat. Rev. Neurol. 10, 68–70 (2014); published online 14 January 2014; doi:10.1038/nrneurol.2013.268
Anaplastic gliomas (WHO grade III) and glioblastomas (WHO grade IV) are collectively termed malignant gliomas. Morphological subclassification of anaplastic gliomas into astrocytic, oligodendroglial and oligoastrocytic (mixed) types is challenging and requires molecular guidance, but has major prognostic significance. By contrast, morphological subtyping of glioblastoma has no impact on clinical decision-making. Major advances in the diagnosis and management of malignant gliomas came with the clarification of the prognostic versus predictive role of three molecular markers: 1p19q c odeletion, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase (IDH) 1 or 2
mutation. 1 High-t hroughput studies have further refined the molecular classification and somatic genomic landscape of glioblastoma.2,3 Maximal safe surgery, as feasible, followed by radiotherapy of the involved brain region, remained the standard of care for malignant gliomas for decades until the introduction of temozolomide (TMZ) chemoradiotherapy (TMZ/RT→TMZ) for newly diagnosed glioblastoma in 2005. The latest results of four major clinical trials, as reported in 2013, suggest further options for the treatment of malignant glioma. Long-term follow-up of patients from two randomized clinical trials—European Organization for Research and Treatment of Cancer (EORTC) 26951 and Radiation www.nature.com/nrneurol
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