- Email: [email protected]
Unruptured brain AVMs: to treat or not to treat
Reflection and Reaction
Unruptured brain AVMs: to treat or not to treat
http://neurology.thelancet.com Vol 7 March 2008
first occurrence of poor outcome (defined as OHS 2–6) included interventional treatment and large AVM size; and progression to significant disability (defined as OHS 2–6) that persisted to the end of the third year of follow-up did not differ between the groups. The key challenges of the study are well outlined by Wedderburn and colleagues. Although their study is very large and population based, few patients were followed after the first 2 years, making delineation of a difference in outcome unlikely. In the analysis of progression to poor outcome (OHS 2–6), only 23 patients in the untreated group and 30 in the treated group remained at risk at the 2-year point. A statistical difference was not detected. Another issue, which is nicely addressed by the investigators, is the difference in baseline characteristics of the two groups. In a non-randomised setting such as the one in this study, the selection of patients for treatment versus no treatment is inherently biased. Not surprisingly, patients who were aggressively treated tended to be younger, present with symptoms (such as seizures), be healthier, and have smaller AVMs. Significant adverse events (ICH, infarct, or progressive focal deficit) occurred between presentation and intervention in seven treated patients but in none of the untreated patients. Whether there was a difference in angioarchitectural factors that could lead to a different
Published Online February 1, 2008 DOI:10.1016/S14744422(08)70027-9 See Articles page 223
Neil Borden/Science Photo Library
Intracranial arteriovenous malformations (AVMs) are relatively uncommon congenital vascular lesions in which multiple arteries and veins are connected as a fistula without the normal intervening capillary bed. Clinically, AVMs present as an intracranial haemorrhage (ICH) in about 50% of cases,1 and as seizures in about 25%; other presentations include headache, focal neurological deficit, and pulsatile tinnitus. AVMs are increasingly being seen in clinical practice in patients who have no associated symptoms, as a result of fortuitous detection during imaging for unrelated reasons.2,3 After an AVM is detected, the key question is how best to manage it. An important issue is the risk of ICH in patients who have conservative management compared with the risk of treatment. Of the 50% of patients who have an AVM and present without ICH, the long-term risk of ICH is about 2–3% per year.3 A heightened future risk of haemorrhage might be predicted by features from imaging at the time of AVM diagnosis, such as a small AVM size, deep venous drainage, impaired venous drainage, a single draining vein, a paraventricular or intraventricular location, and the presence of aneurysms either on the feeding arteries or within the nidus. Unfortunately, population-based data on AVMs are available from only a few studies: that of Olmsted County, Minnesota;2 the New York Islands Project;4 and the Scottish Intracranial Vascular Malformation Study (SIVMS),5 the cohort discussed in this issue of The Lancet Neurology by Wedderburn and colleagues.6 None of these studies has provided long-term natural history data. SIVMS is a large prospective population-based registry that includes all patients 16 years of age or older diagnosed with any type of vascular malformation in Scotland during 1999–2003 and from 2006 onwards. The analysis by Wedderburn and colleagues6 includes 114 people who presented without a history of haemorrhage from 229 adults with AVMs identified in 1999–2003; 63 (55%) patients underwent interventional treatment for the AVM. The AVM was obliterated in about two-thirds of these cases. Comparison of patients who were treated with those who were not led to three key findings: there was no overall difference in functional outcome, whether defined on the Oxford Handicap Scale (OHS) as 2–6 or 3–6, during all available follow-up; in a multivariable Cox proportional hazards analysis, independent predictors of
An intracranial arteriovenous malformation
195
Reflection and Reaction
For the ARUBA website see http://www.arubastudy.org
risk of haemorrhage between the two groups is unclear, because not all patients had arteriography, including half of those who were not treated. Wedderburn and colleagues readily point out that their study is not a treatment trial, so any inherent bias in selection for aggressive intervention is simply part of the overall standard of care in this large population. The duration of follow-up is also important. A long follow-up period might be necessary to detect a slight beneficial effect of a treatment on the low risk of an adverse outcome that occurs without treatment. Followup of the present cohort is ongoing and further results will be of great interest. What effect should the data from Wedderburn and colleagues6 have on clinical practice? The study suggests that intervention for an AVM might not affect the risk of a persistent adverse outcome, at least in the short term. There are no similar population-based comparisons of intervention with conservative management for a large group of patients with AVMs. No benefit from intervention was noted over short-term follow-up in the non-population-based Columbia AVM databank,7 and long-term data remain unavailable. But, despite the limitations, the thoughtful analysis by Wedderburn and colleagues6 provides sobering data on the comparative efficacy of intervention for unruptured intracranial AVMs compared with natural history. Should all unruptured AVMs be treated aggressively on a routine basis? The study by Wedderburn and colleagues6 and those from other population-based or referral populations cannot answer this question definitively. Random allocation of patients with unruptured AVMs in a clinical trial continues to be controversial, with compelling arguments both for and against.8,9 Efforts to randomly assign selected patients with AVMs—those for whom clinical equipoise exists—to the best treatment compared with natural history should be supported. A
Randomized trial of Unruptured Brain AVMs (ARUBA) has been funded by the US National Institutes of Health. The cerebrovascular community looks forward to the successful completion of this study, along with the necessary long-term follow-up. Until then, our patients will continue to be managed on the basis of reviews and guidelines,10,11 natural history data,3 and data from nonrandomised populations. All of these are of interest but, unfortunately for our patients, not the final answer. Robert D Brown, Jr Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA [email protected] I have no conflicts of interest. 1
2
3 4 5
6
7
8 9 10
11
Brown RD Jr, Wiebers DO, Torner JC, O’Fallon WM. Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: a populationbased study of intracranial vascular malformations in Olmsted Country, Minnesota. J Neurosurg 1996; 85: 29–32. Brown RD Jr, Wiebers DO, Torner JC, O’Fallon WM. Incidence and prevalence of intracranial vascular malformations in Olmsted County, Minnesota, 1965 to 1992. Neurology 1996; 46: 949–52. Brown RD Jr, Wiebers DO, Forbes G, et al. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg 1988; 68: 352–27. Stapf C, Mast H, Sciacca RR, et al. The New York Islands AVM Study: design, study progress, and initial results. Stroke 2003; 34: e29–33. Al-Shahi R, Bhattacharya JJ, Currie DG, et al. Scottish Intracranial Vascular Malformation Study (SIVMS): evaluation of methods, ICD-10 coding, and potential sources of bias in a prospective, population-based cohort. Stroke 2003; 34: 1156–62. Wedderburn CJ, van Beijnum J, Bhattacharya J, et al, on behalf of the SIVMS Collaborators. Outcome after interventional or conservative management of unruptured brain arteriovenous malformations: a prospective, population-based cohort study. Lancet Neurol 2008; available online 1 Feb. DOI: 10.1016/S1474-4422(08)70026-7. Mohr JP, Stapf C, Sciacca RR, et al. Natural history versus treatment outcome in patients with unruptured brain arteriovenous malformations (AVM). Stroke 2004; 35: 328 (abstr). Stapf C, Mohr JP. Unruptured brain arteriovenous malformations should be treated conservatively: yes. Stroke 2007; 38: 3308–09. Cockroft KM. Unruptured brain arteriovenous malformations should be treated conservatively: no. Stroke 2007; 38: 3310–11. Ogilvy CS, Stieg PE, Awad I, et al. AHA Scientific Statement: Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke 2001; 32: 1458–71. Brown RD Jr, Flemming KD, Meyer FB, Cloft HJ, Pollock BE, Link ML. Natural history, evaluation, and management of intracranial vascular malformations. Mayo Clin Proc 2005; 80: 269–81.
Get personal with gene therapy for muscular dystrophy The identification of an ever-increasing number of genes that cause disease when mutated or aberrantly expressed is a tribute to the tremendous progress in genomics; however, the therapy dividend from the investment in this research has yet to be realised. Few diseases illustrate this better than Duchenne muscular 196
dystrophy (DMD), which, despite being identified and described clinically in the mid 19th century1 and being genetically characterised in the late 1980s,2 is still almost untreatable, let alone curable. Furthermore, the currently accepted standard-of-care treatment—oral corticosteroids—dates back to before the determination http://neurology.thelancet.com Vol 7 March 2008
Unruptured brain AVMs: to treat or not to treat
http://neurology.thelancet.com Vol 7 March 2008
first occurrence of poor outcome (defined as OHS 2–6) included interventional treatment and large AVM size; and progression to significant disability (defined as OHS 2–6) that persisted to the end of the third year of follow-up did not differ between the groups. The key challenges of the study are well outlined by Wedderburn and colleagues. Although their study is very large and population based, few patients were followed after the first 2 years, making delineation of a difference in outcome unlikely. In the analysis of progression to poor outcome (OHS 2–6), only 23 patients in the untreated group and 30 in the treated group remained at risk at the 2-year point. A statistical difference was not detected. Another issue, which is nicely addressed by the investigators, is the difference in baseline characteristics of the two groups. In a non-randomised setting such as the one in this study, the selection of patients for treatment versus no treatment is inherently biased. Not surprisingly, patients who were aggressively treated tended to be younger, present with symptoms (such as seizures), be healthier, and have smaller AVMs. Significant adverse events (ICH, infarct, or progressive focal deficit) occurred between presentation and intervention in seven treated patients but in none of the untreated patients. Whether there was a difference in angioarchitectural factors that could lead to a different
Published Online February 1, 2008 DOI:10.1016/S14744422(08)70027-9 See Articles page 223
Neil Borden/Science Photo Library
Intracranial arteriovenous malformations (AVMs) are relatively uncommon congenital vascular lesions in which multiple arteries and veins are connected as a fistula without the normal intervening capillary bed. Clinically, AVMs present as an intracranial haemorrhage (ICH) in about 50% of cases,1 and as seizures in about 25%; other presentations include headache, focal neurological deficit, and pulsatile tinnitus. AVMs are increasingly being seen in clinical practice in patients who have no associated symptoms, as a result of fortuitous detection during imaging for unrelated reasons.2,3 After an AVM is detected, the key question is how best to manage it. An important issue is the risk of ICH in patients who have conservative management compared with the risk of treatment. Of the 50% of patients who have an AVM and present without ICH, the long-term risk of ICH is about 2–3% per year.3 A heightened future risk of haemorrhage might be predicted by features from imaging at the time of AVM diagnosis, such as a small AVM size, deep venous drainage, impaired venous drainage, a single draining vein, a paraventricular or intraventricular location, and the presence of aneurysms either on the feeding arteries or within the nidus. Unfortunately, population-based data on AVMs are available from only a few studies: that of Olmsted County, Minnesota;2 the New York Islands Project;4 and the Scottish Intracranial Vascular Malformation Study (SIVMS),5 the cohort discussed in this issue of The Lancet Neurology by Wedderburn and colleagues.6 None of these studies has provided long-term natural history data. SIVMS is a large prospective population-based registry that includes all patients 16 years of age or older diagnosed with any type of vascular malformation in Scotland during 1999–2003 and from 2006 onwards. The analysis by Wedderburn and colleagues6 includes 114 people who presented without a history of haemorrhage from 229 adults with AVMs identified in 1999–2003; 63 (55%) patients underwent interventional treatment for the AVM. The AVM was obliterated in about two-thirds of these cases. Comparison of patients who were treated with those who were not led to three key findings: there was no overall difference in functional outcome, whether defined on the Oxford Handicap Scale (OHS) as 2–6 or 3–6, during all available follow-up; in a multivariable Cox proportional hazards analysis, independent predictors of
An intracranial arteriovenous malformation
195
Reflection and Reaction
For the ARUBA website see http://www.arubastudy.org
risk of haemorrhage between the two groups is unclear, because not all patients had arteriography, including half of those who were not treated. Wedderburn and colleagues readily point out that their study is not a treatment trial, so any inherent bias in selection for aggressive intervention is simply part of the overall standard of care in this large population. The duration of follow-up is also important. A long follow-up period might be necessary to detect a slight beneficial effect of a treatment on the low risk of an adverse outcome that occurs without treatment. Followup of the present cohort is ongoing and further results will be of great interest. What effect should the data from Wedderburn and colleagues6 have on clinical practice? The study suggests that intervention for an AVM might not affect the risk of a persistent adverse outcome, at least in the short term. There are no similar population-based comparisons of intervention with conservative management for a large group of patients with AVMs. No benefit from intervention was noted over short-term follow-up in the non-population-based Columbia AVM databank,7 and long-term data remain unavailable. But, despite the limitations, the thoughtful analysis by Wedderburn and colleagues6 provides sobering data on the comparative efficacy of intervention for unruptured intracranial AVMs compared with natural history. Should all unruptured AVMs be treated aggressively on a routine basis? The study by Wedderburn and colleagues6 and those from other population-based or referral populations cannot answer this question definitively. Random allocation of patients with unruptured AVMs in a clinical trial continues to be controversial, with compelling arguments both for and against.8,9 Efforts to randomly assign selected patients with AVMs—those for whom clinical equipoise exists—to the best treatment compared with natural history should be supported. A
Randomized trial of Unruptured Brain AVMs (ARUBA) has been funded by the US National Institutes of Health. The cerebrovascular community looks forward to the successful completion of this study, along with the necessary long-term follow-up. Until then, our patients will continue to be managed on the basis of reviews and guidelines,10,11 natural history data,3 and data from nonrandomised populations. All of these are of interest but, unfortunately for our patients, not the final answer. Robert D Brown, Jr Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA [email protected] I have no conflicts of interest. 1
2
3 4 5
6
7
8 9 10
11
Brown RD Jr, Wiebers DO, Torner JC, O’Fallon WM. Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: a populationbased study of intracranial vascular malformations in Olmsted Country, Minnesota. J Neurosurg 1996; 85: 29–32. Brown RD Jr, Wiebers DO, Torner JC, O’Fallon WM. Incidence and prevalence of intracranial vascular malformations in Olmsted County, Minnesota, 1965 to 1992. Neurology 1996; 46: 949–52. Brown RD Jr, Wiebers DO, Forbes G, et al. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg 1988; 68: 352–27. Stapf C, Mast H, Sciacca RR, et al. The New York Islands AVM Study: design, study progress, and initial results. Stroke 2003; 34: e29–33. Al-Shahi R, Bhattacharya JJ, Currie DG, et al. Scottish Intracranial Vascular Malformation Study (SIVMS): evaluation of methods, ICD-10 coding, and potential sources of bias in a prospective, population-based cohort. Stroke 2003; 34: 1156–62. Wedderburn CJ, van Beijnum J, Bhattacharya J, et al, on behalf of the SIVMS Collaborators. Outcome after interventional or conservative management of unruptured brain arteriovenous malformations: a prospective, population-based cohort study. Lancet Neurol 2008; available online 1 Feb. DOI: 10.1016/S1474-4422(08)70026-7. Mohr JP, Stapf C, Sciacca RR, et al. Natural history versus treatment outcome in patients with unruptured brain arteriovenous malformations (AVM). Stroke 2004; 35: 328 (abstr). Stapf C, Mohr JP. Unruptured brain arteriovenous malformations should be treated conservatively: yes. Stroke 2007; 38: 3308–09. Cockroft KM. Unruptured brain arteriovenous malformations should be treated conservatively: no. Stroke 2007; 38: 3310–11. Ogilvy CS, Stieg PE, Awad I, et al. AHA Scientific Statement: Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke 2001; 32: 1458–71. Brown RD Jr, Flemming KD, Meyer FB, Cloft HJ, Pollock BE, Link ML. Natural history, evaluation, and management of intracranial vascular malformations. Mayo Clin Proc 2005; 80: 269–81.
Get personal with gene therapy for muscular dystrophy The identification of an ever-increasing number of genes that cause disease when mutated or aberrantly expressed is a tribute to the tremendous progress in genomics; however, the therapy dividend from the investment in this research has yet to be realised. Few diseases illustrate this better than Duchenne muscular 196
dystrophy (DMD), which, despite being identified and described clinically in the mid 19th century1 and being genetically characterised in the late 1980s,2 is still almost untreatable, let alone curable. Furthermore, the currently accepted standard-of-care treatment—oral corticosteroids—dates back to before the determination http://neurology.thelancet.com Vol 7 March 2008