ARTICLE IN BRIEF
In a meta-analysis of 137 observational studies on three types of treatment for cerebral arteriovenous malformations — stereotactic radiosurgery, microsurgery, and embolization — investigators revealed that overall fatalities were decreased in more recent trials, but all three treatments were associated with a considerable risk of complications over time.
Although improved technology and increased experience over the last decade have reduced the risk of death from interventions for cerebral arteriovenous malformations (AVMs), interventional treatment still carries a substantial risk of death and disability regardless of the type of procedure performed, according to a major review of published studies.
Janneke van Beijnum, MD, of the department of neurosurgery at Utrecht University Medical Center in the Netherlands, and colleagues reviewed all papers published up to March 2011 reporting outcomes following microsurgery (craniotomy followed by resection); stereotactic radiosurgery (SRS), or focused irradiation; and embolization for cerebral AVMs.
Published in the Nov. 9 issue of the Journal of the American Medical Association, the meta-analysis revealed that all three treatments were associated with a considerable risk of complications. The researchers were not able to directly compare the techniques, but rather presented the risks, complications, response rates, and patient characteristics for each of the three approaches. Interpreting the data is difficult because the characteristics of specific brain AVMs typically guide treatment decisions, and there were no randomized controlled trials, a shortcoming that needs to be addressed in the future, the researchers said.
A total of 137 observational studies were reviewed involving 13,698 patients. For all patients the fatality rate was 0.68 per 100 person-years — 1.1 for microsurgery; 0.50 after SRS; and 0.96 for embolization procedures with a total of 46,314 patient-years of follow-up. (See “Key Findings” for more data from the review.)
Among trends, there were fewer overall fatalities in more recent studies, suggesting improvements in interventional technologies and experience, but higher rates of hemorrhage. The researchers attributed the increased hemorrhage rates to the greater numbers of patients being treated with SRS, in which the complete obliteration rate is relatively low and the rate of hemorrhage is high compared with microsurgery.
The investigators acknowledged that the review was hampered by limitations that often plague meta-analyses: most studies were retrospective and lacked independent outcome assessment, and none compared treatments in a randomized design. In addition, individual patient and brain AVM characteristics probably influenced decisions on which treatment option was selected, making any comparisons difficult.
Nonetheless, at least one interventional neurologist thinks the meta-analysis is a major contribution to the field. “The number of studies included in this analysis is the largest to date,” said Dileep Yavagal, MD, assistant professor of clinical neurology and neurosurgery, and director of interventional neurology at the University of Miami and Jackson Memorial Hospitals.
The main issue with the scientific literature on AVMs is the lack of controlled studies and, in the absence of such data, a systematic meta-analysis of uncontrolled studies over a substantial period of time is valuable, he said.
Despite the limitations of a meta-analysis, several important results from this study can guide treatment decisions and future AVM clinical research, Dr. Yavagal told Neurology Today in a telephone interview. This is especially true of the authors' “novel” analysis of time trends in case fatality and hemorrhage rates. He noted that a decrease in overall case fatality reported in this study was counterbalanced by an increase in hemorrhage rates over time.
“Advances in current treatment techniques are the likely reason for lower death rates,” he said. “However, the authors accredited the higher hemorrhage rates to bleeding after SRS during the two- to three-year period of waiting for the AVM to be obliterated. I think another reason for this may be that AVMs are being treated more aggressively than in the past. As technology gets better, there is a tendency to address AVMs that we would have left alone in the past.”
Technological advances have allowed neurosurgeons and neuro-interventionalists to start going after more complex AVMs with various treatment modalities, and this may place patients at higher risk of a hemorrhage by changing the natural history of unruptured AVMs, he continued.
“I think the data support treating ruptured AVMs, but taking a more conservative approach for those that have not ruptured,” he said. “Most studies show there is a low risk of hemorrhage in patients with unruptured AVMs unless there are aneurysms, they are very deep in the brain, or very small,” he said.
“In my opinion, unless patients are enrolled in a clinical trial we should avoid treating non-ruptured AVMs until we have more data, and that if there is bleeding, radiosurgery should be the last resort.”
Michael T. Lawton, MD, professor of neurological surgery and the Tong Po Kan Endowed Chair of Neurological Surgery at University of California, San Francisco (UCSF), told Neurology Today that the findings are consistent with what he has seen, although there were some areas of difference.
“Some of the findings contradict what we have found in our research. For example, they found eloquent AVMs — [those located in the brainstem, thalamus, hypothalamus, cerebellar peduncles, or sensorimotor, language, or primary visual cortex] — to be associated with positive outcomes, but in our standard grading scale, they carry increased risk. The same was found with AVMs with deep venous drainage, which they also link to better outcomes, when our research suggests they are risk factor,” he said.
Dr. Lawton, who also serves as chief of the UCSF cerebrovascular disorders program and directs the school's cerebrovascular and skull base surgery programs, said last year, he and his colleagues published a supplementary grading scale to be used with the Spetzler-Martin grade (SMG) scale, which is designed to assess the patient's risk of neurological deficit after open surgical resection, based on characteristics of the AVM itself. [For more about the SMG, see “Assessing Surgical Risks: The Spetzler-Martin Grade Scale.”]
He agreed with the researchers' conclusion that treating AVMs is risky.
“They are probably even riskier than we think,” Dr. Lawton said. “These researchers are preaching caution, and I am all for that. We are trying to encourage better patient selection for surgery. The study showed that surgery can cure the AVM, achieve good outcomes, and protect against cerebral hemorrhage better than the other treatment modalities, but the trick is to pick the surgical patients carefully.”
“If a patient has a high SMG score, but a low one on the supplementary scale, or vice versa, it should raise a red flag,” he said.
OTHER KEY FINDINGS
* More recent studies were associated with lower case-fatality rates (rate ratio [RR], 0.972; 95% CI, 0.955-0.989) but increased rates of hemorrhage (RR, 1.02; 95% CI, 1.00-1.03).
* Intracranial hemorrhage rates were 1.4 (95% CI, 1.3-1.5) per 100 person-years overall, 0.18 (95% CI, 0.10-0.30) after microsurgery, 1.7 (95% CI, 1.5-1.8) after SRS, and 1.7 (95% CI, 1.3-2.3) after embolization.
* Male sex (RR, 0.964; 95% CI, 0.945-0.984), small brain AVMs (RR, 0.988; 95% CI, 0.981-0.995), and those with strictly deep venous drainage (RR, 0.975; 95% CI, 0.960-0.990) were associated with lower case fatality.
* Lower hemorrhage rates were associated with male sex (RR, 0.976, 95% CI, 0.964-0.988), small brain AVMs (RR, 0.988, 95% CI, 0.980-0.996), and brain AVMs with deep venous drainage (0.982, 95% CI, 0.969-0.996).
* Complications leading to permanent neurological deficits or death occurred in a median 7.4 percent (range, 0%-40%) of patients after microsurgery, 5.1 percent (range, 0%-21%) after stereotactic radiosurgery (SRS), and 6.6 percent (range, 0%-28%) after embolization.
* Successful brain AVM obliteration was achieved in 96 percent (range, 0%-100%) of patients after microsurgery, 38 percent (range, 0%-75%) after SRS, and 13 percent (range, 0%-94%) after embolization.
ASSESSING SURGICAL RISKS: THE SPETZLER-MARTIN GRADE SCALE
The Spetzler-Martin Grade scale provides a composite score of:
* nidus size (<3 cm, 3-6 cm, >6 cm; 1-3 points),
* eloquence of adjacent brain (1 point if located in brainstem, thalamus, hypothalamus, cerebellar peduncles,or sensorimotor, language, or primary visual cortex),
* presence of deep venous drainage (1 point if any or all drainage is through deep veins, such as internal cerebral veins, basal veins, or precentral cerebellar veins).
* This system gives an AVM score of 1 to 5, with the surgical risks increasing as the score increases.