Letter to the Editor. Random assignment of patients to intraoperative neuromonitoring for unruptured intracranial aneurysms?

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  • 1 University of Washington, Seattle, WA; and
  • | 2 University of California, San Francisco, CA
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TO THE EDITOR: We read with interest the study by Greve et al.1 in which they compared neurological outcomes of patients with intraoperative neuromonitoring (IONM: somatosensory evoked potentials [SSEPs] and motor evoked potentials [MEPs]) to a historical control without IONM (Greve T, Stoecklein VM, Dorn F, et al. Introduction of intraoperative neuromonitoring does not necessarily improve overall long-term outcome in elective aneurysm clipping. J Neurosurg. 2020;132[4]:1188–1196). No difference was observed for clipping of unruptured intracranial aneurysms. The authors state, “Hence, the ethical burden to perform randomized controlled trials with and without the use of [IONM] in [elective microsurgical clipping of unruptured intracranial aneurysms] might by overcome.”

Clinical equipoise, “genuine uncertainty within the expert medical community,” should be informed by our certainty in the results of studies.2 In their nonrandomized comparative study, the authors did not account for differences in prognostic variables between patients that could also have predicted the use of IONM. This typically requires multivariate methods (regression, propensity analysis) or stratification of effects.3 In fact, patients in the IONM group were older than those in the no-IONM group, and age was correlated with worse postoperative outcomes. Confounding may have resulted in no observed difference when there was a true association between IONM and outcomes. Accounting for confounding in nonrandomized studies is a basic requirement before results can be accepted with confidence.4

As the authors acknowledged, a limitation of their study is the small sample size. Assuming a 10% risk of new neurological deficit and that IONM would cut this in half, 435 procedures in the IONM and no-IONM groups (870 total) would be required for a conventional 80% power (Pearson’s chi-square test). The authors reported results on 138 procedures with IONM and 136 procedures without IONM. Their underpowered study (power = 27%) may have missed an IONM effect on outcomes if one was present.

In the absence of randomized studies, 2 other comparative studies of IONM for middle cerebral artery (MCA) aneurysms might be given more weight in informing medical opinion. Both Byoun et al.5 (SSEPs for unruptured MCA aneurysms) and Yue et al.6 (MEPs for MCA aneurysms, 72% ruptured) used multivariate regression to account for confounding. Contrary to the results reported by Greve et al.,1 both studies reported improved postoperative outcomes for IONM compared with historical cohorts without IONM.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Greve T, Stoecklein VM, Dorn F, et al. Introduction of intraoperative neuromonitoring does not necessarily improve overall long-term outcome in elective aneurysm clipping. J Neurosurg. 2020;132(4):11881196.

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  • 2

    Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317(3):141145.

  • 3

    Agoritsas T, Merglen A, Shah ND, et al. Adjusted analyses in studies addressing therapy and harm: users’ guides to the medical literature. JAMA. 2017;317(7):748759.

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  • 4

    Schünemann HJ, Cuello C, Akl EA, et al. GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence. J Clin Epidemiol. 2019;111:105114.

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  • 5

    Byoun HS, Bang JS, Oh CW, et al. The incidence of and risk factors for ischemic complications after microsurgical clipping of unruptured middle cerebral artery aneurysms and the efficacy of intraoperative monitoring of somatosensory evoked potentials: a retrospective study. Clin Neurol Neurosurg. 2016;151:128135.

    • Search Google Scholar
    • Export Citation
  • 6

    Yue Q, Zhu W, Gu Y, et al. Motor evoked potential monitoring during surgery of middle cerebral artery aneurysms: a cohort study. World Neurosurg. 2014;82(6):10911099.

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  • University Hospital, Ludwig Maximilian University of Munich, Germany

Response

We appreciate the authors’ valuable discussion of statistical methods, which highlights important aspects of IONM and which we actually addressed in our study.

The authors discuss the age difference between the IONM and no-IONM cohort. We stressed that although this difference was significant, the absolute magnitude was low (3 years of median difference), and thus, a potential confounding effect is limited. Of note, all other demographics were similar between groups. Large IONM studies are sparse,1 and part of the significance of our study was the prospect to set up future trials where IONM and no-IONM cohorts are compared in a truly prospective manner.

Although we reported on 2 large cohorts of aneurysm patients, the sample size did not allow us to apply binary logistic regression modeling, which was explicitly mentioned as a limitation. We therefore discussed numbers needed to treat as the parameter of choice to describe differences in both groups. We agree with the authors that future prospective IONM studies will require large sample sizes in both treatment arms to achieve clinical significance, as long-term results may not differ significantly between the two groups, a conclusion also reached in a paper cited by the authors.2

Furthermore, the authors referred to another study1 in which 411 clipping procedures were analyzed. This study only included SSEP monitoring, which has been deemed insufficient by other groups to detect cortical and subcortical ischemia when used without MEP monitoring.3–5 Nevertheless, the authors found that SSEP monitoring is independently associated with a reduced rate of ischemia detected on postoperative imaging. It should be noted that the authors could not detect any difference in postoperative neurological outcome, objectified by the modified Rankin Scale score at early and late postoperative time points, which does not refute but rather confirms our results.

The authors draw attention to a study in which 89 patients were included and divided into two groups of 45 and 44 patients each.2 Of note, this study did not aim exclusively at elective cases like our data but included 64 of 89 ruptured aneurysms. Surprisingly, subarachnoid hemorrhage, preoperative Glasgow Coma Scale score, and motor status were not significant risk factors for the functional long-term outcome, while MEP application was significant only after adjustment for confounding factors in a second multivariate model. The authors admitted that they struggled with a sample size that was too small to apply logistic regression models with statistical confidence. In addition, they reported that randomization was not ideal, as they “inclined to proceed with MEP monitoring for the assumed benefit,” which makes selection bias very likely.

In contrast, our study included a larger sample size of exclusively elective cases, but we still refrained from logistic regression modeling to avoid exactly this kind of bias.

In conclusion, we are confident that our study provides additional evidence that large, prospective cohort trials with prior sample size estimation and a rigorous study protocol are both necessary and ethically justifiable to obtain definitive evidence on the efficacy of IOM during clipping of intracranial aneurysms.

References

  • 1

    Byoun HS, Bang JS, Oh CW, et al. The incidence of and risk factors for ischemic complications after microsurgical clipping of unruptured middle cerebral artery aneurysms and the efficacy of intraoperative monitoring of somatosensory evoked potentials: a retrospective study. Clin Neurol Neurosurg. 2016;151:128135.

    • Search Google Scholar
    • Export Citation
  • 2

    Yue Q, Zhu W, Gu Y, et al. Motor evoked potential monitoring during surgery of middle cerebral artery aneurysms: a cohort study. World Neurosurg. 2014;82(6):10911099.

    • Search Google Scholar
    • Export Citation
  • 3

    Staarmann B, O’Neal K, Magner M, Zuccarello M. Sensitivity and specificity of intraoperative neuromonitoring for identifying safety and duration of temporary aneurysm clipping based on vascular territory, a multimodal strategy. World Neurosurg. 2017;100:522530.

    • Search Google Scholar
    • Export Citation
  • 4

    Holland NR. Subcortical strokes from intracranial aneurysm surgery: implications for intraoperative neuromonitoring. J Clin Neurophysiol. 1998;15(5):439446.

    • Search Google Scholar
    • Export Citation
  • 5

    Florence G, Guerit JM, Gueguen B. Electroencephalography (EEG) and somatosensory evoked potentials (SEP) to prevent cerebral ischaemia in the operating room. Neurophysiol Clin. 2004;34(1):1732.

    • Search Google Scholar
    • Export Citation

Illustration from Bernstock et al. (pp 655–663). Copyright Joshua D. Bernstock, NIH/NINDS. Published with permission.

  • 1

    Greve T, Stoecklein VM, Dorn F, et al. Introduction of intraoperative neuromonitoring does not necessarily improve overall long-term outcome in elective aneurysm clipping. J Neurosurg. 2020;132(4):11881196.

    • Search Google Scholar
    • Export Citation
  • 2

    Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317(3):141145.

  • 3

    Agoritsas T, Merglen A, Shah ND, et al. Adjusted analyses in studies addressing therapy and harm: users’ guides to the medical literature. JAMA. 2017;317(7):748759.

    • Search Google Scholar
    • Export Citation
  • 4

    Schünemann HJ, Cuello C, Akl EA, et al. GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence. J Clin Epidemiol. 2019;111:105114.

    • Search Google Scholar
    • Export Citation
  • 5

    Byoun HS, Bang JS, Oh CW, et al. The incidence of and risk factors for ischemic complications after microsurgical clipping of unruptured middle cerebral artery aneurysms and the efficacy of intraoperative monitoring of somatosensory evoked potentials: a retrospective study. Clin Neurol Neurosurg. 2016;151:128135.

    • Search Google Scholar
    • Export Citation
  • 6

    Yue Q, Zhu W, Gu Y, et al. Motor evoked potential monitoring during surgery of middle cerebral artery aneurysms: a cohort study. World Neurosurg. 2014;82(6):10911099.

    • Search Google Scholar
    • Export Citation
  • 1

    Byoun HS, Bang JS, Oh CW, et al. The incidence of and risk factors for ischemic complications after microsurgical clipping of unruptured middle cerebral artery aneurysms and the efficacy of intraoperative monitoring of somatosensory evoked potentials: a retrospective study. Clin Neurol Neurosurg. 2016;151:128135.

    • Search Google Scholar
    • Export Citation
  • 2

    Yue Q, Zhu W, Gu Y, et al. Motor evoked potential monitoring during surgery of middle cerebral artery aneurysms: a cohort study. World Neurosurg. 2014;82(6):10911099.

    • Search Google Scholar
    • Export Citation
  • 3

    Staarmann B, O’Neal K, Magner M, Zuccarello M. Sensitivity and specificity of intraoperative neuromonitoring for identifying safety and duration of temporary aneurysm clipping based on vascular territory, a multimodal strategy. World Neurosurg. 2017;100:522530.

    • Search Google Scholar
    • Export Citation
  • 4

    Holland NR. Subcortical strokes from intracranial aneurysm surgery: implications for intraoperative neuromonitoring. J Clin Neurophysiol. 1998;15(5):439446.

    • Search Google Scholar
    • Export Citation
  • 5

    Florence G, Guerit JM, Gueguen B. Electroencephalography (EEG) and somatosensory evoked potentials (SEP) to prevent cerebral ischaemia in the operating room. Neurophysiol Clin. 2004;34(1):1732.

    • Search Google Scholar
    • Export Citation

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