Treatment of Unruptured Intracranial Aneurysms and Cognitive Performance: Preliminary Results of a Prospective Clinical Trial

Accepted Manuscript Treatment of unruptured intracranial aneurysms and cognitive performance – preliminary results of a prospective clinical trial Elisabeth Bründl, Christina Böhm, Ralf Lürding, Petra Schödel, Sylvia Bele, Andreas Hochreiter, Judith Scheitzach, Florian Zeman, Alexander Brawanski, Karl-Michael Schebesch PII:

S1878-8750(16)30500-9

DOI:

10.1016/j.wneu.2016.06.112

Reference:

WNEU 4271

To appear in:

World Neurosurgery

Received Date: 22 April 2016 Revised Date:

26 June 2016

Accepted Date: 27 June 2016

Please cite this article as: Bründl E, Böhm C, Lürding R, Schödel P, Bele S, Hochreiter A, Scheitzach J, Zeman F, Brawanski A, Schebesch K-M, Treatment of unruptured intracranial aneurysms and cognitive performance – preliminary results of a prospective clinical trial, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.06.112. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Treatment of unruptured intracranial aneurysms and cognitive performance –

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preliminary results of a prospective clinical trial

3 Bründla,

Böhma

Lürdingb

4

Elisabeth

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([email protected]), Petra Schödela ([email protected]), Sylvia Belea ([email protected]), Andreas

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Hochreitera ([email protected]), Judith Scheitzacha ([email protected]), Florian Zemanc

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([email protected]), Alexander Brawanskia ([email protected]), Karl-Michael Schebescha (karl-

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[email protected])

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a

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b

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c

([email protected]),

Ralf

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Christina

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Department of Neurosurgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany Department of Neurology, University Medical Center Regensburg, Universitätsstraße 84, 93053 Regensburg, Germany

Center for Clinical Studies, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany

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Elisabeth Bründl, MD

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Department of Neurosurgery

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University Medical Center Regensburg

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Franz-Josef-Strauss Allee 11

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93053 Regensburg

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Germany

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Phone

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Facsimile

++49 941 944 9002

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E-mail

[email protected]

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++49 941 944 9001

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Conflict of interest

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None

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Funding

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-

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profit sectors. 1

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Background

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Few studies have addressed the effect of treatment of unruptured intracranial aneurysm (UIA) on cognitive

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function.

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Objective

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Neuropsychological assessment after UIA treatment is underreported, and prospective trials have repeatedly

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been demanded. In 2014, we conducted a prospective controlled study to evaluate the differences in cognitive

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processing caused by the treatment of anterior circulation UIA.

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Patients and methods

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30 patients were enrolled until September 2015. 10 patients received endovascular aneurysm occlusion (EV),

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10 patients were treated microsurgically (MS), and 10 patients with surgically treated degenerative lumbar spine

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disease (LD) served as control. All patients underwent extended standardized neuropsychological assessment

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before (t1) and 6 weeks after treatment (t2). Tests included verbal, visual, and visuospatial memory, psychomotor

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functioning, executive functioning, and its subdomains verbal fluency and cognitive flexibility. We statistically

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evaluated intragroup and intergroup changes.

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Results

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Intragroup comparisons and group-rate analysis showed no significant impairment in overall neuropsychological

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performance, neither postinterventionally nor postoperatively. However, the postoperative performance in

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cognitive processing speed, cognitive flexibility, and executive functioning was significantly worse in the MS

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group than in the EV (p=.038) and LD group (p=.02). Compared to the EV group, MS patients showed

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significant postoperative impairment in a subtest for auditory-verbal memory (WMS-IV, LG II; MS vs. EV

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p=.011). The MS group trended toward posttreatment impairment in subtests for verbal fluency and semantic

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memory (RWT; MS vs. EV p=0.083) and in auditory-verbal memory (WMS-IV, LGII; MS vs. LD p=0.06).

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Conclusion

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Our preliminary data showed no effect of anterior circulation UIA treatment on overall neuropsychological

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function but impaired short-term executive processing in surgically treated patients.

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Running Title

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Unruptured intracranial aneurysms and cognition

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Keywords

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Clip; coil; cognition; neuropsychological assessment; outcome; UIA; unruptured intracranial aneurysms

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Introduction

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The management of unruptured intracranial aneurysms (UIA) remains challenging. The

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prevalence of UIA ranges between 3.2%1 and 6.0%2. Investigations into the natural history of

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untreated UIA3-6 showed differing annual rupture rates of up to 6.0% in the International

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Study of Unruptured Intracranial Aneurysms (ISUIA)7 and a 5-year cumulative rupture rate

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between 2.5% and 50%4, 8 in the Unruptured Cerebral Aneurysm Study of Japan (UCAS)9. In

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untreated patients, the risk of aneurysm rupture is multifactorially mediated10 and has to be

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weighed against the risks associated with preventive aneurysmal obliteration11 consisting of

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either microsurgical clipping (MS) or endovascular embolization (EV). Although the rates of

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neurological complications and mortality associated with UIA treatment have been

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extensively established12,

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psychosocial, and functional patient profiles6,

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neuropsychological outcome in conjunction with the treatment modality has already been

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shown in aneurysmal subarachnoid hemorrhage (aSAH)17-22. ISUIA was the first prospective

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study to define morbidity in patients with UIA not only as functional disability but – to a

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considerable proportion − also as neuropsychological impairment7. Despite attesting a

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favorable outcome, commonly used outcome measures such as the Glasgow Outcome Scale

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(GOS)23, the modified Ranking Scale (mRS)24, or the Mini-Mental State Examination

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(MMSE)25 cannot substitute an elaborated and standardized neuropsychological test battery.

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Thus, restitution of a patient’s pre-treatment condition cannot be guaranteed26. Some studies

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also disregard the level of pre-treatment cognitive and psychosocial performance15,

, limited focus has been placed on neuropsychological,

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. However, the importance of

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systematic review on patients with UIA indicated the possibility of an observable and

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domain-specific − though transient − decline in cognitive and daily functioning. In their meta-

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analysis on UIA patients with cognitive assessment before and after UIA repair Bonares et

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al.27 suggested that the treatment of UIA (either with MS or EV) does not seem to affect

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cognitive functioning in the long term. Only one study16 has compared cognitive outcome in a

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collective of UIA patients treated with both MS and EV. To the best of our knowledge, the

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study by Preiss et al.16 is the only study observing cognitive functions before and after

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treatment with both MS and EV. Due to the limited number of studies available addressing

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this issue, no final conclusion can yet been drawn. In the present prospective controlled study,

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we evaluated the differences of cognitive processing with respect to the treatment modality in

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anterior circulation UIA. For this purpose, all patients with UIA were subjected to

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standardized neuropsychological assessment before and after microsurgical clipping and

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endovascular repair. Patients treated with surgery for degenerative lumbar spine disease

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served as control.

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Patients and methods

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Patient population.

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were enrolled, who underwent occlusion of UIA in the anterior circulation, either by

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microsurgical clipping (MS group) or by endovascular treatment (EV group; n = 10 each).

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10 consecutive patients who underwent surgery for degenerative lumbar spine disease (LD

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group) − either lumbar disc herniation or lumbar spinal canal stenosis − served as control to

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eliminate side effects of general anesthesia or the surgical procedure itself.

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Study selection criteria.

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sexes 2) aged 18 to 75 years after 3) provision of written informed consent. The recruited

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patients 4) either presented with UIA in the anterior circulation or lumbar disc herniation or

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spinal canal stenosis (control) and 5) accordingly underwent microsurgical or endovascular

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obliteration of the UIA or lumbar spine surgery. Additionally, 6) each patient was admitted to

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hospital in excellent preoperative and preinterventional condition 7) without any obvious

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pretreatment cognitive impairment. Exclusion criteria were 1) preceding neurosurgical or

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neurovascular procedures, 2) previous history of intracranial disorders including aSAH, 3)

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previous psychiatric history or neurodegenerative diseases, 4) severe autoimmune or systemic

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diseases such as rheumatic illnesses of the musculoskeletal system, 5) presence of giant

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aneurysms, symptoms of compression by large UIA, and aneurysms in the posterior

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circulation, 6) an accidental dural leak during lumbar spine surgery, or 7) intracranial bleeding

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after UIA treatment.

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All patients underwent physical examinations at hospital admission, before discharge, and at

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the 6-week follow-up (FU), when they were graded according to the GOS score23 and the

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mRS score24. Additionally, all patients completed a questionnaire determining their

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handedness (modified Edinburgh Inventory)28 and had a structured interview. Each patient

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underwent conventional diagnostic digital subtraction angiography (DSA) before treatment

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and at the FU (MS group: before discharge, EV group: 6 months after treatment). The

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number, site, and size of the UIA, the respective treatment modality, and the neurological

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deficits (ND) at discharge and FU were registered. Postsurgical and postinterventional

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Between November 2013 and September 2015, 20 consecutive patients

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cerebral computed tomography (CT) scans were obtained within 24 h. Treatment-associated

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complications were assessed accordingly.

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Therapeutic procedures.

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modality after interdisciplinary consent.

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Surgical procedures: Surgical UIA treatment was provided by three equally experienced

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neurosurgeons (head physician and senior physicians) specialized in neurovascular

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microsurgery. Each of them has performed aneurysm surgery since at least ten to 30 years.

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Standard microsurgical techniques were used for UIA repair. Considering the general trend

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toward „coil-first policy“ our university clinic has an annual volume of 80 patients

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undergoing clipping for both ruptured and unruptured aneurysms. The standardized pterional

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approach included opening of the Sylvian fissure, dissection of the optic nerve, internal

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carotid artery (ICA), dissection of the parent vessel, and clipping of the aneurysm in

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microsurgical technique. Temporary parent vessel occlusion (<5 min) was conducted under

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intravenous thiopental protection (500–1000 mg thiopental applied 90 sec before vessel

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occlusion) during critical phases of UIA preparation and clipping. The time of temporary

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parent artery occlusion during microsurgical aneurysm repair, total procedure time for UIA

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occlusion, and the time of mechanical ventilatory support were recorded in minutes and hours.

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Procedure variables are summarized in Table 1.

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Endovascular procedures:

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maintain activated clotting time at 2 to 2.5 times. In the case of wide neck and large or

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fusiform aneurysms, a stent-assisted system, web device, or flow diverter was applied.

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Neuropsychological assessment.

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neuropsychological assessment before (t1) and 6 weeks after (t2) the respective treatment to

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examine verbal memory, visual memory, visuospatial memory, psychomotor functioning, and

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executive functioning as well as its subdomains verbal fluency and cognitive flexibility. Each

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test was conducted by the same investigator trained by an experienced neuropsychologist. As

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described elsewhere, the cognitive test battery consisted of 1) the German translation of the

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Wechsler Memory Scale – Fourth Edition (WMS-IV)29 including the three subtests Logical

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Memory (LG) I, LG II, and LG recognition, 2) the Rey-Osterrieth Complex Figure Test

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(ROCF)30-32, 3) the Trail Making Test (TMT)33-39, 4) the Regensburg Word Fluency Test

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(RWT; the German version of the Controlled Oral Word Association Test, COWA)40, 5) the

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Neurosurgeons and neuroradiologists decided on the treatment

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Transfemoral route under general anesthesia, heparinization to

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(Forward and Backward) Digit span test41, and 6) the Corsi block-tapping test (forward and

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backward)42, 43.

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Test modifications:

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short stories: the stories ‘B’ and ‘C’ for test persons aged between 19 and 69 years and the

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stories ‘A’ and ‘B’ for patients older than 69 years. In our setting, only one story at a time (at

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t1 story ‘B’ for younger patients vs. ‘A’ for elderly patients, at t2 story ‘C’ for younger patients

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vs. ‘B’ for elderly patients) was presented to prevent adulterant practice effects. Ad 2: At t2,

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the Taylor Complex Figure (TCF) was used as a parallel version of the ROCF to prevent bias

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due to practice effects. Ad 4: All participants completed an abbreviated version of the RWT.

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Subjects had to pronounce as many words as possible referring to a given semantic category

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(food) and a phonemic category (words beginning with the designated letters ‘B’, ‘K’, and

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‘S’).40

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Taken together, the test battery screens for the functions of the bihemispheric frontal and

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temporal lobes and thus the supply territory of the anterior circulation (see Table 2).

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Statistical analysis.

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range (min-max); categorical data as frequency counts. The neuropsychological test results

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are presented either as standardized z-scores or as percentile ranks to account for group

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differences in age and gender. Changes over time within each group were analyzed by using a

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paired t-test. Differences between groups at postinterventional assessment were analyzed by

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using an analysis of covariance with baseline values as covariate and are presented by

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estimated marginal means. A p-value <0.05 was considered as statistical significant.

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Statistical analysis was conducted according to SPSS procedures (version 23.0; SPSS, Inc.,

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Chicago, IL).

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The study protocol was approved by the local institutional ethics committee (14-101-0010).

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Continuous data are presented as mean±standard deviation (SD) and

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Ad 1: The original WMS test version involves the presentation of two

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Results

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Clinical and radiological characteristics.

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clinical variables, handedness, comorbidities, and procedure variables are summarized in

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Table 1. Gender difference did not reach any statistical significance. Intergroup comparisons

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regarding the number of years of education only showed a significant difference between the

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EV and LD group in favor of the EV patients (p=.028). No further significant differences

The baseline data, including demographical and

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were identified between the groups. Diagnosis of UIA was based on unspecific symptoms

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such as cephalgia (n=5), ataxia, syncope, or obliviousness as well as on specific symptoms

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such as cranial nerve (CN) deficits (n=2), epileptic seizure, dysarthria, and paresthesia (n=1

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each) (see Table 3). 1 patient (MS group) postoperatively developed new and persistent

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hemiplegia due to ischemic infarction in the caudate nucleus and the internal capsule.

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20 patients had 24 UIAs. UIA location was divided into three groups: 1) internal carotid

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artery (ICA) and posterior communicating artery (PCoA), 2) anterior cerebral artery (ACA),

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anterior communicating artery (ACoA), and pericallosal artery, and 3) middle cerebral artery

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(MCA). Aneurysm characteristics are summarized in Table 4. The mean aneurysm size did

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not differ significantly between the two treatment groups. 3 of the 4 patients with multiple

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aneurysms underwent one craniotomy for both UIAs in the same session (clipping n=2). The

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mean time from diagnosis to treatment was 4.6 months (ranging from 0 to 28 months).

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Treatment modalities and results.

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diverter n=1, web device n=2) was conducted in 7 ICA and PCoA aneurysms (MS n=1 vs. EV

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n=6), in 8 ACA, ACoA and pericallosal artery aneurysms (n=4 each), and in 8 MCA

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aneurysms (n=7 vs. 1). Intra- and postprocedural findings are shown in Table 1. Dominant-

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side and nondominant-side pterional approaches were used in 5 MS patients each. 4/10

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patients underwent temporary parent vessel occlusion during microsurgical UIA repair.

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Duration of temporary artery occlusion was 1.5 min (n=2), 2 x 3 min (n=1), and 6.2 min x

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2 min x 7.5 min consecutively (n=1). None of the twelve microsurgically clipped UIAs

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intraoperatively ruptured and none of the ten MS patients required blood transfusion. As

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blood loss during skin incision and microsurgical preparation did not exceed normal volumes

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its contribution to posttreatment cognitive performance is negligible. Mean duration of

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surgery was 158 ± 45.9 min, and endovascular UIA occlusion time was 114.3 ± 43.7 min. MS

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patients spent with 8.83 hours significantly longer on mechanical ventilatory support than the

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EV group with 2.84 hours. This fact is predominantly due to our internal posttreatment

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regime. While interventionally treated UIA patients immediately recover from anesthesia and

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are transferred to the normal ward (attached to a bed-side monitor at night) after having spent

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some hours in the anesthetic recovery room, clipped UIA patients are routinely transferred

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under anesthetic from the operating room to the intensive care unit where sedatives are

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gradually reduced. However, time of anesthesia is extremely unlikely to influence cognitive

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performance six weeks after treatment. Peri-interventional complications were recorded in 3

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EV patients (coil n=2, web device n=1): 2 patients with transient thromboembolic events

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Microsurgical vs. endovascular treatment (coil n=8, flow

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lysis

and

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patient

with

temporary

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vasospasm.

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Postinterventional CT scans or magnetic resonance imaging (MRI) proved that none of these

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events resulted in relevant perfusion deficit. Nevertheless, 2 patients were clinically

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symptomatic either with transient aphasia or persistent subjective long-term memory

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impairment. In 3 patients, the CT scans after microsurgical clipping indicated newly

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developed circumscribed cerebral ischemia in the vascular territory of the recurrent artery of

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Heubner (sections of the caudate nucleus and of the internal capsule).

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Postoperative course and short-term outcome.

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patients were clinically asymptomatic or had mild unchanged symptoms (MS n=7 vs. EV

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n=8). The other 5 patients (MS n=3, EV n=2) presented with a new ND: 3 patients had

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transient symptoms (CN deficit, aphasia, and paresis), and 2 patients had persistent deficits

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(hemiplegia and long-term memory impairment). At discharge, 18/20 patients had no or

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unchanged symptoms. According to the GOS grading, outcome at discharge was good in

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9 patients after MS, in 10 after EV, and in 10 after LD (GOS 5) and fair in 1 MS patient with

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new hemiplegia (GOS 3).

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At the 6-week FU, 19 UIA patients were asymptomatic or had mild unchanged symptoms

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such as recurrent headache (n=4/19), subjective amnesic aphasia, or subjective memory

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impairment (n=2/19). Until FU, ND had improved in 1 patient with a preexisting CN III

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paresis. 1 patient showed unchanged hemiplegia. Outcome was stable in all patients during

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the 6-week FU.

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Neuropsychological assessment.

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summarized in Tables 5 and 6. Intragroup comparisons from test t1 to test t2 showed no

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significant postoperative or postinterventional improvement or decline in any tested cognitive

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domain for any of the three groups (see Table 5). The group-rate analysis (see Table 6) of

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overall neuropsychological performance did also not indicate any statistical intergroup

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differences between the MS, EV, and LD groups (LD vs. EV p=.773, LD vs. MS p=.214, EV

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vs. MS p=.331). However, several subtest analyses reached statistical significance:

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Postoperatively, the MS group performed significantly worse in cognitive processing speed,

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cognitive flexibility, and executive functioning (TMT) than the EV group (p=.038) and the

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LD group (p=.02). TMT subtest analysis (part B) also confirmed a significantly poorer

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performance in cognitive flexibility and executive functioning of MS patients than LD

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patients (p=.04). Compared to the EV group, the MS group showed significant postoperative

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impairment in auditory-verbal memory (WMS-IV, LGII; p=.011). Additionally, the MS group

Within 24 h after treatment for UIA, 15/20

The cognitive performance of the study population is

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trended toward a postoperatively worse performance 1) in verbal fluency and semantic

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memory (RWT) compared to the EV group (p=.083), and 2) in auditory-verbal memory

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(WMS-IV, LGII) compared to the LD group (p=.06).

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Discussion

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The present study showed no significant impairment in general cognitive performance after

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microsurgical clipping or endovascular treatment of UIAs. Several neuropsychological

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subtests showed significant postoperative impairment of the MS group, but we neither

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detected intergroup nor intragroup differences in overall neuropsychological outcome within

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the short-term FU of 6 weeks.

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Correspondingly, Bonares and colleagues27 suggested that the treatment of UIA does not

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affect cognitive function in the long term. The authors systematically reviewed the literature

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on the effects of UIA treatment on cognition between 1998 and 2013, including studies on

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UIA patients who had undergone cognitive assessment before and after either microsurgical

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or endovascular UIA repair. Only 8 clinical trials16, 44-50 with a total of 281 patients met the

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inclusion criteria, and 7 of these studies exclusively dealt with surgical clipping. The authors

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analyzed the treatment effect on general cognitive functioning with a focus on four specific

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neuropsychological domains (executive functions, verbal and visual memory, and visuospatial

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functions). Executive functions and verbal memory domains showed a trend toward post-

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treatment impairment, and visual memory tasks a trend toward post-treatment improvement.

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However, this meta-analysis implemented heterogeneous studies with a range of FU periods

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from 1 week up to 12 months. The selected time for FU assessment is likely to exert

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substantial influence on post-treatment cognitive performance. Based on the demand for a

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nationwide standardized neuropsychological assessment for aSAH patients, the Swiss SOS

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study

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neuropsychological, psychosocial, and HRQOL-aspects.22 The authors recommend the

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screening between days 14 and 28 after aSAH and at three and twelve months after bleeding.

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Here, we present our preliminary results reflecting the short time FU after UIA treatment.

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According to our internal standardized treatment regime, posttreatment neuropsychological

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assessment was performed in an outpatient setting at the follow-up presentation six weeks

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after UIA repair. Of course, more extended intervals three, six, twelve and 24 months (or even

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longer, e.g. 36 months) after treatment are recommended, in particular because cognitive

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differences between MS and EV patients might level off over time. Fukanaga et al.45

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evaluated cognitive function in 30 UIA patients before and after neurosurgical clipping.

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Neuropsychological assessment showed significant deterioration in 50% of the patients after

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the first month, but all patients had recovered to preoperative levels at the second cognitive

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evaluation 3 months postoperatively.

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In our study, subtest analyses showed significant postoperative impairment in the MS group

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in the short term. This finding may potentially reflect early postoperative and transient

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sequelae rather than general treatment-dependent differences in neurocognitive long-term

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outcome after UIA repair. No patient of the EV group developed ischemia according to CT

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scan, although one of them with temporary vasospasm during coiling of an ICA aneurysm

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reported subjective long-term memory disorder at FU. Two EV patients required lysis due to

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thromboembolic complications. In the MS group, no perioperative complications were

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recorded. Yet, three MS patients who had undergone clipping for 1) left MCA and ACA

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aneurysm, 2) left MCA aneurysm, and 3) right ACA and MCA aneurysm presented with a

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new Heubner infarct in posttreatment CT scan, and one of them developed persistent

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hemiparesis. These rates seem higher than might be expected for these procedures and are

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possibly biased due to the small sample size. Consequently, this could have influenced the

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outcome. The design of the „International Subarachnoid Aneurysm Trial (ISAT)“51 has given

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rise to heated discussions, in particular concerning the heterogeneity of surgical skills in the

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divers enrolled centers limiting the comparability of the trial’s results. Compared to a high

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volume center treating several aneurysms per day, with microsurgical and endovascular

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aneurysm occlusion of 150 patients per year our institution ranges in the middle field. Thus,

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our institutional neurovascular volume is representative for the majority of neurovascular

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centers. Predictors of surgical outcome appear to be location, size, age, and surgical

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experience.52 One study53 even emphasized that the neurosurgeons’ experience was the most

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important predicting factor in aneurysm surgery. The issue of surgical skills, experience and

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annual treatment volume was a prominent criticism54 of ISAT51 by American neurosurgeons

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alike. The high rebleed rates in the surgical group, compared with previously published

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reports, were thought to be related, at least in part, to the quality of surgical care.55 Due to

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various biases the expertise of the operators in ISAT continues to be contentious, and it will

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be impossible to prove that outcomes are affected by the surgeons' experience until a similar

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randomized trial is undertaken by cerebrovascular surgeons themselves.

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Previous research on possible adverse effects of craniotomy and clipping of UIA per se on

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postoperative cognition yielded divergent results. Several authors proved evidence that

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successful surgical UIA occlusion does not cause cognitive deterioration46-49, whereas others

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suggested a higher incidence of neuropsychological impairment after surgery or after use of

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the interhemispheric approach59,

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cerebral blood flow (CBF) in the ipsilateral perisylvian area was found to be reduced by 10%

324

to 15% in the acute postoperative period, and this reduction was attributed to surgical

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manipulation61. Congruently, significantly reduced CBF − detected by single-photon emission

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tomography before and 1 month after UIA clipping − correlated with neuropsychological

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deterioration60. On T2-weighted MRI, minimal structural lesions could be visualized 6 months

328

after UIA clipping, probably resulting from direct pial and microvascular injury during fissure

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dissection, ischemia due to temporary vessel occlusion, and mechanical or ischemic lesion

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caused by brain retraction. The presence of those MRI changes was identified as an

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independent predictor of subtle but significant postoperative neurocognitive decline62.

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However, Inoue et al.62 stated that this detrimental effect was small. Based on group-rate

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analysis, postoperative neuropsychological assessment scores (verbal IQ, performance IQ,

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WMS-memory, and WMS-attention) were significantly improved in relation to preoperative

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test scores. Thus, the authors concluded that meticulous surgical clipping of UIAs does not

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adversely affect postoperative cognitive function.

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In the current study, treatment did neither affect working (Digit span, left frontal lobe

338

function), nor visual (ROCF, right temporal lobe function), and visuospatial memory (Corsi

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block-tapping, right frontal lobe function). In 2014, a review article6 stated the hypothesis that

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the effect of UIA treatment may be domain-specific. Although sparing of some domains was

341

observed (verbal fluency, cognitive flexibility, working memory, language, visuospatial

342

ability, and psychomotor ability), verbal and visual memory seemed to be particularly

343

susceptible to transient decline. The left fronto-temporal lobe was supposed to encode for

344

these domains. Our results also showed that visual memory was not impaired by UIA

345

treatment. We did not observe any significant intergroup differences regarding the side of the

346

treated aneurysm, its mean size, or the handedness. We caveat the statement with the note that

347

our study is not powered to detect differences due to the small n. Consequently, in our

348

analysis, a further differentiation between the location of the aneurysms does not seem

349

reasonable. In a larger series, an additional power analysis of interactions between

350

handedness, aneurysm location, treatment, and cognitive outcome is recommended. The

351

presented groups are imbalanced in terms of aneurysm location (ICA/PCoA and MS=1 vs.

. When approaching the UIA via the pterional route,

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EV=6; MCA and MS=7 vs. EV=1), which could have a significant confounding effect on

353

outcomes, given very different potential perforator injuries and extent of dissection required.

354

In a larger sample size, this issue should be considered as a covariate in analysis to control for

355

its impact. Hadjivassiliou and coworkers63 analyzing patients with ruptured anterior cerebral

356

artery aneurysms and aSAH found a higher probability of cognitive impairment, other deficits

357

of memory and executive functioning, and subtle personality changes related to the surgical

358

techniques used to access the area of the anterior communicating artery requiring resection or

359

retraction of frontal lobe structures, such as the gyrus rectus and frontal gyri. In accordance

360

with the N-ISAT64, a substudy on the „Neuropsychological Outcomes from the ISAT“, this

361

may account for the cognitive domains that were most adversely affected in the neurosurgery

362

group (verbal memory, processing speed, and executive skills).

363

From a methodological point of view, literature lacks available data dealing not only with the

364

risk of neurological disability and mortality but also with cognitive morbidity associated with

365

UIA treatment. Furthermore, inhomogeneous study designs limit the comparability of

366

appropriate studies. Key points of criticism comprise reduced statistical power due to small

367

sample sizes, inconsistent exclusion criteria for preexisting cognitive deficits, and a narrow

368

range of sensitive neuropsychological tests with a consecutively reduced variety of the tested

369

cognitive domains (e.g. clumping of the multifaceted domain of executive functioning27).

370

Since the publication of ISAT51,

371

circulation aneurysms, there is an ongoing controversy in the literature, whether or not coiling

372

is preferable over surgical clipping with regard to a favorable functional outcome. The authors

373

of ISUIA4 suggested in 2003 that high surgical morbidity was largely attributable to cognitive

374

dysfunction and endovascular UIA occlusion may have a less immediate risk of morbidity and

375

mortality. After the publication of this study, a series of studies with conflicting data

376

complicated the discussion. Ohue et al.60 reported neuropsychological impairment in 40% of

377

their UIA patients 1 month after microsurgical clipping despite the good outcome shown by

378

the GOS. Pereira-Filho et al.48, Tuffiash et al.49, and Otawara et al.47, however, showed that

379

the surgical procedure itself was not associated with cognitive dysfunction, not even in

380

patients older than 69 years46. The latter studies have a bias concerning the treatment

381

approach because they exclusively address the effect of microsurgical clipping on cognition.

382

This aspect curtails the generalizability of the meta-analysis by Bonares27, because they

383

disregarded a treatment modality that is becoming more commonly applied in practice.

384

Besides the neurocognitive outcome, diversified aspects ought to be considered in the

385

decision-making process whether microsurgical or endovascular treatment is individually to

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on good-grade aSAH patients with small anterior

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be favored for patients receiving the diagnosis of an UIA. Depending on the respective

387

treatment modality, the risk of mortality and neurological disability differs with rates

388

estimated at 0.7% and 7.7% for MS and at 0.5% and 2.4% for EV respectively66. Because of

389

inconclusive data3, 4, 67, no consensus has yet been reached, but there is agreement that most

390

UIA can be managed with reasonably low morbidity and mortality rates68, 69. When deciding

391

on microsurgical or endovascular aneurysm-securing procedure the treatment modality

392

dependent risk of aneurysm reperfusion potentially leading to aneurysm re-/rupture and SAH

393

has to be considered.11, 70-74 After endovascular treatment, the exposure rate to radiation in

394

possibly required consecutive control angiographies may result in potential long-term

395

sequelae such as cancer, particularly in younger and middle-aged patients.

396

In 2012, Preiss et al.16 published a prospective series of 65 patients who had undergone

397

cognitive assessment before and 1 year after surgical and endovascular treatment for UIA

398

between 2001 and 2009. Consistent with our preliminary findings in the short term, the

399

authors did not find any neuropsychological differences in the four tested cognitive variables

400

(overall capacity of verbal memory, delayed recall, psychomotor speed, and cognitive

401

flexibility) between surgical and endovascular repair for UIA in patients without any post-

402

treatment restrictions in lifestyle. The reasons for these conflicting results are probably

403

differences in methodology but also the complexity of the issue due to the involvement of

404

various parameters. Wiebers and coworkers formulated variables that predict poor surgical

405

outcome in UIA surgery including larger aneurysm size (>12 mm), older age, and previous

406

ischemic cerebrovascular disease4. Agreeing with Inoue et al.62, the possible adverse effect of

407

surgical manipulation and prolonged general anesthesia may be attenuated via a circumspect

408

and meticulous manipulation approach. We argue that, in our series, the strict exclusion

409

criteria minimize the influence of such confounders. According to the current literature, the

410

risk of UIA treatment appears to be generally low from a neuropsychological point of view.

411

Presumably, the majority of patients may undergo UIA treatment cognitively ‘unscathed’,

412

whereas a minority with profound cognitive impairment may not be detected statistically.

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413 414

Strengths and limitations

415

Limits. The small sample size is a commonly acknowledged methodological limitation which

416

may tremendously affect the results. However, we preferred analyzing homogeneous

417

treatment groups to recruiting a larger but inhomogeneous study population, which might be 13

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susceptible to misinterpretations. The strict and very detailed selection criteria were set up to

419

minimize confounding variables in our preliminary results and to maximize the

420

generalizability by generating valid and robust data. Several previous studies dealing with this

421

issue enrolled similarly circumscribed sample sizes despite having fewer exclusion criteria44,

422

45, 49, 50

423

Early outcome evaluation at acute stages bears the risk of detecting transient and non-final

424

negative effects of brain surgery (such as edema or lesions to adjacent gray or white matter)

425

on cognitive performance, leveling off over time, whereas the less invasive endovascular

426

techniques for UIA embolization may be misattributed to a more favorable cognitive

427

outcome. Long-term outcome assessments are required to verify the severity of cognitive

428

impairment and follow the course of neuropsychological changes in individual patients over

429

several months or years.

430

Strengths.

431

of UIA treatment on cognition, the actual strength of this study lies in its prospective and

432

standardized design. Additionally, an especially extended standardized neuropsychological

433

assessment was used in this study.

434

Eminently, the inclusion of a reference group undergoing surgery for degenerative lumbar

435

spine diseases allowed the exclusion of general anesthesia or the surgical procedure itself as a

436

negative confounding factor for the evaluation of post-treatment neurocognitive outcome. The

437

current study design could be considerably further enhanced by amending another control

438

group with a surgical ‘trauma’ similar to UIA clipping, such as a patient collective undergoing

439

craniotomy for resection of benign intracranial meningioma close to the cortex. Hereby,

440

craniotomy, cerebrovascular manipulation, and loss of cerebrospinal fluid (by opening of the

441

dura) could be eliminated as possible confounders that may result in cognitive decline.

442

Patients with both meningioma and UIA suffer from intracranial, extracerebral, and benign

443

lesions with related pre- and postoperative stress with regard to the duration of hospital stay

444

and time in the intensive care unit, follow-up procedures, risk of recurrence, and the extent of

445

surgery-related stigmatization resulting from hair shaving and scars.77 Due to the time-

446

consuming as extensive neuropsychological assessment and limited neuropsychological

447

manpower in our neurosurgery department, our preliminary results cannot answer this

448

question yet. We have started to enroll and are going to report about the pre- and

449

postoperative cognitve performance of the above mentioned patient collective. In the end,

450

however, this issue is not crucial for differentiating whether MS or EV do impact cognitive

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or ignoring the aspect of pre-interventional neuropsychological assessment15, 75, 76.

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Compared to the high number of inhomogeneous trials dealing with the effects

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outcome to a greater extent since the procedure of EV treatment per se is less invasive than

452

microsurgery.

453

Conclusion

455

Our preliminary data indicate that both microsurgical clipping and endovascular coiling for

456

UIA in the anterior circulation do not affect overall neurocognitive processing in the short

457

term. Interestingly, subtest analyses showed significant impairment in several domains

458

(psychomotor and executive functioning [TMT], auditory verbal memory [WMS-IV, LG II])

459

after microsurgical clipping. Verbal fluency, semantic memory (RWT) and auditory-verbal

460

memory domains (WMS-IV, LG II) trended toward postoperative impairment in the MS

461

group. The lack of available studies dealing with this issue prevents any strong conclusions,

462

although a few recent studies have yielded similar results. We emphasize that our series

463

evaluated cognitive outcome before and after UIA treatment in a standardized

464

neuropsychological assessment with regard to both treatment modalities. Larger prospective

465

trials are mandatory to investigate treatment-associated neuropsychological morbidity in the

466

long run and to advise future care management strategies and rehabilitation approaches.

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Authors’ contributions

469

Authors’ contributions to the study and manuscript preparation include the following:

470

Conception and design: Schebesch, Karl-Michael. Acquisition of data: Böhm, Christina,

471

Bründl, Elisabeth. Analysis and interpretation of data: Böhm, Bründl, Schebesch. Drafting the

472

article: Bründl. Critically revising the article: all authors. Reviewed submitted version of

473

manuscript: all authors. Approved the final version of the manuscript on behalf of all authors:

474

Schebesch. Statistical analysis: Zeman, Florian, Böhm, Bründl, Schebesch. Study supervision:

475

Schebsch, Bründl, Schödel, Petra.

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476 477

Disclosure

478

The authors declare that they have no conflict of interest.

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ACCEPTED MANUSCRIPT Table 1 Demographical, clinical, and intra- and postprocedural patient characteristics. Study population Clinical features and patient characteristics

Male to female ratio

EV

LD

10

10

10

4:6

6:4

3:7

RI PT

Number of patients [n]

MS

Age [years], mean (± SD)

57.9 (± 7.9)

51.3 (± 14.9)

42.6 (± 16.9)

Number of [years] of education, mean (± SD)

12.6 (± 1.6)

13.5 (± 3.1)

11.3 (± 1.1)

Handedness Right

9

8

9

2 (1)

1 (1)

6

4

1

3

1

1

Vascular angiopathy, peripheral arterial disease

3

2

1

Abdominal aortic aneurysm

0

1

1

0

0

1

0

1

2

1

0

0

0

2

0

1

0

0

0

0

1

0

1

1

2.47 ± 5.01 (0 - 15.7) 158 ± 45.9 (103 - 237) 8.83 ± 4.92 (3.25 - 19.45)

-

-

114.3 ± 43.7 (42 - 173) 2.84 ± 1.20 (1.35 - 4.50)

2.92 ± 0.84 (2.25 - 4.25)

At discharge

1

1

0

At FU

1

1

0

1 (1)

SC

Left (retrained) Comorbidities

M AN U

Arterial hypertension Cardiac disorders

Diabetes mellitus Adiposity Nicotine abuse Thyroid dysfunction Asthma Migraine

TE D

Cancer

AC C

EP

Procedure variables Temporary parent artery occlusion [min], mean ± SD (range) Duration of UIA surgery/intervention [min], mean ± SD (range) Time with mechanical ventilatory support [hours], mean ± SD (range) Patients with new neurological deficit [n]

Treatment-associated lesions on CT scan [n] 3 0 MS: microsurgical clipping group; EV: endovascular treatment group; LD: degenerative lumbar spine disease group (control); SD: standard deviation; min: minutes; UIA: unruptured intracranial aneurysm; FU: 6 weeksfollow-up; CT scan: computerized axial tomography scan.

ACCEPTED MANUSCRIPT

Cognitive domain (subdomain)

RI PT

Table 2 Description of cognitive functions as measured by the neuropsychological test battery.

Test[reference no.]

Test measure

Units of measurement

High score indicates

Test points

Good performance

LG I, LG II, LG recognition of the WMS-IV29

Recall of current information, recall of passages, and sustained attention, left temporal-lobe dysfunction

Visual memory

ROCF32

Right hemisphere, in particular right temporal lobe lesions

Test points

Good performance

Visuospatial memory

Corsi block-tapping

Visuospatial short-term working memory span, right hemisphere damage

Test points

Good performance

Psychomotor functioning

Trail Making Test (D-KEFS)34

Visual attention and scanning abilities, as well as basic number- and letter-sequencing abilities and motor function

Seconds

Poor performance

Executive functioning (cognitive flexibility)

Trail Making Test (D-KEFS)34

Cognitive flexibility, associated with dorsolateral prefrontal lesions

Seconds

Poor performance

Executive functioning (verbal fluency)

RWT40

Verbal fluency, semantic memory, divergent and ideational thinking, spontaneity, and imagination, left frontal-lobe dysfunction

Test points

Good performance

Working memory

Digit span (WAIS-III)41

Attention span of immediate verbal material, left hemisphere damage

Test points

Good performance

EP

TE D

M AN U

SC

Verbal memory

AC C

LG: Logical Memory (subtests of the WMS); WMS-IV: Wechsler Memory Scale - Fourth Edition; ROCF: Rey-Osterrieth Complex Figure Test; D-KEFS: Delis and Kaplan Executive Function System; RWT: Regensburg Word Fluency Test (a German version of the Controlled Oral Word Association Test (COWA)); WAIS-III: Wechsler Adult Intelligence Scale III.

ACCEPTED MANUSCRIPT Table 3 Presenting symptoms leading to the diagnosis of unruptured intracranial aneurysms (UIA) in the study population (n = 20). Clinical symptoms

[n]

Neurological deficits 5

Obliviousness, confusion

4

RI PT

Headache Epileptic seizure, absence seizure, syncope

3

Cranial nerve (CN) deficits (CN III, V)

2

Vertigo

2

Aphasia

1 1

Weak concentration Incidental findings due to other diseases

M AN U

Arterial hypertension, coronary heart disease, carotid stenosis

SC

Transient paresthesia

Transient ischemic attack Hypopharynx carcinoma

AC C

EP

TE D

Vestibular neuritis

1

3 2 1 1

ACCEPTED MANUSCRIPT

MS

EV

ICA, PCoA

1

5

ACA, ACoA, pericallosal artery

2

3

MCA

4

1

ACoA + MCA

1

0

ICA* + MCA

1

0

ACoA + MCA

1

0

PCoA + ACoA

0

SC

1

M AN U

Table 4 Aneurysm characteristics. Aneurysm characteristics

1

6

4

4

7

1

12

11

5

4

7

7

Aneurysm size [mm], mean (± SD) Maximum craniocaudal diameter

3.7 (± 1.5)

5.1 (± 2.6)

Maximum diameter in width

4.0 (± 1.8)

4.1 (± 1.4)

RI PT

Aneurysm location Single aneurysms [n]

Multiple aneurysms [n]

Total number of aneurysms [n] ICA, PCoA ACA, ACoA, pericallosal artery MCA

Right

TE D

Side of aneurysms [n] Left

AC C

EP

MS: microsurgical clipping group; EV: endovascular treatment group; ICA: internal carotid artery, PCoA: posterior communicating artery; ACA: anterior cerebral artery, ACoA: anterior communicating artery; MCA: middle cerebral artery. ICA*: ICA-aneurysm occlusion was electively conducted in a second surgical intervention after clipping of the MCA aneurysm and not within the 6 weeks of follow-up. SD: standard deviation.

ACCEPTED MANUSCRIPT Table 5 Changes of cognitive performance within treatment groups from preoperative to 6 weeks after treatment. LD, z-scores

EV, z-scores

MS, z-scores

test t1

test t2

p-value

test t1

test t2

p-value

test t1

test t2

p-value

Logical Memory (WMS-IV)

-0.94

-0.92

0.968

-0.76

-0.59

0.745

-1.08

-1.21

0.726

LG I

-1.13

-1.33

0.711

-1.20

-0.87

0.597

-1.17

-1.33

0.734

LG II

-1.00

-0.90

0.830

-0.70

-0.50

0.730

-1.00

-1.37

0.427

LG II recognition

-0.69

-0.54

0.737

-0.39

-0.40

0.985

-1.07

-0.94

0.726

-1.24

-1.13

0.748

-0.61

-0.71

0.807

-1.18

-1.25

0.914

Copy

-2.08

-2.75

0.357

-1.21

-1.73

0.289

-1.91

-2.44

0.561

Delayed Recall

-0.40

0.50

<0.001

-0.01

0.31

0.451

-0.46

-0.06

0.337

-0.69

-0.13

0.309

-1.09

-0.62

0.446

-0.81

-1.07

0.812

Part A

-0.38

-0.07

0.500

-1.19

-0.59

0.350

-0.92

-0.81

0.925

Part B

-1.00

-0.18

0.253

-0.98

-0.65

0.619

-0.71

-1.34

0.546

0.30

0.60

0.466

-0.01

0.33

0.494

0.16

0.23

0.901

Forward

0.67

0.76

0.823

-0.01

0.48

0.350

0.60

0.74

0.825

Backward

-0.07

0.43

0.333

-0.01

0.19

0.735

-0.28

-0.28

1.000

0.26

-0.04

0.327

-0.61

-1.00

0.413

-1.07

-0.68

0.410

-0.47

-0.34

0.580

-0.56

-0.47

0.704

-0.69

-0.73

0.928

Digit span

Corsi block-tapping Overall neuropsychological performance

K – words S – words Animals

EV, percentile rank

MS, percentile rank

38

47

0.794

41

44

0.711

46

40

0.612

43

52

0.444

32

48

0.201

52

44

0.606

28

29

0.971

29

36

0.521

38

33

0.681

33

49

0.547

50

40

0.335

47

40

0.657

48

40

0.508

36

43

0.772

46

36

0.526

EP

B – words

TE D

LD, percentile rank RWT

SC

TMT

M AN U

ROCF

RI PT

Neuropsychological assessment

AC C

Food 48 42 0.895 60 57 0.840 49 45 0.823 LD: degenerative lumbar spine disease group (control); EV: endovascular treatment group; MS: microsurgical clipping group; test t1: preoperative/preinterventional test; test t2: test 6 weeks after treatment; WMS-IV: Wechsler Memory Scale - Fourth Edition; LG I: subtest Logical Memory I; LG II: subtest Logical Memory II; ROCF: Rey-Osterrieth Complex Figure test; TMT: Trail Making Test; RWT: Regensburg Word Fluency Test (a German version of the Controlled Oral Word Association Test (COWA)).

ACCEPTED MANUSCRIPT

EV

MS

LD - EV

LD - MS

EV - MS

Logical Memory (WMS-IV)

.011

.25

-.203

.482

.528

.190

LG I

-.181

.315

-.167

.254

.973

.268

LG II

.072

.256

-.395

.447

.060

LG II recognition

.175

.302

-.207

.788

.420

.011* .299

ROCF

.096

-.068

-.083

.732

.694

.974

Copy

-.756

-.394

-.573

.625

.797

.807

Delayed Recall

.883

.366

.365

.154

.140

.996

TMT Part A Part B

B - words K - words

Food

AC C

S - words Animals

.565

.471

-.258

.781

.02*

.038*

.422

.517

.095

.757

.286

.170

.809

.325

-.613

.467

.040*

.165

2.056

2.824

-5.999

.876

.114

.083

10.922 13.381 -4.602

.827

.179

.132

-1.849

5.385

-1.135

.545

.953

.590

5.796

-8.189 -5.907

.154

.225

.807

-7.778

2.723

-9.545

.189

.820

.125

-1.418 -3.793

.843

.639

.792

EP

RWT

M AN U

LD

TE D

Neuropsychological assessment

Intergroup comparisons [p - value]

SC

Estimated marginal means (test t1 vs. t2)

RI PT

Table 6 Intergroup comparisons of cognitive tests: Differences between the treatment groups.

.411

Digit span

.332

.303

.073

.914

.333

.388

Forward

.159

.37

.192

.452

.904

.522

Backward

.518

.236

-.57

.527

.203

.512

Corsi block-tapping

.07

-.462

.094

.133

.949

.102

Overall neuropsychological performance

.135

.092

-.053

.773

.214

.331

(*Statistical significance: p < .05) test t1: preoperative/preinterventional test; test t2: test 6 weeks after treatment; test t1 - t2: intergroup development from t1 to t2; MS: microsurgical clipping group; EV: endovascular treatment group; LD: degenerative lumbar spine disease group (control).WMS-IV: Wechsler Memory Scale - Fourth Edition; LG I: subtest Logical Memory I; LG II: subtest Logical Memory II; ROCF: Rey-Osterrieth Complex Figure test; TMT: Trail Making Test; RWT: Regensburg Word Fluency Test (a German version of the Controlled Oral Word Association Test (COWA)).

Bründl

ACCEPTED MANUSCRIPT Abbreviations list

anterior cerebral artery

ACoA

anterior communicating artery

aSAH

aneurysmal subarachnoid hemorrhage

CBF

cerebral blood flow

CN

cranial nerve

COWA

Controlled Oral Word Association Test

CT scan

computed tomography scan

D-KEFS

Delis and Kaplan Executive Function System

DSA

digital subtraction angiography

EV

endovascular aneurysm occlusion

FU

follow-up

GOS

Glasgow Outcome Scale

h

hour/s

ICA

internal carotid artery

IQ

intelligence quotient

ISAT

International Subarachnoid Aneurysm Trial

ISUIA

International Study of Unruptured Intracranial Aneurysms

LD

degenerative lumbar spine disease

LG

Logical Memory (subtest of WMS-IV)

LG I

Logical Memory I (subtest of WMS-IV)

LG II

Logical Memory II (subtest of WMS-IV)

MCA

middle cerebral artery

min

minute/s

minimum – maximum

mm

millimeter

SC

M AN U

TE D

EP

AC C

min-max

RI PT

ACA

MMSE

Mini-Mental State Examination

MRI

magnetic resonance imaging

mRS

modified Ranking Scale

MS

microsurgical clipping

ND

neurological deficit

no., [n]

number

p

p-value 1

Bründl

ACCEPTED MANUSCRIPT posterior communicating artery

ROCF

Rey-Osterrieth Complex Figure Test

RWT

Regensburg Word Fluency Test

sec

second/s

SD

standard deviation

TCF

Taylor Complex Figure

TMT

Trail Making Test

test t1

preoperative/preinterventional test

test t2

test 6 weeks after treatment

test t1 - t2

intergroup development from t1 to t2

UCAS

Unruptured Cerebral Aneurysm Study of Japan

UIA

unruptured intracranial aneurysm

WAIS-III

Wechsler Adult Intelligence Scale III

WMS-IV

Wechsler Memory Scale – Fourth Edition

AC C

EP

TE D

M AN U

SC

RI PT

PCoA

2

ACCEPTED MANUSCRIPT Highlights

Neuropsychological assessment before and after UIA treatment is underreported.

•

Treatment modality-dependent effects on cognition in UIA patients are proposed.

•

Anterior circulation UIA treatment didn’t affect overall neuropsychological function.

•

Surgically treated patients showed impaired short-term executive processing.

AC C

EP

TE D

M AN U

SC

RI PT

•