Long-Term Outcome and Quality of Life After Cavernoma Resection: Eloquent vs. Non-Eloquent Areas.

doi:10.21203/rs.3.rs-173091/v1

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Long-Term Outcome and Quality of Life After Cavernoma Resection: Eloquent vs. Non-Eloquent Areas.

https://doi.org/10.21203/rs.3.rs-173091/v1

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Objective: To analyze the long-term quality of life after surgery of cavernoma.

Methods: A monocentric retrospective study was conducted on 69 patients with cavernoma treated microsurgically between 2000 and 2016. The eloquence was adopted from Spetzler-Martin definition. A most recent follow-up was elicited between 2017 and 2019, in which the quality of life (QoL) was evaluated with the Short Form-12 questionnaire (SF12).

Results: 41 lesions were in eloquent group (EG), 22 in non-eloquent group (NEG), 3 in orbit and 3 in the spinal cord. Postoperative worsening of the modified Rankin scale (mRS) occurred in 19.5% of cases in EG versus 4.5% in NEG. After a mean follow-up of 6.5 years, the neurological status was better or unchanged compared to baseline in 85.4% of EG and 100% of NEG.

44 patients (EG n =27, NEG n = 14) attended the last follow-up. The EG had mostly comparable QoL results matched to NEG except for the physical role (RP). The study population when compared to the norms, did well on only half of the parameters of SF12. Yet, the general health (GH), vitality, physical (RP) and emotional roles (RE) were significantly inferior.

Conclusion: At a late follow-up, the surgical morbidity was transient in the NEG and mostly recovered in the EG. Regarding QoL, Patients after eloquent cavernoma resection reported a non-inferior QoL in most SF12 domains (except for physical role) compared to NEG. However, they reported general health perception inferior to norms, which was affected by the limited physical and emotional roles.

Developmental Neuroscience

Neurosurgery

cavernoma

cavernous malformation

eloquent area

quality of life

surgical resection

neurological outcome

Cavernoma or cavernous malformation (CM) is a benign non-shunting vascular malformation that is prone to bleed.[25] They account for 5–15% of central nervous system (CNS) vascular malformations,[10] and present with seizures, focal neurologic deficits (FND), or incidentally.[19] Disease prevalence ranges from 0.4–0.8%.[13, 4, 23] The overall annual bleeding risk is 2.4% patient/year.[12] In previously unruptured CM, the bleeding risk is 0.3–2.8% patient/year, but the risk reaches 6.3%-32.2% patient/year once the cavernoma bled.[2, 31]

In asymptomatic cavernomas, a “wait and see” conservative management could be the first choice.[16, 20] Previous publications reported, however, that a bad preoperative performance level at the presentation is a predictive factor of a poor outcome. That means, “wait and see” strategy for eloquent CM after the first hemorrhage will leave these patients at risk of neurological deterioration from substantial bleedings, therefore decreasing the chance for complete recovery after surgery.[5, 6, 8] Given the increased risk of rehemorrhage, microsurgical resection remains the definitive treatment for CNS cavernomas.[11]

The main concern is the outcome of surgical treatment. There is a need to validate the quality of life of the patients after surgical resection of the cavernoma, especially in deep or eloquent areas. By reviewing the literature, we found many studies that assess the outcome after CNS cavernoma surgery and to a lesser extent after surgery of cavernomas located in eloquent regions, [6, 14, 15, 24, 28, 30, 36, 39] However studies that assess the QoL are still rare. Only four studies assess the quality of life of these patients, including three studies that evaluated brainstem cases only. [7, 8, 9, 17]

We performed this study to investigate two main aspects: 1) the neurological outcome and 2) quality of life after CNS cavernoma resection.

Participants and study design

From January 2000 to December 2016, 74 patients with cavernoma treated surgically at the University Hospital Greifswald, were evaluated in this retrospective clinical study. This study was approved by the local ethics committee (study number BB 031/18).

Inclusion criteria and information gathered

The inclusion criteria were a histopathological confirmation of CNS cavernoma and complete data sets of the patients. Five patients were excluded from the study. Two had no clear histopathological confirmation of CM, and the remaining three patients were lost to follow up, leaving a total of 69 subjects included in the study. Clinical charts, imaging studies, operation notes, and follow up notes were reviewed.

Information regarding the patient's gender, mean age at the surgery, location of the lesion, signs and symptoms, duration of the complaint, medications including antiepileptic drugs (AED) past medical history, preoperative MRI findings (including location and size [maximum diameter] of CMs and Zabramski classification[37] associated developmental venous anomaly (DVA)), length of stay, and length of the operation were gathered. Genetic counseling was offered to patients with a positive family history of CMs and multiple cavernomas.

The neurological examination (alertness/consciousness, orientation, dizziness, headache, cranial nerve status, sensomotoric deficit, gait, epilepsy) was standardized pre-and postoperatively according to the modified Rankin Scale (mRS).[22] Based on the mRS, patients who presented with debilitating seizures or headaches were given mRS 1. In contrast, the presentation of simple non-disabling fit or chronic sporadic recurrent headaches that are controlled on medications considered a mRS 0. Postoperative change of at least one grade of mRS was defined as better or worse. Table 1 shows the distribution of the patients according to mRS.

Table 1
Modified Rankin Scale demonstrates the corresponding results from the study.
mRS ²²	at presentation: EG	NEG	late follow-up: EG	NEG
0	6	7	21	14
1	23	14	9	7
2	4	0	6	0
3	3	0	1	0
4	5	1	1	0
5	0	0	3	0
6	0	0	0	1+
EG = eloquent group; mRS = modified Rankin scale; NEG = non-eloquent group.
# some patients had a transient FND and they had mRS 0 at the presentation
+ died from another disease
22. New PW, Buchbinder R (2006) Critical appraisal and review of the Rankin scale and its derivatives. Neuroepidemiology 26:4–15

Eloquence

Eloquence was adopted from Spetzler-Martin definition [29]. The following CM locations were treated: sensorimotor n = 14, basal ganglia n = 2, language n = 8, visual pathway n = 5, deep cerebellar nuclei or cerebellar peduncles n = 4, and brainstem n = 8. 22 cavernomas were found in non-eloquent areas. Three lesions were located in the orbit and 3 in the spinal cord. Eight patients had multiple cavernomas. Detailed localization is summarized in Table 2.

Table 2
Anatomical and functional location distribution of the surgically resected CM.
Anatomical location distribution		Functional location distribution
	No. of patients		No. of patients
supratentorial	47	Eloquent²⁹	41
frontal	18	sensomotoric region	14
temporal	13	language	8
parietal	7	visual	5
parietooccipital	5	basal ganglia	2
occipital	2	cerebellum deep nuclei, and peduncles	4
basal ganglia	2	brainstem	8
cerebellar	8	Non-Eloquent	22
brainstem	8	frontal	7
midbrain	1	temporal	8
pons	4	parietal	3
ponto-medullary	1	cerbellar hemisphere	4
medualla oblongata	2	occipital	0*
Other: spinal cord n = 3, orbital n = 3, multiple n = 8
*all occipital lesions were in the visual eloquence
29. Spetzler RF, Martin NA (1986) A proposed grading system for arteriovenous malformations. J Neurosurg 65:476–483

The patients were categorized into two groups: eloquent group (EG) and non-eloquent group (NGE). The orbital and spinal cord cavernomas were excluded from the subgroup statistics for a reasonable comparison between the EG and NEG.

Imaging protocols

Brain MRI was routinely performed within one week before surgery, mostly for neuronavigation purposes. A standard presurgical workup was made, including functional MRI, neurophysiology testing, and epilepsy work-up when needed. Postoperative MRI was done within the first three months, then yearly, or at the last follow-up. The imaging studies were read by a neuroradiologist (MK).

Postoperative bleeding was defined as an extension of the bleeding outside the resection bed in the postoperative imaging studies.

Surgical strategy

The patients were operated on in our institute by different neurosurgeons. The aim of the surgery was a total lesionectomy. The treatment approach was harmonious in all cases. Different microsurgical approaches were selected depending on the case. A combination of intraoperative neuronavigation, ultrasound, awake surgery or neurophysiologic monitoring was used as needed.

Last Follow-up

The patients were invited for a follow-up, so-called last follow-up, in which 44 patients of the present study population could attend, and they were distibuted as follows: EG n = 27, NEG = 14, orbital n = 2, spinal cord n = 1. These patients were interviewed between 2017 and 2019.

In this follow-up, neurological status with an updated MRI were reviewed. The individuals were then asked to answer validated questionnaires of Quality of Life (QoL) of short-form 12 (SF12),[32] overall satisfaction, and reemployment status.

Quality of life via Short Form 12 (SF12)

The overall respondents’ rate of the SF12 questionnaire was 63.8% (44 out from 69). The mean interval between the surgery and the survey was 8.7 years.

SF12 survey contains 8 domains: (1) general health perceptions (GH general health); (2) limitations in usual role activities due to physical problems (RF functional role); (3) bodily pain(BP); (4) physical activities limitations due to health problems (PF physical functioning) ; (5) energy and fatigue (VT vitality); (6) limitations in social activities due to physical and emotional problems (SF social functioning); (7) limitations in usual role activities because of emotional problems (RE emotional role); and (8) general mental health, psychological distress and well-being (MH mental health).

The first 4 domains represent physical health and the last 4 represent mental health. The sum of each 4 domains generates a global score; Physical Composite Scale (PCS) and Mental health Composite Scale (MCS).

The sum of the questions in each of these 8 sections and the 2 global scores are transformed into a 0 to 100 scale. A lower score (0) represents more disability, whereas a higher score means less disability, and 100 points equivalent to no disability. Results from this test were re-calculated as described in SF-12 Health Survey Manual,[32] and compared to normative data from the general German population. [35]

The evaluation of these results focused on a comparison between 1) the two groups EG and NEG, 2) the study population, EG, and NEG with a normative German population, respectively.[35]

Statistical analysis

All data were expressed as mean and standard deviation. For subgroup analysis, Fisher's exact test was used for categorical variables. An independent two-sample t-test was performed for continuous variables. Statistical analyses were performed using commercially available software (SPSS, Ver. 20.0, IBM Corp., Armonk, New York, USA). Two-tailed P value < 0.05 was considered significant, and P < 0.01 as highly significant.

Demographic data and clinical presentation

69 patients made up the study cohort, including 30 women (43.48%) and 39 men (56.52%). The average age at surgery was 41.3 years (SD 16.2, range 16–78 years). Table 3 demonstrates a summary of demographic and clinical characteristics of the whole study population, EG, and NEG.

Table 3
Demographic and clinical characteristics of 69 patients with CM divided into two groups: eloquent group (EG) and non-eloquent group (NEG).
No. of patients	Study population 69	Eloquent group 41	Non-eloquent group 22	Significance
Mean Age at the operation in years Female (%)	41.7 (SD 16.2) (range, 16–78 years) 30 (43.5%)	42.4 (SD 16.6) 22 (53.7%)	40.0 (SD 16.2) 7 (31.8%)
Mean duration of presentation in months	40.2 (SD 80.9) (range, 1–400)	48.4 (SD 94,5)	26.3 (SD 63.2)
Symptoms (%) - FND - seizure - FND and Seizure - Incidental - Headache	-29 (42.0%) -24 (34.9%) -8 (11.6%) -4 (5.8%) -4 (5.8%)	-19 (46.3%) -13 (31.2%) -6 (14.6%) -1 (2.4%) -2 (4.9%)	-4 (18.1%) -11 (50.0%) -2 (9.1%) -3 (13.6%) -2 (9.1%)
Mean Follow up in years	6.5 (SD 4.6) (range, 1–18)	5.8 (SD 4.0)	7.6 (SD 5.6)
Mean CM size in mm	18.1 (SD 10.4) (range 4–56)	18.4 (SD 9.8)	16.1 (SD 9.0)	NS
Mean operation time in minutes	223.0 (SD 100.0) (range, 82–573)	240.2 (SD 100.1)	184.6 (SD 94.6)	P Value = 0.0362 †
Mean length of stay in days	9.9 (SD 4.3) (range, 5–28)	10.2 (SD 4.9)	9.5 (SD 3.4)	NS
Zabramski Class ³⁷ I/II/III/IV Rate (%)	22/40/7/0 32/58/10/0	13/27/1/0 32/66/2	5/11/6/0 23/50/27/0
CM = cavernous malformation; FND = focal neurological deficit; NS = non-significant; SD = standard deviation.
Values represent numbers of cases (%) unless otherwise indicated. Mean values are presented with standard deviations. p values are for comparison of the difference between subgroups.
† T-test.
37. Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G (1994) The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422–432

Among these patients, 29 (42.0%) presented with FND, 24 (34.8%) with symptomatic focal epilepsy, and 8 patients (11.6%) with both FND and seizures.

Four patients (5.8%) presented only with long-standing nonspecific headaches, and in 4 (5.80%) patients the cavernoma was an incidental finding, where 2 of them presented because of remote bleeding and the other 2 due to non-cavernoma-related epilepsy.

The mean duration of preoperative clinical history was 40.2 months (SD 80.9) of all cavernomas. The mean last available follow-up was 6.5 years.

Genetic profiles

Since a positive family history and multiple CMs are indicative of the familial form of CCM, genetic counseling was offered to all study participants who met these criteria. Three of the eight patients gave their written informed consent for genetic analyses of the three disease-associated genes CCM1 (also known as KRIT1), CCM2, and CCM3 (also known as PDCD10). A pathogenic CCM1 frameshift variant was identified in one patient and a CCM2 splice site mutation, which was also classified as pathogenic, according to the American College of Medical Genetics and Genomics (ACMG) guidelines,[26] was detected in two brothers. [21]

Imaging and surgical outcome

The most common type of MRI presentation was type 2 Zabramski grade (58.0%).

Complete resection was achieved in 67 patients (97.1%) determined by intraoperative inspection and postoperative MR imaging. An accompanying DVA was detected in 19 patients (27.5%) and was preserved in all cases (Fig. 1). The duration of the operation in EG was longer than for the NEG; the difference was significant ( P = 0.0362, T-Test).

Complications and surgical morbidity

Directly postoperatively, new FND or worsening of the presenting symptoms, as noted in Table 4, was observed in 31.7% of the EG and 4.5% of the NEG. An immediate worsening of one or more grades of the mRS was seen in 19.5% of patients with eloquent cavernomas and 4.5% of patients with non-eloquent cavernomas corresponding to the surgical morbidity. There were no cases of mortality.

Table 4
List of the postoperative complications.
FND -Paresis -Paresthesia -Dysphasia -Cognitive dysfunction -Ataxia -Diplopia -Visual field defect Postoperative bleeding#	No. 5 4 1 1 2 3 1 4	Comments: some patients had mixed FND
Medical problem Deep vein thrombosis Pulmonary embolism	1 1	PE occurred in a patient with brainstem cavernoma
Wound infection	1	1 reoperation
CSF Fistula	2	1 reoperation
# bleeding that slightly extended from the resection bed in the post-operative imaging
-CSF = cerebrospinal fluids; CRE = cavernoma related epilepsy; FND = focal neurological deficit; PE = pulmonary embolism.

At the late follow-up, after a mean follow-up time of 6.5 years, the status was equal or better than the baseline at presentation in 85.4% of patients in the EG vs 100% in the NEG (Fig. 2).

Twelve out of 63 patients (19.0%) who presented with intracranial CM had preoperatively chronic disabling headaches. At the last follow-up, only one patient (1.6%) had persisting headache episodes.

Rebleeding and reoperation

Postoperative bleeding was detected in the routine postoperative brain image in 4 patients (5.7%) without any clinical manifestation. None of them required surgical evacuation.

As demonstrated in Table 4, two postoperative complications necessitated a reoperation, due to CSF fistula, and postoperative wound infection.

Epilepsy outcome and Antiepileptic drugs (AED)

Regarding cavernoma-related epilepsy, 23 out of 29 patients (79.3%) reported seizure-free or only rarely disabling seizures after surgery (Engel classification 1) [34], while 31.0% of the patients were able to discontinue the AED and 17.2% of patients could decrease at least one AED.

Return to work and patient satisfaction.

In response to the supplementary question at the last follow-up (n = 44) (“Did the operation meet your expectations about the postoperative course of the treatment”), 88.8% of the patients expressed their satisfaction with the treatment, while 11.2% found that the surgical treatment did not meet their expectations.

Regarding reemployment or return to baseline activity, 16 out of 27-asked patients (59.3%) in the EG were able to return to work compared to 12/14 patients (85.7%) in the NEG, including two retired patients that were able to do the housework as before the operation. This difference between the two groups was not significant.

Health-related quality of life (QoL)

The assessment of QoL with the SF12 questionnaire was performed during the last follow-up.

The overall respondents’ rate of the SF12 questionnaire was 44 cases (63.8%). The mean interval between the surgery and the survey was 8.7 years.

The results are demonstrated in Table 5 and illustrated in Fig. 3.

Table 5
Results of SF-12 Questionnaire for Study Population, Subgroups and Healthy Population (Germany) ³⁵
	Study n44* Mean (SD)	German population n 2524 Mean (SD)	Study vs norms	EG n 27 Mean (SD)	NEG n 14 Mean (SD)	EG vs norms	NEG vs norm	EG vs NEG
GH	42.73 (27.05)	59.79 (23.10)	P < 0.0001 T-Test	47.59 (26.36)	38.93 (27.89)	P = 0.0064 T-Test	P = 0.0007T-Test	NS
PF	85.80 (27.70)	86.76 (24.32)	NS	85.19 (27.09)	82.14 (30.11)	NS	NS	NS
RP	75.85 (27.41)	83.61 (22.55)	P = 0.0243 T-Test	73.61 (30.29)	76.79 (23.95)	P = 0.0225 T-Test	NS	NS
BP	85.80 (21.16)	85.66 (23.15)	NS	87.96 (17.50)	78.57 (27.49)	NS	NS	NS
VT	63.64 (22.53)	70.40 (18.56)	P = 0.0171 T-Test	63.89 (25.32)	60.71 (18.90)	NS	NS	NS
SF	85.23 (23.08)	87.83 (20.10)	NS	86.11 (21.18)	82.14 (28.47)	NS	NS	NS
RE	77.27 (26.72)	87.51 (20.45)	P = 0.0011 T-Test	76.85 (27.89)	75.89 (27.50)	P = 0.0073 T-Test	P = 0.0344 T-Test	NS
MH	74.72 (16.06)	80.10 (22.73)	NS	76.85 (17.92)	73.21 (11.87)	NS	NS	NS
PCS	47.81 (6.00)	50.00 (10.12)	NS	48.04 (5.97)	46.31 (5.97)	NS	NS	NS
MCS	50.11 (9.12)	49.99 (10.08)	NS	50.69 (9.61)	49.43 (9.12)	NS	NS	NS
* n = 44 divided in EG n = 27, NEG = 14, orbital n = 2 and spinal cord n = 1
- BP = bodily pain; EG = Eloquent group; GH = general health perceptions; MCS = Mental Health Composite Scale; MH = mental health; NEG = non-eloquent group; NS = not significant; PCS = Physical Composite Scale; PF = physical functioning; RE = role emotional; RP = role physical; SF = social functioning; VT = vitality.
35. Wirtz MA, Morfeld M, Glaesmer H, Brähler E (2018) Normierung des SF-12 Version 2.0 zur Messung der gesundheitsbezogenen Lebensqualität in einer deutschen bevölkerungsrepräsentativen Stichprobe. Diagnostica 64:215–226

QoL according to eloquence, EG vs. NEG: the subgroup analysis showed no statistical difference between both subgroups after a long follow up. The EG showed a slightly better score in general health (GH) and bodily pain (BP) Domains, where the physical role (RP) was more limited in the EG.

comparison with the normative German population (norms): The physical and mental component score of the entire study population and the subgroups when compared with norms showed no statistically significant difference. The patients scored equal to the norms regarding the mental component score.

Regarding physical health analysis; the general health (GH) was significantly better in norms compared to subgroups.

The physical role (RP) also showed a better score in norms; this difference was significant compared to EG and the study population (p < 0.05, T-test), but not to the NEG.

In mental health analysis; the patients reported vitality (VT, energy level) and emotional role (RE) perception significantly inferior to the normative population as Table 5 illustrated.

Neurosurgical outcome:

In this study, 94.1% of patients were symptomatic, 88.4 % of the patients presented with new neurological symptoms before surgery. Short-term morbidity after surgery was seen in 19.5% of cases in the EG versus 4.5% in the NEG. Long-term morbidity was in 14.6% of cases in the EG versus 0% in the NEG.

The results in the presented study were comparable to the outcome stated in the literature. A larger study (n = 79) reported 97.4% of the patients had better or identical status after supratentorial cavernoma resection in eloquent areas at last follow-up.[6] Wostrack et al (n = 41) reported 47 % of patients had a new postoperative deficit. At follow-up, 80% recovered to at least preoperative status.[36] In a recent study by Sanmillan et al. that assessed the surgical outcome of 20 patients who presented with cavernoma in eloquent location, 50% of patients had transient deterioration that all recovered after one year.[28]

Regarding brainstem cavernomas, 62.5% of our patients had a better or identical neurological outcome at the last follow-up. A study of a larger cohort of brainstem cavernomas (n = 260), showed a rate of new postoperative FND in 53% of the patients and permanent morbidity with new deficits remained in 36% of them after a mean follow-up of 51 months.[1]

When left untreated, the eloquent lesions and especially brainstem lesions will deteriorate due to the increased rebleeding rate (estimated 6.3% patient/year for non-brainstem and 32.2% patient/year for brainstem lesions that could also reach up to 52.7% patient/year).[31] Knowing the natural history of eloquent cavernomas and to a lesser extent brainstem cavernomas, justifies the decision of surgery in these eloquent areas.[18] [27] [36]

The fear of surgical morbidity should be reconsidered when we look at the prolonged follow-up of the patients, where the neurological deficits will mostly recover and the risk of hemorrhage from the cavernoma will decrease or even be eliminated by the complete resection.

Return to work

The rate of patients to return to work in EG was lower than the NEG (59.3% vs 85.7%). correlated to QoL and mRS results, the limiting physical role (RP) and mRS > 2 at the last follow up (12.2% vs 0% as shown in Table 1) could contribute to the difference between the two groups. Other factors such as Age, Gender, and AED status did not show a correlation to this difference.

Our results from patients in the EG returned to work compared to a larger multicentric survey from Zanello et al. showed a lower proportion of patients returning to work (59.3% vs 88.6%, respectively). [38] This difference between our results and this survey is hard to explain since both studies lack a suppurative socioeconomic data of these patients. The mean age of both populations (42.4 vs. 40.2 years) as well as the slight female predominance (53.7% vs 59.6%), and functional worsening at the follow-up (14.6% vs 12.9%) were similar.

Health-related quality of life

Previous publications about the QoL of patients after cavernoma resection was assessed in four previous publications, including three studies for brainstem cavernomas only. Cornelius et al. compared the quality of life between the brainstem and non-brainstem cavernomas. They found, expectedly, that patients with a brainstem lesion were far more inferior regarding physical health domains of the QoL. Previous studies about QoL of patients after brainstem cavernoma surgery reported a favorable QoL in terms of mental health aspects.[7, 9, 17]

Another study has been conducted considering patients' satisfaction with cavernoma-related epilepsy. The assessment, however, took part through a survey per mail.[33]

The difference in this study is seen in the physical functioning (PF) domain. Our patients reported a good score in this domain, in contrast to previous studies. Our explanation is as follows: The previous studies included brainstem cavernomas as a group and compared it with the normative population,[7, 9, 17, 8], or with non-brainstem group.[7] Unsurprisingly, the brainstem group reported an inferior score regarding physical functioning. In the present study, patients in the eloquent group could have a visual field defect or mild hemiparesthesia and still report a good physical functioning perception compared to the brainstem group; this could explain the observed difference.

Furthermore, none of the studies mentioned above assessed the QoL of their study population sorted by functional location of the lesion (eloquence). They instead compared brainstem with non-brainstem cavernoma or normal population. The non-brainstem cavernomas have a wide range of presentations from asymptomatic to significant disability depending on the eloquence. The perception of QoL in patients with disabilities differs from patients with oligosymptomatic state. Moreover, some recommendations from the Angioma Alliance for cavernoma management from Akers et al. relied on the eloquence of the lesion.[3] Hence, the present study assesses the QoL distributed accordingly.

To summarize the results about the QoL, we found that patients with cavernoma located in eloquent regions after surgery mostly had a non-inferior QoL compared to NEG except the physical role (RP) domain. Compared to their normative correspondence, the EG reported general health (GH) perception inferior to norms, which was related to limited physical and emotional roles.

Our results in line with the results of the previous studies show that the QoL accompanied by the neurological outcome is an essential and powerful element to support the decision for treating CNS cavernomas, especially if the cavernoma is in an eloquent area.

This observation of how these patients are doing years after surgery could improve patient counseling for future encountered cases.

Strength and limitation of the study

A major strength of this study is that we conducted face-to-face interviews for QoL measurements in more than half of the patients in a prolonged period after surgery (mean time-to-interview 8.7 years). Some previous studies conducted such interviews via mail or telephone only.[7, 9, 33] Moreover, the correlation to the normal German population was from the same survey done in 2018, that time is comparable to the time of the follow-up of this study.

However, there are some limitations to our study. First, we only recruited participants from a single tertiary care center and the results might not be generalized to other settings or populations. Second, the sample size for the QoL assessment (n = 44) with further subdivision of EG (n = 27) and NEG (n = 14) is relatively small. Third, as the previously conducted studies about QoL of cavernoma patients, there was no preoperative QoL assessment or socioeconomic data of our patients to correlate the improvement of QoL postoperatively due to the retrospective design of the study.

In summary, the present study adds information to the literature about QoL after cavernoma surgery, which is needed to validate patients’ well-being after surgical treatment. The comparison between eloquent and non-eloquent cavernomas, created interesting and new results after prolonged follow-up. The assessment of CNS Cavernoma QoL has only rarely been performed.[7, 8, 9, 17]

At a late follow-up, the surgical morbidity was transient in the NEG and mostly recovered in the EG (85.4% of patients). Regarding QoL, Patients after eloquent cavernoma resection reported a non-inferior QoL in most SF12 domains (except for physical role) compared to NEG. However, they reported general health perception inferior to norms, which was affected by the limited physical and emotional roles.

Funding: No funds, grants, or other support was received.
Conflicts of interest/Competing interests All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
Ethics approval: The questionnaire and methodology for this study were approved by the Human Research Ethics committee of the University of Greifswald (Study ID: BB 031/18).
Consent to participate This retrospective anonymised study did not require consent to participate from all individual participants. Informed consent was only obtained from the individuals that participated in the last elicited follow-up.
Consent for publication Not applicable.
Acknowledgments: None

Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF (2011) Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery 68:403–14; discussion 414–5
Aiba T, Tanaka R, Koike T, Kameyama S, Takeda N, Komata T (1995) Natural history of intracranial cavernous malformations. J Neurosurg 83:56–59
Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whitehead K (2017) Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery 80:665–680
Al-Holou WN, O’Lynnger TM, Pandey AS, Gemmete JJ, Gregory Thompson B, Muraszko KM, Garton HJL, Maher CO (2012) Natural history and imaging prevalence of cavernous malformations in children and young adults. J Neurosurg Pediatr 198–205
Bertalanffy H, Gilsbach JM, -R. Eggert H, Seeger W (1991) Microsurgery of deep-seated cavernous angiomas: Report of 26 cases. Acta Neurochirurgica 108:91–99
Chang EF, Gabriel RA, Potts MB, Berger MS, Lawton MT (2011) Supratentorial cavernous malformations in eloquent and deep locations: surgical approaches and outcomes. Journal of Neurosurgery 114:814–827
Cornelius JF, Kürten K, Fischer I, Hänggi D, Steiger HJ (2016) Quality of Life After Surgery for Cerebral Cavernoma: Brainstem Versus Nonbrainstem Location. World Neurosurgery 95:315–321
Dammann P, Herten A, Santos AN, Rauschenbach L, Chen B, Darkwah Oppong M, Schmidt B, Forsting M, Kleinschnitz C, Sure U (2020) Multimodal outcome assessment after surgery for brainstem cavernous malformations. J Neurosurg 1–9
Dukatz T, Sarnthein J, Sitter H, Bozinov O, Benes L, Sure U, Bertalanffy H (2011) Quality of Life After Brainstem Cavernoma Surgery in 71 Patients. Neurosurgery 69:689–695
Goldstein HE, Solomon RA (2017) Epidemiology of cavernous malformations. Handb Clin Neurol 143:241–247
Gross BA, Du R (2017) Hemorrhage from cerebral cavernous malformations: a systematic pooled analysis. J Neurosurg 126:1079–1087
Gross BA, Lin N, Du R, Day AL (2011) The natural history of intracranial cavernous malformations. Neurosurg Focus 30:E24
Horne MA, Flemming KD, Su I-C, Stapf C, Jeon JP, Li D, Maxwell SS, White P, Christianson TJ, Agid R, Cho W-S, Oh CW, Wu Z, Zhang J-T, Kim JE, Ter Brugge K, Willinsky R, Brown RD Jr, Murray GD, Al-Shahi Salman R, Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators (2016) Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol 15:166–173
Jung YJ, Hong SC, Seo DW, Hong SB (2006) Surgical resection of cavernous angiomas located in eloquent areas--clinical research. Acta Neurochir Suppl 99:103–108
Kivelev J, Koskela E, Setälä K, Niemelä M, Hernesniemi J (2012) Long-term visual outcome after microsurgical removal of occipital lobe cavernomas. J Neurosurg 117:295–301
Kupersmith MJ, Kalish H, Epstein F, Yu G, Berenstein A, Woo H, Jafar J, Mandel G, De Lara F (2001) Natural history of brainstem cavernous malformations. Neurosurgery 48:47–53; discussion 53–4
Lashkarivand A, Ringstad G, Eide PK (2019) Surgery for Brainstem Cavernous Malformations: Association between Preoperative Grade and Postoperative Quality of Life. Oper Neurosurg (Hagerstown). doi: 10.1093/ons/opz337
Mathiesen T, Edner G, Kihlström L (2003) Deep and brainstem cavernomas: a consecutive 8-year series. J Neurosurg 99:31–37
Morris Z, Whiteley WN, Longstreth WT Jr, Weber F, Lee Y-C, Tsushima Y, Alphs H, Ladd SC, Warlow C, Wardlaw JM, Al-Shahi Salman R (2009) Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 339:b3016
Mouchtouris N, Chalouhi N, Chitale A, Starke RM, Tjoumakaris SI, Rosenwasser RH, Jabbour PM (2015) Management of Cerebral Cavernous Malformations: From Diagnosis to Treatment. The Scientific World Journal 2015. doi: 10.1155/2015/808314
Much CD, Schwefel K, Skowronek D, Shoubash L, von Podewils F, Elbracht M, Spiegler S, Kurth I, Flöel A, Schroeder HWS, Felbor U, Rath M (2019) Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations. Front Neurol 10:1219
New PW, Buchbinder R (2006) Critical appraisal and review of the Rankin scale and its derivatives. Neuroepidemiology 26:4–15
Otten P, Pizzolato GP, Rilliet B, Berney J (1989) [131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies]. Neurochirurgie 35:82–3, 128–31
Pinsker M, Nabavi A, Mehdorn H (2007) Neuronavigation and Resection of Lesions Located in Eloquent Brain Areas under Local Anesthesia and Neuropsychological-Neurophysiological Monitoring. min - Minimally Invasive Neurosurgery 50:281–284
Raychaudhuri R, Huntington Batjer H, Awad IA (2005) Intracranial cavernous angioma: a practical review of clinical and biological aspects. Surg Neurol 63:319–328
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Others (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405
Samii M, Eghbal R, Carvalho GA, Matthies C (2001) Surgical management of brainstem cavernomas. J Neurosurg 95:825–832
Sanmillan JL, Lopez-Ojeda P, Fernández-Conejero I, Fernández-Coello A, Plans G, Ali-Ciurana Y, Gabarrós A (2018) Treatment of cavernous malformations in supratentorial eloquent areas: experience after 10 years of patient-tailored surgical protocol. Acta Neurochir 160:1963–1974
Spetzler RF, Martin NA (1986) A proposed grading system for arteriovenous malformations. J Neurosurg 65:476–483
Sun G-C, Chen X-L, Zhao Y, Wang F, Song Z-J, Wang Y-B, Wang D, Xu B-N (2011) Intraoperative MRI with integrated functional neuronavigation-guided resection of supratentorial cavernous malformations in eloquent brain areas. Journal of Clinical Neuroscience 18:1350–1354
Taslimi S, Modabbernia A, Amin-Hanjani S, Barker FG 2nd, Macdonald RL (2016) Natural history of cavernous malformation: Systematic review and meta-analysis of 25 studies. Neurology 86:1984–1991
Turner-Bowker D, Hogue SJ (2014) Short Form 12 Health Survey (SF-12). In: Encyclopedia of Quality of Life and Well-Being Research. pp 5954–5957
Van Gompel JJ, Marsh WR, Meyer FB, Worrell GA (2010) Patient-assessed satisfaction and outcome after microsurgical resection of cavernomas causing epilepsy. Neurosurg Focus 29:E16
Walczak T (1994) Surgical treatment of the epilepsies, ed 2. Edited by Jerome Engel, Jr, New York, Raven Press, 1993, 786 pp, illustrated, $135.00. Ann Neurol 35:252–252
Wirtz MA, Morfeld M, Glaesmer H, Brähler E (2018) Normierung des SF-12 Version 2.0 zur Messung der gesundheitsbezogenen Lebensqualität in einer deutschen bevölkerungsrepräsentativen Stichprobe. Diagnostica 64:215–226
Wostrack M, Shiban E, Harmening K, Obermueller T, Ringel F, Ryang Y-M, Meyer B, Stoffel M (2012) Surgical treatment of symptomatic cerebral cavernous malformations in eloquent brain regions. Acta Neurochir 154:1419–1430
Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G (1994) The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422–432
Zanello M, Meyer B, Still M, Goodden JR, Colle H, Schichor C, Bello L, Wager M, Smits A, Rydenhag B, Tate M, Metellus P, Hamer PDW, Spena G, Capelle L, Mandonnet E, Robles SG, Sarubbo S, Martino González J, Fontaine D, Reyns N, Krieg SM, Huberfeld G, Wostrack M, Colle D, Robert E, Noens B, Muller P, Yusupov N, Rossi M, Conti Nibali M, Papagno C, Visser V, Baaijen H, Galbarritu L, Chioffi F, Bucheli C, Roux A, Dezamis E, Duffau H, Pallud J (2019) Surgical resection of cavernous angioma located within eloquent brain areas: International survey of the practical management among 19 specialized centers. Seizure 69:31–40
Zanello M, Wager M, Corns R, Capelle L, Mandonnet E, Fontaine D, Reyns N, Dezamis E, Matsuda R, Bresson D, Duffau H, Pallud J (2017) Resection of cavernous angioma located in eloquent areas using functional cortical and subcortical mapping under awake conditions. Outcomes in a 50-case multicentre series. Neurochirurgie 63:219–22

Table 1. Modified Rankin Scale demonstrates the corresponding results from the study.

mRS ²²	at presentation: EG	NEG	late follow-up: EG	NEG
0	6	7	21	14
1	23	14	9	7
2	4	0	6	0
3	3	0	1	0
4	5	1	1	0
5	0	0	3	0
6	0	0	0	1+

EG = eloquent group; mRS = modified Rankin scale; NEG = non-eloquent group.

# some patients had a transient FND and they had mRS 0 at the presentation

+ died from another disease
22. New PW, Buchbinder R (2006) Critical appraisal and review of the Rankin scale and its derivatives. Neuroepidemiology 26:4–15

Table 2. Anatomical and functional location distribution of the surgically resected CM.

Anatomical location distribution		Functional location distribution
	No. of patients		No. of patients
supratentorial	47	Eloquent ²⁹	41
frontal	18	sensomotoric region	14
temporal	13	language	8
parietal	7	visual	5
parietooccipital	5	basal ganglia	2
occipital	2	cerebellum deep nuclei, and peduncles	4
basal ganglia	2	brainstem	8
cerebellar	8	Non-Eloquent	22
brainstem	8	frontal	7
midbrain	1	temporal	8
pons	4	parietal	3
ponto-medullary	1	cerbellar hemisphere	4
medualla oblongata	2	occipital	0*

Other: spinal cord n=3, orbital n=3, multiple n=8

*all occipital lesions were in the visual eloquence
29. Spetzler RF, Martin NA (1986) A proposed grading system for arteriovenous malformations. J Neurosurg 65:476–483

Table 3. Demographic and clinical characteristics of 69 patients with CM divided into two groups: eloquent group (EG) and non-eloquent group (NEG).

No. of patients

Study population 69

Eloquent group

Non-eloquent group

Significance

Mean Age at the operation in years

Female (%)

41.7 (SD 16.2)

(range, 16-78 years)

30 (43.5%)

42.4 (SD 16.6)

22 (53.7%)

40.0 (SD 16.2)

7 (31.8%)

Mean duration of presentation in months

40.2 (SD 80.9)

(range, 1 - 400)

48.4 (SD 94,5)

26.3 (SD 63.2)

Symptoms (%)

- FND

- seizure

- FND and Seizure

- Incidental

- Headache

-29 (42.0%)

-24 (34.9%)

-8 (11.6%)

-4 (5.8%)

-19 (46.3%)

-13 (31.2%)

-6 (14.6%)

-1 (2.4%)

-2 (4.9%)

-4 (18.1%)

-11 (50.0%)

-2 (9.1%)

-3 (13.6%)

-2 (9.1%)

Mean Follow up in years

6.5 (SD 4.6)

(range, 1-18)

5.8 (SD 4.0)

7.6 (SD 5.6)

Mean CM size in mm

18.1 (SD 10.4)

(range 4-56)

18.4 (SD 9.8)

16.1 (SD 9.0)

Mean operation time in minutes

223.0 (SD 100.0)

(range, 82-573)

240.2 (SD 100.1)

184.6 (SD 94.6)

P Value = 0.0362 †

Mean length of stay in days

9.9 (SD 4.3)

(range, 5-28)

10.2 (SD 4.9)

9.5 (SD 3.4)

Zabramski Class ³⁷

I/II/III/IV

Rate (%)

22/40/7/0

32/58/10/0

13/27/1/0

32/66/2

5/11/6/0

23/50/27/0

CM = cavernous malformation; FND = focal neurological deficit; NS = non-significant; SD = standard deviation.

Values represent numbers of cases (%) unless otherwise indicated. Mean values are presented with standard deviations. p values are for comparison of the difference between subgroups.
† T-test.

37. Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G (1994) The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422–432

Table 4. List of the postoperative complications.

FND -Paresis -Paresthesia -Dysphasia -Cognitive dysfunction -Ataxia -Diplopia -Visual field defect Postoperative bleeding#	No. 5 4 1 1 2 3 1 4	Comments: some patients had mixed FND
Medical problem Deep vein thrombosis Pulmonary embolism	1 1	PE occurred in a patient with brainstem cavernoma
Wound infection	1	1 reoperation
CSF Fistula	2	1 reoperation

# bleeding that slightly extended from the resection bed in the post-operative imaging

-CSF = cerebrospinal fluids; CRE = cavernoma related epilepsy; FND = focal neurological deficit; PE = pulmonary embolism.

Table 5. Results of SF-12 Questionnaire for Study Population, Subgroups and Healthy Population (Germany) ³⁵

Study n44*

Mean (SD)

German population

n 2524

Mean (SD)

Study vs norms

n 27

Mean (SD)

NEG

n 14

Mean (SD)

EG vs norms

NEG vs norm

EG vs NEG

42.73

(27.05)

59.79

(23.10)

P < 0.0001

T-Test

47.59

(26.36)

38.93

(27.89)

P=0.0064

T-Test

P=0.0007T-Test

85.80

(27.70)

86.76

(24.32)

85.19

(27.09)

82.14

(30.11)

75.85

(27.41)

83.61

(22.55)

P=0.0243

T-Test

73.61

(30.29)

76.79

(23.95)

P=0.0225

T-Test

85.80

(21.16)

85.66

(23.15)

87.96

(17.50)

78.57

(27.49)

63.64

(22.53)

70.40

(18.56)

P=0.0171

T-Test

63.89

(25.32)

60.71

(18.90)

85.23

(23.08)

87.83

(20.10)

86.11

(21.18)

82.14

(28.47)

77.27

(26.72)

87.51

(20.45)

P= 0.0011

T-Test

76.85

(27.89)

75.89

(27.50)

P=0.0073

T-Test

P=0.0344

T-Test

74.72

(16.06)

80.10

(22.73)

76.85

(17.92)

73.21

(11.87)

PCS

47.81

(6.00)

50.00

(10.12)

48.04

(5.97)

46.31

(5.97)

MCS

50.11

(9.12)

49.99

(10.08)

50.69

(9.61)

49.43

(9.12)

* n=44 divided in EG n= 27, NEG = 14, orbital n=2 and spinal cord n= 1

- BP = bodily pain; EG = Eloquent group; GH = general health perceptions; MCS = Mental Health Composite Scale; MH = mental health; NEG = non-eloquent group; NS = not significant; PCS = Physical Composite Scale; PF = physical functioning; RE = role emotional; RP = role physical; SF = social functioning; VT = vitality.

35. Wirtz MA, Morfeld M, Glaesmer H, Brähler E (2018) Normierung des SF-12 Version 2.0 zur Messung der gesundheitsbezogenen Lebensqualität in einer deutschen bevölkerungsrepräsentativen Stichprobe. Diagnostica 64:215–226

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Long-Term Outcome and Quality of Life After Cavernoma Resection: Eloquent vs. Non-Eloquent Areas.

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Abstract

Figures

Introduction

Methods

Participants and study design

Inclusion criteria and information gathered

Eloquence

Imaging protocols

Surgical strategy

Last Follow-up

Quality of life via Short Form 12 (SF12)

Statistical analysis

Results

Demographic data and clinical presentation

Genetic profiles

Imaging and surgical outcome

Complications and surgical morbidity

Rebleeding and reoperation

Epilepsy outcome and Antiepileptic drugs (AED)

Health-related quality of life (QoL)

Discussion

Neurosurgical outcome:

Return to work

Health-related quality of life

Strength and limitation of the study

Conclusion

Declarations

References

Tables

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