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Quality of life and mood assessment in conservatively treated cavernous malformation‐related epilepsy

  • University Medical Centre Essen

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Background To estimate the quality of life, anxiety, depression, and illness perception in patients with medically treated cerebral cavernous malformation (CCM) and associated epilepsy. Methods Nonsurgically treated patients with CCM‐related epilepsy (CRE) were included. Demographic, radiographic, and clinical features were assessed. All participants received established questionnaires (short‐form 36 health survey, SF‐36; hospital anxiety and depression score, HADS‐A/D; visual analogue scale score, VAS) assessing the functional and psychosocial burden of disease. To some extent, calculated values were compared with reference values from population‐based studies. Test results were related to seizure control. Results A total of 37 patients were included. Mean age was 45.8 ± 14.4 years, and 54.1% were female. Diagnosis of CRE was significantly associated with attenuated quality of life and increased level of anxiety, affecting physical and psychosocial dimensions. The assessment of illness perception identified considerable burden. HADS was significantly associated with VAS and SF‐36 component scores. Efficacy of antiepileptic medication had no restoring impact on quality of life, anxiety, depression, or illness perception. Conclusions CRE negatively influences quality of life and mood, independent of seizure control due to antiepileptic medication. Screening for functional and psychosocial deficits in clinical practice might be useful for assessing individual burden and allocating surgical or drug treatment.
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Received: 10 January 2022 Revised: 3 March 2022 Accepted: 4 April 2022
DOI: 10.1002/brb3.2595
Quality of life and mood assessment in conservatively treated
cavernous malformation-related epilepsy
Laurèl Rauschenbach1Pauline Bartsch1Alejandro N. Santos1
Annika Lenkeit1Marvin Darkwah Oppong1Karsten H. Wrede1
Ramazan Jabbarli1Witold X. Chmielewski1Börge Schmidt2Carlos M. Quesada3
Michael Forsting4Ulrich Sure1Philipp Dammann1
1Department of Neurosurgery and Spine
Surgery, University Hospital Essen, Essen,
2Institute for Medical Informatics, Biometry
and Epidemiology, University Hospital of
Essen, Essen, Germany
3Department of Neurology, Division of
Epilepsy, University Hospital Essen, Essen,
4Department of Diagnostic and Interventional
Radiology and Neuroradiology, University
Hospital Essen, Essen, Germany
Laurèl Rauschenbach, Department of
Neurosurgery and Spine Surgery, University
Hospital Essen, Hufelandstrasse 55, 45147
Essen, Germany.
This article was presented at the Annual
Meeting German Society of Neurosurgery
(DGNC) 2021.
Background: To estimate the quality of life, anxiety, depression, and illness perception
in patients with medically treated cerebral cavernous malformation (CCM) and associ-
ated epilepsy.
Methods: Nonsurgically treated patients with CCM-related epilepsy (CRE) were
included. Demographic, radiographic, and clinical features were assessed. All partici-
pants received established questionnaires (short-form 36 health survey, SF-36; hospi-
tal anxiety and depression score, HADS-A/D; visual analogue scale score, VAS) assess-
ing the functional and psychosocial burden of disease. To some extent, calculated val-
ues were compared with reference values from population-based studies. Test results
were related to seizure control.
Results: A total of 37 patients were included. Mean age was 45.8 ±14.4 years, and
54.1% were female. Diagnosis of CRE was significantly associated with attenuated
quality of life and increased level of anxiety, affecting physical and psychosocial dimen-
sions. The assessment of illness perception identified considerable burden. HADS was
significantly associated with VAS and SF-36 component scores. Efficacy of antiepilep-
tic medication had no restoring impact on quality of life, anxiety, depression, or illness
Conclusions: CRE negatively influences quality of life and mood, independent of
seizure control due to antiepileptic medication. Screening for functional and psychoso-
cial deficits in clinical practice might be useful for assessing individual burden and allo-
cating surgical or drug treatment.
anxiety, cerebral cavernous malformation, depression, epilepsy, quality of life
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.
Brain Behav. 2022;e2595. 1of9
Cerebral cavernous malformations (CCMs) are the second most com-
mon type of neurovascular malformation in the central nervous sys-
tem, representing between 10% and 15% of all vascular malformations
(Washington et al., 2010). Although there is low blood pressure and
slow blood flow within these lesions, CCMs carry considerable risk of
intracerebral hemorrhage (Taslimi et al., 2016). Irrespective of bleed-
ing occurrence, CCMs can implicate headaches, seizures, or focal neu-
rological deficits (Horne et al., 2016). CCM-related epilepsy (CRE) is
a common phenomenon in CCM, with an incidence of 30% (Al-Shahi
Salman et al., 2012; Dammann, Wrede, et al., 2017; Horne et al., 2016).
Even though the underlying mechanisms are poorly understood, few
studies identified associations between CRE and CCM multiplicity, cor-
tical involvement, or CCM-related hemosiderin deposition (Dammann,
Schaller, et al., 2017; He et al., 2017; Menzler et al., 2010; Moul-
trie et al., 2014). Notably, CCM treatment is still subject to debate.
Evidence-based treatment guidelines are scarce and decision-making
is often limited to clinical experience (Dammann et al., 2021; Rosenow
et al., 2013). Although lesion removal in CRE patients seems justi-
fied in selected cases, brain surgery remains a delicate procedure, and
noninvasive treatment approaches must be considered, particularly
in patients who have minor or no functional impairments (Dammann,
Wrede, et al., 2017).
Epileptic seizures can have a considerable impact on health-related
quality of life (HRQOL) (Mahrer-Imhof et al., 2013), and treatment
pathways should take into account not only neurological but also psy-
chosocial burden. While the vast majority of CCM studies focus on
different treatment strategies and risk factors leading to hemorrhage
(Al-Shahi Salman et al., 2016), literature reporting on HRQOL is rare
(Bicalho et al., 2017; Rinkel et al., 2019). Recently published data high-
light the impact of CCM disease on self-reported quality of life but
HRQOL and mood have never been studied exclusively in medically
treated CRE patients (Herten et al., 2021).
In this study, conservatively treated patients were screened for
disease-related functional and psychosocial burden. Moreover, the
results were compared to the average population and related to seizure
2.1 Study design
A prospective cross-sectional study was performed of all patients who
were admitted to our specialized outpatient clinic for CCM disease
between November 2017 and January 2020. During consultation, all
patients were given general information about diagnosis, treatment
strategies, and prognosis. Participants needed to fulfill the inclusion
criteria mentioned below. Informed consent was obtained from all
participants. The study was conducted in accordance with the princi-
ples expressed in the Declaration of Helsinki. A local ethics commit-
tee approved all procedures (Review Board Identification Number: 15-
6636-BO). The trial was performed in accordance with Strengthening
the Reporting of Observational Studies in Epidemiology protocol. Parts
of the data were published previously in a study, investigating HRQOL
in patients with untreated cavernous malformations of the central ner-
vous system (Herten et al., 2021).
2.2 Inclusion and exclusion criteria
We included patients aged between 18 and 80 years and diagnosed
with CRE according to the definition by Rosenow et al. (2013). CCM
diagnosis was based on magnetic resonance imaging (MRI) includ-
ing T1, T2, contrast-enhanced, and susceptibility-weighted or T2*-
weighted gradient echo imaging. Patients were treated conservatively.
Individuals who received invasive treatment and were hospitalized
within 3 months prior to study were excluded. Patients required suf-
ficient knowledge of the German language to cope with the testing.
2.3 Data collection
Clinical data and imaging data were assessed prospectively and in
accordance with CCM reporting standards (Al-Shahi Salman et al.,
2008). An experienced neuroradiologist evaluated imaging data. The
following clinical and radiological features were assessed: age, sex,
number of CCMs, lesion localization, occurrence of CCM-related hem-
orrhage (Taslimi et al., 2016), physical or psychiatric comorbidities,
epilepsy semiology, number of seizures, antiepileptic medication, time
between first and last CCM-related seizure, time between first CCM-
related seizure and neuropsychological testing, and time between last
CCM-related seizure and neuropsychological testing. The degree of
disability was determined using the modified Rankin Scale (mRS). Out-
come was considered favorable if the patient had a mRS less than or
equal to 2 and unfavorable if the mRS was greater than 2. HRQOL
was assessed in a standardized interview using the German version of
the 36-item short form health survey (SF-36). Depression and anxiety
were addressed using the hospital anxiety and depression rating scale
(HADS-A/D). Moreover, subjective perception of disease and burden of
CRE were evaluated using a visual analog scale (VAS). Testing was con-
ducted by one interviewer to avoid interobserver effects.
The SF-36 questionnaire addresses two main domains comprised
of 8 subdomains with 36 questions items: physical functioning (PF),
social functioning (SF), role limitations due to physical problems (RP),
role limitations due to emotional problems (RE, three items), men-
tal health (MH, 5 items), vitality (VT, four items), bodily pain (BP, two
items), and general health perceptions (GH, five items). Additionally,
we determined two overall component scores: physical health compo-
nent score (PCS) and mental health component score (MCS). For each
subdomain, an overall score was assessed (0 =worst subjective health
state; 100 =best subjective health state). The HADS-A/D scaleconsists
of a questionnaire containing 14 questions, with 7 referring to anxiety
and seven referring to depression. With the VAS score, the individual
patient burden was determined. This psychometric scale ranges from 1
(no burden) to 10 (maximum burden).
SF-36 and HADS-A/D scores were compared with data from Ger-
man reference population studies. For SF-36 testing, the reference
data were provided by the population-based Heinz Nixdorf Recall
Study and the associated MultiGeneration study (Schmermund et al.,
2002). Participants were randomly selected from three German cities
(i.e., Essen, Bochum, and Mülheim a.d. Ruhr). Individual matching (1:3)
was applied to ensure that CCM cases and population-based controls
had the same distribution over strata defined by age (5-year groups)
and sex. For HADS-A/D testing, reference values were derived from a
large population-based investigation (Hinz & Brähler, 2011).
2.4 Statistical analyses
Statistical analysis was performed using SPSS version 22 (IBM Corp.).
Data were tested for normal distribution by performing a Shapiro-
Wilk test. For interval-scaled data, mean values, and standard deviation
were calculated, while absolute numbers and valid percent were used
for nominal data. The unpaired t-test (normally distributed data) or the
Mann-Whitney U test (non-normally distributed data) were used to
compare continuous variables. Effect size was reported using Cohen’s
d, and values were categorized according to an established classifica-
tion system: small effect (>0.2), medium effect (>0.5), and large effect
(>0.8) (Rice & Harris, 2005). The degree of correlation was calculated
using the Spearman’s rank correlation test. For linear regression anal-
yses, R2values were determined. All tests were two tailed, and p-
values <.05 were defined as significant.
3.1 Patient demographics
A total of 37 patients were included in this study. Mean age was
45.8 ±14.4 years, and 20 participants (54.1%) were female. Six
patients (16.2%) exhibited multiple CCMs. Lesions were most com-
monly located in the temporal lobe. CCM-related hemorrhage was a
common phenomenon and affected 18 (48.6%) individuals. The major-
ity of patients (97.3%) were in good clinical condition (mRS2). Fif-
teen participants (40.4%) had diseases that were not related to CCM
disease, including 13 patients (35.1%) suffering from physical and two
patients (5.4%) from psychiatric comorbidities. Detailed information
on demographic, anatomic, and clinical data is provided in Table 1.
3.2 Cavernoma-related epilepsy
At the time of testing, all participants had experienced at least one
epileptic seizure. Most patients (64.9%) had a history of one single
seizure, but several individuals (35.1%) were admitted with a history
of recurrent seizures. In the majority of cases (75.7%), anticonvulsant
treatment was administered at the time of testing, mainly consisting
of one single drug. According to treatment guidelines, the most com-
TAB LE 1 Demographic, anatomic, and clinical characteristics
Characteristic Frequency
Total number of patients with CRE, n37
Age, years, mean ±SD 45.8 ±14.4
Sex, n(%)
Male 17 (45.9)
Female 20 (54.1)
CCM number, n(%)
Solitary (1 CCM) 31 (83.8)
Multiple (2 CCM) 6 (16.2)
CCM localization, n(%)
Frontal lobe 9 (24.3)
Parietal lobe 5 (13.5)
Temporal lobe 10 (27)
Occipital lobe 3 (8.1)
Multiple lobes 7 (18.9)
Subcortical 3 (8.1)
CCM-related hemorrhage, n(%) 18 (48.6)
mRS, n(%)
0 2 (5.4)
1 31 (83.8)
2 3 (8.1)
3 1 (2.7)
Comorbidities, n(%)
Physical comorbidities 13 (35.1)
Psychiatric comorbidities 2 (5.4)
CRE semiology, n(%)
Focal epilepsy 11 (29.7)
Generalized epilepsy 23 (62.2)
Absence epilepsy 3 (8.1)
No. of seizures, n(%)
1 CCM-related seizure 24(64.9)
2 CCM-related seizures 13 (35.1)
Antiepileptic treatment, n(%)
No treatment 9 (24.3)
Monotherapy (1 drug) 22 (59.3)
Combination therapy (2 drugs) 6 (16.2)
Antiepileptic medication, n(%)
Carbamazepine 1 (2.9)
Clonazepam 1 (2.9)
Lacosamide 1 (2.9)
Lamotrigine 5 (14.7)
Levetiracetam 19 (55.9)
Oxcarbazepine 1 (2.9)
Pregabalin 1 (2.9)
Valproate 3 (8.8)
Zonisamide 2 (5.9)
TAB LE 1 (Continued)
Characteristic Frequency
Time between first and last CCM-related
seizure, months, mean ±SD
33.2 ±88.7
Time between first CCM-related seizure and
survey,months, mean ±SD
60.1 ±101.5
Time between last CCM-related seizure and
survey,months, mean ±SD
28.9 ±59.6
Abbreviations: CCM: cerebral cavernous malformation; CRE: cavernoma-
related epilepsy; mRS: modified Rankin Scale; n: number; n/a:not applicable;
SD: standard deviation.
mon medication was levetiracetam (55.9%) and lamotrigen (14.7%).
Patients with multiple seizures featured a relatively low seizure fre-
quency. At admission, these patients had a history of 33.2 ±88.7
months between first and last seizure. In the total cohort, participants
were interviewed 60.1 ±101.5 months after their first seizure and 28.9
±59.6 months after their last seizure. Detailed information on clinical
data is provided in Table 1.
3.3 Health-related quality of life
HRQOL was assessed using the German version of the SF-36. The
results for CRE patients and for the age- and gender-matched German
reference population are presented in Figure 1. Compared to the ref-
erence population, CCM patients with CRE had decreased scores in all
domains and component scores. In 18 patients (48.6%), the PCS was
2 points lower than the mean score of the average population. Thirty-
three participants (89.2%) experienced a similar decrease in the MCS.
Notably, a two-point decrease is regarded as relevant (McHorney &
Ware, 1995; Ware et al., 1995). Statistical testing demonstrated signif-
icantly impaired scores in overall mental health score and in six addi-
tional subdomains (p<.001). Patients experienced limitations in usual
role activities due to physical impairment (RP, p=.0001), attenuated
general health (GH, p=.0001), decreased vitality (VT, p=.0001), limita-
tions in social activities because of physical or emotional problems (SF,
p=.0001), limitations in usual role activities due to emotional problems
(RE, p=.0001) and worsened mental health (MH, p=.0001). Detailed
analyses are provided in Table 2. Further investigation revealed dif-
ferences in physical health component scores of patients with single
(52.0 ±7.7) or multiple (39.9 ±13.8) CCM (p=.004), and differences
in mental health component scores of patients with (37.7 ±11.6) or
without (44.9 ±8.9) history of CCM-related hemorrhage (p=.039).
Notably, there were no differences in test performance between male
and female individuals.
3.4 Perception of illness, anxiety, and depression
Subjective perception of illness and burden of CRE were evaluated
using a visual analog scale (VAS). The mean VAS score was 5.4 ±
FIGURE 1 Short Form-36 (SF-36) domains including physical
health, mental health, and component scores. Physical functioning
(PF), social functioning (SF), role limitations due to physical problems
(RP), role limitations due to emotional problems (RE), mental health
(MH), vitality (VT), bodily pain (BP), and general health perceptions
(GH), physical health score (PCS), mental health score (MCS).
Asterisks indicate statistical significance compared to reference
population (unpaired-t-test)
2.3, indicating considerable symptom severity. Depression and anxiety
were determined using the hospital anxiety and depression rating scale
(HADS-A/D). In the CRE population, the mean HADS-A score was 7.9 ±
4.4 with 19 patients (51.4%) revealing a score more than or equal to 8,
indicating relevant levels of anxiety. Compared to the average German
population, values were considerably elevated (Hinz & Brähler, 2011).
In contrast to anxiety, depression was less common in CRE patients.
The mean HADS-D score was 5.6 ±4.2 with 10 patients (27%) scor-
ing 8 or more. These values were comparable to data derived from the
German reference population (Hinz & Brähler, 2011). Detailed analy-
ses are listed in Table 3. Notably, HADS-A, HADS-D, and VAS scores
demonstrated a high degree of concordance among each other, indi-
cating a correlation between the level of anxiety, depression, and per-
ception of illness. Moreover, HADS-A and HADS-D were significantly
associated with SF-36 component scores (p.003), except for HADS-
D and PCS. Detailed analyses are provided in Table S1. Subsequent
analyses demonstrated differences in HADS-D scores of patients with
TAB LE 2 HRQOL testing in CRE and healthy populations
SF-36 scale
CRE population,
mean ±SD
Reference population,
mean ±SD pa
Physical health subdomains
PF 86.2 ±19.6 91.6 ±13.5 .0638 0.40 +
RP 67.6 ±39.0 89.3 ±25.4 .0001 0.85 +++
BP 75.9 ±26.8 81.7 ±22.3 .1954 0.26 +
GH 58.1 ±21.8 72.5 ±15.5 .0001 2.62 +++
VT 53.0 ±20.4 67.1 ±17.2 .0001 0.82 +++
Mental health subdomains
SF 67.9 ±26.4 95.9 ±10.8 .0001 2.59 +++
RE 65.7 ±37.8 94.5 ±22.9 .0001 1.26 +++
MH 61.4 ±19.9 80.8 ±13.8 .0001 1.42 +++
Component scores
PCS 49.9 ±9.9 52.8 ±17.1 .3302 0.17 +
MCS 41.7 ±10.8 55.2 ±18.1 .0001 0.75 ++
Cohort matching
Age (y), mean ±SD 45.8 ±14.4 45.8 ±14.3 n/a n/a n/a
Sex, n(%)
Male 17 (45.9%) 51 (45.9%) n/a n/a n/a
Female 20 (54.1%) 60 (54.1%)
Note: Control-to-case ratio was 3:1. Significant p-values are in bold font.
Abbreviations: BP, bodily pain; CRE, cavernoma-related epilepsy; GH, general health perception; MCS, mental health score; MH, Mental health; n/a, data not
available; PCS, physical health score; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; VT, vitality.
aTwo-tailed Student’s t-test.
bInterpretation of d according to Cohen: 0.2– 0.5 small effect size (+), 0.5–0.8 medium effect size (++), >0.8 large effect size (+++).
TAB LE 3 Anxiety, depression, and subjective disease burden in CRE, CCM, and healthy populations
Tota l <88Total<88Total
Mean ±SD n(%) n(%) Mean ±SD n(%) n(%) Mean ±SD
CRE (n=37) 7.9 ±4.4 18 (48.6) 19 (51.4) 5.6 ±4.2 27 (73.0) 10 (27.0) 5.4 ±2.3
Male 4.4 ±3.3 1580 (81.9) 349 (18.1) 4.8 ±4.0 1468 (76.1) 461 (23.9) n/a
Female 5.0 ±3.6 1905 (76.8) 576 (23.2) 4.7 ±3.9 1898 (76.5) 583 (23.5) n/a
Abbreviations: CRE, cavernoma-related epilepsy; HADS, hospital anxiety and depression rating scale; n/a, not available; VAS, visual analogue scale.
aData on normative values of the German population according to Hinz & Brähler (2011).
(7.3 ±4.9) or without (4.3 ±3.2) history of CCM-related hemor-
rhage (p=.030). Again, there were no differences in test performance
between male and female individuals.
3.5 Seizure control and seizure frequency
In the majority of cases, anticonvulsant medication resulted in suf-
ficient seizure control, but some patients experienced pharmacore-
sistant epilepsy. We thus investigated the impact of seizure control
on HRQOL, anxiety, depression, and perception of illness. Compar-
ison between patients with good seizure control for more or less
than 6, 12, or 24 months demonstrated no significant differences
in SF-36 component scores (p>.05), HADS-A/D scores (p>.05),
or VAS scores (p>.05), indicating minor impact of seizure con-
trol on quality of life, mood, and illness perception. Detailed val-
ues are presented in Figure 2a. Comparable with seizure control,
frequency of experienced seizures had no influence on psychomet-
ric test results. Values for HRQOL, anxiety, depression, and percep-
tion of illness revealed no differences between patients who had
experienced one or multiple seizures. The results are provided in
Figure 2b.
FIGURE 2 Short Form-36 (SF-36) component score, hospital anxiety, and depression rating scale (HADS-A/D) score and visual analogue scale
(VAS) score assessment in patients with seizure control for (A1) 6, (A2) 12, or (A3) 24 or in patients with (B) seizure multiplicity. Unpaired t-test
was applied
Abbreviations: MCS, mental health score; ns, not significant; PCS, physical health score
3.6 Time since diagnosis
Due to the cross-sectional design of this study, patients were examined
at different time points. Accordingly, time between first seizure and
testing was referred to SF-36 component scores, HADS-A/D scores,
and VAS scores. Data were visualized in scattered plots, and linear
regression analyses revealed low R2values, indicating that none of the
variance in test results was explained by the time between first seizure
and testing. The results are illustrated in Figure 3.
In this cross-sectional study, we investigated the impact of medically
treated CRE on quality of life and mood in a subset of patients who
were not referred to surgery for various reasons. Patient-reported sur-
veys were used to assess data, and results were related to seizure
Although seizure diseases are one of the most common presenta-
tions in CCM patients (Rosenow et al., 2013), functional and psychoso-
cial burden is rarely discussed. Moreover, literature dealing with qual-
ity of life in CRE is exclusively limited to studies investigating the out-
come after CCM removal (Dammann, Wrede, et al., 2017; Ruan et al.,
2015; Van Gompel et al., 2010). Since treatment is often personal-
ized, particularly in the case of CRE, patients and surgeons often face
the difficult question of whether to opt for surgery or continue drug
treatment (Dammann et al., 2021). Recently published data have high-
lighted the value of open and minimally invasive surgery for epilepto-
genic CCM lesions, including pediatric and adult patients (Dammann,
Wrede, et al., 2017; Kapadia et al., 2021; Lee et al., 2017; Lin et al.,
2018; Ozlen et al., 2021; Satzer et al., 2020;Schussetal.,2020; Willie
et al., 2019). Nevertheless, although early CCM removal is often fea-
sible and effective, this topic is still a matter of debate, and high-
quality evidence-based recommendations are missing (Awad & Polster,
2019; Zanello et al., 2019). In this scenario, clinical decision-making
should not only rely on neurological assessment, due to the following
Recently, Herten et al. (2021) tested quality of life in noninvasively
treated patients and concluded that CCM strongly decreases HRQOL,
even in the absence of functional impairment or neurological symp-
toms. Moreover, while numerous authors have described the negative
impact of epileptic seizures on quality of life (Mahrer-Imhof et al., 2013;
Villanueva et al., 2013), the impact of CRE in CCM patients has yet not
been considered. To this end, we present a novel study investigating
quality of life, anxiety, depression, and illness perception in medically
treated CRE patients. In this trial, we were able to confirm the negative
impact of epileptic seizures on quality of life and mood, even though
the rating of burden showed pronounced interindividual differences.
FIGURE 3 Correlation between time since epilepsy onset and testing and Short Form-36 (SF-36) component scores, hospital anxiety, and
depression rating scale (HADS-A/D) scores or visual analogue scale (VAS) scores. Linear regression analyses were applied
Abbreviations: MCS, mental health score; PCS, physical health score
Furthermore, the calculated effect sizes ranged from small to large,
underlining the high degree of heterogeneity in patient burden. Inter-
estingly, neither the number of seizures experienced nor the length of
time with sufficient seizure control had an influence on the patient-
reported outcome. One might speculate that it is the diagnosis of
CRE, but not the extent of neurological impairment, which is the most
important contributing factor to the reduced quality of life and mood
observed in our study.
In light of the promising seizure outcome after surgery for CRE
(Dammann, Wrede, et al., 2017; Rosenow et al., 2013) and the increas-
ing HRQOL after CCM removal in general (Cornelius et al., 2016;
Dukatz et al., 2011), one might hypothesize that patients with strongly
decreased quality of life could be eligible for lesionectomy. Patient-
reported outcome parameters, for example, testing with SF-36 or
HADS-A/D, could be used as benchmarks to assess the individual
degree of functional and psychosocial deficits and to improve clinical
The shortcomings of this study are mainly related to the small sam-
ple size, the missing disease specificity of test instruments, and the
reporting on data of a previously published patient cohort. Since symp-
tomatic CCMs are often referred to surgery, the number of drug-
treated CRE patients remains low. However, compared to large stud-
ies on CCM, our cohort exhibits typical characteristics with similar
baseline data (Al-Shahi Salman et al., 2012; Horne et al., 2016). Thus,
patients included in this study can be regarded as a representative sam-
ple of CCM patients, increasing the external validity of our reported
results. Notably, SF-36, HADS-A/D, and VAS scores were not estab-
lished to assess burden in CCM or CRE patients, limiting the specificity
and sensitivity of testing. Nevertheless, disease-specific test instru-
ments are missing, and SF-36, HADS-A/D, and VAS are established, val-
idated, and convenient. These parameters might reflect disease bur-
den beyond neurological impairment or seizures, making them use-
ful for clinical application. Since parts of the data were published
previously in a trial investigating HRQOL in patients with untreated
cavernous malformations of the central nervous system, novelty of
data is limited.
Our report uncovers previously unrecognized functional and psy-
chosocial deficits in medically treated CRE patients and highlights the
clinical importance of psychometric testing. Seizure control had no
restoring effect on outcome, underlining the value of surgical CCM
removal irrespective of sufficient anticonvulsant treatment. A system-
atic analysis in a larger cohort is warranted.
The authors thank PD Dr. phil. Bernd-Otto Hütter for supporting neu-
ropsychological assessment.
The authors have declared that no competing interest.
Laurèl Rauschenbach: responsible for designing the study protocol,
summarized data, provided data, conducted data analysis, interpreted
results, created figures and tables, wrote the manuscript, and reviewed
the manuscript. Pauline Bartsch: summarized data, provided data, con-
ducted data analysis, created figures and tables, and reviewed the
manuscript. Alejandro N. Santos: summarized data, provided data, and
reviewed the manuscript. Annika Lenkeit: summarized data, provided
data, and reviewed the manuscript. Marvin Darkwah Oppong:sum-
marized data, provided data, interpreted results, and reviewed the
manuscript. Karsten H. Wrede: responsible for designing the study
protocol and reviewed the manuscript. Ramazan Jabbarli: responsible
for designing the study protocol and reviewed the manuscript. Witold
X. Chmielewski: responsible for designing the study protocol, con-
ducted data analysis, interpreted results, and reviewed the manuscript.
Börge Schmidt: responsible for designing the study protocol, con-
ducted data analysis, interpreted results, and reviewed the manuscript.
Carlos M. Quesada: interpreted results and reviewed the manuscript.
Michael Forsting: provided data, reviewed the manuscript. Ulrich
Sure: responsible for designing the study protocol, provided data,
interpreted results, and reviewed the manuscript. Philipp Dammann:
responsible for designing the study protocol, summarized data, pro-
vided data, interpreted results, wrote the manuscript and reviewed the
The authors of this study thank the anonymous reviewers for their
careful reading and improving this work. The peer review history for
this article is available at
The data that support the findings of this study are available in the sup-
plementary material of this article and from the corresponding author
upon reasonable request.
Laurèl Rauschenbach 8348-4298
Alejandro N. Santos
Marvin Darkwah Oppong 1021-5024
Karsten H. Wrede 3503
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Aim: To present one of the largest retrospective cavernoma related epilepsy (CRE) studies which include divergent supratentorial locations operated and followed up at least 2 years. We also investigated the factors affecting the seizure outcome. Material and methods: This study includes a total of 56 patients with drug-responsive (n=40) and drug-resistant (n=16) CRE who underwent resective surgery. Age at seizure onset, age at surgery, gender, duration of epilepsy, seizure frequencies/type before and after treatment, EEG and brain MRI findings, prescribed AEDs, preoperative and post-operative neurological status, histopathological diagnosis, post-operative seizure outcomes and surgical information were documented. Results: The average follow-up period was 69.6 months (range 24-216 months). The seizure outcome was assessed according to Engel?s classification at the last follow-up. Engel class I was achieved in 53 patients (95%); there was one patient at class II and two patients at class III. All patients in the drug-responsive group were at Engel class I after the surgery, while all patients at Engel classes II and III were in the drug-resistant patient group. This clearly shows that there were better outcomes in DRP group (p < 0.01). Neither the locations of cavernomas nor the duration of epilepsy had any impact on seizure outcome (p > 0.05). Conclusion: An earlier surgical intervention may prevent the patients from becoming drug-resistant such that their chances of being seizure free after surgery increase.
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Objective: To estimate health related quality of life (HRQOL) in patients with untreated cavernous malformation of the CNS (CCM). Methods: We performed a cross-sectional observational study on patients with CCM admitted to our department from 01.11.2017-10.01.2020 using standardized interviews (short-form -36 questionnaire, hospital anxiety and depression score (HADS-A/D), CCM-perception questionnaire). Including criteria was diagnosis of an untreated CCM and information about the diagnosis in a specialized CCM consultation. HRQOL data was analyzed and compared to German normal population. Uni- and multivariate analyses were carried out to identify variables with impact on outcome. Results: 219 (93%) of 229 eligible patients were included. Mean age was 46.3 ±14.7 (18-86) years, 136 (62%) were female. 98 (45%) patients presented with symptomatic hemorrhage and 17 (8%) with repetitive SH. 92 (42%) patients were asymptomatic. 37 (17%) suffered from cavernoma-related epilepsy. 28 patients (13%) suffered from familial CCM. Patients showed significantly decreased component scores and subdomain scores compared to normal population with effects ranging from small to large. This accounted largely also for asymptomatic patients (except for physical component score and main physical subdomains). Multivariate regression analysis confirmed impact of functional impairment on physical component score. HADS-A was significantly increased. HADS-A/D strongly correlated with mental component score and individual perception of the CCM. Interpretation: Patients with the diagnosis of a CCM showed decreased HRQOL compared to normal population even when not suffering functional impairment or neurological symptoms. Our data may function as benchmark in evaluation of different (future) management strategies.
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Introduction: We aimed to evaluate the preferred treatment strategy for patients with symptomatic cerebral cavernous malformations (CCM). Methods: In a decision model, we compared neurosurgical, radiosurgical, and conservative management. A literature review yielded the risks and outcomes of interventions, intracerebral hemorrhage (ICH), and seizures. Patients with CCM rated their quality of life to determine utilities. We estimated the expected number of quality-adjusted life years (QALYs) and the ICH recurrence risk over five years, according to mode of presentation and CCM location (brainstem vs. other). We performed analyses with a time horizon of five years. Results: Using the best available data, the expected number of QALYs for brainstem CCM presenting with ICH or focal neurological deficit was 2.84 (95% confidence interval [CI]: 2.54-3.08) for conservative, 3.01 (95% CI: 2.86-3.16) for neurosurgical, and 3.03 (95% CI: 2.88-3.18) for radiosurgical intervention; those for non-brainstem CCM presenting with ICH or focal neurological deficit were 3.08 (95% CI: 2.85-3.31) for conservative, 3.21 (95% CI: 3.01-3.36) for neurosurgical, and 3.19 (95% CI: 2.98-3.37) for radiosurgical intervention. For CCM presenting with epilepsy, QALYs were 3.09 (95% CI: 3.03-3.16) for conservative, 3.33 (95% CI: 3.31-3.34) for neurosurgical, and 3.27 (95% CI: 3.24-3.30) for radiosurgical intervention. Discussion and conclusion: For the initial five years after presentation, our study provides Class III evidence that for CCM presenting with ICH or focal neurological deficit conservative management is the first option, and for CCM presenting with epilepsy CCM intervention should be considered. More comparative studies with long-term follow-up are needed.
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Purpose: The practical management of cavernous angioma located within eloquent brain area before, during and after surgical resection is poorly documented. We assessed the practical pre-operative, intra-operative, and post-operative management of cavernous angioma located within eloquent brain area. Method: An online survey composed of 61 items was sent to 26 centers to establish a multicenter international retrospective cohort of adult patients who underwent a surgical resection as the first-line treatment of a supratentorial cavernous angioma located within or close to eloquent brain area. Results: 272 patients from 19 centers (mean 13.6 ± 16.7 per center) from eight countries were included. The pre-operative management varied significantly between centers and countries regarding the pre-operative functional assessment, the pre-operative epileptological assessment, the first given antiepileptic drug, and the time to surgery. The intra-operative environment varied significantly between centers and countries regarding the use of imaging systems, the use of functional mapping with direct electrostimulations, the extent of resection of the hemosiderin rim, the realization of a post-operative functional assessment, and the time to post-operative functional assessment. The present survey found a post-operative improvement, as compared to pre-operative evaluations, of the functional status, the ability to work, and the seizure control. Conclusions: We observed a variety of practice between centers and countries regarding the management of cavernous angioma located within eloquent regions. Multicentric prospective studies are required to solve relevant questions regarding the management of cavernous angioma-related seizures, the timing of surgery, and the optimal extent of hemosiderin rim resection.
OBJECTIVE Indication for surgery in brainstem cavernous malformations (BSCMs) is based on many case series, few comparative studies, and no randomized controlled trials. The objective of this study was to seek consensus about surgical management aspects of BSCM. METHODS A total of 29 experts were invited to participate in a multistep Delphi consensus process on the surgical treatment of BSCM. RESULTS Twenty-two (76%) of 29 experts participated in the consensus. Qualitative analysis (content analysis) of an initial open-ended question survey resulted in 99 statements regarding surgical treatment of BSCM. By using a multistep survey with 100% participation in each round, consensus was reached on 52 (53%) of 99 statements. These were grouped into 4 categories: 1) definitions and reporting standards (7/14, 50%); 2) general and patient-related aspects (11/16, 69%); 3) anatomical-, timing of surgery–, and BSCM-related aspects (22/37, 59%); and 4) clinical situation–based decision-making (12/32, 38%). Among other things, a consensus was reached for surgical timing, handling of associated developmental venous anomalies, handling of postoperative BSCM remnants, assessment of specific anatomical BSCM localizations, and treatment decisions in typical clinical BSCM scenarios. CONCLUSIONS A summary of typical clinical scenarios and a catalog of various BSCM- and patient-related aspects that influence the surgical treatment decision have been defined, rated, and interpreted.
Objective To describe seizure outcome and complications in patients with cavernous malformations (CM) undergoing early versus late surgery. Methods A database was created for all CM patients who presented with seizure referred to the neurosurgical clinic at an academic center. A telephone survey and chart review were conducted to evaluate for preoperative and postoperative seizure frequency. Postoperative seizure-free outcome of patients who had ≤2 preoperative seizures versus those that had >2 preoperative seizures was compared. Results A total of 35 CM patients were included for analysis. Nineteen patients had ≤2 preoperative seizures and 16 patients had >2 preoperative seizures, six of them drug resistant for over two years. Among the ≤2 seizure group, 15 had only a single seizure before surgical resection. 94.7% of patients with ≤2 preoperative seizures and 62.5% of patients with >2 preoperative seizures were seizure free one year following surgical resection (p = 0.019). 78.9% of patients with ≤2 preoperative seizures and 25% of patients with >2 preoperative seizures were able to wean off AEDs (p < 0.001). Among those patients who had a single preoperative seizure, 100% of patients were seizure free at one year. Conclusions Early surgical resection for CM patients who present after a CM-related seizure is an effective, well tolerated treatment and has good chance to offer seizure freedom without the need for long-term antiepileptic medications. Outcome for patients operated with only one or two preoperative seizures may lead to better results than patients who delay the procedure.
Objective: The authors sought to perform a preliminary assessment of the safety and effectiveness of stereotactic laser interstitial thermal therapy (LITT) for patients with cerebral cavernous malformation (CCM)-related epilepsy. Methods: The authors retrospectively analyzed 6 patients with CCM-related epilepsy who underwent LITT. Pre-, intra-, and postoperative brain MRI studies were used to characterize preoperative CCM volume, ablation volume, and postablation hemosiderin volume. Clinical outcomes were assessed postoperatively during clinic follow-up visits or phone interviews. Results: LITT was performed in 7 CCMs in 6 patients. Two patients had familial CCM disease with multifocal lesions. Four treated CCMs were extratemporal, and 3 were in or near the visual pathways. The median follow-up was 25 (range 12-39) months. Five of 6 (83%) patients achieved seizure freedom (Engel I classification), of whom 4 (67%) were Engel IA and 1 was Engel IC after a single seizure on postoperative day 4. The remaining patient had rare seizures (Engel II). One patient had a nondisabling visual field deficit. There were no hemorrhagic complications. All patients were discharged within 24 hours postablation. MRI 3-11 months after ablation demonstrated expected focal necrosis and trace hemosiderin-related T2 hypointensity measuring 9%-44% (median 24%) of the original lesion volume, with significant (p = 0.04) volume reduction. Conclusions: LITT is a minimally invasive option for treating CCM-related epilepsy with seizure outcomes comparable to those achieved with open lesionectomy. The precision of LITT allows for the obliteration of eloquent, deep, small, and multifocal lesions with low complication rates, minimal postoperative discomfort, and short hospital stays. In this study the feasibility and benefits of this method were demonstrated in 2 patients with multifocal lesions.
Objective: Cavernoma-related epilepsy (CRE) is a frequent symptom in patients with cerebral cavernous malformations (CCMs). Reports on surgical management and seizure outcome of epileptogenic CCM often focus on intracranial cavernoma in general. Therefore, data on CCMs within the temporal lobe are scarce. The authors therefore analyzed their institutional data. Methods: From 2003 to 2018, 52 patients suffering from CCMs located within the temporal lobe underwent surgery for CRE at University Hospital Bonn. Information on patient characteristics, preoperative seizure history, preoperative evaluation, surgical strategies, postoperative complications, and seizure outcome was assessed and further analyzed. Seizure outcome was assessed 12 months after surgery according to the International League Against Epilepsy (ILAE) classification and stratified into favorable (ILAE class I) versus unfavorable (ILAE classes II-VI). Results: Overall, 47 (90%) of 52 patients with CCMs located in the temporal lobe and CRE achieved favorable seizure outcome. Pure lesionectomy was performed in 5 patients, extended lesionectomy with resection of the hemosiderin rim in 38 patients, and anterior temporal lobectomy in 9 patients with temporal lobe CCM. Specifically, 36 patients (69%) suffered from drug-resistant epilepsy (DRE), 3 patients (6%) from chronic CRE, and 13 patients (25%) sustained sporadic CRE. In patients with DRE, favorable seizure outcome was achieved in 32 (89%) of 36 patients. Patients with DRE were significantly older than patients with CCM-associated chronic or sporadic seizures (p = 0.02). Furthermore, patients with DRE more often underwent additional amygdalohippocampectomy following the recommendation of presurgical epileptological evaluation. Conclusions: Favorable seizure outcome is achievable in a substantial number of patients with epileptogenic CCM located in the temporal lobe, even if patients suffered from drug-resistant CRE. For adequate counseling and monitoring, patients with CRE should undergo a thorough pre- and postsurgical evaluation in dedicated epilepsy surgery programs.
Cavernous angioma (CA) is also known as cavernoma, cavernous hemangioma, and cerebral cavernous malformation (CCM) (National Library of Medicine Medical Subject heading unique ID D006392). In its sporadic form, CA occurs as a solitary hemorrhagic vascular lesion or as clustered lesions associated with a developmental venous anomaly. In its autosomal dominant familial form (Online Mendelian Inheritance in Man #116860), CA is caused by a heterozygous germline loss-of-function mutation in one of three genes— CCM1 / KRIT1, CCM2 / Malcavernin , and CCM3 / PDCD10 —causing multifocal lesions throughout the brain and spinal cord. In this paper, the authors review the cardinal features of CA’s disease pathology and clinical radiological features. They summarize key aspects of CA’s natural history and broad elements of evidence-based management guidelines, including surgery. The authors also discuss evidence of similar genetic defects in sporadic and familial lesions, consequences of CCM gene loss in different tissues at various stages of development, and implications regarding the pathobiology of CAs. The concept of CA with symptomatic hemorrhage (CASH) is presented as well as its relevance to clinical care and research in the field. Pathobiological mechanisms related to CA include inflammation and immune-mediated processes, angiogenesis and vascular permeability, microbiome driven factors, and lesional anticoagulant domains. These mechanisms have motivated the development of imaging and plasma biomarkers of relevant disease behavior and promising therapeutic targets. The spectrum of discoveries about CA and their implications endorse CA as a paradigm for deconstructing a neurosurgical disease.
Objective Magnetic resonance (MR) thermography–guided laser interstitial thermal therapy, or stereotactic laser ablation (SLA), is a minimally invasive alternative to open surgery for focal epilepsy caused by cerebral cavernous malformations (CCMs). We examined the safety and effectiveness of SLA of epileptogenic CCMs. Methods We retrospectively analyzed 19 consecutive patients who presented with focal seizures associated with a CCM. Each patient underwent SLA of the CCM and adjacent cortex followed by standard clinical and imaging follow‐up. Results All but one patient had chronic medically refractory epilepsy (median duration 8 years, range 0.5‐52 years). Lesions were located in the temporal (13), frontal (five), and parietal (one) lobes. CCMs induced magnetic susceptibility artifacts during thermometry, but perilesional cortex was easily visualized. Fourteen of 17 patients (82%) with >12 months of follow‐up achieved Engel class I outcomes, of which 10 (59%) were Engel class IA. Two patients who were not seizure‐free from SLA alone became so following intracranial electrode‐guided open resection. Delayed postsurgical imaging validated CCM involution (median 83% volume reduction) and ablation of surrounding cortex. Histopathologic examination of one previously ablated CCM following open surgery confirmed obliteration. SLA caused no detectable hemorrhages. Two symptomatic neurologic deficits (visual and motor) were predictable, and neither was permanently disabling. Significance In a consecutive retrospective series, MR thermography–guided SLA was an effective alternative to open surgery for epileptogenic CCM. The approach was free of hemorrhagic complications, and clinically significant neurologic deficits were predictable. SLA presents no barrier to subsequent open surgery when needed.