SUPPLEMENTARY FILES
1. Search strategies
2. Signaling questions (according to QUADAS-2)
3. PRISMA checklist
4. Protocol (January 30, 2014)
1. SEARCH STRATEGIES
Pubmed:
(subarachnoid hemorrhage) AND ((EEG OR "continuous EEG" OR "cEEG" OR
"quantitative EEG" OR "QEEG" OR "ICU EEG monitoring" OR "neurotelemetry")
AND ("1980/01/01"[PDat] : "2015/12/31"[PDat])) NOT (((((subarachnoid hemorrhage)
AND ((EEG OR "continuous EEG" OR "cEEG" OR "quantitative EEG" OR "QEEG"
OR "ICU EEG monitoring" OR "neurotelemetry") AND ("1980/01/01"[PDat] :
"2015/12/31"[PDat]))) AND ((infant[MeSH] OR child[MeSH] OR
adolescent[MeSH])))) NOT (((subarachnoid hemorrhage) AND ((EEG OR "continuous
EEG" OR "cEEG" OR "quantitative EEG" OR "QEEG" OR "ICU EEG monitoring" OR
"neurotelemetry") AND ("1980/01/01"[PDat] : "2015/12/31"[PDat]))) AND
adult[MeSH]))
(subarachnoid bleeding) AND ((EEG OR "continuous EEG" OR "cEEG" OR
"quantitative EEG" OR "QEEG" OR "ICU EEG monitoring" OR "neurotelemetry")
AND ("1980/01/01"[PDat] : "2015/12/31"[PDat])) NOT (((((subarachnoid hemorrhage)
AND ((EEG OR "continuous EEG" OR "cEEG" OR "quantitative EEG" OR "QEEG"
OR "ICU EEG monitoring" OR "neurotelemetry") AND ("1980/01/01"[PDat] :
"2015/12/31"[PDat]))) AND ((infant[MeSH] OR child[MeSH] OR
adolescent[MeSH])))) NOT (((subarachnoid hemorrhage) AND ((EEG OR "continuous
EEG" OR "cEEG" OR "quantitative EEG" OR "QEEG" OR "ICU EEG monitoring" OR
"neurotelemetry") AND ("1980/01/01"[PDat] : "2015/12/31"[PDat]))) AND
adult[MeSH]))
EMBASE:
(subarachnoid haemorrhage or subarachnoid hemorrhage or subarachnoid bleeding)
AND (exp electroencephalogram/ or exp electroencephalography/ OR EEG or
"continuous EEG" or "cEEG" or "quantitative EEG" or "QEEG" or "ICU EEG
monitoring" or "neurotelemetry")
Scopus:
(TITLE-ABS-KEY((subarachnoid haemorrhage OR subarachnoid hemorrhage OR
subarachnoidbleeding)) AND TITLE-ABS-KEY((electroencephalogram OR
electroencephalography OR eeg OR"continuous EEG" OR "cEEG" OR
"quantitative EEG" OR "QEEG" OR "ICU EEG monitoring"
OR"neurotelemetry"))), hvilket gav 50 referencer, hvoraf de 33 var fra 1980 eller
nyere.
Cochrane:
(subarachnoid haemorrhage OR subarachnoid hemorrhage OR subarachnoid
bleeding) AND (electroencephalogram or electroencephalography or EEG or
"continuous EEG" or "cEEG" or "quantitative EEG" or "QEEG" or "ICU EEG
monitoring" or "neurotelemetry")
Clinicaltrials.gov:
subarachnoid hemorrhage AND (electroencephalogram or electroencephalography
or EEG or "cEEG" or "QEEG")
2.
SIGNALING QUESTIONS
DOMAIN 1: PATIENT SELECTION
A Risk of Bias (LOW/HIGH/UNCLEAR):
1) Was a consecutive sample of patients enrolled?
YES/NO/UNCLEAR
2) Did the study avoid inappropriate exclusions?
YES/NO/UNCLEAR
3) Was the study prospective?
YES/NO/UNCLEAR
4) Was the study a multicenter trial?
YES/NO/UNCLEAR
B Concerns regarding applicability (LOW/HIGH/UNCLEAR):
Is there concern that the included patients do not match the review question; thus, is
there concern that the included patients were not patients with an acute subarachnoid
hemorrhage admitted to an ICU and monitored using cEEG (as outlined in the protocol
3.1.2)?
DOMAIN 2: INDEX TEST
A Risk of Bias:
1) Were the results of the index test (cEEG) interpreted without knowledge of the
reference standard (seizures: spot EEG, clinical evaluation; DCI: TCD/TCCD, CT/MR
angiography and perfusion, catheter-based angiography)?
2) Did the authors use state-of-the-art cEEG equipment and were all technical details
stated?
3) Were EEG correlates of seizures and DCI clearly defined?
B Concerns regarding applicability:
Is there concern that the index test (cEEG), its conduct or interpretation differ from the
review question?
DOMAIN 3: REFERENCE STANDARD
A Risk of Bias:
1) Was the type of reference standard (seizures: spot EEG, clinical evaluation; DCI:
TCD/TCCD, CT/MR angiography and perfusion, catheter-based angiography) clearly
specified and according to state-of-the-art clinical practice?
2) Were the results of the reference standard interpreted without knowledge of the
index test (cEEG)?
B Concerns regarding applicability
Is there concern that the target condition as defined by the reference standard dos not
match the review question?
DOMAIN 4: FLOW AND TIMING
Risk of Bias:
1) Was there an appropriate interval betjene the index test and the reference standard?
2) Did all patients receive a reference standard?
3) Did the patients receive the same reference standard?
4) Were all patients monitored by cEEG included in the analysis?
3.
PRISMA CHECKLIST
# Checklist item
Reported on
page #
1
Identify the report as a systematic review, meta-analysis, or
both.
2, 5
2
Provide a structured summary including, as applicable:
background; objectives; data sources; study eligibility criteria,
participants, and interventions; study appraisal and synthesis
methods; results; limitations; conclusions and implications of
key findings; systematic review registration number.
2
Rationale
3
Describe the rationale for the review in the context of what is
already known.
2,3
Objectives
4
Provide an explicit statement of questions being addressed
with reference to participants, interventions, comparisons,
outcomes, and study design (PICOS).
4
Protocol and
registration
5
Indicate if a review protocol exists, if and where it can be
accessed (e.g., Web address), and, if available, provide
registration information including registration number.
5,
supplemental
files
Eligibility criteria
6
Specify study characteristics (e.g., PICOS, length of follow-up)
and report characteristics (e.g., years considered, language,
publication status) used as criteria for eligibility, giving
rationale.
5-7
Information
sources
7
Describe all information sources (e.g., databases with dates of
coverage, contact with study authors to identify additional
studies) in the search and date last searched.
5-7
Search
8
Present full electronic search strategy for at least one
database, including any limits used, such that it could be
repeated.
5-7
Study selection
9
State the process for selecting studies (i.e., screening,
eligibility, included in systematic review, and, if applicable,
included in the meta-analysis).
5-7
Data collection
process
10
Describe method of data extraction from reports (e.g., piloted
forms, independently, in duplicate) and any processes for
obtaining and confirming data from investigators.
5-7
Data items
11
List and define all variables for which data were sought (e.g.,
PICOS, funding sources) and any assumptions and
simplifications made.
5-7
Risk of bias in
individual
studies
12
Describe methods used for assessing risk of bias of individual
studies (including specification of whether this was done at the
study or outcome level), and how this information is to be used
in any data synthesis.
5-7
Summary
measures
13
State the principal summary measures (e.g., risk ratio,
difference in means).
5-7
Synthesis of
results
14
Describe the methods of handling data and combining results
of studies, if done, including measures of consistency (e.g., I2)
for each meta-analysis.
Section/topic
TITLE
Title
ABSTRACT
Structured
summary
INTRODUCTION
METHODS
Page 1 of 2
Section/topic
# Checklist item
Reported
on page
#
Risk of bias
across studies
15
Specify any assessment of risk of bias that may affect the
cumulative evidence (e.g., publication bias, selective reporting
within studies).
5-7
Additional
analyses
16
Describe methods of additional analyses (e.g., sensitivity or
subgroup analyses, meta-regression), if done, indicating which
were pre-specified.
5-7
Study selection
17
Give numbers of studies screened, assessed for eligibility, and
included in the review, with reasons for exclusions at each stage,
ideally with a flow diagram.
7-10
Study
characteristics
18
For each study, present characteristics for which data were
extracted (e.g., study size, PICOS, follow-up period) and provide
the citations.
7-10
Risk of bias
within studies
19
Present data on risk of bias of each study and, if available, any
outcome level assessment (see item 12).
7-10
Results of
individual
studies
20
For all outcomes considered (benefits or harms), present, for
each study: (a) simple summary data for each intervention group
(b) effect estimates and confidence intervals, ideally with a forest
plot.
7-10
Synthesis of
results
21
Present results of each meta-analysis done, including confidence
intervals and measures of consistency.
7-10
Risk of bias
across studies
22
Present results of any assessment of risk of bias across studies
(see Item 15).
7-10
Additional
analysis
23
Give results of additional analyses, if done (e.g., sensitivity or
subgroup analyses, meta-regression [see Item 16]).
7-10
Summary of
evidence
24
Summarize the main findings including the strength of evidence
for each main outcome; consider their relevance to key groups
(e.g., healthcare providers, users, and policy makers).
10-13
Limitations
25
Discuss limitations at study and outcome level (e.g., risk of bias),
and at review-level (e.g., incomplete retrieval of identified
research, reporting bias).
10-13
Conclusions
26
Provide a general interpretation of the results in the context of
other evidence, and implications for future research.
10-13
27
Describe sources of funding for the systematic review and other
support (e.g., supply of data); role of funders for the systematic
review.
13
RESULTS
DISCUSSION
FUNDING
Funding
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic
Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
For more information, visit: www.prisma-statement.org.
Continuous EEG monitoring for non-convulsive seizures and delayed
cerebral ischemia in subarachnoid hemorrhage - a systematic review
and meta-analysis
(Protocol from January 30, 2014)
Daniel Kondziella,1,3,4 Christian Friberg,2 Ian Wellwood,4 Clemens Reiffurth,4,5 Martin
Fabricius,2 Jens P. Dreier 4,5,6
Departments of Neurology1 and Clinical Neurophysiology,2 Rigshospitalet,
Copenhagen University Hospital, Copenhagen, Denmark
Institute of Neuroscience,3 Norwegian University of Science and Technology,
Trondheim, Norway
Center for Stroke Research Berlin,4 and Departments of Neurology5 and Experimental
Neurology,6 Charité - Universitätsmedizin Berlin, Berlin, Germany
Corresponding author:
Daniel Kondziella, MD, PhD, FEBN
Department of Neurology
Rigshospitalet, Copenhagen University Hospital
DK-2100 Copenhagen
daniel_kondziella@yahoo.com
0045-3545 6368
1. B A C K G R O U N D
Aneurysmal subarachnoid hemorrhage (SAH) results in 27% of stroke-related years of
life lost before age 65, a burden of premature mortality comparable with ischemic stroke
(Johnston et al. 1998). Once a ruptured aneurysm has been secured, delayed cerebral
ischemia (DCI) and epileptic seizures put the patient at risk. DCI can be defined as a
new focal or global neurological deficit and/or a new cerebral infarction revealed by
neuroimaging after other causes than intracranial vasospasm have been excluded
(Schmidt et al. 2008). Vasospasms affect 70% of patients who survive the initial SAH,
and DCI occurs in 20-25% (Frontera et al. 2006). Of note, approximately 20% of DCI
episodes consist of cerebral infarction in the absence of obvious clinical symptoms
(Schmidt et al. 2008). DCI may also occur without radiological evidence of intracranial
vasospasm (Dreier et al. 2009; Woitzik et al. 2012). Epileptic seizures, including nonconvulsive seizures and non-convulsive status epilepticus (NCSE), are equally
important complications. NCSE may be present in 8% to 31% of SAH patients with
coma or unexplained neurological deterioration (Dennis et al. 2002). Although it
remains unclear whether non-convulsive seizures contribute to neuronal damage or are
merely an indicator of underlying brain injury, NCSE is associated with high mortality
and morbidity (Dennis et al. 2002; Claassen et al. 2004).
At present, detection of vasospasms and DCI relies on clinical neurological evaluation
as well as serial transcranial Doppler (TCD) or color-coded duplex (TCCD)
measurements (Lindegaard et al. 1988). CT or MRI perfusion and angiography studies
can confirm vasospasms but catheter-based angiography remains the gold standard.
However, clinical evaluation in sedated or comatose patients can be unreliable; TCD is
user-dependant; CT- or MR-based neuroimaging of intubated patients is a logistic
challenge; and catheter-based angiography is an invasive procedure. Yet the most
significant disadvantage of all these techniques is that they can only be performed on an
intermittent basis and therefore, real-time detection of compromised cerebral blood flow
is not possible. Consequently, spasmolytic treatment may come too late to prevent
ischemic infarction. Furthermore, the true frequency of non-convulsive seizures and
NCSE following SAH is unknown because clinical evaluation again may be unreliable
and because standard (30 minutes) electroencephalography (EEG) only identifies about
one-third of non-convulsive seizures in intensive care patients with seizures of any
cause (Claassen and Hirsch, 2009).
EEG is the only routine method that offers real-time registration of neuronal activity.
Recent technical advances have made continuous EEG (cEEG) monitoring in the
intensive care unit feasible. Quantitative EEG (qEEG) software programs allow the
condensation of many hours of raw EEG data into a few screen shots which can be
assessed instantly and thus, real-time detection of adverse events seems possible.
Therefore, cEEG is increasingly used in neurocritical care units to monitor patients with
SAH for non-convulsive seizures and NCSE, as well as DCI and vasospasms. However,
rhythmical and periodic patterns of uncertain significance are frequently encountered
during cEEG monitoring, and it is unknown if and how rigorously they should be
treated (Chong and Hirsch, 2005). For instance, treating EEG changes on the ictalinterictal spectrum too aggressively may induce serious adverse effects such as arterial
hyortension and prolonged need for ventilator support. It therefore remains unclear
whether intensified monitoring by cEEG, an expensive and labor-intensive diagnostic
tool, translates into better clinical outcome or if it may indeed lead to overtreatment and
potentially harms the patient.
The Neurointensive Care Section of the European Society of Intensive Care Medicine
recently recommended EEG to rule out non-convulsive seizures in all SAH patients
with unexplained and persistent altered consciousness and to detect DCI in comatose
SAH patients, in whom neurological examination is unreliable (Claassen et al. 2013).
These recommendations were based on a review of English language manuscripts in the
PubMed database of the use of EEG (standard or cEEG) in critically ill patients with
various diagnoses. Yet, a SAH specific, more comprehensive review of cEEG likely
would allow more specific questions to be addressed. Therefore the aim of this
systematic review and meta-analysis (including non-English literature, ongoing studies
from registers of trials, and congress abstracts, as well as consulting several databases)
is to assess:
1) The utility and sensitivity of cEEG as a confirmatory test to detect non-convulsive
seizures and DCI;
2) Whether EEG patterns suggestive of seizures or DCI predict clinical outcome, and;
3) Whether intensified neuromonitoring using cEEG translates into better clinical
outcome of patients with aneurysmal SAH.
1.1. Target condition being diagnosed
The target condition is non-traumatic aneurysmal SAH and associated epileptic
seizures, including non-convulsive seizures and NCSE, and/or vasospasms with or
without DCI. The estimated frequencies of epileptic seizures and DCI have been stated
above. Although both NCSE and DCI are associated with increased mortality and
morbidity following SAH, it remains unknown whether non-convulsive seizures
directly cause neuronal injury or merely represent an epiphenomenon. Similarly, it is
unknown whether rigorous antiepileptic drug treatment improves outcome or whether it
may be detrimental due to systemic side effects including arterial hypotension, organ
toxicity and prolonged stay in the intensive care unit. As to DCI, its early recognition
may allow for spasmolytic therapy, both systemic (nimodipine, hypervolemic-
hypertensive-hemodilution) and intra-arterial (papaverine, verapamil, nicardipine;
angioplasty). Other complications following SAH such as hydrocephalus and rebleeding will not be covered in this review.
1.2. Index test
The index test that will be evaluated is cEEG which comprises both prolonged
measurement of raw EEG data and qEEG. EEG monitoring can be performed using a
standard EEG montage (21 elec-trodes) or a reduced amount of EEG channels. Many
different qEEG methods are available and are typically used in combination; these
include amplitude-based qEEG (amplitude integrated qEEG, envelope trends),
frequency-based qEEG (spectral arrays, spectrograms), qEEG based on rhythmicity, and
asymmetry-based qEEG. Invasive prolonged monitoring using electrocorticography
may be used in patients with acute SAH as well; however, electrocorticography will not
be reviewed here because of the considerable methodological differences to cEEG.
1.3. Clinical pathway
Following an aneurysmal SAH, prevention of re-bleeding is of utmost importance,
which is why the aneurysm typically will be treated by an endovascular procedure (e.g.,
coiling or stenting using a flow diverter device) or neurosurgery (placement of a clip).
Observation for a prolonged period in the neurocritical care unit is necessary in order to
prevent and/or detect and treat secondary brain damage due to hydrocephalus, epileptic
seizures, ischemia and systemic complications. Standard monitoring for DCI includes
regular clinical evaluation and intermittent assessment of blood flow using TCD/TCCD,
which, however, is rarely performed more than once or a few times per day.
Vasospasms can be confirmed using CT- or MR-based perfusion or angiography
studies, although catheter-based angiography has the highest sensitivity and specificity
and is needed to provide intra-arterial spasmolytics. The burden of infarction can be
assessed using CT and MRI. Standard monitoring for epileptic seicures, including nonconvulsive seizures and NCSE, comprises regular neurological examination and routine
EEG monitoring but many episodes will be missed without prolonged EEG recordings.
Thus, in analogy to telemetry for cardiac arrhythmias and coronary events, cEEG is
more and more often used in order to provide real-time monitoring for both ischemic
and epileptic episodes (“neurotelemetry”).
1.4. Rationale
cEEG is increasingly implemented in intensive care units for monitoring of SAH
patients. Whereas EEG patterns of ischemia are well-described (subtle loss of alpha and
beta is followed by excessive theta and delta and finally, suppressions of all
frequencies), there is lack of consensus about clear electrophysiological criteria for nonconvulsive seizures (see the July 2009 version of the American Clinical
Neurophysiology Society Standardized EEG Research Terminology and Categorization;
Hirsch and Brenner, 2010). In addition, it is unknown if rigorous treatment of nonconvulsive seizures in the intensive care unit improves clinical outcome in patients with
SAH. Because of these controversies related to the use of cEEG in SAH, we aim to
review systematically the literature in order to: 1) assess the diagnostic accuracy of
cEEG in detecting non-convulsive seizures and DCI as compared with conventional
monitoring (as outlined above), 2) assess the prognostic value of cEEG, and 3) examine
whether intensified neuromonitoring using cEEG is reflected in an improved outcome
of patients with aneurysmal SAH.
2. O B J E C T I V E S
2.1. Primary objective
The main objective is to determine the diagnostic accuracy of cEEG for detecting nonconvulsive seizure, including NCSE, and DCI in patients with aneurysmal SAH.
To put it in different words, using the PICO approach: In patients with acute
subarachnoid hemorrhage admitted to an intensive care unit (P), does neuromonitoring
using cEEG (I) as compared to conventional clinical monitoring (C) lead to detection of
an increased number of episodes with DCI or non-convulsive seizures, including NCSE
(O)?
2.2. Secondary objectives
Secondary objectives include the following:
1. Do rhythmical and periodic EEG patterns during cEEG (suggesting non-convulsive
seizures or NCSE) predict clinical outcome of patients with acute SAH?
2. Do EEG correlates of ischemia during cEEG (suggesting episodes of vasospasm with
or without DCI) predict clinical outcome of patients with acute SAH?
3. In patients with acute SAH does treatment of EEG patterns suggestive of ischemic
episodes (vasospasms with or without DCI) or seizures (including NCSE) lead to
improved clinical outcome in terms of reduced mortality (at any time point) and
morbidity (as evaluated by an established outcome scale such as the modified Rankin
Scale or the Barthel Index)?
2.3. Investigation of sources of heterogeneity
We will attempt to explore possible sources of heterogeneity. These will likely be
related to variances in methods of clinical diagnosis and heterogeneity in
electrophysiological evaluation and vascular imaging techniques.
As to cEEG, the evaluation by the neurophysiologist may be performed once or several
times daily, which will impact the delay to diagnosis of relevant epileptic or ischemic
events. Further, there remains controversy of how to interpret certain EEG patterns on
the ictal-interictal continuum, which affects the diagnosis of epileptic seizures,
including non-convulsive seizures and NCSE. Lastly, it is not established which qEEG
trends have the best sensitivity and specificity for detecting DCI and non-convulsive
seizures.
As to vascular imaging techniques, several methods are available including bedside
TCD/TCCD, CT/MR-based angiography and catheter-based angiography. All of these
techniques have different sensitivity and specificity for the diagnosis of vasospasms and
DCI.
If the selected studies do not state the precise methods used for electrophysiological
evaluation and vascular imaging techniques, we will try to contact the relevant
corresponding author for further information. This information will be tabulated and
analyzed for possible heterogeneity with respect to definitions, inclusion criteria,
techniques and other methods. As outlined below (3.3.6.) we will analyze the identified
studies for possible puclication bias using a funnel plot.
3. M E T H O D S
3.1. Criteria for considering studies for this review
3.1.1. Types of studies
We will include all studies (as detailed below) comparing cEEG with conventional
neuromonitoring (clinical evaluation, routine EEG, neuroimaging including CTA,
MRA, and TCD/TCCD) in patients with acute SAH if all participants have been
examined using both the index test and one or several of the reference standards within
30 days following onset of symptoms. We will include prospective cohort studies and
randomized controlled studies in which participants have been randomized to cEEG and
compared with the reference standards. In addition, we will include diagnostic casecontrol studies and case series. We will also consider retrospective studies for inclusion
when the original population sample was recruited prospectively but the results were
analyzed retrospectively. Single case reports will not be considered. We will include
studies published in all languages if a reliable translation into English is possible. We
will exclude articles that concern patients already used in another article by the same
authors (or the same institution) unless the methods sections make it clear that the
patients do not overlap. Studies will ideally define the relevant clinical and
electrophysiological parameters; however, if the authors do not explicitly state the
electrophysiological criteria for non-convulsive seizures and NCSE or signs of DCI, we
will attempt to contact the corresponding author for further information.
3.1.2. Participants
Adults (age 16 or elder) presenting in neurocritical care units, general intensive care
units or specialist units (i.e. stroke units, neurological and neurosurgical departments)
with non-traumatic and aneurismal SAH confirmed by imaging (CT or MR) and who
have been evaluated by cEEG during the acute period (defined as from day 0 to day 30
after bleeding onset). We will include patients irrespective of the severity of their
disease or co-morbidities.
3.1.3. Index tests
See above (1.2.).
3.1.4. Target conditions
See above (1.1.).
3.1.5. Reference standards
With respect to non-convulsive seizures and NCSE we will consider clinical evaluation
and routine EEG as reference standards. With respect to vasospasms and DCI we will
consider clinical evaluation and neuroimaging (TCD/TCCD; CT and MR angiography
and perfusion; catheter-based angiography) as reference standards.
3.2. Search methods for identification of studies
3.2.1. Electronic searches
We will search the following databases for relevant English literature from January 1,
1980 to January 31, 2014 (this search will be updated shortly before submission of the
manuscript in order to include also the newest references): Cochrane Central Register of
Controlled Trials (The Cochrane Library), Medline (PubMed), EMBASE, SSCOPUS
and clinicaltrials.gov. We will use the following search terms: "subarachnoid*
hemorrhage”, “subarachnoid* bleeding”, "electroencephalography”, “EEG”,
“continuous EEG”, “cEEG”, “quantitative EEG”, “QEEG”, “ICU EEG monitoring”, and
“neurotelemetry”. Non-English literature will be included if an English Abstract is
available and a reliable translation of the manuscript into English possible. Reports
exclusively dealing with data on pediatric patients (age below 16 years) will not be
included. The references of relevant articles will be manually searched to identify
additional articles. Further, papers will be cross-referenced using the ‘cited by’ function
on Scopus and PubMed. If necessary, personal communication with authors will be
attempted via email or phone in order to obtain additional relevant data. The search
strategies (including MeSH headings for searches in PubMed) will be saved and
recorded in an appendix.
3.3. Data collection and analysis
3.3.1. Selection of studies
A comprehensive literature search will be performed without language restriction (other
than specified in 3.1.2.) in order to identify relevant studies for this review. The search
will be limited from January 1980 onwards as cEEG had not been introduced into
clinical practice prior to this date. Titles will be reviewed first, followed by evaluation
of the abstracts with titles suggesting that a study might be of relevance. Then eligible
studies will be identified on the basis of their full text. The initial selection will be
performed by one author (DK), whereas quality assessment will be done blind by two
assessors. Thus, all potentially relevant articles (as listed in 3.1.1.) will be reviewed and
graded according to the quality and level of evidence by DK, using QUADAS-2
(Whiting et al. 2011; see below), and confirmed for inclusion by a second author (see
3.3.3.). We will use proprietary reference manager software to manage the large number
of studies, and we will document the study selection in a detailed flow chart.
3.3.2. Data extraction and management
Following identification of relevant studies, one of the authors (DK) will extract the
relevant information from each study, which will be double-checked by a second author.
In addition to the information listed in the Methods section we will record 1) journal
name and Vancouver-style reference, 2) study design (e.g. systematic review, crosssectional study), 3) method of recruitment (e.g. prospective or retrospective), 4) study
setting, 5) characteristics of the patient population (e.g. age, gender, co-morbidities).
This information will be stored in a dedicated database. This review will be reported
following the PRISMA criteria (Liberati et al. 2009)
3.3.3. Assessment of methodological quality
Using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), a recent
modified version of QUADAS (Whiting et al. 2011), two of the authors will
independently assess the methodological quality of each included study, as outlined
above. The QUADAS-2 comprises four domains: (1) participant selection, (2) index
test, (3) reference standard, and (4) flow of participants through the study and timing of
the index tests and reference standard (flow and timing). Each domain is assessed for
risk of bias, and the first three domains are also assessed for concerns regarding
applicability. Risk of bias and concerns about applicability are judged as “low”, “high”
or “unclear”. (For assessment of possible reporting bias see 3.3.6.) We will resolve
disagreement between the two reviewing authors by consensus. If this is not possible, a
third author will make the final decision (JD).
3.3.4. Statistical analysis and data synthesis
Depending on the results of the literature search and review, we will propose to conduct
a meta-analysis on all available numerical data which report on 1) the diagnostic
accuracy of cEEG in detecting non-convulsive seizures and NCSE, as well vasospasms
and DCI, 2) the positive and negative predictive values of cEEG for clinical outcome
after SAH in terms of mortality and morbidity, and 3) potential clinical benefits from
adjustment of therapy in response to intensified neuromonitoring using cEEG. This will
be subject to the quality of the studies, study design, risk of bias and the clinical case for
combination. The quality of evidence for clinical recommendations will be evaluated
using the grades of recommendation, assessment, development and evaluation
(GRADE) system. The GRADE system classifies quality of evidence as high (grade A),
moderate (grade B), low (grade C), or very low (grade D). Recommendations can then
be classified as strong (grade 1) or weak (grade 2) (Atkins et al. 2004).
3.3.5. Investigations of heterogeneity
See above (2.2.).
3.3.6. Assessment of reporting bias
In order to address possible publication bias or exaggeration of treatment effects in
small studies of low quality we will analyze the identified studies using a funnel plot
(scatter plot of the treatment effects estimated from individual studies on the horizontal
axis against a measure of study size on the vertical axis (Egger et al. 1997).
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