the modern management of surgical lesion …...latest techniques and procedures of patients with...
TRANSCRIPT
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DOCTORAL THESIS
THE MODERN MANAGEMENT OF
SURGICAL LESION LOCATED IN
ELOQUENT BRAIN AREAS
Doctoral Thesis Abstract
THESIS ADVISOR:
Professor Ph.D. M.D. POEATĂ Ion
PH.D. CANDIDATE:
COŞMAN Mihaela
2020
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Key words – intraoperative neurophysiological monitoring, awake
craniotomy, eloquent areas, neurocognitive assessment, direct
cortical stimulation.
The doctoral thesis comprises:
• 188 pages, 47 of which are devoted to the General Part
• 108 figures, 15 of which in General Part
• 6 tables, one in General Part
• 437 references.
Note: in this abstract, the table of contents, figure numbering and
abbreviation list have the same form as in the doctoral thesis.
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Table of contents
Table of contents………………………………………………….…i
List of abbreviations…..…………………………..………..............iii
CURRENT STATE OF KNOWLEDGE …..………………..…...1
1. Introduction: eloquent (functional) area………………..….1
2. Short history…..…………………………………………...2
2.1. Study of speech disorders – aphasia…………………...2
2.2. Study of the use of electric current in medicine……….4
3. Neuroanatomy and cortical landmarks…………….............5
4. Surgical anatomy of the central lobe….……… …………..8
5. Somatotopy – primary motor and sensitive area ………....10
6. Broca’s area……………………………………….….….13
7. Wernicke’s area….……………………………………....15
8. Types of aphasia..………………………………….……..17
9. Neuroplasticity …………………………………….…….18
9.1. Neuroplasticity – primary motor area …..…………….21
9.2. Neuroplasticitytea – speech areas …………………….22
10. Modern therapy of functional area tumors...………............24
11. Perioperative assessment…………………………..……..26
11.1. Conventional and functional nuclear magnetic
resonance…………………………………………………………..26
11.2. Tractography (DTI – Diffusion Tensor Imaging)…….28
11.3. Transcranial magnetic stimulation….…….............….31
12. Intraoperative techniques………………………...............32
12.1. Intraoperative neurophysiological monitoring.............32
12.2. Awake craniotomy……………………….……….......39
12.3. Intraoperative fluorescein surgery ………………........41
12.4. Intraoperative ultrasonography…………………….....42
12.5. Neuronavigation system……………………………...44
12.6. Intraoperative nuclear magnetic resonance ………..…44
13. Neurocognitive / aphasia assessment tests..……………………45
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PERSONAL CONTRIBUTION.……………………..………....48
1. Motivation and goals of the doctoral research………...…..….....48
1.1. Motivation for choosing the doctoral research topic….48
1.2. Research goals…….………...………….………….....48
2. Material and method………………………………………..…...49
2.1. Study of primary motor area, group definition ……….49
2.1.1. Intraoperative neurophysiological monitoring...50
2.2. Study of speech areas, group definition ……….……..53
2.2.1. Awake craniotomy ……….…………………...57
2.3. Intraoperative ultrasonography …..……......................60
2.4. Neuronavigation system …………..………………....61
3. Results…..………………………………………...….……..…..62
3.1. Results – primary motor area ……………….……….62
3.2. Results – speech areas …………...………….……….62
3.3. Clinical cases ……...……………….........................103
Clinical case no.1….…..….…………………...103
Clinical case no.2…………..…..……………...108
Clinical case no.3………...………….………...110
4. Discussions………………………….……….………………...112
5. Conclusions………………………….………………………...161
ORIGINALITY AND IMPORTANCE OF THE THESIS….…...163
RESEARCH PROSPECTS………… ………………...…………163
REFERENCES…………………………………………………...164
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List of abbreviations
AA anaplastic astrocytoma
AC awake craniotomy
AF fibrillary astrocytoma
Ant anterior
art. artery
CST corticospinal tract
CT computed tomography
FA arcuate fasciculus
GB glioblastoma
GTR gross total resection
HGG high grade gliomas
IOM intraoperative neurophysiological monitoring
LCR cerebrospinal fluid
LGG low grade gliomas
m. muscle
M1 primary motor area
MEP motor evoked potentials
Mg meningioma
MTS metastasis
NN neuronavigation
NTR near total resection
OA oligoastrocytoma
ODG oligodendroglioma
OS overall survival
PFS progression-free survival
Postop postoperative
Preop preoperative
RMN functional nuclear magnetic resonance
RMNi intraoperative nuclear magnetic resonance
S1 primary sensitive area
SC central sulcus
SCD direct cortical stimulation
v
sdr syndrome
SMA supplementary motor area
STR subtotal resection
vs versus
WHO world health organization
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1.1. Motivation for choosing the doctoral research topic
Special emphasis is placed nowadays on the postoperative
neurological status and quality of life of cancer patients. The classical
tumor treatment is based on surgery, radiotherapy and chemotherapy
or a combination of them, depending on the histology. Literature
research has shown that as long as low-grade gliomas are concerned,
the extent of resection is a predictive factor for anaplastic
transformation, recurrence and most importantly for the overall
survival rate. They are most commonly located in the eloquent areas;
hence, gross total resection is not always feasible or risk-free. At the
same time, the incidence of gliomas has been constantly increasing,
being the most common primary brain tumors in adult patients. Hence
the importance of achieving a modern management involving the
latest techniques and procedures of patients with lesions in the
eloquent areas (Larjavaara et al., 2007, Ostrom et al., 2018, Duffau,
2018a, Monticelli et al., 2018).
Considering the above, the gold standard in the treatment of
lesions located in functional areas is a resection as extensive as
possible with the smallest postoperative neurological deficits. This
goal is even more important in the case of asymptomatic patients, of
patients with rough manifestations, young onset age and histological
subtype associated with increased overall survival rate (Kelm et al.,
2017, Ritaccio et al., 2018, Sala, 2018).
1.2. Research goals
This doctoral research includes two parts, the first part being
devoted to the surgical management of tumors located in the primary
motor area and especially to the use of modern pre and intraoperative
techniques, with a focus on intraoperative neurophysiological
monitoring. The second part tackles the surgical conduct of tumors in
the speech areas, by placing greater emphasis on the role of their
neurocognitive assessment and on cases operated awake to which
IOM was also associated.
One of the goals was the introduction in current clinical
practice of intraoperative neurophysiological monitoring in order to
achieve brain mapping in all cases with lesions in the primary motor
area. The practical approach consisted of establishing the protocols
for this type of surgery from the point of view of anesthesia, the
technical approach with setting of the stimulation parameters and all
the stages, starting from the patient’s arrival in the operating room
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until the end of the procedure. We assessed the impact of using this
technique on the extent of resection, postoperative deficits and
recurrence rate. Another goal was the clinical implementation of the
protocol for awake craniotomy associated with intraoperative
neurophysiological monitoring in eligible cases.
Last but not least, we aimed at determining the differences
that occur depending on the extent of resection and histological type,
as well as the potential predictive role for tumor recurrence of the
neurocognitive tests suggested. We researched more thoroughly the
elements of speech in order to detect even the smallest speech
disorders, which would otherwise go unnoticed in regular general
tests, in order to choose candidates for awake craniotomy and to
determine the neurological changes that the tumor also generates
remotely, not just locally.
2. Material and method
2.1. Study of primary motor area, group definition
As concerns the primary motor area, we performed a two-
way (retrospective and prospective) observational analytical study
comparing our findings in the study group and in the control group,
in terms of resection extent, new postoperative neurological deficits,
neurological evolution and imaging findings on the 6-month follow-
up examination.
The study group (Ls) included patients with surgical lesions
in primary motor area or in its vicinity, diagnosed using
craniocerebral MRI scanning with contrast enhancement, who
underwent surgery in the 3rd neurosurgery department of Prof. Dr. N.
Oblu Clinical Emergency Hospital of Iasi, between 1 January 2015
and 1 July 2018. 76 patients were initially enrolled in the group, but
6 of them were excluded because they did not come to the 6-month
follow-up examination after surgery, and 4 were excluded because
they had a pacemaker. In the end, the group included 66 patients.
Inclusion criteria in the study group: tumor in the primary
motor area diagnosed by medical imaging; age over 18 years;
intraoperative use of IOM; consent to be included in the study.
Exclusion criteria in the study group: tumor localized in the
motor area, but inoperable; cases in whom only stereotactic biopsy
was performed; patients with pacemaker; patients who failed to come
for their 6-month follow-up examination; incomplete patient data.
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The control group (Lm) included patients with tumors in
their primary motor area or in its vicinity, diagnosed using
craniocerebral MRI scanning with contrast agent, who underwent
surgery without intraoperative neurophysiological monitoring in the
3rd neurosurgery department of Prof. Dr. N. Oblu Clinical Emergency
Hospital of Iasi, between 1 January 2011 and 1 July 2014. 75 patients
were initially enrolled in the group, but only 70 remained in the end,
since 4 of them failed to come to their 6-month follow-up
examination, and one died 2 weeks after surgery.
Inclusion criteria in the control group: tumor in the primary
motor area diagnosed by medical imaging; age over 18 years;
performed procedure: surgical resection.
Exclusion criteria in the control group: tumor localized in
the motor area, but inoperable; cases in whom only stereotactic
biopsy was performed; patients who failed to come for their 6-month
follow-up examination; incomplete patient data.
2.1.1. Intraoperative neurophysiological monitoring
This technique was performed using the Nim Eclipse device
from Medtronic. Here are the steps of this procedure: preparation of
the necessary material (the device, recording and stimulation
electrodes) and selection of the type of stimulation probe; patient
anesthesia – according to a special protocol for this type of procedure;
placement of recording, neutral and stimulation electrodes (for
MEPs) and connecting them to the control panel; selection of the
working program with the necessary parameters; patient positioning;
performing of the bone flap; removal of artifact sources after using
the device (craniotome, electrocautery); opening of the dura mater;
identification of tumor using ultrasonography and/or neuronavigation
and of its connections with obvious functional structures; beginning
of the brain mapping process; actual resection relying on the collected
functional information; ablation and alternation with subcortical
stimulation; ultrasound examination of the possible tumor remnant;
suture in anatomical planes.
Direct cortical stimulation was achieved by means of the
short-train technique or train of five, which uses a 1-5 Hz current
stimulation frequency, which sends 5 to 7 pulses lasting 500μsec and
with a 4 msec inter-stimuli interval. Thus, according to this method,
5-7 stimuli are sent in one second. The values of the parameters used
in all patients included in the Ls groups were the following: frequency
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3 Hz, number of pulses - five, duration = 500µsec, inter-stimuli
interval = 4 msec.
The technique used was the regular one, recommended by
international guidelines. The parameters were set based on these data,
at the time of presentation of the device by Medtronic, together with
the operating room bioengineer and in compliance with the protocol
of Borgo Trento Hospital - Azienda Ospedaliera Universitaria
Integrata of Verona, where I attended a training course under the
guidance of Prof. Ph.D. M.D. Francesco Sala.
2.2 . Study of speech areas, group definition
The study group (Ls-v) included patients with surgical
lesions in classical speech areas (Broca’s area and Wernicke’s area,
and also right temporal area in left-handed patients) or in their
vicinity, who underwent surgery in the 3rd neurosurgery department
of Prof. Dr. N. Oblu Clinical Emergency Hospital of Iasi, between 1
January 2015 and 1 July 2018. The diagnosis was set based on MRI
imaging with enhancement. 56 patients came to our hospital during
that time, with tumors localized in the areas described above, yet the
final group only included 43 cases. This was due to the fact that they
did not meet all the inclusion criteria.
In addition to brain tumor localization, other inclusion
criteria were: age over 18 years; attendance of 1-month and 6-month
follow-up examinations by radiological imaging and neurological
evaluation; consent to participate in the study; performed procedure:
surgical resection.
The exclusion criteria were: lack of 1-month and 6-month
follow-up examinations either by radiological imaging, or by
neurological evaluation; contraindications for surgery (other severe
conditions that prevent general anesthesia); inoperable cases
(multiple brain lesions, bulky lesion extending to vital centers);
performance of stereotactic diagnostic biopsy; refusal to be included
in the study.
A prospective observational analytical study of the patients
included in the study group was carried out, which consisted of
preoperative neurocognitive and speech evaluation one and six
months after surgery, respectively. Thus, for purposes of aphasia and
superior cognitive functions evaluation, we used a set of tests adapted
from those used by specialized centers to assess aphasia of stroke
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patients, as well as tumor-specific tests, which are currently used
worldwide.
This set of tests was aimed at assessing the expressive
function of language (spontaneous, automatic, repeated speech and
naming), lexia (we used special fragments of text that the patient had
to read, these being part of the exercises used for aphasia therapy),
executive function, praxis, writing, drawing (the patient was shown
three cards with geometric figures from the simplest to the most
complex, and they were asked to reproduce them, as well as the image
of a clock), calculation and memory (five words were used: cat, glass,
water, grass, plane, which were repeated twice and which the patient
was asked to remember 15 minutes later). Below you will find a more
detailed example of the set of tests used in our study.
1. EXPRESSIVE FUNCTION:
A) SPONTANEOUS SPEECH: Open discussion based on
autobiographical elements: what is your name? where do you live?
the name of the spouse, the name of the parents, how many children
you have?, the names of your children.
B) REPEATED SPEECH: letters: m,p, z, a,t, d ,i; words:
plane, bird, blooming, blue, rose; sentences: it is hot outside, he
goes to the theater.
C) AUTOMATIC SPEECH: days of the week, seasons,
months of the year, counting: from 1-10, from 100-, every 5 numbers.
D) NAMES: colors, shapes, objects, images (examples of
representations on the cards used)
2. READING: A. words B. sentences – text.
3. EXECUTIVE FUNCTION: executes verbal orders:
close your eyes, lift your right arm, touch your left eye with your left
hand, clap twice than touch your right knee with your left hand;
executing simple actions involving objects: put the telephone on the
right side of your bed.
4. WRITING: write your name, dictation (words, sentences).
5. PRAXIS: take the cap off a pen and put it back on, military
salute.
6. CALCULATIONS: 6+0; 22+38; 7–5; 54–16; 8x1; 10:2.
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7. DRAWING
8. MEMORY: glass, rose, cat, plane, grass.
Each participant took these tests before and after the surgery
– on discharge (7days after operation), one month and then six months
afterwards. A score was granted for each parameter, depending on the
patient’s answers: normal or impaired function were the preoperative
variants; after surgery, the variants were: stationary,
improved/favorable, aggravation for the executive and receptive
function, reading and praxis; writing – writing all the letters properly;
the calculation score is equal to the number of exercises solved
correctly, 6 – the highest and 0 – the lowest; drawing – correct
reproduction of the images shown; short-term memory – 5 was the
highest score (5 words remembered) and 0 was the lowest (the patient
remembered none of the words), which means that the score is
actually equal to the number of words remembered by the patient. The
patient’s evolution was considered favorable if they did better in at
least three of the tests. Similarly, the patient’s condition was
considered to have worsened if they did worse in at least three of the
tests.
2.2.1. Awake craniotomy
Awake craniotomy associated with IOM was performed in
10 of all patients with brain tumors localized in the speech areas or in
their vicinity, diagnosed using craniocerebral MRI scanning, who
underwent surgery in the 3rd neurosurgery department of Prof. Dr. N.
Oblu Clinical Emergency Hospital of Iasi, between 1 January 2015
and 1 July 2018. Inclusion criteria: above-mentioned tumor
localization; absence of preoperative speech disorders or presence of
very mild deficits; patient’s consent. Exclusion criteria: mental
conditions like: behavioral disorders, anxiety, claustrophobia,
schizophrenia; neurological conditions: severe speech impairments
(mixed, motor or sensitive aphasia), dementia, confusion syndrome,
drowsiness, pre-existing cognitive impairment; individual
characteristics: very old age, morbid obesity, lack of patient
compliance, highly vascularized tumor revealed by radiological
imaging. Relative contraindications: difficult intubation history;
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obstructive airways disorders; treatment-refractory epilepsy.
Absolute contraindications: sleep apnea syndrome; patient refusal.
IOM was also used in these cases. We collected the data of these
patients in an Excel file, which included the patients’ age, sex, onset
symptoms, extent of resection, pathological anatomy, tumor
localization, postoperative evolution on discharge, one and six
months after surgery, respectively. They underwent neuro-imaging
assessment.
2.3. Intraoperative ultrasonography
The lesions or tumor remnants, especially the deep ones, were
localized on real-time images recorded by intraoperative
ultrasonography (Esaote ultrasound scanning device).
2.4. Neuronavigation system
Neuronavigation may help choose the shortest lesion-focused
approach and thus prevent any eloquent area impairment. Our clinic
uses the Stealthstation S7 system from Medtronic.
The Microsoft Excel and SPSS 24.0 programs were used for
the statistical processing of data, which allowed us to make a both
descriptive and analytical assessment. From the point of view of
descriptive statistics, standard parameters such as mean, median,
modulus, standard deviation, confidence interval, and minimum and
maximum value were calculated for numerical data. For qualitative
data, we performed the frequency distribution on the study group. We
presented the results in the form of tables and Pie, Column, Bar and
Line Charts. From the point of view of analytical statistics, we used
significance tests, a with significance level of p = 0.05, for the
comparative evaluation of variables (elements from the set of tests)
between the successive evaluations within the same group.
We used the following classification to quantify the extent
of resection in all patients: description of gross total resection (GTR)
– in glioblastomas, gross total resection means ablation of the areas
with contrast agent uptake revealed by MRI, whereas in LGG, it refers
to ablation of the areas with altered signal in the T2 and FLAIR
sequences. In LGG, near total resection (NTR) is considered when a
FLAIR signal change lower than 3mm persists, whereas subtotal
resection (STR) means there is a tumoral nodular remnant in HGG
and a FLAIR signal change higher than 3 mm (McGirt, 2008).
According to the RANO – Response Assessment in Neuro-Oncology
criteria, high grade gliomas were said to have recurred when the
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medical imaging techniques showed at least 25% extra enhancement
compared to the best previous MRI scan or when a new uptake/node
occurred. LGG was considered to have recurred when the T2 or
FLAIR infiltrate showed a minimum 25% increase, whereas
metastases were said to have occurred when the diameter of the
remnant lesion increased by at least 20% or when a new lesion
occurred (Chukwuele și Wen, 2019). If the MRI scans recorded 7
days or one month after surgery reveal a peripheral contrast uptake,
this is usually a sign of fibrous organization of blood or of healing
reaction and not of recurrence.
3.1. RESULTS – PRIMARY MOTOR AREA
The study group (Ls) included 66 cases, whereas the control group
(Lm) included 70 patients. The following parameters were assessed
and compared for the two groups of patients with primary motor area
tumors: demographic data (age, sex), clinical manifestation,
topographical tumor localization (prerolandic, rolandic,
retrorolandic), stimulation intensity parameters, histological
subtypes, extent of resection, immediate postoperative evolution,
characteristics of the cases whose condition worsened after surgery,
response to direct cortical stimulation, 6-month neurological follow-
up, 6-month imaging follow-up.
Age group distribution was 18 – 79 years for the Ls group,
and 19 – 79 years for the Lm group. As concerns sex distribution, we
found the following results: the male/female ratio in the Ls group was
32 (48.48%) / 34 (51.51%), whereas in the Lm group it was 39
(55.71%) / 31 (44.28%). As far as the clinical manifestation is
concerned, Jacksonian seizures ranked first in both groups. The
topographical distribution of Ls patients was dominated by rolandic
tumors (43.93%), whereas prerolandic tumors predominated in the
control group (43.28%).
The most frequent stimulation value that generated motor
response was 12mA, then 8mA, followed by 10 mA and 9 mA; 13mA,
14mA, 15mA and 16mA, respectively, were necessary in a smaller
number of cases. The peak value 18mA was used only when the
stimulation produced no motor response (fig 3.1.6).
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Fig. 3.1.6 Threshold intensity distribution on cases in the Ls group
In the Ls group, the anatomopathological findings revealed
a GB predominance – 21 cases (31.81%) , followed by Mg – 19
patients (28.78%), MTS – 12 patients (18.18%), AA – 4 cases
(6.06%), AF – 4 cases, OA – 4 cases and ODG – 2 cases (3.03%).
According to Simpson’s scale, the 19 cases of meningiomas
underwent the following extents of resection: 2 patients – S0, 5
patients – S1, 9 patients – S2 and 3 patients – S3. A histological group
distribution revealed that 9 (36%) of the 25 HGG patients underwent
GTR, also 9 (36%) underwent NTR and 7 (28%) underwent STR. A
50/50 ratio was found in the LGG category represented by AF, i.e. 2
patients underwent total resection and 2 underwent subtotal resection.
In the OA and ODG category (6 cases), the GTR/NTR/STR ratio was
3/1/2. As far as the 12 MTS cases are concerned, GTR was performed
in 10 patients (83.33%), and STR in the other 2 (16.66%). In the Lm group, the anatomopathological findings revealed
the following: 21 GB (30%), 3 AA (4.28%), 5 AF (7.14%), 2 OA
(2.85%), 1 ODG (1.42%), 18 MTS (25.71%) and 20 Mg (28.57%).
In the Lm group, ablation of meningiomas (which occurred
in 20 cases – 28.57%) took the following form: S1 in 4 cases, S2 in
11 cases and S3 in 5 cases. Extent of resection of glial tumors (50
cases – 71.42%): GTR – 14 patients (28%), NTR – 14 patients (28%)
and STR – 22 patients (44%). Among these, 24 cases were HGG
(34.28%) and they underwent GTR – 1 patient (4.16%), NTR – 11
patients (45.83%) and STR – 12 patients (50%). There were 21
glioblastomas, of which only 1 case underwent GTR (4.76%), NTR
was performed in 9 patients (42.85%) and STR in 11 patients
(52.38%). 5 patients had LGG and they were represented by AF, and
the extent of resection was GTR/NTR/STR = 2/1/2.
0
5
10
15
20
2 4 9 8 8 4 14 1 3 3 4 6
6 7 8 9 10 11 12 13 14 15 1618
Inte
nsi
ty(m
A)
No. of cases
10
NTR was performed in 1 of the 3 patients with OA and
ODG, and STR in the other 2 (fig. 3.1.18a). Metastases occurred in
25.71% (18 cases) of all the patients in the control group. They
underwent the following extents of resection: GTR – 11 cases
(61.11%) and STR – 7 cases (38.88%).
As concerns the postoperative neurological condition, the
symptoms improved in both groups (65.15% vs 51.42%) and their
positive evolution was the first effect of surgical resection. The
neurological condition worsened in 19.70% of the cases in the Ls
group vs 11.42% in the Lm group. The condition of 15.15% of the Ls
patients and 35.71% of the Lm patients, respectively, was found to be
stationary.
From the statistical point of view, the p value of the
postoperative evolution of Ls patients was as follows: p=0.008 for
the patients whose condition worsened; p=0.006 for the stationary
patients, and p= 0.001 for the patients whose condition improved.
The confidence interval was [2.43;2.8], with a 95% confidence level.
In the Lm group, p = 0.001 for the patients whose condition
worsened, p = 0.0003 for the stationary patients, and p = 0.002 for
the patients whose condition improved. Confidence interval:
[2.24;2.57], with a 95% confidence level.
From the point of view of symptoms onset, 3 of the 10 cases
in the preoperative Ls group with newly acquired motor deficits has
Jacksonian seizures, 2 patients had brachial paresis (3/5MRC), 2
patients had crural paresis (3/5MRC and 4/5MRC), 2 patients had
sensitive hemiparesis, 1 had headache, 1 had intracranial
hypertension, 1 had dysarthria and 1 had grand mall seizure. After
surgery, these patients suffered motor deficits, namely: brachial
paresis (2/5 MRC – 2 patients; 1/5MRC – 2 patients), crural paresis
(3/5 MRC – 2 patients, 2/5MRC – 1 patient), facio-brachial paresis (2
cases) and dysarthria (2 cases).
As far as tumor localization is concerned in the aggravated
cases in the Ls group, 7 tumors were rolandic, 1 was prerolandic and
2 were postrolandic. Histology was represented by: GB – 3 patients
(14.28%), Mg – 3 patients, 1 patient with AF, 1 patient with OA and
1 patient with AA. As for the extent of resection,
GTR/NTR/STR=4/3/0 was performed in these cases, whereas in
meningiomas we accomplished S2 in 2 cases and S3 in 1 case.
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The 6-month follow-up examination revealed that 2 patients
among those whose condition worsened immediately after surgery
were stationary from the neurological point of view, which means that
the permanent motor deficit rate was 3.03% in the study group. The
other 8 patients had a positive evolution, i.e. symptom remission, thus
the total transient motor deficit rate was 12.12%.
From a clinical point of view, 1 of the 8 patients in the Lm
group whose condition worsened suffered brachial paresis (3/5MRC),
1 patient had crural paresis (3/5 MRC), 1 patient had HIC syndrome
and 5 patients suffered seizures. After surgery, 6 patients had brachial
paresis (1/5 MRC 3 cases, and 2/5MRC 3 cases) and 2 patients had
crural paresis (1/5MRC).
As for their localization, there were 3 rolandic, 3 prerolandic
and 2 retrorolandic tumors. The anatomopathological distribution
was the following: 2 – GB (9.52%), 2 – AF, 2 – Mg, 1 MTS and 1
ODG. The extent of resection of meningiomas was S1 and S3,
respectively and for the remaining glial tumors:
GTR/NTR/STR=1/3/2. The 6-month follow-up examination revealed
that 5 patients (7.14%) had no improvement of their motor deficits.
No direct cortical stimulation response was received in 6
of all patients (9.09%) (18mA was the peak intensity value that we
used). Preoperative lesions localization revealed by MRI were: 3
rolandic, 2 prerolandic and 1 retrorolandic tumors. From the
histological point of view, there were 2 patients with AF, 1 with GB,
1with AA, 1 with OA and 1 with ODG.
After surgery, the neurological condition of 3 patients
worsened, while 3 had a favorable evolution with symptom
remission. The functional status and extent of resection overlapped.
Thus, 3 cases who underwent GTR showed motor deficit, while in the
other 3 cases, where the resection was subtotal, the clinical
manifestation improved.
Among the 47 intraneuraxial lesions in the Ls group,
intraoperative ultrasonography was used in 40 cases (85.10%), and
neuronavigaton in 38 cases (80.85%). As concerns the 50
intraneuraxial tumors in the Lm group, intraoperative
ultrasonography was employed in 45 cases (90%), and
neuronavigation in 20 cases (40%).
The medical imaging techniques used on the 6-month
follow-up in the Ls group revealed tumor recurrence in 6 patients (5
12
GB cases (23.80% of the total number of cases) and 1 MTS case
(8.33%), STR or NTR was initially performed in these patients). The
p value in the Ls group on the 6-month follow-up examination was as
follows: p=0.003 for patients whose condition worsened (7 cases);
p=0.02 for stationary patients (13 cases), and p= 0.007 for patients
whose condition improved (46 patients). The confidence interval was
[2.61;2.86], while the confidence level was 95%.
The 46 cases with positive evolution were distributed as
follows: 10 GB (47.61%), 3 AA (75%), 2 AF (50%), 3 OA (75%), 1
ODG (50%), 10 MTS (83.33%), 17 Mg (89.47%). The 13 stationary
cases were distributed as follows: 5 GB (23.80%), 1 AA (25%), 2 AF
(50%), 1 OA (25%), 1 ODG (50%), 1 MTS (8.33%), 2 Mg (10.52%).
6 of the aggravated patients had GB (28.57%) and 1 MTS (8.33%).
The percentage refers to the total number of cases included in that
histological type.
12 patients (who make up 17.14% of the total number of
cases) in the Lm group showed surgical tumor recurrence on their 6-
month follow-up examination, 10 of whom had been histologically
diagnosed with glioblastoma (43. 47%), 1 with MTs and 1 with AA.
The p value in the Lm group on the 6-month neurological follow-up
examination was as follows: p=0.001 for patients whose condition
worsened (15 cases); p=0.002 for stationary patients (20 cases), and
p= 0.001 for patients whose condition improved (35 patients). The
confidence interval was [2.32; 2.6], while the confidence level was
95%.
Among the 35 cases with positive evolution, 3 were GB
(14.28%), 1 AA (33.33%), 2 AF (40%), 1 OA (50%), 10 MTS
(55.55%), 18 Mg (90%). Among the 20 stationary cases, 5 were GB
(23.80%), 1 AA (33.33%), 3 AF (60%), 1 OA (50%), 1 ODG (100%),
7 MTS (38.88%), 2 Mg (10%). As for the aggravated patients, 13
were GB (61.90%), 1 AA (33.33%) and 1 MTS (5.55%). The
percentage refers to the total number of cases of that histological type. Fig. 3.1.42. shows a comparative description of the
neurological condition of the two groups 6 months after surgery. In
the Ls group, there were virtually 10.60% aggravated cases, 19. 69%
stationary cases and 69.69% favorable evolution cases. As for the Lm
group, there were 21.42% aggravated cases, 28.57% stationary cases
and 50% favorable evolution cases.
13
Fig.3.1.42 Comparative neurological evolution of the two groups 6 months after
surgery.
3.2. RESULTS – SPEECH AREAS
The proposed set of neurocognitive tests that focuses on the
detailed evaluation of speech function along with other superior
cognitive functions (executive function, praxis, memory) described in
the material and method section was also used on the 43 patients of
the Ls-v study group. The demographic structure of the group
includes 24 men (55.81%) and 19 women (44.18%).
Some of the symptoms detected in the hospitalized patients
were: motor aphasia – 9 cases (20.93%), sensitive aphasia – 6 cases
(13.95%), mixed aphasia – 7 cases (16.27%), episodes of aphasia –
10 cases (23.25%), grand mall seizures – 7 cases, Jacksonian seizures
– 4 cases (9.30%), sensitive-motor hemiparesis – 8 cases (18.60%),
intracranial hypertension syndrome (HIC sdr.) – 7 cases, auditory
hallucinations – 1 case (2.32%), echolalia – 1 case.
The clinical manifestation onset period was less than 4
weeks in 55.81% of the cases (24 patients), and over a month in the
remaining 44.18% (19 patients).
Histologically speaking, there were: GB – 20 cases and AA
– 3 cases, followed by 8 Mg – 18.60%; 6 MTS – 13.95% and 6 LGG
– 13.95%. The extent of resection of gliomas and metastases (35
cases) was: GTR – 9 patients (5 MTS, 2 LGG, 2 AA), NTR – 15
patients (10 GB, 3 LGG, 1 MTS, 11 AA), STR – 11 patients (10 GB,
1 LGG). As concerns Mg ablation, we recorded the following results:
S1 – 2 patients, S2 – 5 patients and S3 – 1 patient.
46
137
35
2015
0
10
20
30
40
50
favorable stationary aggravated
Ls Lm
no.cases
14
Awake craniotomy associated with IOM was possible in 10
cases. The presentation age of patients in this subcategory was 20 to
50 years, the group median being 28 years. Seizures were the clinical
manifestation of 80% of the cases (8 patients), whereas aphasia
affected the remaining 20% (2 patients).
According to anatomopathological findings, we had: 4 AF
cases, 3 AA cases, 2 ODG cases and 1 GB case. All the patients in
this subgroup underwent direct cortical and subcortical stimulation.
Stimulation intensity ranged from 4 to 8 mA. Other statistical
stimulation current indicators were: median – 7mA, modulus – 8mA,
mean – 6.5mA. No poststimulation response was received in 3 cases.
During surgical resection, one patient suffered an intraoperative
neurocognitive test response alteration post stimulation, materialized
in paraphasia and speech impairment. 20% had postoperative
complications, 20% were stationary and 60% had a favorable
evolution. GTR was performed in half of the cases and NTR in 40%
of them.
Fig. 3.2.22. synthesizes the data of the set of tests
administered preoperatively to whole patients form the group. The
findings of the 7-day and 1-month follow-up examinations are shown
in fig. 3.2.23 – 3.2.24.
Fig. 3.2.22 Representation of the results of the test battery elements before the
surgery
15
Fig.3.2.23 Results of neurocognitive assessment at 7th day after surgery
Postoperative memory assessment revealed – a score
improvement in 8 cases, stationary results in 28 cases and worsening
condition in 7 patients, after 7 days; stationary results were detected
in 19 patients, favorable evolution in 15 and worsening condition in
9, one month after surgery.
Fig.3.2.24 Results of neurocognitive assessment at one month after surgery
16
Calculation evaluation revealed: 26 stationary patients, 7
aggravated patients and 7 improved patients, after 7 days; 15 cases –
stationary, 9 cases – worsened, 16 cases – improved, 1 month after
surgery.
The overall HGG postoperative evolution revealed: 14
improved patients, 6 stationary patients, 3 aggravated patients. LGG:
3 improved patients, 2 stationary patients, 1 aggravated patient. Mg:
4 improved patients, 3 aggravated patients, 1 stationary patient. MTS:
5 improved patients, 1 stationary patient. Thus, the postoperative
evolution of the 43 patients in the Ls-v group was as follows:
favorable – 21 cases (48.80%), stationary – 15 cases (34.80%),
aggravated – 7 cases (16.20%). 1-month neurological evolution:
favorable/improved – 46.51%, stationary – 41.18%, aggravated –
9.30%. 6-month neurological evolution: favorable/improved –
44.18%, stationary – 20.93%, aggravated – 33.88% (recurrence: 1
MTS – 6.66%, 14 GB – 60.86%).
Of all the items included in the set of tests, only executive
function (p=0.002), reading (p=0.002), naming (p=0.001) and
memory (p=0.002) had a statistically significant value in relapsed
patients.
4. Discussions
Intraoperative neurophysiological monitoring virtually
includes direct cortical/subcortical stimulation, also called brain
mapping, as well as monitoring the integrity of white matter tracts by
generating motor or sensory evoked potentials (Sala, 2018). The
motor response after SCD may be also obtained outside the
anatomical limits of the primary motor area. Here are some of the
causes of this phenomenon: displacement of anatomical structures by
the tumor, activation of the neuroplasticity process or stimulation of
the supplementary motor area (So et al., 2018). The absence of a
response after stimulation may also be due to a smaller craniotomy
with more limited cortex exposure. Other causes of negative mapping
may be: stimulation with an intensity below the threshold value,
shorter pulse duration, electric current transmission through the LCR,
stimulation during the refractory period (Pallud et al., 2017, Eseonu
et al., 2018).
17
There were 6 cases (9.09 %) in the study group that had no
motor response. The technique consisted in stimulating the entire
exposed cortex starting from an intensity of 4 mA, which was
subsequently progressively increased by 1 mA until a peak value of
18 mA. From a histological point of view, the vast majority of cases
have a common feature, namely slow development. In a study, from
literature, discussing primary motor area tumor surgery in 53 patients,
the positive response to cortical stimulation was 91% (Magill et al.,
2018).
The special anesthesia protocol avoids the medication that
causes muscle relaxation. Synthetic opioids such as Fentanyl and
sedative-hypnotic agents (Propofol) are preferred when IOM is used,
since they have the ability to maintain a constant serum concentration
(Isik et al., 2017). These were also used on the patients in our study.
With all this technology preoperative techniques are not to
be neglected, given the information they bring us about the tumor-
functional tissue relationship. The integration of DTI images in
neuronavigation leads to an increase in the extent of resection. One
study has found that GTR in patients in whom tractography was also
used was 72% compared to 51.7% in those with no tractography
(Henderson et al., 2020). The combined use of preoperative MEG and
RMNf aims to increase the chances of correctly determining the
functional areas of the brain (Ellis et al., 2020).
Although they are frequently located in the functional areas,
LGGs clinically manifest themselves by seizures without any
significant neurological deficit (Duffau et al., 2009). The extent of
resection has been shown to be an important prognostic factor for
their overall survival (McGirt et al., 2008). Whereas for a while
resection with safety margins was the most used approach to for
tumors in functional areas, Duffau published a study in 2010 in which
this theory is challenged. Instead, he suggests a subpial dissection and
cortical-subcortical stimulation with the highlighting of the functional
cortex and of the white matter tracts (Gil-Robles and Duffau, 2010).
Unlike the Ls group, the extent of resection in the Lm group
was mainly represented by GTR and NTR (80%). This also triggered
the occurrence of new neurological deficits in 2 patients, of whom
18
only one still had a motor deficit on the 6-month follow-up
examination, which means that permanent worsening of the patient’s
stage virtually occurred in 20% of LGG cases. The fact that the
percentage of patients with GTR or NTR is smaller in the group in
which IOM was also used is apparently paradoxical, but this is due to
the intraoperative determination of functional tissue, which caused
the ablation to be stopped.
Whereas the extent of resection was most often taken into
account in glioblastoma surgery, Grabowski published a paper in
2014 where he argued for the first time that the residual volume of
the contrast agent uptake has a greater impact than the extent of
resection (Grabowski et al., 2014). The use of IOM in Ls patients
allowed us to perform GTR in 23.80% of glioblastoma cases
compared to only 4.76% in the Lm group. The clear difference is
obvious in terms of subtotal resection (33.33% vs 52.38%).
Postoperative neurological worsening occurred in 14.28% of the GB
patients in the Ls group, compared to 9.52% in the Lm group.
However, this was a transient phenomenon, since the symptoms of
the Ls patients were in a remission process on the 6-month follow-up
examination. The 6-month follow-up examination also revealed
tumor recurrence in 47.61% of the GB patients in the control group
vs 23.80% in those in the Ls group.
A comparative study, performed on gliomas, between the
use or non-use of IOM was published by Zhang in 2018. The paper
proven again that there was an increase in transient motor deficit
(26.5% vs 23.3%), yet this increase had no statistical significance
(Zhang et al., 2018). One of the techniques used to assess the extent
of resection is Doppler ultrasound, and Haider et al. published, in
2019, the results of the ‘double intraoperative viewing’ of 37 HGGs,
i.e. the use of 5-ALA and RMNi (Haider et al., 2019).
As concerns Mg, the extent of resection and the newly
occurred motor deficits (15.78%) were greater in the Ls group than in
the Lm group, but these are in agreement of the literature data, namely
7.1% (Ostry et al., 2012) and 22.2% (Ottenhausen et al., 2018). The
permanent worsening percentages of the two groups 6 months after
19
surgery were virtually the same, i.e. 5.26% in the Ls group vs 5% in
the Lm group. As far as MTS was concerned, GTR was predominant in the
Ls group (83.33%), compared to only 61.11% of the cases in the Lm
group. From the neurological point of view, 16.6% of the Ls group
patients had transient deficit and 0% permanent deficit vs 11.1% and
5% in the Lm group. The 6-month follow-up medical imaging
examination revealed one relapsed patient in each group (8.33% vs
5%) who required new surgical procedures. According to a study
conducted by Sanmillan in 2017 on 33 M1 metastases, GTR
amounted to 93.9%, and neurological worsening occurred in 18.2 %
of the cases; control was fully regained 3 months after surgery
(Sanmillan et al., 2017).
Although the postoperative deficit was greater in the study
group, 65.15% of the patients had a positive evolution (p = .007),
compared to 51.42% in the Lm group, and the 6-month follow-up
revealed twice as many recurrences in the Lm group compared to the
Ls group (12.76% vs 24%). Literature studies are generally carried
out on certain types of histological tumors, the evolution of which
was described above.
Regarding language area tumors, conventional aphasia tests
are done to assess speech disorders caused by a brain infraction. Due
to the different pathophysiological mechanisms applying to patients
with brain tumors, it is necessary to develop sets of specific tests that
determine more thoroughly the degree of speech and superior
cognitive function impairment (Papagno et al., 2012, DeWitte et al.,
2015, Faulkner et al., 2017). Results may be shown as overall or test-
specific deficits (Tucha et al., 2000). Hence the 38% vs 79%
differences (Talacchi et al., 2012). In our Ls-v group 90.6% of the
cases showed changes in specific tests. The impact of the use of AC and IOM may be proven by the
fact that we managed to achieve GTR in 50% of the cases and NTR
in 40%. This is especially important because the mean age of these
patients was 28 years. According to literature, overall survival was
higher when the two techniques were combined (16. 87 vs 12.04
months), the extent of resection was greater and the complication rate
was lower (0.13 vs 0, 21) (Gerritsen et al., 2019).
20
The analysis of the results of various studies conducted on
groups of patients diagnosed with the same histological type of tumor
showed a correlation between the degree of neurocognitive
impairment, especially the components of speech in patients with
high-grade gliomas, i.e. fast-growing lesions have more altered
results (Faulkner et al., 2017).
In the present study, none of the patients diagnosed with
LGG or meningioma had more than 4 (out of a total of 11) elements
affected from the test battery. The possible explanation for this is that
LGGs have a slow growth compared to GB. Half of the metastasis
cases studied (3 patients) had more than half (six) components
affected preoperatively.
Although more than half of the postoperative results show
improvements, these improvements do not reach the normal level of
the tested functions. More than half of the glioblastomas in our study
group showed an improvement 7 days after surgery (60.86%).
The most obvious correlation between the changes in the
neurocognitive tests and the imaging ones was noted on the 6-month
follow-up. Radiological images revealed tumor recurrence in 34.88%
of the patients included in the group, while 11.72% of them relapsed
and had to undergo surgery again. In these cases, we noticed an
alteration of the tests with a predominance for statistically significant
unfavorable evolution of the executive function, memory, reading (p
= 0.002) and naming (p = 0.001) in about 86.66% of the cases (13
patients). Spontaneous speech was the next item affected in the vast
majority of cases. Our results were in agreement with other authors’
findings: Teixidor et al., 2006, Lee et al., 2015, Barzilai et al., 2018,
Trimmel et al., 2019.
The high recurrence rate is accounted for by the fact that
glioblastomas predominated from the histological point of view, for
which we performed mainly STR in 47.82% of cases and by the fact
that only 68, 96% of the total number of tumor patients requiring
adjuvant radiotherapy actually underwent it.
5. CONCLUSIONS
After evaluating the results of the researched parameters in
the groups of patients with tumors in the primary motor area, we may
safely say that IOM determined: ablation of tumors initially
considered inoperable, clear distinction between truly eloquent and
false eloquent lesions aimed to allow the performance of an ablation
21
as extended as possible, increase of the chance to perform more
extensive resections – the use of IOM allowed us to perform GTR in
a higher number of patients diagnosed with HGG, ODG and MTS,
compared to patients with the same histological subtypes in the Lm
group. A secondary consequence of the above results is the possibility
of increasing overall survival, decreasing the risk of malignant
transformation and increasing progression-free survival, lowering
the permanent postoperative neurological deficit rate, lowering the
recurrence risk – 6 months after surgery, positive impact on the
patient’s quality of life and favorable socio-economic side effects, due
to limited occurrence of neurological disabilities, faster social
reintegration and work resuming, maintaining independence without
the need for specialized help.
Speech preservation is as important as motor integrity, since
speech is an essential element of communication in everyday life. The
set of specific tests developed for assessing the speech and superior
cognitive functions of cancer patients allowed us to: determine their
preoperative clinical condition, degree of speech impairment and
selection of cases on which awake craniotomy may be performed,
assessment of the impact of the surgical procedure – both the specific
function of tumor localization and overall neurocognitive impact, differences due to histological type – fast-growing tumors like
glioblastomas were associated with more severe test alteration
compared to slow-growing tumors like LGG and Mg. These findings
were in agreement with those shown in literature. We noted an
association between postoperative test alteration and recurrence
occurrence – patients in whom medical imaging showed no relapse
after 6 months had stable or even better test results. We also pointed
out the correlation between executive function, reading, naming
images/objects, memory and tumor recurrence – the changes in these
neurocognitive tests had a statistically significant value for the
association and prediction of tumor recurrence.
Originality and importance of the thesis
The originality of the thesis consists of: the development and use
of a set of tests designed to assess the speech and superior cognitive
functions of patients with speech area tumors, the inclusion in the
study groups of several histological types and parameter follow-up
22
depending on the tumor subtype –for tumors located both in the
primary motor area and in the speech areas, unlike the vast majority
of literature studies that assess only one subtype, the definition of four
parameters in the set of tests (executive function, reading, naming
objects and memory) the worsening of which six months after surgery
was associated with tumor recurrence. Also, from a statistical point of
view, this thesis includes important qualitative and quantitative
information about the modern therapy of tumors located in functional
areas.
Research prospects
Here are some research prospects created by this doctoral
thesis: the development of postoperative neurocognitive evaluation
protocols and the definition of the precise moment after surgery when
to perform them, depending on the histological tumor subtype, in
order to prevent or detect recurrence in due time; stratification of the
set of tests according to the patient’s education level; introduction and
routine use of the grid electrode for patients with tumors in the
primary motor area, a clearer understanding of the neuroplasticity
process by researching anatomo-functional discrepancies.
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