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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

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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

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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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