Generating Evidence on NonEpileptic, Stereotypical and Intermittent Symptoms (NESIS) in Chronic Subdural Hematomas
Phase: PHASE4
Conditions: Chronic Subdural Hematoma, Epilepsy; Seizure, Cortical Depression; Cortical Depolarization, Nonepileptic, Stereotypical and Intermittent Symptoms, NESIS
Sponsor: Université de Sherbrooke

Research protocol 
 
 
 
 
 
 
 
GENESIS study 
Generating Evidence on NonEpileptic, Stereotypical and Intermittent Symptoms (NESIS) 
in chronic subdural hematomas 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.0 version 
September 2020 

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Summary 
Patients presenting with transient neurological symptoms in the context of subdural 
hematoma may present a diagnostic challenge. Many of these patients end up with a 
probable diagnosis of epilepsy (or acute symptomatic seizures), despite a negative 
electroencephalogram. We believe that the origin of these transient neurologic 
symptoms in a significant subpopulation of these patients may in fact be cortical 
depolarization, rather than epileptiform activity. Very specific characteristics have already 
been identified that differentiate these patients from those who ultimately have epilepsy. 
The NESIS entity (nonepileptic, stereotypical, and intermittent symptoms) has been 
proposed to represent this group of patients. A NESIS score was then designed to help 
distinguish patients with epileptiform activity (confirmed by EEG) from those likely to 
have cortical depolarization. In other diseases presenting cortical depolarizations, certain 
antiepileptic treatments (including Topiramate) have already been recognized as 
effective. We therefore want to perform a prospective, multicenter, randomized-
controlled study (Topiramate group and Levetiracetam group) to determine whether a 
significant difference in the response to treatment exists between Topiramate and 
Levetiracetam in the NESIS group compared to the non-NESIS group. In addition, in a few 
eligible patients, we will implant electrocortigography electrodes to demonstrate the 
existence of cortical depolarizations. 
Abbreviations 
§ CHUS : Centre Hospitalier Universitaire de Sherbrooke 
§ ECoG : Electrocorticography 
§ EEG : Electroencephalogram 
§ SDH : Subdural hematoma  
§ HSDC : Hémorragie sous-durale chronique 
§ LEV : Levetiracetam 
§ LTG : Lamotrigine 
§ NESIS : Non-epileptic, stereotyped, intermittent syndrome 
§ TNS : Transient neurological symptoms 
§ TPM : Topiramate 
 
 

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Table des matières 
Summary ..................................................................................................................... 2 
Abbreviations .............................................................................................................. 2 
Introduction ................................................................................................................. 5 
Problematic ......................................................................................................................... 5 
Literature review ................................................................................................................. 6 
Outcomes ..................................................................................................................... 7 
Primary outcome ................................................................................................................. 7 
Secondary outcomes ........................................................................................................... 7 
Possible scope of conclusions .............................................................................................. 8 
Study quote ......................................................................................................................... 8 
Characteristic summary of Topiramate (Topamax)26 ............................................................................ 8 
Characteristic summary of Levetiracetam (Keppra)27 ........................................................................... 9 
Placebo ................................................................................................................................................. 9 
Obtaining treatments for the study ...................................................................................................... 9 
Population ................................................................................................................. 10 
Target population .............................................................................................................. 10 
Accessible population ........................................................................................................ 10 
Patients selection – sampling ............................................................................................. 10 
Inclusion criteria ................................................................................................................ 10 
Exclusion criteria ............................................................................................................... 10 
Sample size ........................................................................................................................ 11 
Sample disponibility .......................................................................................................... 13 
Patient recruitment ........................................................................................................... 13 
Sampling bias control ........................................................................................................ 14 
Measures to avoid dropouts .............................................................................................. 14 
Variables and data collection ............................................................................................. 15 
Initial data ......................................................................................................................... 15 
Variables ........................................................................................................................... 17 
Measuring instrument ....................................................................................................... 18 
Process ....................................................................................................................... 19 
Initial meeting ................................................................................................................... 19 
Electrocorticography .......................................................................................................... 20 
Intervention ...................................................................................................................... 20 

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Follow-up .......................................................................................................................... 21 
Participant calendar ........................................................................................................... 22 
Collection method ...................................................................................................... 22 
Data analysis ............................................................................................................. 22 
Statistics ............................................................................................................................ 22 
Degree of significance ........................................................................................................ 23 
Missing data ...................................................................................................................... 23 
Limitations of the study .............................................................................................. 23 
Selection bias .................................................................................................................... 23 
Measurement bias ............................................................................................................. 24 
Compliance bias ................................................................................................................. 24 
Desirability bias ................................................................................................................. 24 
Other limitations : ............................................................................................................. 25 
Time and personnel management .............................................................................. 25 
Ethics ......................................................................................................................... 25 
Consent ............................................................................................................................. 25 
Confidentiality ................................................................................................................... 25 
Risks of participating in the study ...................................................................................... 25 
Anticipated impact ..................................................................................................... 26 
Dissemination of results ............................................................................................. 26 
Timeline ..................................................................................................................... 26 
Budget ....................................................................................................................... 27 
Signatures of the researcher and supervisor ............................................................... 27 
References ................................................................................................................. 29 
Appendix .................................................................................................................... 32 
Appendix 1 – NESIS score ................................................................................................... 32 
Appendix 2 – Consent form ................................................................................................ 33 
Appendix 3 – Initial form ................................................................................................... 34 
Appendix 4 – Follow-up form ............................................................................................. 37 
Appendix 5 – Participant notebook .................................................................................... 39 
 

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Introduction 
Problematic 
Subdural hematomas (SDH) represent a major problem in the healthcare system, with a 
reported incidence of 14.1 to 20.6 / 100,000 patients each year1,2. Several have no 
indication for surgery, but still present significant complications for patients with 
significant implications for the health system. Transient neurological symptoms (TNS) are 
one of those complications frequently encountered by neurologists and neurosurgeons. 
Many of these patients will be diagnosed with induced focal epilepsy, despite often 
negative investigations (electroencephalogram (EEG)). In the literature, epilepsy is 
reported in nearly 25% of post-evacuating patients for SDH3. 
 
According to the clinical experience of our community, at the Centre Hospitalier 
Universitaire de Sherbrooke (CHUS), many patients with TNS and SDH do not correspond 
to what one would expect focal epileptic seizures. In fact, the number of negative EEG in 
these patients appears to be greater than the 50%4 rate found in the literature of epilepsy 
in a corresponding population and the same is true for the response rate to antiepileptics 
which seems less than the usual expected rate of 70%4. 
 
It was therefore important to determine whether an entity distinct from epilepsy could 
be the cause of the transient neurological symptoms in subdural hematomas. A first 
retrospective study evaluating patients with SDH and TNS, who presented at the CHUS 
from 1996 to 20175 was initially completed by our research team. Fifty-nine patients (39 
cases (EEG +) and 20 controls (EEG-)) were included in the study and analyzed. Dysphasia 
and prolonged neurologic episodes (more than 5 minutes) were associated with negative 
EEG, while clonic movements, altered consciousness, positive symptoms, complete 
response to antiepileptics, and mortality were associated with positive EEG (p <0.001). 
These data, combined with an exhaustive review of the literature, allowed us to conclude 
that an entity other than epilepsy, at the origin of these distinctions, probably existed, 
and to propose the term NESIS (nonepileptic, sterotypical, and intermittent symptoms) 
to distinguish it. Subsequently, the NESIS score (see appendix 1) was designed with the 
distinctions described above, with a score of ≥4 predicting with a sensitivity of 96.6% and 
a specificity of 100% the group to which a patient belongs5.  
 
Then, we wanted to evaluate in a preliminary and retrospective way the incidence of this 
syndrome in the population of chronic SDH (cSDH). A descriptive and retrospective study 
aimed at comparing groups based on the NESIS score was then started. This study 
identified 22 patients from 2016 to 2018 who presented to the CHUS with TNS in the 
context of cSDH. Of these, 13 (59%) had a NESIS score of 4 or more. Particularly 
interestingly, and consistent with the initial hypotheses developed in relation to the 
existence and pathophysiology of NESIS, the NESIS and non-NESIS groups had significantly 
different responses to treatments. In fact, the response to standard antiepileptics 
(resolution of TNSs) was 100% in the non-NESIS group (probable epilepsy) compared to 
14% in the NESIS group (p = 0.02, Fisher's exact test). In addition, 100% of patients in the 

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NESIS group who did not respond to standard antiepileptics responded with Topiramate 
or Lamotrigine (LTG) (2 antiepileptic treatments recognized for their impact on cortical 
depolarization) (article in process of submission, unpublished data )28. 
 
Following this preliminary study which described a significant difference in the response 
to treatment of TNS depending on the type of antiepileptic drug used and the NESIS score 
obtained, it is now more than relevant to validate this difference through a prospective 
randomized study. Indeed, a significant difference between the efficacy in the drugs 
studied and the NESIS groups would make it possible to offer a new therapeutic avenue 
for NESIS patients who do not seem to respond to usual treatments in addition to 
validating the existence of this new entity (NESIS). On the other hand, a better response 
to certain drugs known to have an incisive impact on cortical depolarization in the NESIS 
subgroup would strengthen the hypothesis of cortical depolarizations as a 
pathophysiological phenomenon underlying the NESIS entity. Prospective identification 
of these patients would also make it possible to better characterize the pathophysiology 
of symptoms. 
 
Literature review 
Cortical depressions are massive waves of depolarization propagating at a rate of 2-9 
mm/minute through gray matter6. They are caused by a sudden and sustained alteration 
of balance of transmembrane ion gradients, a release of neurotransmitters, an increase 
in energy metabolism and ultimately a decrease in electrical activity. Cortical depressions 
are now recognized in various pathologies such as subarachnoid hemorrhages, migraines, 
head trauma and intra-parenchymal hemorrhages7.  
 
As migraines are frequent, the phenomenon of cortical depression has been further 
studied in this situation. In fact, it was in migraines that the phenomenon was first 
described in 1942 by Laeo. 20-30% of migraine sufferers have auras (in any form). These 
auras are in fact the clinical manifestation of cortical depression8. Several antiepileptics, 
including Topiramate (TPM), are used for migraine prophylaxis. TPM is known to have 
different mechanisms making it effective against migraines9. It is thought to act by 
modulating voltage-gated sodium and calcium channels, by potentiating the inhibition of 
GABA-a and by blocking the excitatory effect of glutamate9. Regarding the efficacy of 
Topiramate in migraine headaches, a meta-analysis of 201210 identified four class 1 
studies and seven class 2 studies, all demonstrating significant efficacy of TPM compared 
to placebo12,13,14,15,16,17. In addition, despite a monthly reduction in the frequency, 
intensity and duration of migraines in the Propanolol and Topiramate groups, the TPM 
group reported a significantly greater mean reduction than the Propanolol group18. In the 
other hand, Levetiracetam (LEV) reports more conflicting data. In fact, a 2011 
randomized-controlled study showed no benefit of LEV in migraine (n = 96)19. In contrast, 
another randomized-controlled study from 2013 was able to demonstrate a significant 
reduction in migraines (n = 65), however, the large number of losses at follow-up, more 
in the LEV group than in the placebo group, makes this result difficult to interpret 
according to several authors20. 

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Some more fundamental studies have also evaluated the response to antiepileptics 
directly at the level of cortical depressions induced in laboratory. Four studies between 
2005 and 201221,22,23,24 have evaluated cortical depressions in rats and cats before and 
after injection of Topiramate (10 and 30 mg / kg). They have demonstrated a significant 
dose-dependent reduction in cortical depressions 30 minutes after an injection of 
Topiramate. Regarding Levetiracetam, a fundamental study from 2017 could not 
demonstrate his efficacy in the treatment of cortical depressions in the hippocampus of 
mice25. 
 
Considering the presence of cortical depressions in several irritative brain conditions, we 
consider that these could also be the cause of NESIS in the context of SDH. Moreover, 
according to our preliminary studies, NESIS has a better respond to Topiramate and 
Lamotrigine than to other antiepileptics, treatments which are nevertheless all 
considered to have similar efficacy29 in focal epilepsy. LEV specifically has an efficacy rate 
judged to be comparable to TPM for the control of epilepsy. A recent study has also 
demonstrated a response rate of 28% for TPM compared to 50% for LEV in a refractory 
population.30 This could be explained by the presence of causal cortical depolarizations in 
patients with NESIS, with TPM and LTG being proven to be both effective in cortical 
depolarizations, which is not the case with other common antiepileptics (Levetiracetam, 
Phenytoin). It therefore becomes relevant to begin the study of this hypothesis, which if 
confirmed, would offer a new therapeutic avenue for these patients who are usually 
refractory to standard treatments. 
Outcomes 
Primary outcome 
The aim of this study is to demonstrate the efficacy of Topiramate for patients with 
transient neurological symptoms in the context of chronic subdural hematomas with a 
positive NESIS score, in whom usual epilepsy treatment appears to be less effective. For 
this purpose, the efficacy of Topiramate (shown to be effective in cortical depressions) 
will be compared with that of Levetiracetam (which has not been shown to be effective 
in cortical depressions). 
 
Secondary outcomes 
- 
Validate the existence of the NESIS entity: if we manage to demonstrate a 
significant difference between the response to TPM and LEV in the NESIS group 
compared to the non-NESIS group, the evidence concerning the existence of a 
different process at the origin of the NESIS group will then be more numerous. 
Cortical depolarizations will be the main hypothesis. 
- 
Confirm cortical depolarizations as the main etiology of NESIS by 
electrocorticography. 
- 
Validate the NESIS score: If we are able to demonstrate a significant difference 
between the effectiveness of TPM and LEV between the NESIS and non-NESIS 

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groups, we will be able to demonstrate the success of the NESIS score in 
distinguishing patients with TNS into two distinct groups. 
 
Possible scope of conclusions 
If our hypotheses are confirmed, in addition to an additional demonstration of the NESIS 
entity, a treatment targeting cortical depressions could be offered to patients with TNS, 
cSDH and NESIS score ≥4. In addition, a better knowledge of this syndrome will allow 
subsequent studies to evaluate other therapeutic avenues having fewer side effects or 
being more effective, in addition to being able to characterize the course and prognosis 
of NESIS syndrome in order to avoid diagnostic delay and additional investigations. 
 
Study quote 
To meet our objectives, we offer a multicenter, prospective study of randomized-
controlled clinical trial type validating therapeutic efficacy . 
 
Figure 1  Study groups 
 
 
Characteristic summary of Topiramate (Topamax)26 
- 
Class : anticonvulsivant. 
- 
Indications : Focal and generalized epilepsy, migraine prophylaxis. 
- 
Mechanisms of action: Blockage of voltage-gated sodium channels, increased 
GABAa activity, AMPA/glutamate receptor antagonist, weak inhibition of carbonic 
anhydrase. 
- 
Dosage: 50 mg BID, to be increased by 50 mg per week up to 200 mg daily. Can 
then be increased by 100 mg per week, to a maximum of 400 mg daily. 
- 
Recommended renal adjustment: Clearance <70 mL/minute/1.73m2: dose 
reduction by 50% and slower titration. 
- 
No adjustment for hepatic insufficiency. 
- 
Frequent side effects: paresthesia, fatigue, dizziness, weight loss, abdominal pain, 
anorexia, nausea and vomiting. 
- 
Serious side effects: depression, nephrolithiasis. 
Contraindications: history of hypersensitivity. 
Interactions: may increase the depressant effect on central nervous system by 
other drugs. 
Basé sur le score NESIS
cSDH + TNS
NESIS ≥4
TPM
LEV
ECoG for some participants
NESIS <4
TPM
LEV

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Characteristic summary of Levetiracetam (Keppra)27 
- 
Class : anticonvulsivant. 
- 
Indications: focal and generalized epilepsy, convulsive prophylaxis (perioperative, 
subarachnoid hemorrhage, head trauma). 
- 
Mechanisms of action: SV2A inhibitor/modulator. Likely inhibition of voltage-
gated calcium channels, enhancement of the inhibiting effect of GABA, 
modulation of neurotransmitter release. 
- 
Dosage: To be start at 500 mg BID, increase by 500 mg every two weeks to a 
maximum of 1500 mg BID. 
- 
Recommended renal adjustment: 
o Clearance 80-130 mL/minute/1.73m2 : 500-1500 mg BID 
o Clearance 50-<80 mL/minute/1.73m2 : 500-1000 mg BID 
o Clearance 30-<50 130 mL/minute/1.73m2 : 250-750 mg BID 
o Clearance 15-<30 130 mL/minute/1.73m2 : 250-500 mg BID 
o Clearance <15 130 mL/minute/1.73m2 : 250-500 mg daily (expert opinion) 
- 
No adjustment for hepatic insufficiency. 
- 
Common side effects: increased blood pressure, behavioral changes, headache, 
psychotic symptoms, fatigue, dizziness. 
- 
Serious side effects: depression, suicidal thoughts. 
- 
Contraindications: history of hypersensitivity. 
- 
Interactions: may increase the depressant effect on central nervous system by 
other drugs. 
 
Placebo 
No placebo will be used, as patients with transient neurological symptoms require 
treatment with antiepileptics. Topiramate and Levetiracetam are currently approved 
drugs for the treatment of focal seizures29. We will therefore take TPM as an intervention 
(drug shown to be the most incisive, to date, in cortical depressions) and LEV as an active 
control. 
 
Obtaining treatments for the study 
As TPM and LEV are approved treatments in the treatment of focal seizures and are 
already acceptable choices for the treatment of patients with transient neurological 
symptoms, even with negative EEGs, we will treat patients with one or the other of these 
treatments through a usual prescription that will be taken to the community pharmacy. 
These two treatments can therefore be approved for reimbursement either by the RAMQ 
or by private patient insurance. 
Moreover, since TPM is approved by Health Canada for the treatment of TNS in the 
context of SDH, even with negative EEG, additional approval by Health Canada will not be 
necessary30. 

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Population 
Target population 
All adult patients with transient neurological symptoms with negative EEG in the context 
of chronic subdural hemorrhage. 
 
Accessible population 
All adult patients presenting to any of the participating centers with transient neurologic 
symptoms in the setting of cSDH. The study will be multi-center and Sherbrooke will be 
the coordinating center. 
 
Patients selection – sampling 
- 
All patients presenting to one of the participating centers with transient 
neurological symptoms in the context of cSDH. 
- 
Convenience non-probability sampling.  
- 
Systematic sampling, recruiting all patients presenting at one of the participating 
centers, regardless of the time of admission (night, weekend). As all patients 
presenting with TNS in the setting of cSDH will be eligible for the study, the sample 
should be representative of the population. Of course, they will be included 
according to their willingness to participate in the study, so a bias of voluntarism 
is unmissable. 
 
Inclusion criteria 
• 
≥ 18 years old 
• 
Chronic subdural hematoma 
• 
Transient neurological symptoms (Sensory, motor, cerebellar or speech 
symptoms, lasting 6 hours or less) 
• 
Initial negative EEG  
 
Exclusion criteria 
- 
Contraindications to Levetiracetam 
o Psychiatric history (major depression, psychosis, risk of suicide) 
o History of hypersensitivity to LEV (anaphylaxis, angioedema, skin 
reaction) 
- 
Contraindications to Topiramate 
o History of hypersensitivity to TPM 
o Glaucoma 
o Past nephrolithiasis 
- 
Known epilepsy or seizure before the current subdural hemorrhage 
- 
Actual take of antiepileptic 
- 
Intracranial pathology not caused by SDH (intra-parenchymal hemorrhage, 
neoplasia) 
- 
Pregnancy or planning to be 

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- 
Inability to carry out the necessary follow-ups for the study 
- 
Refusal of the attending physician 
 
Sample size 
The studies directly concerning our subject being few or even zero, we decided to 
calculate our sample size based on two calculations and two types of data (which do not 
perfectly represent our variables, each in their own way) in order to optimize our chances 
of obtaining a size approaching the one we need for adequate power. 
Based on the means and standard deviations of reduction in cortical depressions with 
TPM and LEV in the fundamental studies previously described24,25, it is possible for us to 
calculate the sample size that should allow us to establish a significant difference between 
our groups, if possible. 
 
Indeed, in the first study verifying the effect of different drugs against cortical depressions 
in rats, the controls had 14.3 +/- 2 cortical depressions/2 hours24. After chronic treatment 
with TPM, cortical depressions were reduced to 7.8 +/- 2 cortical depressions/2 hours. 
Then, if we calculate the average reduction in cortical depressions, we get: 14.3 - 7.8 = 
6.5. The standard deviations of each adding up, we get 2 + 2 = 4. We therefore have an 
average reduction of 6.5 +/- 4 cortical depressions/2 hours after treatment with TPM. 
 
Regarding LEV, in a study evaluating the reduction of cortical depressions from various 
treatments in mice, LEV increased cortical depressions insignificantly (control group 
having 2.75 +/- 0.34 cortical depressions/minute and LEV group having 5.24 +/- 2.47 
cortical depressions/minute). Given a non-significant trend towards an increase in cortical 
depressions, we will retain that the LEV is not effective and therefore has an average 
reduction in cortical depressions of 0. 
Based on fundamental animal studies, here is the sample size calculation using the means 
reduction  : 
𝑁(𝑏𝑦 𝑔𝑟𝑜𝑢𝑝) = 2 .(𝑧𝛼+ 𝑧𝛽)𝜎
Δ
5
!
 
𝑁= 2 .(1,960 + 1,282)4
6,5
5
!
 
                                     𝑁= 8 
 
The number of patients needed per group would therefore be 8. As the values used come 
from fundamental studies, their validity in humans for the calculation of the sample size 
is difficult to predict. In addition, since our outcome 
is a dichotomous variable (resolution or not of 
symptoms) and not a continuous variable (number 
of episodes), more patients must be expected to 
demonstrate a significant difference. 
 
Légende 
a = 0,05 by convention 
b = 0,10 by convention 
D = reduction means difference of cortical 
depressions between TPM and LEV (6,5 – 0 = 6,5) 
s = standard deviation (2 + 2 = 4) 
Z = normalized form of the error according to 
values constantes sans unités 

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So, to optimize our chances of getting a sufficient sample size, we also calculate the 
sample size with a proportion calculation. 
 
In the retrospective study carried out at the CHUS by our research team28, the results of 
which have not yet been published, the NESIS group had complete resolution of TNS in 
14% when treated with usual antiepileptics. Upon failure of usual treatments and after a 
change to recognized treatments for cortical depression (Topiramate and Lamotrigine), 
100% of patients had resolution of symptoms. It is important to understand that the 
treatment of the patients in this study was administered entirely within the hospital, a 
poorer compliance is therefore to be expected for our patients who will continue their 
treatment at home, which could affect the power of our study. However, these 
proportions are still those which come closest to what could be found in our study. 
 
 
Calculation of sample size from proportions : 
 
2𝑁(𝑏𝑦 𝑔𝑟𝑜𝑢𝑝) = 4(𝑧𝛼+ 𝑧𝛽)!𝑝̅(1 −𝑝̅)
(𝑝𝑐−𝑝𝑒𝑥𝑝)!
 
2𝑁(𝑏𝑦 𝑔𝑟𝑜𝑢𝑝) = 4(1,960 + 1,282)!0,57(1 −0,57)
(0,14 −1)!
 
                   2𝑁= 14 
                    𝑁= 7 
 
The size calculated with the core studies as well as with the proportions taken in the 
retrospective study in our center are similar (8 and 7, respectively). In order to prevent a 
lack of potency for the reasons mentioned above, a slightly larger size will be preferred, 
and 15 patients seems a reasonable number. This calculation represents the sample size 
that one should aim for in each group (intervention and active comparator) within the 
NESIS subgroup. It will therefore be necessary to 
analyze the results of nearly 30 patients in the NESIS 
group. 
 
As the non-NESIS patients are not part of our primary 
outcome and are less numerous than the NESIS (72% 
compared to 28%28), they will be included in the study 
without a specific target, up to a maximum of 30 
patients and their results will be analyzed descriptively. 
 
Considering the dropout or loss rate at follow-up, 
probably around 30-40%, a sample of a total of 42 patients with NESIS seems justified. 
Then, considering that nearly a third of patients will have a NESIS score of less than 4 (non 
NESIS), 56 patients should be included in the study. Finally, given the number of refusals 
to participate in the study, probably nearly half of the patients, we plan to approach at 
least 120 patients. 
Légende 
a = 0,05 by convention 
b = 0,10 by convention 
p = Mean proportion between 2 groups 
((0,14+1)/2 = 0,57) 
pc = comparator’s proportion (14% = 0,14) 
pexp = intervention’s proportion (100% = 1) 
Z = normalized form of the error according 
to constant values without units  

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The final recruitment target is therefore 56 patients (Figure 2). 
Figure 2 – Patients distribution 
 
 
Sample disponibility 
The number of participants to be randomized is acceptable and feasible but will require 
a multi-center design. In fact, during the retrospective study at the CHUS from March 
2016 to March 201828, 18 patients with TNS in the context of cSDH with negative EEGs 
were identified. Thus, considering at least 4 centers participating in the study, the 
inclusion of 56 patients in 3 years seems realistic. Moreover, the NESIS entity being newly 
recognized (mentioned only since 2018), the incidence of NESIS is probably higher than 
what was found between 2016-2018, the patients being now more easily identified and 
classified. 
 
 
Patient recruitment 
Patients will initially be identified by neurosurgeons and neurologists from participating 
centers. These physicians will be aware of the existence of our study and will have the list 
of inclusion and exclusion criteria. They will therefore be able to inform us when a 
potential candidate is hospitalized. 
 
These patients will then be seen during an initial visit by the research nurse. This meeting 
will take place during their hospitalization, in the patients' respective rooms or in a closed 
room (if multiple bed in the same room) (in order to avoid any external influence on the 
consent, in addition to better maintaining the confidentiality of the candidates). The 
purpose of this visit will be to assess the patient's eligibility for the study, to explain the 
purpose of the study and its interventions. If the patient wishes to participate in the study, 
a consent form will be read and signed by the patient (Appendix 2). The consent must 
meet the same criteria as what is applied in the clinic, or a patient must be able and offer 
free and informed consent. Substituted consent in the event of incapacity (permanent or 
temporary) with the most significant relative, at the bedside or by telephone will also be 
authorized. This form will contain the frequent and serious side effects of the two 
proposed treatments. All the patients who sign will be randomized in the study, into the 
TPM or LEV group. The method and location of recruitment will therefore be the same for 
all patients (intervention and active comparator). 
Based on NESIS 
score
SDH + TNS
n = 56
NESIS ≥4 
n = 42
TPM
n = 21
LEV
n = 21
NESIS <4 
n < 42 (~14)
TPM
n < 21 (~7)
LEV
n < 21 (~7)

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14 
 
 
Randomization will be made by random block allocation. A number will be assigned to 
each patient and will be entered into a software that will allow patient randomization, 
which can be found on the site: https://www.randomizer.at. Patients will be matched 
there for their NESIS scores (≥4 or <4), their home sites (CHUS or other centers) and the 
presence of SDH evacuating surgery (yes or no). These factors seem to us to be the ones 
that could have the greatest impact on the results. When starting the randomization, the 
software must be blocked in order to allow its use, so no modification of the 
randomization parameters can be added when the process is going to be started. 
 
As recruitment and randomization take place during hospitalization of patients, no travel 
or additional testing will be required. 
 
Sampling bias control 
The use of a multicenter study comprising more than one center, which will be several 
kilometers apart, will limit the possible geographical and environmental impact on the 
results of our sample in relation to the target population. In addition, routine screening 
of all patients presenting with TNS and negative EEG, in the setting of cSDH, regardless of 
the time of admission, will also ensure a more representative sample of the population. 
 
In order to limit the bias of voluntarism, we have implemented several measures. First, it 
is important to minimize the number of patients who might decline to participate in the 
study. For that, we have constructed our study so that participation in the study does not 
involve additional testing or traveling than is already indicated by the primary pathology. 
In addition, we will educate patients on the equal effectiveness of the treatments that 
will be offered in the study and the fact that these two treatments are currently approved 
for the treatment of their condition. This should be reassuring. In addition, the availability 
of a member of the research team for any questions or side effects will also be a positive 
reason to participate. Ultimately, the substituted consent clause will help maintain 
eligibility for a significant proportion of patients, given the prevalence of confusion and 
neurocognitive disorder in the population with cSDH. 
 
Measures to avoid dropouts 
Once the randomization, it will be necessary to minimize the dropouts in order to 
maintain the random effect of the randomization and therefore a representative sample 
of the population. To begin with, it will be important to be readily available. Patients will 
have our contact details and a telephone follow-up will be carried out when problems 
arise. If necessary, a clinic appointment can be set. When side effects, it will be discussed 
with the patient to lower the dose, in order to reduce the side effects, before stopping 
the antiepileptic permanently. Of course, the final decision will be up to the patient. 
 
In addition, the medication will be started in increasing doses, in order to limit side 
effects. 

VERSION 3.0 -10/20/2020 
15 
 
 
Limiting clinical appointments to what patients would have had without participating in 
the study, namely neurology follow-up and neurosurgery follow-up, should also limit 
dropouts by limiting the involvement required by patients. 
 
Variables and data collection 
Initial data 
First, several demographic and characteristic data regarding subdural hematomas and 
transient neurological symptoms will be collected. These data will allow us to assess 
whether certain factors have an impact on the response to treatment. 
 
Table 1 - Demographic data and characterization of subdural hematoma  
Demographic data 
Age 
Sex 
Dominant hand (right or left) 
Life habits 
Tobacco 
Alcohol 
Drugs 
Comorbidity 
High blood pressure 
Diabetes (with or without insulin) 
Dyslipidemia 
Auricular fibrillation 
Coronary disease 
Peripheric vascular disease 
Migraines (with or without aura) 
Past medical history 
Stroke, transient ischemic attack 
SDH 
Cranial lesion 
Cranial surgery 
Drugs 
Antiplatelet 
Anticoagulant 
Beta-blocker 
Magnesium  
SDH type (Nakaguchi 
classification) 
Homogeneous 
Laminaria 
Separated 
Trabecular 
SDH location 
Right 
Left 
Both 
SDH cause 
Traumatic (light, moderate, hard) 
Autre 
SDH thickness 
Millimeters 

VERSION 3.0 -10/20/2020 
16 
 
Middle line shift 
Millimeters 
Initial Glasgow score 
3-15 
Draining surgery 
Yes 
No 
Surgery location 
Right 
Left 
Both 
Concomitant subarachnoid 
hemorrhage 
Yes 
No 
Electrocorticography 
Yes 
No 
MRI 
Yes 
No 
Particularities 
 
Table 2 – TNS characteristics 
Visual symptoms 
Visual loss 
Twinkling light 
Other 
Sensory symptoms 
Hypoaesthesia 
Paresthesias 
Other 
Motor symptoms 
Paresis 
Clonies 
Change in tone 
Other 
Speech symptoms 
Aphasia 
Dysarthria 
Mutism 
Other 
Cerebellar symptoms 
Balance disorder 
Nausea and vomiting 
Dizziness / Vertigo 
Other 
Altered state of consciousness 
Yes or No 
Duration of symptoms 
Minutes 
Number of episodes 
 
Migration of symptoms 
Yes or No 
Stereotyped symptoms 
Yes or No 
Prodrome 
Type 
Postictal 
Yes or No 
NESIS score at randomization 
-8 à 13 
 

VERSION 3.0 -10/20/2020 
17 
 
Variables 
Research question: Is Topiramate more effective than Levetiracetam in patients with TNS 
and negative EEG in the context of SDH, in the NESIS group (increased probability of 
cortical depolarization), compared to the non-NESIS group (increased likelihood of 
epilepsy) ? 
 
As indicated in our research question, our study mainly aims to verify the effectiveness of 
TPM (dependent variable) compared to LEV in the NESIS group compared to the non-
NESIS group (independent variable). For this, evaluations with standardized 
questionnaires will make it possible to assess the resolution of neurological symptoms 
(dichotomous variable). In addition, reductions in the frequency, intensity and duration 
of TNS will be assessed (continuous variables). 
 
The tolerance of the two study drugs will also be compared. There will be a comparison 
of the number of failures in the two groups (dichotomous variable) and the percentage 
of patients with side effects (continuous variable). 
 
Table 3 - Variables 
Variables 
Measurement method 
Measuring instrument 
Topiramate 
efficacy 
Complete reduction of neurological 
symptoms (yes or no) 
Medical assessment using 
a form 
Average reduction in TNS frequency 
(nb/week) 
Average reduction in TNS duration 
(minutes) 
Levetiracetam 
efficacy 
Complete reduction of neurological 
symptoms (yes or no) 
Medical assessment using 
a form 
Average reduction in TNS frequency 
(nb/week) 
Average reduction in TNS duration 
(minutes) 
Topiramate 
tolerance 
Type of side effects (e.g. dysphasia, 
paraesthesia, fatigue, drowsiness, 
dizziness) 
Medical assessment using 
a form 
Severity of side effects (graded 
according to CTCAE terminology) 
Number of dropouts (%) 
Medication deemed useful by the 
patient (yes or no) 
Levetiracetam 
tolerance 
Type of side effects (e.g. irritability, 
depression, drowsiness, headache, 
fatigue) 
Medical assessment using 
a form 

VERSION 3.0 -10/20/2020 
18 
 
Severity of side effects (graded 
according to CTCAE terminology) 
Number of dropouts (%) 
Medication deemed useful by the 
patient (yes or no) 
Demographic 
data 
 
See table 1 above 
Standardized 
questionnaire completed 
by a member of the 
research team 
TNS 
characteristics 
See table 2 above 
Standardized 
questionnaire completed 
by a member of the 
research team 
Electrocorticogra
phy 
Two "strip" type ECoG electrodes, 
followed by 72-hour monitoring or 
until recording for 5 episodes of 
transient neurological symptoms. 
Search for epileptiform 
activity or cortical 
depolarizations. 
 
Measuring instrument 
Our collection data will take the form of a questionnaire. However, the characterization 
of neurological symptoms requiring some training, in order to be able to adequately 
distinguish relevant neurological symptoms (those transient likely caused by SDH) from 
those unrelated to SDH, the main measuring instrument will be a medical evaluation by a 
person trained in neurology or neurosurgery. This assessment will be based on a 
questionnaire (appendix 4), so as not to omit the assessment of all areas relevant to the 
study. Our study being the first on the subject, no questionnaire already approved in 
other studies can be used. For these reasons, we have constructed a questionnaire 
including a part on TNS and another on side effects. Doctors or residents evaluating 
patients won’t forget items and will also be encouraged to further specify the various 
positive items found during the evaluation. 
 
During the initial visit, a standardized questionnaire including demographic data, 
characteristics of cSDH and transient neurological symptoms will be completed by a 
member of the research team using the hospital and patient record (appendix 3). This 
questionnaire will be administered by a physician, resident or research nurse. We 
consider that characterization of the current episode at the initial visit will not require full 
training in neurology or neurosurgery. Indeed, the patient will have already been seen 
closely by a neurologist or neurosurgeon who will have considered TNS as relevant and 
secondary to the SDH. However, before administering this questionnaire, the nurse will 
receive a training, which will be given by a member of the research team. 
 
During follow-ups, by telephone or in clinic, the patient will have in hand his research 
notebook (appendix 5) in which he will have made a calendar of neurological episodes 

VERSION 3.0 -10/20/2020 
19 
 
that have occurred, or side effects noted. This notebook will limit recall bias and will be 
analyzed as a secondary outcome, in order to compare the reliability of the information 
noted by patients with that reported by doctors. Subsequently, an assessment by a 
resident, neurologist or neurosurgeon will be done using the form described above 
(appendix 4). 
 
The existence of propagated cortical depolarizations will be assessed by 
electrocorticography (ECoG) for some operated patients (see below for the detailed 
procedure) as well as by a surface EEG and a near infrared spectroscopy monitor. These 
paraclinical examinations will help to rule out a diagnosis of epilepsy and will provide the 
physiological data necessary for the confirmation of cortical depolarizations. 
 
Side effects will be assessed and graded using CTCAE terminology (Common Terminology 
Criteria for Adverse Events)31. 
 
After a first negative pre-randomization EEG, 2 more EEGs will be performed at 24 hour 
intervals in order to increase the diagnostic sensitivity of ictal activity. If an EEG is positive, 
there will be no further EEG. These EEG results will help for further validation of the NESIS 
score. 
 
Magnetic resonance imaging will be recommended in patients with 3 negative EEGs, in 
order to rule out another structural cause, such as transient ischemic events. This will 
remain at the discretion of the clinician, depending on clinical relevance and availability 
of the examination.. 
 
Process 
Initial meeting 
Patients will be seen during their initial hospitalization following the diagnosis of TNS and 
their first negative EEG. If SDH evacuating surgery is planned for a patient who has already 
been randomized, they will be offered the installation of an ECoG monitor during the 
same surgery. This step will be optional. Subsequently, the patients will be reviewed 
postoperatively and the intervention will be started if transient neurological symptoms 
persist. 
 
The meeting will be conducted by a research nurse or a member of the research team. An 
explanation of the study, drugs, goals, and intended patient involvement will be 
discussed. At this point, patients will have the choice of whether or not to sign the consent 
form. They will be given time for reflection, if desired. If the patient is participating in the 
study, demographic data, clinical characteristics of the subdural hematoma and 
characteristics of transient neurological symptoms will be collected using a standardized 
questionnaire (Appendix 3). Thereafter, treatment (TPM or LEV) will be assigned by 
randomization and started during hospitalization with a planned increase up to 

VERSION 3.0 -10/20/2020 
20 
 
therapeutic doses according to the protocol below. A notebook containing the 
information discussed, the contact information and forms (appendix 5) for weekly 
monitoring of neurological symptoms and side effects will be given. 
 
In parallel, after starting the treatment (TPM or LEV), two other daily EEGs will be 
performed. If an EEG is positive, there will be no further EEG needed. Additionally, if an 
EEG is positive, the patient will remain in the same treatment group, however, a sub-
analysis may compare the correlation between EEG and NESIS score results. In addition, 
brain magnetic resonance imaging will be recommended for patients with three negative 
EEGs to rule out an alternative diagnosis, such as transient ischemic events. This test is 
already part of the usual assessment of transient neurological symptoms with negative 
EEG and therefore does not represent an additional test for patients. However, this 
examination will be at the discretion of the clinician, depending on the clinical relevance 
and availability of the examination. 
 
Electrocorticography 
If the patient has TNS preoperatively, the installation of electrocorticography electrodes 
in the subdural space will be suggested. We anticipate that approximately 5 to 10 patients 
out of the 56 enrolled will be eligible and be offered this option. This step is optional and 
will not influence subsequent medical treatment. However, it will help to demonstrate 
the existence of propagated cortical depolarizations and potentially prove the 
effectiveness of a non-invasive screening strategy. If the patient agrees, two ECoG strip 
electrodes will be inserted into the subdural space along with the installation of the 
subdural drain during the surgery. The electrodes will be located at the level of the upper 
temporal line and oriented anteroposterior in order to cover the frontal operculum as 
well as the inferior parietal lobule. This procedure is identical to that carried out routinely 
in the surgical assessment of patients with epilepsy. The patient will then be transferred 
to the EEG monitoring unit where a surface EEG and a bi-frontal near infrared 
spectroscopy monitor will be installed. The patient will then be monitored continuously 
until at least 5 episodes of TNS are recorded, or for a maximum of 72 hours. The 
electrodes will then be removed by traction at the bedside and a stitch will be performed 
under local anesthesia. The data will be analyzed by an epileptologist. 
 
Intervention 
The intervention (Topiramate versus Levetiracetam) will be initiated in the hospital and 
then, initially, a prescription will be given to the patient for the community pharmacy. 
 
Topiramate will be initiated at 50 mg BID, with an expected increase of 50 mg per week 
until symptoms are controlled or up to a maximum titration of 100 mg BID. 
 
Levetiracetam will be initiated at 500 mg BID, with an expected increase of 1000 mg 
divided into 2 doses per week until symptoms are controlled or up to a maximum titration 
of 1500 mg BID. 

VERSION 3.0 -10/20/2020 
21 
 
 
The drugs could be reduced or stopped after discussion with a doctor because of side 
effects or no improvement in TNS. 
 
Follow-up 
There will be two phone follow-ups (2nd week and 6th month), as well as two clinical 
follow-ups (2nd and 4th month). 
 
Phone follow-up: Medical evaluation by a resident, neurologist or neurosurgeon 
participating in the study. The person administering the assessment will follow a 
standardized questionnaire so as not to omit information relevant to the study. This 
assessment includes characterization of transient neurological symptoms and 
investigation of side effects. 
Clinical follow-up: The patient will bring his study notebook to the appointment, in which 
he will have recorded the various TNS or side effects that have occurred in recent weeks. 
The appointment will be made by a neurologist or a neurosurgeon (all patients will have 
a meeting with each of the two specialists). The doctor will therefore carry out an 
evaluation of TNS and side effects, by completing the standardized questionnaire, which 
will help to limit the missing data. 
 
The last follow-up will take place at 6 months, a date that we have based on the various 
studies in cortical depression which have demonstrated maximum effectiveness of TPM 
at 17 weeks23. As we did experience in our community, we believe that a significant 
difference could emerge even earlier. 
 
Losses during follow-up: patients who do not come to the follow-up appointment will be 
contacted again. In the event of a refusal to attend follow-up or a second absence from 
an appointment, with the patient's consent, a medical assessment may be completed by 
phone. 
 
If the patient wishes to stop the antiepileptic drug, a trial of smaller doses of the same 
treatment will be offered. Upon refusal, or failure despite a reduction in doses, TPM will 
be offered to the patient if he had LEV and vice versa. This change of group will only be 
possible after 2 months from the beginning of treatment. These data will not be included 
in the calculation of the primary outcome, but can still be analyzed as a secondary 
outcome to assess whether changing patients from one group to another allows them to 
fully resolve the TNS. Patients who fail both treatments, or who refuse to attempt the 
treatment in the other group will be excluded from the remainder of the study and 
treatment with another antiepileptic recognized in the treatment of focal seizures as well 
as an usual follow-up will be offered. 
 

VERSION 3.0 -10/20/2020 
22 
 
Participant calendar 
Table 4 – Participant calendar 
Recruitment  
(Day 1) 
Randomizatio
n 
(After 
recruitment) 
Phone  
follow-up 
(Week 2) 
Clinic follow-up 
(Month 2) 
Clinic follow-up 
(Month 4) 
Phone  
follow-up 
(Month 6) 
Standardized 
questionnaires : 
Epidemiological 
data 
Clinical features 
Start of 
treatment 
 
EEG daily x 2 
 
MRI if needed 
Medical 
assessment 
with 
standardized 
questionnaire 
Medical 
assessment 
with 
standardized 
questionnaire 
Medical 
assessment 
with 
standardized 
questionnaire 
Medical 
assessment 
with 
standardized 
questionnaire 
Collection method 
Sources: Data will be collected initially with the help of the patient's medical record. 
Subsequently, the rest will be completed entirely by the patient or his family. The 
evaluations will be guided by standardized questionnaires.  
 
For patients with ECoG, continuous waveforms will be recorded for the entire period the 
electrode will be implanted, either up to the recording of 5 TNS episodes or up to 72 hours 
of recording. 
 
The data will be collected double blind. The person administering the questionnaire and 
the person analyzing the data will not know the patient’s group. In addition, a study 
number will be assigned to all patients during randomization and this is going to identify 
the patients on the questionnaires. Thus, the data will be entered into the Excel software 
anonymously. Following the study, the data will be kept for a period of 25 years, in a file 
locked with a password that will be in the research nurse's locked filing cabinet. 
 
Data analysis 
Statistics 
Statistical analysis of the various data will be done with the help of the Statistical Package 
for the Social Sciences (SPSS) software. Most of the data will be analyzed by members of 
the research team. If necessary, the statistician of the CRC (Clinical Research Center) will 
be consulted. 
 
The results will be analyzed by "intension-to-treat" given the expected dropouts in the 
two treatment groups. 
 
Primary outcome: To assess the efficacy of TPM compared to LEV in the treatment of TNS 
in the context of SDH with negative EEG. To do this, it will be necessary to compare the 
rate of complete resolution of symptoms between the two groups. Our study comprising 
two independent groups and this variable being dichotomous (resolution: yes or no), a 
Chi-Square test will be used. This same test will also be used to compare the response of 
TPM in the NESIS versus non-NESIS subgroups and the same comparison with LEV will also 

VERSION 3.0 -10/20/2020 
23 
 
be performed. Subsequently, as sub-analyzes, the decrease in the frequency, intensity 
and duration of episodes (continuous variables) will also be compared in the two groups 
using a Student's T-test after validation of assumptions underlying the test. 
 
Secondary outcome: tolerance to the antiepileptics used. To do this, we will analyze the 
comparison of the dropout rate (dichotomous variable: yes or no) and the side effect rate 
(categorical variable) using a chi-square test. 
 
Degree of significance 
We retained a significance level corresponding to an error a of 5%, whether a value 
p<0.05. The accepted beta error (b) is 10%, for a power of 90%. 
 
Missing data 
Patients with a large number of missing data or not including the data necessary to 
calculate the primary outcome will be excluded from the study. Those with some missing 
data that do not allow certain calculations of secondary outcomes will be kept in the 
study, however, the sample sizes of these analyzes will be clarified during writing. 
 
Oversight mechanism 
An independent results and dropout rate monitoring committee will not be necessary. 
However, monitoring will be carried out by the project team. 
 
Safety monitoring: Every month, from the time when 10 patients have been 
recruited, safety data (dropout, major side effects (requiring discontinuation of 
treatment) and persistence of neurological symptoms (yes or no)) will be compared 
in both groups. If a difference of more than 50% is identified for any of these data, 
the ethics committee will immediately be informed. A modification or 
discontinuation of the study will then be evaluated for reasons of safety, theoretical 
efficacy or futility. 
 
Limitations of the study 
Obviously, our study includes several sources of bias that we anticipate, however we will 
try to limit their impacts. 
 
Selection bias 
The patients who will be selected in our study may not represent the target population of 
our study. Indeed, a bias of voluntarism is inherent in the estimate of our study. Patients 
agreeing to participate in a study often do not have the same characteristics as those 
refusing, causing a gap between the study population and the target population. To limit 
the impact of this bias, we have designed our study so that it does not represent 
additional displacement or test for patients, in order to limit refusals to participate. In 

VERSION 3.0 -10/20/2020 
24 
 
addition, the use of a non-probability sample can lead to a reference bias. Patients 
attending the coordinating center may differ from those attending another, for 
environmental, geographic or other reasons. To limit this bias, by using a multicenter 
study, we took several centers that are geographically distant, which will represent the 
general population more fairly. In addition, the recruitment being done in a similar way 
for the two groups and the matching according to the home hospitals will allow to balance 
these possible differences which could interfere during the recruitment. 
 
Measurement bias 
Some fluctuation in the measuring instrument (questionnaire) may occur. In fact, over 
time, the patient may find the questionnaire redundant and become bored, and 
therefore respond less well to it. To limit the impact of this factor, we have limited the 
number of follow-ups. In addition, in order to balance this fluctuation in the two groups, 
we will use the same questionnaires in both groups. 
Compliance bias 
Because TPM causes more side effects than LEV, compliance in this group may be lower. 
To limit the impact of this bias, active monitoring will be carried out with patients in the 
event of significant side effects, in order to reduce the dose of their treatment. This will 
limit drop-outs, as well as encourage better compliance. Then, the antiepileptics will be 
introduced gradually, in order to limit the side effects which would lead to a decrease in 
compliance. 
 
Desirability bias 
Because patients will know with which antiepileptic drug they will be assigned to, they 
could involuntarily change their different responses during assessments. Indeed, they 
might be tempted to demonstrate that TPM, treatment intervention, is more effective 
than it actually is. The same goes for side effects, which might be exaggerated by a patient 
knowing to take TPM, which is known to cause more side effects. To limit this bias, with 
the agreement of the ethics committee, we will approach patients during consent in a 
non-nominal manner. Indeed, while explaining that the two treatments are as effective 
as each other in epilepsy, we will explain that we want to demonstrate whether there is 
superiority of one of the two drugs over the other. Our hypothesis considering TPM being 
more efficient would remain confidential especially as this remains hypothetical. In the 
same sense, upon consent, all possible side effects will be presented in the form of a list, 
not distinguishing which are found more with which antiepileptic. Thus, even knowing the 
antiepileptic medication prescribed, patients will not be able to influence their responses 
for or against a particular treatment, not knowing which characteristics belong to which 
treatment. The two groups will therefore have the same potential information regarding 
their antiepileptic drug. 
 

VERSION 3.0 -10/20/2020 
25 
 
Other limitations : 
The effect of Leveracetam on cortical depolarizations remains conflicting, however, if 
present, it may lessen the impact of our results. In addition, the favorable natural course 
of cortical depolarizations could mask the significant difference between our two groups. 
Time and personnel management 
Initial and follow-up in-clinic assessments will be performed during regular hospital hours. 
Telephone assessments will be carried out during the day or evening by a member of the 
research team. 
Ethics 
Consent 
Before signing the consent form, patients will be informed about the subject and purpose 
of the study. There will also be an explanation of the antiepileptics used. A list of common 
and serious side effects of the two treatments will be provided and explained. This list will 
not indicate which side effect is attributed to which antiepileptic drug, in order to limit 
the desirability bias (see desirability bias above). The consent must meet the same criteria 
as usual; the patient must be able to offer free and informed consent. Substituted consent 
in the event of incapacity, with the most significant relative, at the bedside or by phone 
will also be authorized. Patients will be clearly informed, verbally and in writing, that 
participation in the study is voluntary and that they can withdraw at any time during the 
study. We will also explain that termination of participation in the study will not limit the 
treatment of their condition and medical monitoring will be provided. 
 
Confidentiality 
The confidentiality of personal information and patient results will be ensured throughout 
the study. Indeed, during the randomization, a random number will be provided to each 
patient. A file indicating these identification numbers associated with the names of the 
patients and their contact information will be designed separately from the data 
collection file. These two documents will be kept separately in the research nurse's office. 
They will stay at the CHUS at all times. 
 
By agreeing to participate in the study, patients agree that research staff have access to 
their medical records during recruitment and then subsequently as needed. Eventually, 
the results of the study will be published in a medical journal, ensuring patient 
confidentiality. 
 
Risks of participating in the study 
The two drugs used in the study carry certain risks and side effects. Levetiracetam can 
cause depression or psychosis. These effects may rarely be severe but are reversible. In 
addition, it is important to understand that this drug would likely be the one proposed 
without this study, being the best tolerated and easiest to use of all antiepileptics. This 
risk would therefore be the same, with or without the study. As for Topiramate, it mainly 

VERSION 3.0 -10/20/2020 
26 
 
causes gastrointestinal side effects. These are relatively frequent, but reversible and 
mainly lead to stopping the drug. Its use is therefore less in usual clinic, because 
compliance is more difficult to obtain. Thus, by participating in the study, some patients 
may experience these side effects and have to stop this medication, causing some loss in 
follow-up. They can stop the medicine without prejudice at any time during the study. 
 
Finally, the insertion of an ECoG electrode is associated with a minimal, but higher risk of 
postoperative infection (1%). Continuous monitoring for a maximum of 72 hours will also 
require the patient to remain connected to the devices in their room during this period. 
ECoG is not expected to increase the length of hospital stay, as the protocol is designed 
to respect the usual recovery of patients following cSDH drainage. 
Anticipated impact 
We believe that the results of this project, negative or not, will be of great importance. 
Indeed, this study being the first on the subject and the pathology in question being 
frequent, our intervention could offer a new treatment for patients with cSDH and TNS 
not responding to the usual treatments but could also interest other researchers. TNS 
have a major impact on lives of patients. For example, as long as there is a suspicion of 
epilepsy, a patient loses his driver’s license for 6 months after each neurological episode. 
This can have a significant impact on the life of a patient, but also for society. So, now that 
we know from our preliminary study that there is possibly an effective treatment for this 
condition, it is our duty to test this hypothesis. 
Dissemination of results 
We plan to publish our results in a scientific journal, whether negative or positive. We 
would also like to present them at neurology and neurosurgery congresses. The target 
audience therefore represents people working in research, neurology and neurosurgery. 
 
Timeline 
Table 5 - Timeline 
Date 
Intervention 
04/2020 
Submission of the protocol to the ethics 
and research committee 
08/2020 
Final approval of the research protocol 
09/2020 
Final agreements on the participation of 
other participating centers 
10/2020 
Hiring of the research nurse 
10/2020 
Start of randomization 
10/2022 
End of randomization 
12/2022 
End of writing and submission 
 
 

VERSION 3.0 -10/20/2020 
27 
 
Budget 
- 
There will be no cost for antiepileptics, which will be prescribed and obtained from 
the patients' respective community pharmacies. 
- 
There will be no charge for administration of questionnaires, these being done in 
the context of the patient's clinical follow-up. Since there is no additional follow-
up than what would be expected without our study, there will be no additional 
office costs. 
- 
There will be no financial compensation for patients, as no additional follow-up 
will be required of them. 
- 
ECoG electrodes will need to be purchased. We anticipate that approximately 25% 
of patients will present TNS preoperatively and that 50% of these will accept 
monitoring, thus totaling 6-10 patients out of 60.  
 
 
Table 6 - Budget 
 
The budget necessary for the realization of our study will be provided through the 
research funds of the project supervisor, Christian Iorio-Morin. Once the protocol is 
approved by the ethics committee, formal grant applications will be made to provincial 
and federal granting agencies, as well as to trauma, stroke or epilepsy associations. 
Dissemination costs will be covered by the neurology department of the CHUS. 
 
Signatures of the researcher and supervisor 
 
Expenses 
Cost by patient 
Total cost 
Research nurse 
(35$/hour)  
(Let's assume that she will 
do all of the initial 
meetings in order to have 
a sufficient budget) 
Initial meeting of 1h30 for 60 
patients 
 
Meetings with patients 
refusing to participate in the 
study (30 min for about 60 
patients) 
3150$ 
 
 
1050$ 
Resident salary when 
drafting  (2 months) 
2 x 1400$ 
2800$ 
Statistician help  
(50$/hour) 
3h x 50$ 
150$ 
ECoG electrodes 
10 x 500$ 
5000$ 
Stationery and printing 
costs 
N/A 
120$ 
Diffusion costs 
N/A 
1500$ 
TOTAL 
13 770$ 

VERSION 3.0 -10/20/2020 
28 
 
________________________________          __________________________________ 
Suzie Adam                                                                      Christian Iorio-Morin 
Main researcher.                                                            Supervisor 
Neurology department.                                                Neurosurgery department 
Université de Sherbrooke                                             Université de Sherbrooke 
 
Date : ___________________________                    Date : ______________________________ 
                           (JJ/MM/AAAA)                                                                   (JJ/MM/AAAA) 
 
 

VERSION 3.0 -10/20/2020 
29 
 
References 
1. Cousseau DH, Echevarría Martín G, Gaspari M, Gonorazky SE. Chronic and 
subacute subdural haematoma. An epidemiological study in a captive population. 
Rev Neurol. 2001;32(9):821-824. 
2. Toi H, Kinoshita K, Hirai S, et al. Present epidemiology of chronic subdural 
hematoma in Japan: analysis of 63,358 cases recorded in a national administrative 
database. J Neurosurg. 2018;128(1):222-228 
3. Won S-Y, Dubinski D, Herrmann E, et al. Epileptic seizures in patients following 
surgical treatment of acute subdural Hematoma-Incidence, risk factors, patient 
outcome, and development of new scoring system for prophylactic antiepileptic 
treatment (GATE-24 score). World Neurosurg. 2017;101:416-424. 
4. King MA, Newton MR, Jackson GD, et al. Epileptology of the first-seizure 
presentation: a clinical, electroencephalographic, and magnetic resonance 
imaging study of 300 consecutive patients. Lancet North Am Ed. 
1998;352(9133):1007-1011. 
5. Levesque M, Iorio-Morin C, Bocti C, Vézina C, Deacon C. Nonepileptic, 
Stereotypical, and Intermittent Symptoms (NESIS) in Patients With Subdural 
Hematoma: Proposal for a New Clinical Entity With Therapeutic and Prognostic 
Implications. 
Neurosurgery. 
2019 
Sep 
25. 
pii: 
nyz355. 
doi: 
10.1093/neuros/nyz355. [Epub ahead of print] PubMed PMID: 31555809 
6. Woitzik J, Hecht N, Pinczolits A, et al. Propagation of cortical spreading 
depolarization in the human cortex after malignant stroke. Neurology 2013; 80: 
1095–1102. 
7. Klass A, Sánchez-Porras R, Santos E. Systematic review of the pharmacological 
agents that have been tested against spreading depolarizations. J Cereb Blood 
Flow Metab. 2018 Jul;38(7):1149-1179. doi: 10.1177/0271678X18771440. Epub 
2018 Apr 20. PubMed PMID: 29673289; PubMed Central PMCID: PMC6434447 
8. Harriott AM, Takizawa T, Chung DY, Chen SP. Spreading depression as a preclinical 
model of migraine. J Headache Pain. 2019 May 2;20(1):45. doi: 10.1186/s10194-
019-1001-4. Review. PubMed PMID: 31046659; PubMed Central PMCID: 
PMC6734429. 
9. Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical 
aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of 
action. Epilepsia 2000; 41:S3–S9. 
10. Bagnato F, Good J. The Use of Antiepileptics in Migraine Prophylaxis. Headache. 
2016 Mar;56(3):603-15. doi: 10.1111/head.12781. Epub 2016 Mar 3. Review. 
PubMed PMID: 26935348. 
11. Ashtari F, Shaygannejad V, Akbari M. A double-blind, randomized trial of low-dose 
topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand 
2008;118:301–305. 
12. Storey JR, Calder CS, Hart DE, Potter DL. Topiramate in migraine prevention: a 
double-blind, placebo-controlled study. Headache 2001;41:968–975. 

VERSION 3.0 -10/20/2020 
30 
 
13. Brandes JL, Saper JR, Diamond M, et al. ; MIGR-002 Study Group Topiramate for 
migraine prevention: a randomized controlled trial. JAMA 2004;291:965–973. 
14. Millán-Guerrero RO, Isais-Millán R, Barreto-Vizcaíno S, et al. Subcutaneous 
histamine versus topiramate in migraine prophylaxis: a double-blind study. Eur 
Neurol 2008;59:237–242. 
15. Diener HC, Matias-Guiu J, Hartung E, et al. Topiramate in migraine prophylaxis–
results from a placebo-controlled trial with propranolol as an active control. J 
Neurol 2004;251:943–950 
16. Mei D, Capuano A, Vollono C, et al. Topiramate in migraine prophylaxis: a 
randomised double-blind versus placebo study. Neurol Sci 2004;25:245–250.  
17. Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group Topiramate in 
migraine prevention: results of a large controlled trial. Arch Neurol 2004;61:490–
495. 
18. Gupta P, Singh S, Goyal V, Shukla G, Behari M. Low-dose topiramate versus 
lamotrigine in migraine prophylaxis (the Lotolamp study). Headache 2007;47:402–
412. 
19. Beran RG, Spira PJ. Levetiracetam in chronic daily headache: a double-blind, 
randomised placebo-controlled study. (The Australian KEPPRA Headache Trial 
[AUS-KHT]). Cephalalgia. 2011 Apr;31(5):530-6. doi: 10.1177/0333102410384886. 
Epub 2010 Nov 8. PubMed PMID: 21059626 
20. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Antiepileptics other than 
gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic 
migraine in adults. Cochrane Database Syst Rev. 2013 Jun 24;(6):CD010608. doi: 
10.1002/14651858.CD010608. Review. PubMed PMID: 23797674 
21. Unekawa M, Tomita Y, Toriumi H, Suzuki N. Suppressive effect of chronic peroral 
topiramate on potassium-induced cortical spreading depression in rats. 
Cephalalgia. 2012 May;32(7):518-27. doi: 10.1177/0333102412444015. Epub 
2012 Apr 20. PubMed PMID: 22523186 
22. Akerman S, Goadsby PJ. Topiramate inhibits cortical spreading depression in rat 
and cat: impact in migraine aura. Neuroreport. 2005 Aug 22;16(12):1383-7. 
PubMed PMID: 16056144. 
23. Unekawa M, Tomita Y, Toriumi H, Suzuki N. Suppressive effect of chronic peroral 
topiramate on potassium-induced cortical spreading depression in rats. 
Cephalalgia. 2012 May;32(7):518-27. doi: 10.1177/0333102412444015. Epub 
2012 Apr20. PubMed PMID: 22523186. 
24. Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading 
depression in migraine prophylaxis. Ann Neurol. 2006 Apr;59(4):652-61. PubMed 
PMID: 16450381. 
25. Lin CH, Hsu SP, Cheng TC, Huang CW, Chiang YC, Hsiao IH, Lee MH, Shen ML, Wu 
DC, Zhou N. Effects of anti-epileptic drugs on spreading depolarization-induced 
epileptiform activity in mouse hippocampal slices. Sci Rep. 2017 Sep 
19;7(1):11884. doi: 10.1038/s41598-017-12346-y. PubMed PMID: 28928441; 
PubMed Central PMCID: PMC5605655 

VERSION 3.0 -10/20/2020 
31 
 
26. Up to date. Topiramate: Drug information. 2019. 
https://www.uptodate.com/contents/topiramate-drug-
information?search=topiramate&source=panel_search_result&selectedTitle=1~
148&usage_type=panel&kp_tab=drug_general&display_rank=1#references [En 
ligne] 
27. Up to date. Levetiracetam : Drug information. 2019. 
https://www.uptodate.com/contents/levetiracetam-drug-
information?search=keppra&source=panel_search_result&selectedTitle=1~82&
usage_type=panel&kp_tab=drug_general&display_rank=1 [En ligne] 
28. Keiss Douri, Mathieu Lévesque M.D., David Mathieu M.D. and Christian Iorio-
Morin M.D., Ph.D. Incidence of Non-Epileptic, Stereotypical and Intermittent 
Symptoms (NESIS) in the chronic subdural hematoma population, 2018 (EN 
COURS DE SOUMISSION) 
29. Bassel W, Abou-Khalil. Update on Antiepileptic Drugs 2019, AAN CONTINUUM 
(MINNEAP MINN) 2019;25(2, EPILEPSY):508–536. 
30. Zhuo, C., Jiang, R., Li, G. et al. Efficacy and Tolerability of Second and Third 
Generation Anti-epileptic Drugs in Refractory Epilepsy: A Network Meta-
Analysis. Sci Rep 7, 2535 (2017). https://doi.org/10.1038/s41598-017-02525-2 
31. Santé-Canada, Registre des produits pharmaceutiques, https://hpr-
rps.hres.ca/details.php?drugproductid=636&query=APO-TOPIRAMATE 
32. CTCAE, classification des effets secondaires, 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTC
AE_v5_Quick_Reference_8.5x11.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

VERSION 3.0 -10/20/2020 
32 
 
Appendix 
Appendix 1 – NESIS score 
 
NESIS 
Valeur des points pour 
le calcul du score 
Features supporting NESIS 
 
Negative symptoms 
+4 
Duration of ≥ 5 min 
+3 
Dysphasia 
+3 
Migration 
+1 
≥ 5 episodes 
+1 
Stereotypy 
+1 
Characteristics against NESIS 
 
Altered state of consciousness 
-4 
Clonic movements 
-4 
Diagnosis of NESIS if total score ≥ 4 and no positive EEG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

VERSION 3.0 -10/20/2020 
33 
 
Appendix 2 – Consent form 
 
Filed as a separate document  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

VERSION 3.0 -10/20/2020 
34 
 
Appendix 3 – Initial form 
 
Initial form 
 
… 
 
Inclusion and exclusion criterias : 
Inclusion criteria 
Exclusion criteria 
Age ≥ 18 ans 
 
Contraindications to Levetiracetam 
• 
Psychiatric history (depression, psychosis, 
risk of suicide) 
• 
History of hypersensitivity (anaphylaxis, 
angioedema, skin reaction) to LEV 
 
Transient neurological 
symptoms 
 
Contraindications to Topiramate 
• 
History of hypersensitivity to TPM 
• 
Glaucoma 
• 
History of urinary lithiasis 
 
Subdural hematoma 
 
Known epilepsy or seizure before current subdural 
hemorrhage 
 
 
 
Taking an antiepileptic 
 
 
 
Intracranial pathology other than SDH 
(subarachnoid hemorrhage, intraparenchymal 
hemorrhage, neoplasia) 
 
 
 
Pregnancy or planning to be 
 
 
 
Inability to carry out the necessary follow-ups for 
the study 
 
 
 
Refusal of the attending physician 
 
 
Demographic datas : 
Data type 
Answers 
Specification 
types 
Specifications  
Age 
 
 
 
Sex 
 
 
 
Dominant hand 
(Right or left) 
 
 
 
Tobacco 
 
Active, ceased, 
never 
 
Alcohol 
 
Type et 
quantity 
 
Drugs 
 
Type et 
quantity 
 

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35 
 
High blood pressure 
 
Adequate 
control 
 
Diabetes 
 
With or 
without insulin 
Type 1 or 2 
 
Dyslipidemia 
 
 
 
Auricular fibrillation 
 
 
 
Coronary disease 
 
Event types 
 
Peripheral vascular 
disease 
 
Location 
 
Migraines 
 
With or 
without aura 
Aura type 
 
Past stroke, TIA 
 
Event type 
 
Past SDH 
 
Location 
Past TNS 
 
Past intracranial 
injury 
 
Type 
Treatment 
 
Past intracranial 
surgery 
 
Indication 
Type 
 
Antiplatelet used 
 
Indication 
Type 
 
Anticoagulant used 
 
Indication 
Type 
 
 
 
SDH characteristics : 
Characteristics 
Answer type 
Answers 
Specifications 
SDH type 
Homogeneous 
Laminar 
Separated 
Trabecular 
 
 
SDH location 
Droit, gauche ou 
bilatéral 
 
 
SDH cause 
Traumatic or others 
 
 
SDH thickness 
Millimeters 
 
 
Median line shift 
Millimeters 
 
 
Initial Glasgow score 
3-15 
 
 
Drainage surgery  
Yes/no 
 
 
Surgery location 
Right, left or both 
 
 
Associated subarachnoid 
hemorrhage 
Yes/no 
Location 
 
 
 

VERSION 3.0 -10/20/2020 
36 
 
TNS characteristics : 
Characteristics 
Answers 
Specification types 
Specifications 
Visual symptoms 
 
Location 
Visual loss 
Flash, llight 
 
Speech symptoms 
 
Aphasia 
Dysarthria 
Mutism 
 
 
 
Cerebellar symptoms 
 
Balance disorder 
Nausea / vomiting 
Dizziness / vertigo 
 
Motor symptoms 
 
Paresis / paralysis 
Clonic movements 
Change in tone 
 
Sensory symptoms 
 
Hypoaesthesia 
Paresthesia 
 
Altered state of 
consciousness 
 
Duration 
 
Duration of symptoms 
 
Seconds/minutes 
 
Number of episodes 
 
Per unit of time 
 
Symptom migration 
 
How long 
From what place to what 
place 
 
Stereotypy of 
symptoms 
 
If not: try to distinguish 
the different episodes 
 
Prodrome 
 
How long before the 
episode 
Type of symptoms 
 
Postictal 
 
Duration 
 
 
Other comments : 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________ 
 
 
 
 
 
 
 
 

VERSION 3.0 -10/20/2020 
37 
 
Appendix 4 – Follow-up form 
 
Follow-up form 
 
Part 1 – Neurological symptoms 
Persistence of transient neurological symptoms?   Yes ☐  No ☐ 
- 
If no : go to part 2.  
- 
It is still important to validate all types of neurological symptoms with the patient in 
order to be sure that they are absent. 
 
TNS characteristics : 
Characteristics 
Answers 
Specification types 
Specifications 
Visual 
symptoms 
 
Location 
Visual loss 
Flash, llight 
 
Speech 
symptoms 
 
Aphasia 
Dysarthria 
Mutism 
 
 
 
Cerebellar 
symptoms 
 
Balance disorder 
Nausea / vomiting 
Dizziness / vertigo 
 
Motor 
symptoms 
 
Paresis / paralysis 
Clonic movements 
Change in tone 
 
Sensory 
symptoms 
 
Hypoaesthesia 
Paresthesia 
 
Altered state of 
consciousness 
 
Duration 
 
Duration of 
symptoms 
 
Seconds/minutes 
 
Number of 
episodes 
 
Per unit of time 
 
Symptom 
migration 
 
How long 
From what place to 
what place 
 
Stereotypy of 
symptoms 
 
If not: try to distinguish 
the different episodes 
 
Prodrome 
 
How long before the 
episode 
Type of symptoms 
 
Postictal 
 
Duration 
 
 

VERSION 3.0 -10/20/2020 
38 
 
Other comments:  
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
 
Part 2 – Side effects 
Was the antiepileptic treatment discontinued by the patient ?     Yes ☐  No ☐ 
If yes, why ? _________________________________________________________ 
 
Has the dose already been changed during a previous follow-up ?         Yes ☐  No ☐ 
(Do not ask for the patient's dose in order to stay blind) 
 
Are there any missed doses ?       Yes ☐  No ☐ 
If yes, at what frequency ? _________________________________________________ 
 
Possible side effects 
Type 
Yes/no 
Type CTCAE 
grade 
Specifications 
Fatigue/sleep 
 
 
 
 
Appetite/weight 
 
 
 
 
Gastrointestinal symptoms 
 
 
 
 
Psychiatric symptoms 
 
 
 
 
High blood pressure/orthostatic 
hypotension 
 
 
 
 
Change in behavior/irritability 
 
 
 
 
Headaches 
 
 
 
 
Dizziness/vertigo 
 
 
 
 
Paresthesia 
 
 
 
 
 
Other side effects (specify CTCAE grade) : 
________________________________________________________________________
________________________________________________________________________ 
 
Other comments: 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________ 

VERSION 3.0 -10/20/2020 
39 
 
 
Appendix 5 – Participant notebook 
 
Notes section 
Neurological symptoms 
- 
We are looking for transient neurological symptoms (lasting less than 60 
minutes). 
- 
To complete the table - types of neurological symptoms: 
A. Visual symptoms 
§ Specifications :  
1. Visual loss 
2. Light flash 
3. Sparkles 
4. Other (Specify) 
B. Sensory symptoms 
§ Specifications :  
5. Numbness 
6. Loss of sensation of the skin 
7. Other (specify) 
C. Vertigo/dizziness 
§ Specifications : 
8. Spinning part 
9. Impression of turning on oneself 
10. Other (specify) 
D. Nausea and vomiting 
E. Gait disturbances 
§ Specifications : 
11. Balance disorders such as when consuming too much 
alcohol 
12. Other (specify) 
F. Motor symptoms : 
§ Specifications : 
13. Paralysis or sudden weakness 
14. Abnormal involuntary movements of a limb 
15. Other (specify) 
G. Speech disorder : 
§ Specifications : 
16. Inability to understand others 
17. Inability to speak 
18. Inability to articulate properly 
19. Other (specify) 
H. Loss of consciousness 
I. Others 

VERSION 3.0 -10/20/2020 
40 
 
§ Specify in : Other comments 
 
Date and time of 
the event 
Type of symptoms 
Description 
 
Type of symptoms (A-B-C-D-
E-F-G-H-I): 
 
 
 
Duration of symptoms (seconds): 
 
Onset of symptoms: 
☐ Sudden 
☐ Gradual 
Specifications (See those 
proposed under the type of 
symptom) (1-2-3…): 
 
 
 
 
 
 
 
 
Other comments : 
… 
 
Side effects 
- 
Try to answer the questions in the table once every two weeks, even if no new 
symptoms have arisen. 
- 
If bothersome or severe symptoms: notify a member of the research team, the 
dose could be adjusted or discontinued. 
- 
List of symptoms that could occur: 
A) In general: 
1. Fatigue 
2. Dizziness 
3. High blood pressure 
4. Skin rashes 
5. Hair loss 
6. Fever 
7. Joint pain 
B) Intestinal: 
1. Weight loss 
2. Appetite loss 
3. Abdominal pain 
4. Nausea and vomiting 
5. Diarrhea 

VERSION 3.0 -10/20/2020 
41 
 
6. Gastroesophageal reflux disease 
C) Urinary: 
1. Urinary infection 
2. Kidney stones 
D) Neuropsychiatrics: 
1. Fatigue  
2. Anxiety  
3. Irritability 
4. Agressivity 
5. Agitation 
6. Emotional lability 
7. Psychosis 
8. Depression  
9. Memory impairment 
10. Confusion 
E) Neurologics: 
1. Headaches 
2. Gait disturbance, loss of balance 
3. Numbness 
F) Infectious: 
1. Sinus infection 
G) Ocular: 
1. Glaucoma 
H) Others: 
1. Specify 
 
Date 
Symptoms 
description 
Characteristics 
 
Type of 
symptoms (ex: 
A3): 
 
If category 
Others (H), 
please specify: 
Intensity (mild-moderate or severe) : 
Frequency (rarely, sometimes, often) : 
… 
 
Other comments 
________________________________________________________________________
________________________________________________________________________