Neurochirurgie 67 (2021) 265–275

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Original article

Second Impact Syndrome. Myth or reality?

J. Engelhardt a , D. Brauge b , H. Loiseau c,∗
a
Department of Neurosurgery, University of Bordeaux, Hôpital Pellegrin, 33076 Bordeaux cedex, France
b
Department of Neurosurgery, University of Toulouse, Hôpital Pierre-Paul Riquet, place du Dr Baylac TSA, 40031, 31059 Toulouse, France
c
Department of Neurosurgery, University of Bordeaux, Hôpital Pellegrin, EA 7435 - IMOTION (Imagerie moléculaire et thérapies innovantes en oncologie)
Université de Bordeaux, 146, rue Leo-Saignat, Case 127, site Carrière - Zone Nord, Batiment 3B, 3e étage, 33076 Bordeaux, France

a r t i c l e i n f o a b s t r a c t

Article history: Introduction. – Second impact syndrome (SIS) is a devastating condition occurring in sport-induced mild
Received 21 August 2019 brain injury. SIS is drastically defined by anamnestic, clinical and radiological criteria, which is unusual
Received in revised form in the field of cranial traumatology. The purpose of this study was to provide a literature review of this
21 December 2019
syndrome.
Accepted 27 December 2019
Material and methods. – We conducted a literature review of all published studies on PubMed. The key-
Available online 10 March 2020
words were “second impact syndrome and catastrophic head injury”, “second impact syndrome and
sport”, “repeat concussion and catastrophic brain injury”, “catastrophic head injury and concussion”,
Keywords:
Second impact syndrome
“catastrophic head injury”, “concussion and second impact syndrome”, “concussion and repetitive head
Talk and deteriorate injury”.
Mild brain injury Results. – Eighty-two full-text articles were assessed for eligibility. Finally, 41 studies were included in
qualitative synthesis and 21 were included in quantitative synthesis.
Discussion. – The number of cases reported in the literature was extremely small compared to the popu-
lation at risk, i.e., the number of athletes exposed to repeated concussions. SIS was similar to talk and die
syndrome, with which it shares certain characteristics. If we consider SIS according to “talk and deteri-
orate tables”, it opens up interesting perspectives because they are specific in children and adolescents.
Taking into account the scarcity of this syndrome, one may question whether athlete-intrinsic features
may be involved in at least some cases of SIS. On a pathophysiological level, many explanations remained
unsatisfactory because they were unable to explain all the clinical phenomena and observed lesions.
Triggering the trigeminocardiac reflex is a crucial element in explaining the sequence of clinical events.
Its association with a state of neurogenic inflammation provides an almost complete explanation for this
particular condition. Finally, on a practical level, a concussion occurring during the playing of a sport
must be considered as any other injury before allowing a return to play.
© 2020 Published by Elsevier Masson SAS.

1. Introduction Literature analysis is difficult because semantic questions have

Second Impact Syndrome (SIS) is a term used in cranial trauma-
tology during sports. Historically, the first clinical description was
made in 1881 by Otto Bollinger who used the term “traumatische
spät-apoplexie” [1]. This condition was then updated by Schneider
in 1973, concerning two cases [2] and the term second impact syn-
drome was proposed by Saunders and Harbaugh [3]. These authors
defined it as a catastrophic brain injury following minor impact [3].
That is to say, this particular traumatic condition is defined by the
occurrence of a cascade of clinical events, most frequently lead-
ing to dramatic brain lesions without any measure of the observed
impact.
been raised, over time, by the various authors and different cur-
rents of thought. Thus, the chronology of events following a recent
initial head trauma, the persistence of clinical signs and the type
of lesions observed, etc., will be questioned. For some authors, the
second impact must be clearly identified, whereas a concussion
can occur without direct head impact. For others, there should be
no associated subdural hematoma, or this latter condition must be
minimal, not taking into accountthe brain swelling. The variations
in the criteria used are significant and lead to very variable counts
of the number of cases observed [4,5].
In 1998, McCrory & Berkovic performed a review of the literature
using strict definition criteria. Their criteria were:

∗ Corresponding author. • medical evaluation after initial trauma;

E-mail address: hugues.loiseau@chu-bordeaux.fr (H. Loiseau). • documentation of persistent clinical signs;

https://doi.org/10.1016/j.neuchi.2019.12.007
0028-3770/© 2020 Published by Elsevier Masson SAS.
J. Engelhardt, D. Brauge, H. Loiseau et al.
• identification of a second impact followed by rapid clinical dete-
rioration;
• radiological evidence or pathology of cerebral swelling without
significant intracranial hematoma or presence of another cause
of cerebral edema (e.g. encephalitis).
Finding 17 cases, whose ages ranged from16 to 24, they subse-
quently retained only 5 cases strictly meeting their criteria [6].
Another study focused specifically on these definition problems
[7]. These authors suggested that the heterogeneity of definitions
used in the literature, the variations in typology of lesions and
the player outcomes corresponded to a situation where differ-
ent pathophysiological events were mixed. Under such conditions,
information in terms of SIS risk must be treated with caution[7].
These allegations, moreover, are in agreement with the convictions
of Paul McCrory. Paul McCrory and coworkers recently wrote: “The
phenomenon of the second impact syndrome (SIS) continues to
appear in the medical literature in spite of the lack of systemic
evidence for its existence” [8].
Another approach was made by Hebert and coworkers [9]. These
authors compiled literature data in order to determine whether
the nosographic, clinical and radiological data were sufficiently
accurate to result in WHO coding of this condition. These authors
concluded that a unique presentation scheme of SIS was insuffi-
ciently lacking to support a standardized WHO case definition [9].
Therefore, it could be considered that SIS represents a contro-
versial diagnosis whereby malignant cerebral edema ensues after
minor trauma in the setting of a recent brain injury (assigned to
Cantu [10]).
Stovitz et al. concluded that the most commonly used definition
is: a syndrome requiring catastrophic brain injury (e.g., cerebral
edema) in a person who suffers a head trauma while still recovering
from the effects of a recent concussion [7]. This sequence is, in fact,
often difficult to identify.
Using the strictest definition of SIS (subjects with a second
head injury while concussion-related symptoms related to previ-
ous trauma have not disappeared) would indicate that:
• SIS is a rare condition;
• Validated cases nearly exclusively concerned males athletes;
• SIS occurs, almost exclusively, before the age of 20;
• SIS has been mainly, but not exclusively, reported among Amer-
ican football players;
• The typology of lesions observed in SIS (primary traumatic
lesions, brain swelling and/or aSDH) is extremely difficult to ana-
lyze with accuracy;
• The collected body of information is too limited to produce indi-
vidual data e.g. migraine [11].
In fact, the present review aimed at drawing attention to the
discrepancies and open questions found in the literature.
2. Material and methods
A literature search was performed using PubMed. The keywords
were “second impact syndrome AND catastrophic head injury”
(n = 20), “second impact syndrome AND sport”, (n = 85), “repeat
concussion AND catastrophic brain injury”, (n = 5), “catastrophic
head injury AND concussion”, (n = 62), “catastrophic head injury”,
(n = 290), “concussion AND second impact syndrome”, (n = 83),
“concussion AND repetitive head injury”, (n = 312). Among them,
820 were recorded after deleting duplicates [12].
266
Neurochirurgie 67 (2021) 265–275
3. Results
Eighty-two full-text articles were assessed for eligibility. At last
41 studies were included in qualitative synthesis and 21 were
included in quantitative synthesis. The references cited by the var-
ious identified studies were cross-checked and extracted in case
of relevance [2–4,10,13–30]. Results are summarized in Table 1. In
the vast majority of reported or suspected SIS cases, the observed
events and anomalies were stereotyped (Table 1).
4. Discussion
4.1. Clinico-radiological presentation
On the anamnestic level, there were:
• the notion of benign head trauma during the previous days;
• the persistence of symptoms related to the initial trauma;
• the occurrence of a new trauma, usually moderate, without nec-
essarily a loss of consciousness.
Clinically, onset, within seconds or minutes of the second
impact, involved collapse and/or severe coma with pupillary abnor-
malities (e.g., uni- or bilateral mydriasis and respiratory disorders)
[20].
Radiologically, there was evidence of cerebral swelling often
associated with acute subdural hematoma (aSDH) and anoxic-
ischemic lesions [27,31].
Death was observed in more than 50% of cases and favorable
neurological recoveries are exceptional.
4.2. Epidemiologic data
The number of reported cases, finally reduced and/or heteroge-
neous, raises some questions.
4.2.1. SIS is a rare condition while the at risk-population is high
All sports, especially during competitions rather than leisure,
can lead to a concussion [32]. Most of the 300,000 head injuries
observed annually in the USA during sports, are concussions [33]. In
a more recent study, Yard and Comstock estimated the annual num-
ber of concussions during sports to be approximately 400,000 for
High School athletes, with an index of 23.2 concussions per 100,000
athletes [34]. In the study by Yang and colleagues, the annual con-
cussion rate was 39.8 per 100,000 athlete exposures [35]. In the
study by Lincoln et al. conducted in high schools, the incidence was
0.24/1000 with an increase over time by a factor 4.2 in 11 years
[36]. Other types of indexation indicate that a concussion occurs
for 7.97/1000 player hours [37].
These figures are likely to be much lower than in reality because
it is considered that only about 50% of concussions are reported
[38,39]. The reasons are variable and dependent on the level of the
athlete. A major review was recently published [40]. The figures
provided by the High School Reporting Information Online Obser-
vatory (RIO) are quite similar, ranging between 2.09 and 5.03 per
10,000 athlete exposures (1 athlete participating in a competition
or training session). These data indicate a significant increase over
time during the 2005–2014 period, possibly related to the impact
of the laws enacting the declaration of concussions since 2009 [41].
Yang and coworkers estimated that the risk of repeated concussion
was 3.1 to 4.5 per 100,000 event athletes [35].
SIS concerns subjects who have suffered a second head injury,
while previous trauma concussion-related symptoms have not dis-
appeared in the strictest sense. The number of reported cases was,
paradoxically quite small. Indeed, all studies agree that concussions
 J. Engelhardt, D. Brauge, H. Loiseau et al.
Table 1

Authors Sport Age Sex Previous Evaluation Residual Delay Acute Collapse Coma Clinical Surgery Radiology and/or Other Outcome SIS McLendon
recent symp- headaches trau- autopsy lesions McCrory
trauma toms matic
lesions

Fekete Ice 16 M Yes Yes 4d no NA yes 3 contusions Died Probable Yes

1968 hockey cerebral edema, SAH

Schneider American 16 M NA NA NA Unilateral brain Died No

1973 football swelling
brainstem hemorrhage
thin a SDH
American M NA NA brainstem hemorrhage Died No
football

American 17 M NA NA Yes aSDH, midbrain Died No

football hemorrhage
brain swelling
American 17 M NA NA Yes NA Recovery No
football

Saunders American 19 M Yes Yes Yes 5d No Yes Yes No Yes Unilateral brain Died No
& Har- football swelling
baugh small SDH
1984 frontal contusion (first
trauma)
267

McQuillien Ski 18 M Yes No UK 2w Yes UK NA Brain swelling, a SDH Vegetative No

et al. lymphocytic infiltrates state
1988
Boxing 24 M disputable No NA < 1d Yes Yes NA Died No
Kelly American 17 M Yes No Yes 1w Yes Yes UK Brain swelling, small Died Probable
et al. football SDH, SAH
1991 obstructive
hydrocephalus
Shell American 17 M Yes UK No 5w Yes Yes Brain swelling, small Good No
et al. football aSDH recov-
1993 old contusion ery

Litt 1995 American 16 M Yes clinical yes 17j No Yes Yes no Yes Unilateral brain Favorable
football swelling
CT- small SDH
scan
Kersey American 19 M Yes Yes Yes 5w Yes No Yes no Yes Huge SDH Favorable

Neurochirurgie 67 (2021) 265–275

1998 football chronic and acute?

Cantu & Amateur 17 M Yes Yes 2d No Yes NA Yes Small SDH Died Probable Yes
Voy boxing cerebral edema
1995

Amateur 19 M Yes Yes 1d No Yes NA Small SDH Died Probable Yes

boxing
 J. Engelhardt, D. Brauge, H. Loiseau et al.
Table 1 (Continued)

Authors Sport Age Sex Previous Evaluation Residual Delay Acute Collapse Coma Clinical Surgery Radiology and/or Other Outcome SIS McLendon
recent symp- headaches trau- autopsy lesions McCrory
trauma toms matic
lesions

Cantu Seizure Unilateral brain

&1998 swelling
Amateur 17 M Yes Yes 6h No Yes NA Severe cerebral edema Died Probable Yes
boxing bilateral uncal
herniation
Boxing 21 M Yes UK Yes 2d No Yes Yes NA NA Died No
Amateur 24 M Yes Yes UK <1d No Yes Yes Brain swelling, no sSDH Died No
boxing midbrain necrosis

CDC 1997 American 17 M Yes <1 h Yes Yes Bilateral brain swelling Died No
football small aSDH, cortical
ischemia
American 19 M No Yes <1d Yes Yes Bilateral brain swelling Died No
football small aSDH
temporal herniation

Cantu American 13 M Yes UK Yes <1d Yes yes Unilateral brain Severely Yes
&Gean football swelling
1998 small aSDH
Disabled
268

American 16 M Yes UK Yes 7d Yes yes Unilateral brain Severely

football swelling
small aSDH Disabled
American 17 M Yes UK Yes 14d Yes yes Unilateral brain Died
football swelling
small aSDH
tonsillar herniation
American 19 M yes UK Yes 32d Yes Yes Unilateral brain Severely Yes
football swelling
small aSDH Disabled
American 15 M ? UK Yes 7d Yes Yes Unilateral brain Disabled Yes
football swelling
small aSDH
American 15 M Yes UK Yes 14d Yes Yes Unilateral brain Moderately Yes
football swelling
small aSDH Disabled
multifocal ischemic
infarction

Neurochirurgie 67 (2021) 265–275

American 17 M Yes UK Yes < 1d Yes Yes Unilateral brain Moderately Yes
football swelling
small aSDH Disabled
American 16 M Yes UK Yes 3d Yes No Unilateral brain Died
football swelling
small aSDH
 J. Engelhardt, D. Brauge, H. Loiseau et al.
Table 1 (Continued)

Authors Sport Age Sex Previous Evaluation Residual Delay Acute Collapse Coma Clinical Surgery Radiology and/or Other Outcome SIS McLendon
recent symp- headaches trau- autopsy lesions McCrory
trauma toms matic
lesions

American 16 M Yes CT- Yes 28d Yes Yes Unilateral brain Died Yes
football scan swelling
large aSDH; ischemic
infarction
American 10 F Yes UK Yes 3d yes Yes Yes Yes Unilateral brain Died
football swelling
small aSDH, severe HIE
Logan American 18 M Oui No Oui < 1d no No No No No Small aSDH Favorable
et al. football no swelling
2001
Seizure
Miele Boxing 24 F Yes No Yes 2w No No No cSDH Good
et al. recov-
2004 ery

Mori American 22 M Yes UK Yes 15d Yes No Small aSDH Good NA Yes
et al. football no brain swelling recov-
2006 ery

Karate 20 M Yes No Yes 4d No UK Small a SDH Good NA Yes

mild brain swelling recov-
ery
269

Boxing 23 M Yes UK Yes 2w Yes UK aSDH Good NA Yes

recov-
ery
Skiing 22 M Yes No Yes 2d No UK aSDH Good NA Yes
recov-
ery
Wetjen American 17 M Yes UK Yes 1w Yes Yes Bilateral brain swelling
et al. football
2010

Adler American 13 M Yes No Yes < 1d Yes Yes No Yes Disabled

et al. football
2011

Potts American 13 M Yes No Yes 3w no Yes Yes No Significant SDH Disabled NA Yes
et al. football brain swelling
2012

Neurochirurgie 67 (2021) 265–275

Yes
Weinstein American 17 M Yes Yes Yes 5d Yes Yes No No Bilateral a SDH Disabled NA
et al. football brain swellingHIE:
2013 splenium corpus
CT- Seizure callosum, thalami,
scan frontal lobes
 J. Engelhardt, D. Brauge, H. Loiseau et al.
Table 1 (Continued)

Authors Sport Age Sex Previous Evaluation Residual Delay Acute Collapse Coma Clinical Surgery Radiology and/or Other Outcome SIS McLendon
recent symp- headaches trau- autopsy lesions McCrory
trauma toms matic
lesions

Bonfield Ice 29 M Yes No Yes UK Yes Ears, No Massive brain swelling Died
and mouth
Kondzi- and
olka
2016
hockey Nose
bleed

Scramstad Judo 16 M Yes no Yes 1d Yes? NA Yes No No Unilateral brain

et al. swelling
2017 aSDH
small temporal
contusion
midbrain haemorrhage
Yengo- American 13 M No NA NA NA No UK Yes Bifrontal aSDH Good
270

Kahn football recov-

et al. ery
2017
Seizure?
American 15 M Yes yes NA 15d No UK Yes Yes aSDH, brain swelling Good
football HIE: splenium corpus recov-
callosum, ery
Seizure frontal lobes

American 16 M Yes Yes Yes < 1d No Yes Yes Large aSDH VA Severely
football dis-
abled
or HIE: splenium corpus Dissection
4-5w callosum, frontal lobes,
midbrain
Tator Rugby 17 F Yes No Yes 2d No Yes Yes Yes Brain swelling, small a
et al. SDH diffuse HIE micro
2019 temporal contusion

Neurochirurgie 67 (2021) 265–275

HIE: hypoxic-ischemic encephalopathy; aSDH: acute subdural hematoma; SAH: subarachnoid hemorrhage; NA: not applicable; D: day; W: week.
J. Engelhardt, D. Brauge, H. Loiseau et al.
are underreported and that the subjects return to play at an early
stage. The range is 15 to 40% depending on the rules established by,
the American Association of Neurology or the Prague consensus
conference respectively [34]. Recent research indicates that there
were 7,980,886 high school athletes in the United States, 7% of these
athletes had a concussion and 13.2% had a risk of repeated con-
cussion (e.g. 72,626 athletes per year) [35,40,41]. These data were
extrapolated by indexing the number of SIS cases identified as such
and the number of players at risk. A study reported by Randolph and
Kirkwood demonstrated that of 1.8 million high school and colle-
giate athletes, there was one instance of “possible” SIS for every
205,000 player seasons. In other words, this is comparable to a sin-
gle possible case of SIS for a team of 50 players every 4100 seasons.
Certainly, the proposed scarcity of SIS contributes to the difficulty
in diagnosis [42].
4.2.2. Validated cases concern male athletes.
This can be explained by the fact that 90% of the deaths occur-
ring during sporting activity concern males [43–45]. In contrast, an
equal number of concussions were observed in male and female
athletes [36]. Female athletes are twice as likely as males to suffer
repeat concussion [40]. These data validate the information pro-
vided in soccer [40].
4.2.3. SIS occurs, almost exclusively, before the age of 20.
Data from the NCAA and the National Federation of State High
School Associations were recently published. Thus, there were
7960,886 athletes in high school, 497,600 in college and 18,000 pro-
fessionals [40]. For American football, there were approximately
1,500,000 players in high school, 75,000 in college and 2000 [46,47].
Brain-related mortalities in sports was considered to be more fre-
quent at the high school level than at the college level, in other
words in younger subjects. It could be argued that this is simply a
size effect.
4.2.4. SIS has mainly been reported among American football
players
In fact, cases of SIS have been reported in other sports (box-
ing, skiing, ice hockey, etc.) [20,24]. In contrast, it has never been
reported by professional NFL footballers and, with rare exceptions,
by non-American teams [24,48]. Thus, McCrory, examining sports-
related deaths in Australia, did not find any cases of SIS [49].
4.2.5. The typology of lesions observed in SIS (brain swelling
and/or aSDH) is extremely difficult to compare accurately with
mortality data during sports
For example, data from the National Center for Catastrophic
Sports Injury Research (NCCSIR) have been published on several
occasions. Unfortunately, these publications have time-overlaps,
making counting difficult.
NCCSIR, 1980 and 1993 periods: 35 suspected cases of SIS and
17 confirmed by MRI or autopsy [20].
NCCSIR 1945-1999 period: 712 deaths occurred during games.
Of these, 491 were related to head trauma (69%) and 368 (75%)
to high school players. The combination of head trauma and aSDH
could account for more than 80% of brain-related deaths [47].
NCCSIR 1989-2002 period: 100 deaths were identified, of which
97.9% at the high school level versus 2% at the college level. Sub-
dural hematoma was diagnosed in 75 cases, subdural hematoma
associated with cerebral edema in 10 cases and isolated cerebral
edema in 5 cases. Fifty-nine percent of investigated cases had a
history of head trauma, although the date was not clearly speci-
fied, but it occurred during the same season. Out of 54 athletes for
whom traumatic history was identifiable, although 21 had returned
to play despite the persistence of neurological symptoms. Mortality
271
Neurochirurgie 67 (2021) 265–275
was 9% (n = 8), with a residual neurological disability of 51% (n = 48)
[45].
NCCSIR 1980-2009 period: 1827 deaths occurred during sports,
all sports combined, in athletes under the age of 21 years. In addi-
tion to 1139 cardio-vascular deaths, 261 were linked to sports
injuries, with a predominance of football (57% of deaths). The
authors identified 17 high school athletes who suffered from sec-
ond impact syndrome in American football players. These authors
indicated that, of the 138 footballers who died of head or neck
trauma and had a subdural hematoma, 17 (12%) had a history of
concussion in previous days, up to 4 weeks earlier [44].
NCCSIR 2005-2014 period: 28 deaths were related to head
(n = 26) or medullary trauma. Twenty-two deaths related to head
trauma had occurred in high school. Acute subdural hematoma was
observed in 46% of deceased players. Four (18%) of the 22 high
school players had suffered a concussion in the previous 4 weeks
[50].
ASDH, without associated contusion, can be observed in brain
trauma if the ballistics and the forces involved are sufficient to
tear the cerebral convexity veins. These are simply primary direct
lesions, as Bailes and coworkers recently reminded us [51]. The 16
intracranial hematomas leading to 6 deaths, published by Albright,
may fall into this category, all the more so because venous rup-
tures have been observed in [22]. This is extremely well-illustrated
by analyzing the brain trauma mortality of American footballers
over time corresponding to the successive rules intended to limit,
in part, the kinetic energy involved, mainly by modifying the impact
rules [52].
Finally, the problem was addressed in another way. Thus, some
authors have performed an analysis of the literature from the
angle of brain damage observed during sports practice, what they
called “structural brain injury”. Their methodological approach is
not that of a comprehensive register. Nevertheless, they identified
pre-existing lesions such as aneurysms or arteriovenous malforma-
tions, but also arachnoid cysts and direct shock lesions (e.g. epidural
hematomas) [53].
In other words, brain mortality occurring during the playing of
a sport can have 3 different causes:
• The manifestation of a pre-existing vascular malformations, such
as aneurysm or arteriovenous malformation responsible for cere-
bral hemorrhage: from 1 to 1.4% of deaths [47,50];
• Primary traumatic lesions, direct shock and inertia, identified by
the presence of a fracture of the skull: from 3.7% to 7% [47,50],
hematoma or intracerebral hemorrhage (6.5% to 15%) [47,50];
• Secondary aggravation including SIS.
Traumatology is governed by broad mechanical rules: the
observed lesions are proportional to the energy involved at the
time of injury and the manner in which it dissipates at the level of
the cephalic extremity. Nevertheless, the observed lesions and their
clinical tolerance are variable. Under these conditions, cranial trau-
matology uses most frequently pragmatic classifications because
they directly impact management. The most characteristic example
is the Glasgow Coma Scale. These classifications, and hence these
injury categories, are independent of the injury mechanisms, the
type of lesions observed, etc. In the same way, and with regard
to clinical tolerance, special clinical conditions, defined as “Talk
and Die”, were described in the 1970s by Reilly et al. [54]. These
entities are more or less comparable to the “Talk and deteriorate”
situations [12] described in the 1980s and that can be compared to
those of “Walk and Die” [55]. These situations can be observed in
10 to 15% of brain trauma cases [12,54,56]. These entities encom-
pass a set of primary traumatic injuries where it is now admitted
that they can be deployed for several hours after the injury [56], the
clinical tolerance can vary from one patient to another and which
J. Engelhardt, D. Brauge, H. Loiseau et al.
also applies to secondary lesions. Although there were extradu-
ral hematomas and sometimes significant contusions, aSDH was
present in about one-third of these cases [12,54,56]. In the work of
Reilly and coworkers, 25% of their patients had intracranial hyper-
tension with ischemic or hypoxic lesions, but without parenchymal
hematoma [54]. These aspects are more or less identical to those
observed during autopsies and/or MRIs in players suffering from
SIS (Table 1).
SIS belongs, at a nosographic level, to these categories of “Talk
and Die” and/or “Talk and Deteriorate”.
The next question is whether teenagers and young adults, the
main population at risk for SIS, can incur particular situations of
“talk and deteriorate”?
A particular picture was described by Walton at the end of the
19th century and retrieved in the 1950s by W. Pickles. The sequence
is characterized by the onset, in the hour following benign head
trauma, of a clinical picture with pallor, drowsiness, headaches and
vomiting. This often spectacular picture regresses within the hour
[57]. On a physiopathological level, the picture was attributed to
cerebral edema.
In 1975, this very peculiar picture, that tends to occur mainly
in childhood and adolescence, is considered a migraine equiva-
lent [58]. A comprehensive literature review of traumatic migraine
headaches suggests that this type of situation may occur beyond
early childhood [59]. Thus, cases 3 and 10 reported by Cantu and
Gean could be consistent with this picture given the significant
visual disturbances and headache intensity, respectively [31].
In children, the most common cause of secondary deterioration
is cerebral swelling with disappearance of fluid spaces and venous
congestion [60]. In this study, these authors indicated that 12% of
patients have a clinical outcome that corresponds more or less to
the picture described by Pickles. The most frequent radiological
aspect is cerebral swelling (41% of cases), though this occurs pref-
erentially in the most seriously injured. In 1984, an important study
reported this “Talk and Deteriorate” situation among injured sub-
jects aged 0 to 17 years [61]. Various situations were observed,
intersecting the data observed in SIS, these particular forms of
migraines induced by trauma and the entities described later. The
authors concluded that very severe delayed brain swelling syn-
dromes can be observed in children [61]. This particular situation
was the subject of another study where it appeared that cere-
bral swelling has a better prognosis in children and that there
is, probably, a difference between diffuse cerebral swelling and
those satellites of an acute subdural hematoma [62]. These three
important studies presented the major pitfall of mixing different
categories of trauma (e.g. from mild to severe brain injury).
Very similar cases of “delayed cerebral edema” have been
reported in subjects with mutations in the CACNA1A gene [63].
In contrast, there was no acute subdural hematoma observed dur-
ing the autopsies performed. Cases have been reported sporadically
[64].
A review of malignant cerebral edemas in children was con-
ducted by Duhaime and Durham [65]. These authors concluded
that these situations of “big black brain” (i.e. association of an aSDH
and ipsilateral hemispherical lesions) were on the one hand age-
dependent, and on the other hand required repeated trauma. With
the exception of mistreatment, there is scarcely anything but sports
which exposes individuals to this necessary repetition. Moreover,
some situations were dominated by cerebral swelling, while in oth-
ers, brain swelling was associated with acute subdural hematoma.
In contrast, these clinical pictures concerned, in a certain way, a
population only a little younger than that concerned by SIS.
A few years later, one study made the reasonable assumption
that some of these situations were related to the activation of the
trigeminocardiac reflex (TCR) [66]. This explanation, however, only
concerned the “trivial” brain [66]. The onset of this reflex, observed
272
Neurochirurgie 67 (2021) 265–275
quite frequently in neurosurgical practice, leads to bradycardia, sig-
nificant blood pressure drop and significant cerebral vasodilation
[67,68].
4.2.6. Pathophysiological considerations
The absence of a clear pathophysiological explanation is an argu-
ment often put forward to challenge the existence of SIS.
The most common explanation given is to consider aSDH as
related to a rupture of the convexity bridging-veins. This results
in venous compression and cerebral engorgement leading to
cerebral swelling [19,20,31]. The next step will be to consider
post-traumatic brain dysregulation [31]. The most frequent mod-
eling is to consider the initial trauma as being responsible for
age-dependent cerebral vasoreactivity alteration. The inability to
respond to a catecholaminergic storm, linked to the 2nd impact,
results in an increase in BP and therefore a rise in cerebral blood
volume. This in turn causes an increase in intracranial pressure and
cerebral herniation responsible for collapse and death. An approxi-
mation is made, partially with the syndrome of cerebral malignant
edema occurring in children [60,65].
Two robust arguments run counter to these proposals:
• It is in fact a diffuse cerebral edema [69]. These authors have
shown that there is a reduction in cerebral blood volume and
cerebral blood flow related to a state of cerebral vasoconstric-
tion. This was, however, a study of severe traumatic brain injury
with several types of traumatic lesions according to the Marshall
classification. In a second study, they showed that it was a cellu-
lar edema analyzed by the apparent diffusion coefficient in MRI
[70];
• Rupture of the bridging veins has never been observed in oper-
ated patients (Table 1). One can argue that this finding is difficult
to make in a case of brain swelling. Nevertheless, in a more recent
study where this was sought, the authors clearly indicated the
absence of venous tearing [10].
Until the early 2000s, there was a succession of unfounded
mechanical assumptions that cannot explain all the clinical and
radiological phenomena.
In the early 2000s, the concept of a vulnerability window linked
to metabolic disorders appeared [71]. This is mentioned in SIS [5]. In
mild head injuries, there is an alteration of cerebral autoregulation
[72]. The time required for its normalization is age-dependent, both
in humans and in animal models. In children, normalization occurs
only between the 14th and 30th day [73,74]. In practical terms,
all hemodynamic parameters (cerebral blood flow, self-regulation,
cerebrovascular reactivity, flow/metabolism coupling, oxygen con-
sumption and cardiovascular regulation) are altered more or less
intensely and in a more or less prolonged fashion [75]. A correlation
between the extent of clinical abnormalities and cerebral perfusion
abnormalities has been demonstrated [76,77]. Perfusion abnormal-
ities were dependent on the topography, but the time required for
their normalization was not indicated. Overall, there is an alteration
in cerebral energy metabolism, with major sensitivity to hypoten-
sion. In fact, the cerebral blood flow is decreased (with a trauma
severity-dependent duration), PaCO2 -dependent cerebrovascular
reactivity is impaired, and oxygen demand increases in proportion
to metabolic and neural activity with a decoupling between oxygen
demand and consumption. This may explain the risk of ischemic
lesions in the event of a profound decrease in cerebral blood flow.
The concept of a window of cerebral vulnerability after mild
head trauma is subsequently reinforced by solid work [78]. This
window is approximately 7 to 10 days and is age-dependent. In
other words: “the younger the subject, the wider the window”. This
was confirmed in animal models providing additional information.
Thus, experimental data have demonstrated the risk associated
J. Engelhardt, D. Brauge, H. Loiseau et al.
with the early repetition of head trauma [79,80], thus confirming
older data [81] and sensitivity to hypotension [82].
This notion of a cascade of events ascribes a major role to the
catecholamines released during cranial trauma [25].
Two arguments limit these extrapolations to SIS:
• the often benign nature of the second trauma, unable to trigger
the required “catecholaminergic storm”;
• the absence of an identified cause of collapse [65].
In addition to the SIS debates, an impressive accumulation of
recent data on the pathophysiology of concussion and its con-
sequences has been added to previous information [78,83–85].
Thus, clinical [86,87], electrophysiological [88] and neuroradiolog-
ical [89–91] studies have been conducted. In most cases, observed
abnormalities disappeared within a few days regardless of the
parameter being analyzed (Lovell et al., 2007). Thus, abnormalities
identified in spectro-NMR (N-acetylaspartate/choline ratio and N-
acetylaspartate/creatine ratio normalize within 30 days after head
trauma [92]. This validates the concept of a cerebral vulnerabil-
ity window. Biochemically, data were derived both from human
and animal work [93–96]. Nevertheless, many of these studies con-
cerned severe head injuries where tissue lesions can generate such
cascades of biochemical events. Information on mild head injuries
is more scarce [71,83,91].
Schematically, we must distinguish between two physiopatho-
logically distinct situations. The first is the inflammatory state
associated with the cascade of events triggered by primary and sec-
ondary traumatic tissue injuries. It can be said that, as the head
injuries were associated in relation to SIS, this pathway cannot
be solicited. The second is the situation described as neurogenic
inflammation. Several families of peptides play a major role in this
situation. Thus, expression of aquaporins is associated proportion-
ally with cyotoxic edema and inversely proportional to vasogenic
edema [97]. Four neuropeptides have been the subject of exten-
sive study and are mainly expressed in this situation: substance P
(SP), neurokinin A and B and calcitonin gene-related peptide (CGRP)
[93,94]. These neuropeptides contribute to hemodynamic alter-
ations [98]. Substance P alters the permeability of the blood-brain
barrier [96,99–101]. CGRP is a very potent vasodilator [102].
A speculative question would be whether post-traumatic
headaches are the clinical expression of the neurogenic inflamma-
tion situation and in particular the expression of neuropeptides, a
bit like migraines.
Head injury, however, generates several cascades of events
that impact brain function in the broad sense and that reversible
in an age-dependent manner. Nevertheless, the intensity of the
phenomena observed in SIS indicates that this is not an addi-
tion but rather a potentiation. Moreover, at the clinical level, the
sequence is stereotyped with a modest impact, a free interval, col-
lapse and coma. Collapse may explain the severe hypoxia/ischemia
lesions observed. In contrast, it is difficult to accept that the kinetic
energy of the second impact can explain the observed subdural
hematomas.
An essential study was published a few years ago by Waney
Squier and coworkers [103]. This study offers a robust frame-
work to the various clinical, radiological and operative findings.
In summary, these authors associated two essential elements: the
trigeminocardiac reflex [68,104] and the neurogenic inflammation
process [102], which previously was mostly described in cases of
migraine disease.
The trigeminal nerve is also responsible for the innerva-
tion of intracranial vessels (intracranial arteries, meningeal, dural
venous sinuses and sphincters of the bridging veins that con-
trol venous outflow) and meninges (dura mater of the anterior
and middle stages with mechanoreceptors) and leptomeninges.
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Neurochirurgie 67 (2021) 265–275
It interacts with the ortho- and parasympathetic system. At the
meningeal level, the trigeminal nerve possesses mechanoreceptors
and chemoreceptors, which are, in fact, sensitive to mechanical
variations, but also to the mediators of inflammation. It is con-
sidered as the brain’s nociceptor, using two main neuropeptides:
substance P and CGRP. Moreover, the development of trigeminal
nerve endings is age-dependent.
For SIS, Squier et al. proposed that TCR triggering in combination
with a neuroinflammatory state [103]. This provides a robust expla-
nation for the decoupling between trauma and its consequences,
collapse and the situation of brain swelling. An initial trauma gen-
erates a neurogenic inflammation via the trigeminal nerve, one of
the particularities of which is hypersensitization. TCR triggering,
by CGRP release is responsible for the collapse. It is also respon-
sible for significant cerebral vasodilatation [67]. The amplitude of
responses related to TCR activation varies, given the developmen-
tal data, with age. This provides a very interesting explanation of
the child’s secondary aggravation charts, brain swelling situations,
and possibly “Walk and Die” [55].
The question of subdural hematoma thus arises. Squier et al.
proposed as an explanation the state of neurogenic inflammation.
It is responsible for plasma extravasation and osmotic exchange
responsible for exudate. Substance P is a perfect candidate. In ani-
mal models, the administration or overexpression of substance
P is responsible for significant protein extravasation within the
dura itself [96]. CGRP potentiates the effects of substance P. CGRP
is highly expressed in the vessels and the trigeminal nerve. It is
clear that, in all operated or autopsied cases of SIS, acute subdu-
ral hematoma remains minimal and considered not responsible for
brain swelling [4,22,24,27,30,31].
Clinically, collapse induced by the TCR puts the subject in a dan-
gerous situation of hypoxia-ischemia that can lead to permanent
lesions. The topography of ischemia-hypoxia lesions observed in
these situations can also be discussed. Indeed, substance P, CGRP
and other peptides involved in neurogenic inflammation display
brain topography-dependent expression. They are more strongly
expressed in the amygdala, caudate nucleus, putamen and some
structures of the midbrain and brainstem. The morphological and
autopsy data of some SIS victims correspond fairly well to this
expression-dependent topography, especially brainstem lesions
(Table 1). Could an exaggerated release of these neuropeptides in
their preferred brain topographies explain this pattern of lesions as
opposed to hypoxia-ischemia lesions associated with tissue inflam-
matory mediators such as those seen in other trauma situations
[105,106]?
Finally, the fact remains that cases of SIS are reported primar-
ily among males. Experimentally, substance P receptor antagonists
have sex-dependent efficacy [94,96,107] and experimental work
has indicatedthat the observed alterations are significantly sex-
different [94,96,107].
4.3. Medicolegal data
Whether its existence is real or not and regardless of the num-
ber of cases, SIS has led to the promulgation of laws in different
countries [108,109]. It is interesting to note that these two cases
are not listed as SIS.
In contrast, despite the amount of work published on concus-
sion, its diagnosis and its management, the rules are not followed,
especially on the players’ side [34,110]. The publications seem to
have their main impact essentially on the medical field.
McLendon et al. wrote “currently, each state has some type of
legislation for return to play after concussion” [11]. However, this
legislation varies from state to state [11,29]. One may wonder why?
J. Engelhardt, D. Brauge, H. Loiseau et al.
5. Conclusions
The existence of SIS is debatable for the simple reason of def-
inition. In traumatology there is no situation defined so strictly
by precise and exclusive anamnestic, clinical and radiological data.
Pragmatic data for the management of mild head injuries have been
redefined for sport for multiple reasons. It nevertheless remains
that:
• sports can cause brain injuries, many, but not all, of which are
mild;
• sport is characterized by the possible repetition of trauma;
• concussion must be considered in a pragmatic way. This is a brain
injury. It should be considered, in the very sense of an injury, as
are orthopedic injuries and care according to the different rec-
ommendations that were established and not only because of the
potential threat of a SIS as was pointed out by Paul McCrory [8].
So that recommendations provided by World Rugby are accurate
and effective (http://playerwelfare.worldrugby.org/concussion)
either in sports or in daily practice;
• “Talk and Die” or “Talk and Deteriorate” situations may be
observed following benign and/or repeated head trauma. The
identification of collapse, cerebral swelling unrelated to the acute
subdural hematoma, evokes the triggering of a TCR associated
with a residual state of post-traumatic neuro-inflammation;
• we cannot eliminate some form of genetic predisposition,
but some cases reported as SIS are probably trauma-induced
migraines.
Disclosure of interest
The authors declare that they have no competing interest.
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