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\begin{document}

\title{A novel pharmacological treatment concept for neuroprotection in severe
traumatic brain injury -- two case reports}



\author[1]{Helmut Trimmel}%
\author[1]{Guenther Herzer}%
\author[1]{Christoph Derdak}%
\author[1]{Joachim Kettenbach}%
\author[1]{Ivan Grgac}%
\affil[1]{Landesklinikum Wiener Neustadt}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Severe traumatic brain injury is a leading cause of death and disability
worldwide, resulting in a significant individual and socioeconomic
burden. We present two cases of severe traumatic brain injury with
surprisingly encouraging outcomes. We attribute this to the additional
combined administration of citicoline and cerebrolysin.%
\end{abstract}%



\sloppy


\textbf{A novel pharmacological treatment concept for neuroprotection}

\textbf{in severe traumatic brain injury -- two case reports.}

Trimmel H\textsuperscript{1,2,3}, Herzer G\textsuperscript{1}, Derdak
C\textsuperscript{1}, Kettenbach J\textsuperscript{3,4}, Grgac
I\textsuperscript{1,5}

From the Department of Anesthesiology, Emergency and Critical Care
Medicine\textsuperscript{1}, Karl Landsteiner Institute of Emergency
Medicine\textsuperscript{2}, General Hospital Wiener Neustadt, Austria;
Danube Private University\textsuperscript{3}, Krems, Austria; Institute
of Diagnostic, Interventional Radiology and Nuclear Medicine,
Landesklinikum Wiener Neustadt, Austria\textsuperscript{4}; Institute of
Anatomy, Faculty of Medicine, Comenius University\textsuperscript{5},
Bratislava, Slovakia.

Helmut Trimmel, M.D., M.Sc. Helmut.Trimmel@wienerneustadt.lknoe.at

Guenther Herzer, M.D., M.Sc Guenther.Herzer@wienerneustadt.lknoe.at

Christoph Derdak, M.D. Christoph.Derdak@wienerneustadt.lknoe.at

Joachim Kettenbach, M.D., EBIR, MBA
joachim.kettenbach@wienerneustadt.lknoe.at

Ivan Grgac, M.D. Ivan.Grgac@wienerneustadt.lknoe.at

Address for correspondence:

Prof. Helmut Trimmel, M.D., M.Sc.,

Department of Anaesthesiology, Emergency and Critical Care Medicine

General Hospital Wiener Neustadt, Corvinusring 3-5, A 2700 Wiener
Neustadt, Austria

Helmut.Trimmel@wienerneustadt.lknoe.at

Words:

Abstract: 376

Article: 2.904

\textbf{Patient consent statement:} Both patients gave their written
consent to this publication. Consent form is available from the authors.

\textbf{Running head} : A multimodal concept for neuroprotection in sTBI

Abstract

Background

Severe traumatic brain injury (sTBI) is a leading cause of death and
disability worldwide, resulting in a significant individual and
socioeconomic burden. In current guidelines recommendations for
neuroprotective or neuoregenerative drugs are missing. On the basis of
two cases, we present a combined treatment with Cerebrolysin and
Citicoline. Both drugs are well proven experimentally and clinically in
their own effectiveness, but clinical data of the combination has hardly
been reported. Our experience sheds light on a promising approach that
may improve neurological outcome after sTBI.

Case presentation

A 29y male motorcyclist suffers polytrauma in the context of a
high-speed accident. In addition to severe bilateral chest trauma, he
sustained fractures in both thighs and an sTBI. In addition to surgical
and standard neurocritical care according to the evidence-based
guidelines, he receives neuroprotective therapy with Cerebrolysin
(50ml/d) and Citicoline (3g/d), continuously administered intravenously
(IV) for 21 days. The second patient of this case report, a 30y male ski
tourer is admitted also by HEMS, after a after a fall over 300 m in open
terrain. In addition to the sTBI, he suffers fractures in the cervical
spine, ribs, pelvis and lower extremities, as well as lung contusions
and massive soft tissue trauma. After first aid in a peripheral
hospital, he is also treated in our department and receives the same
neuroprotective drugs, like all of our patients with sTBI. With regard
to the severity of the injuries (Injury Severity Score {[}ISS{]}: 43/50,
Revised Trauma Score {[}RTS: 5.0304, 2.7794{]}) and an unfavourable
outcome probability (Hukkelhoven Score) of 93.1\% and 82.6\%, the
outcome of both patients is surprisingly encouraging one year after the
accident. They achieved a Glasgow Outcome Score of 6 and 5 and graded 2
and 4 on the modified Rankin Scale, respectively. Currently, both are
able to take care of themselves in matters of daily life to a large
extent.

Conclusions:

The administration of neuroprotective drugs may improve the regeneration
of cell membranes, improve blood brain barrier integrity and reduce
neuroinflammation leading to secondary damage to the injured brain. Our
clinical experience and data suggest that the combined administration of
Citicoline and Cerebrolysin may contribute to better recovery, without
relevant side effects. However, validating these results by means of a
controlled, prospective study is required.

Keywords

case series, severe TBI, multi-modal therapy, neuroprotection,
Citicoline, Cerebrolysin, secondary brain damage

Background

Severe traumatic brain injury (sTBI) is a leading cause of death and
disability, especially among young male adults in low- and middle-income
countries, shifting to elderly patients in developed countries. This so
called ''hidden pandemic'' affects more than 13 million patients
annually in Europe and the US alone. sTBI causes the death of about
11.8/10\textsuperscript{5} people in Austria, which is comparable to
data from other European countries. In survivors, sequelae of sTBI often
bring life-changing consequences such as motor- and cognitive deficits,
which lead to a life of dependency. Thus, sTBI represents not only a
significant individual but also a socio-economic burden worldwide. The
mechanisms of injury and underlying physiological and cellular processes
accompanying the primary and secondary brain injuries are complex and
require multimodal treatment. Nevertheless, current guidelines, e.g.
from the Brain Trauma Foundation (BTF), aim to provide evidence-based
recommendations for the various manifestations of sTBI. Outcomes may be
improved by adequate early care on scene, in the emergency department
(ED), and in the intensive care unit (ICU). In addition, sTBI should not
be understood as purely acute or static, but as a complex, acute to
chronic neurodegenerative disease. This suggests the existence of a
longer therapeutic window of time for pharmacological intervention and
questions whether sTBI-induced damage can only be treated within a few
hours after the trauma. In reducing secondary damage, anti-oxidants,
branched-chain amino acids, and \selectlanguage{greek}ω\selectlanguage{english}-\selectlanguage{english}3 polyunsaturated fatty acids have
shown promising pre-clinical results for altering TBI outcome. However,
up to now pharmacological research has not yet identified a ''gold
standard'' to prevent secondary brain damage. Although there are
promising data from animal studies, only Citicoline or Cerebrolysin have
led to some positive findings in retrospective and prospective ``real
life'' clinical trials. There were hints for reduced mortality and
better functional outcome, measured by enhanced Glasgow Outcome Score
(GOSE) and modified Rankin Scale (mRS). However, these agents -- whether
administered orally or intravenously - have fallen short to produce
significant improvements when administered as single drugs and are
critically discussed in large, randomized prospective trials.

Case 1

A 29-year-old caucasian male collides as motorcyclist head-on with a car
at about 65 mph. Helmet is busted when colliding with the frame of the
car's windscreen. Status on arrival of emergency medical service (EMS)
on scene, pattern of injuries as well as measures of emergency care are
displayed in Table 1. Whole-body CT scan in the ED reveals punctiform
cerebral haemorrhages (especially in the left temporal lobe), bilateral
serial rib fractures, a left scapular fracture, prehospitally drained
pneumothorax on the left, laceration and atelectasis of the left lower
lobe, ventrocranial edge detachment on the11\textsuperscript{th} and
12\textsuperscript{th} thoracic vertebrae, wedge shaped compression
fractures of the 1\textsuperscript{st} and 4\textsuperscript{th} lumbar
vertebrae, and multiple fractures in both hip joints. After placement of
a probe to measure the intracranial pressure (ICP) in the ED, patient is
admitted to ICU with stable ventilation and haemodynamic parameters
(norepinephrine 0.2 \selectlanguage{greek}µ\selectlanguage{english}g/kg/min). Citicoline (3g/day) is added to usual
standard care. ICP increases repeatedly up to 19 mmHg during the first
days, responding to deepening of analgosedation and osmotherapy.
Laboratory findings and haemodynamic support in the first 24 hours are
displayed in Table 3.

The further course is relatively stable with regard to the ICP and
receding brain oedema; weaning from ventilation is initiated from day
10. Subsequently, the patient shows extreme vegetative imbalance, so
that in addition to the established antisympathetic (carvedilol) and
antipsychotic medication (quetiapine, tiapride, oxazepam), continuous
administration of propofol has to be re-established repeatedly. Three
weeks after the accident, magnetic resonance tomography (MRT) reveals
signs of intracranial axonal injuries and microbleeds (Figure 1) seen as
spotted susceptibility artifacts on the anterior temporal lobe and in
the frontobasal region (left \textgreater{} right), in the basal ganglia
on both sides, as well as in the left posterior border zone and in the
white matter on both sides too, high frontal to occipital. In summary,
this matches with multilocular small shear haemorrhages, left
frontobasal and temporal contusion zones, compatible with a diffuse
axonal trauma stage 1. On day 21, patient finally undergoes
stabilization of both femoral necks with interlocking nails. A
dilatative tracheostomy is performed, too. Somatosensory evoked
potentials (SSEPs) on day 23 show missing central answer on the
right-brain side, on the left a central answer can be derived with
limited accessibility. During the following days, the patient appears
stressed, shows repeated periods of restlessness with sweating and
tremors and moves the extremities in completely uncontrolled, stretching
manner. Electroencephalogram (EEG) on day 28 shows signs of general
diffuse brain dysfunction (moderate to severe) and reduced reactivity to
photogenic stimuli, but no typical epileptic potentials.

On day 31, more or less with very limited hope for recovery, a
supportive therapy with Cerebrolysin is initiated -- a novel therapeutic
approach for us at that time. 10 days later, the patient starts to react
targeted to verbal stimulation for the first time. Improvement is
growing rapidly, and neurological examination before transfer to open
ward on day 45 states: the patient is now awake and keeps eye contact,
gaze tracking is easier to the right than to the left, the muscular tone
is generally increased. No cooperation can be achieved while examining
facial muscles, but he shows indicated movement when prompted with
fingers and forearm. There is a tendency for stretching spasm of the
left leg spontaneously but uncontrolled, but no active movement of the
lower extremities when requested.

One month later, at the time of discharge from hospital (day 73) the
patient presents himself awake and mobile in the armchair. He clearly
follows now simple prompts; questions can be adequately answered with a
nod of the head. He shows signs of a tetraparesis, pronounced on the
left and a grasping reflex on the right.

One year after the accident, and after a series of botulinum toxin
treatments in the rehabilitation centre, the disabling spastic increase
in muscular tone of the right leg has significantly regressed. The
patient is safely mobile, using a three-wheeled bicycle. Further six
months later, patient is mobile on his own by public transportation and
regular bicycle, visiting friends and cafes.

GOSE/mRS at discharge: 4/4, one year after the accident: 5/3, and after
18 months: 6/2

Findings of the final MRT examination 18 months after the accident
(Figure 2) shows gliotic cicatricial high parietal left as sequelae of
the axonal trauma, and a small defect on the left temporal lobe in the
area of the previously recognizable contusion. In total -- a clear
improvement, especially the frontal contusion zone on the left has
receded.

Case 2

A 30-year-old sportsman falls from a great height (approx. 300 m, Figure
2) during a ski tour. Rescue is delayed due to missing cell-phone
connection in this remote area, as well as to weather conditions.
Helicopter emergency service (HEMS) arrives approximately two hours
after the accident. Status on arrival of HEMS, pattern of injuries as
well as emergency measures are displayed in Table 1. The patient is
admitted at the nearest trauma centre (level II) four hours after the
accident. CT scan reveals cerebral contusions, traumatic subarachnoid
(SAH) and subdural haemorrhage (SDH), an unstable fracture of the 4th
cervical vertebra with spinal cord injury, a pneumothorax with rib
fractures and multiple fractures of the upper and lower extremities. An
external fixator is placed on both lower extremities, followed by
plating and screwing of the cervical spine and the left hip on the next
day. In a postoperative CT scan, extensive brain oedema and a new
ischemic zone in the area of the posterior circulation compressing of
the 4th ventricle.

After being rejected by the nearest neurosurgical university hospital
because of the obviously hopeless situation, the patient was transferred
to our institution (for lab findings and hemodynamic support on
admission see Table 3). A CT scan (Figure 2) on arrival shows oedematous
swelling of both cerebellar hemispheres and the right occipital lobe
with space-occupying effect in the posterior cranial fossa, and a
persistent dislocation fracture of the 4\textsuperscript{th} cervical
vertebra. An external ventricular drainage (EVD) was placed, followed by
suboccipital decompressive craniotomy with dural expansion surgery on
the next day, after interdisciplinary discussion of prognosis, supported
by deducible SSEPs over both hemispheres. In addition to standard
medical care (comprising ``optimal handling'', deep analgosedation,
haemodynamic and respiratory optimization) the patient received
Cerebrolysin and Citicoline. After prolonged weaning, characterized by
vegetative disbalances and delayed recovery from analgosedation, EEG
findings stated severe abnormal EEG curves with general slowing, no
distinct focus, nor typical epileptic potentials. On day 33 after the
trauma, the consulting neurologist states: Contact via blink of an eye
possible, pat. can follow this request. During the examination
evaluation of pain is possible. Pat. can keep eye contact only for a
short time. The right corner of the mouth can be raised a little if
requested. Tongue cannot be stuck out. Upper extremities (UE): left
distal increased tone in the sense of spasticity, right rather flaccid.
Lower extremities (LE): both legs immobilized, no examination possible.

After 50 more days in acute rehabilitation process in ICU including
changing the EVD to a ventriculo-peritoneal shunt, the patient was
transferred to a specialized clinic for neurorehabilitation. At that
time, the report of the neurologist reads as follows: Patient is awake,
follows simple prompts, speech comprehension appears to be well
preserved, simple linguistic utterances are possible. Mimic muscles
appear bilaterally symmetrical. UE can be lifted and held on the same
side against gravity on request, degree of strength 3-4, increase in
tone right \textgreater{} left. LE: Tone spastically increased on both
sides, right \textgreater{} left. Left leg painful when moving the hip,
right leg can be lifted on request.

One year after the accident, the patient is finally discharged from the
rehabilitation centre, able to move by himself with a rollator, and can
independently manage the transfer from bed to wheelchair and vice versa.
He shows pronounced deficits in short-term memory, long-term memory is
well preserved. He is usually in a euthymic mood and looks forward to
further development steps.

GOSE/mRS at discharge from hospital: 3/4, one year after the accident:
5/4, and after 18 months: 6/4

Treatment

Immediately after admission to the ICU of our level 1 trauma centre
(General Hospital of Wiener Neustadt, Austria), all patients with sTBI
(Glasgow Coma Score {[}GCS{]} 3-8, intubated on scene), who are not
deemed hopeless in terms of survival, receive Cerebrolysin (50 ml/day)
and Citicoline (3g/day), both given intravenously for 21 days,
continuous via motor syringe, in addition to all standard measures
according to BTF guidelines. We hypothesize that the combined effects of
these two pleiotropic agents due to their anti-inflammatory properties,
reconstitution of blood-brain-barrier, stimulation of membrane and
axonal regeneration can optimize the neurocognitive outcome.
Cerebrolysin is a standardized, lipid-free, low-molecular weight
neuropeptide preparation, which passes the blood-brain-barrier and
mimics the actions of endogenous neurotrophic factors. Proteins present
in soluble tissue extracts and in the extracellular matrix have been
shown to influence the survival and development of cultured neurons. The
tissue extracts derived neuropeptides contained in Cerebrolysin promote
neurotrophic stimulation (survival and maintaining the phenotype of
highly differentiated neuronal cells), neuromodulation (changes in
neuronal and synaptic plasticity synapses) , and metabolic regulation
such as prevention of lactic acidosis as well as increasing the
resilience against hypoxic conditions\{Muresanu:2020dm\}. In addition,
Cerebrolysin significantly reduces tissue Plasminogen Activator (tPA)-
and fibrin-damaged endothelial cell permeability, which is associated
with a significant reduction in proinflammatory and procoagulatory
activity. Citicoline (Cytidine 5\selectlanguage{ngerman}´-diphosphocholine) is chemically
identical to the essential endogenous intermediate in the biosynthetic
pathway of phosphatidylcholine. It is hydrolysed to choline and cytidine
triphosphate and crosses the blood-brain barrier to be reassembled to
Citicoline inside the brain. It mediates neuronal membrane integrity and
repair, accelerates the reabsorption of cerebral oedema and the
restoration of the blood-brain barrier integrity after TBI. Furthermore,
Citicoline increases cerebral dopamine and norepinephrine levels, which
causes improved hypoxia tolerance.

Discussion

In these case reports, we describe the clinical development of two
patients with sTBI, presenting with GCS 3-4 on site. After surgical
intervention both required long-term care at the ICU, followed by
intense rehabilitation measures. Motor vehicle accidents and falls from
heights resulting from sports activities are typical causes in this age
group and of high individual and socio-economic impact. It is of
enormous importance to give especially young patients every chance for a
life that is as free of disabilities as possible and to reintegrate them
into their social environment and working process. Recovery of motor
functions and cognitive abilities leads to a significant improvement of
activities of daily living. The optimal care for sTBI patients must be
started at the emergency site, must be continued through the emergency
department- (ED) and the early surgical phase, with consequent ICU
treatment as recommended by the BTF guidelines.(4,5) Starting at the
earliest possible time, at the latest when the patient is admitted to
the ICU, the described supplementary therapeutic concept should
complement the standard treatment of sTBI patients. As to our knowledge,
these are the first cases reporting this specific pharmacological
combination in sTBI, resulting in unexpected favourable outcome (Table
2). In the recent literature, we found only one paper reporting a
combined administration of Citicoline and Cerebrolysin in moderate TBI,
a RCT with remarkable positive results.

There are two aspects, that we attribute to the continuous and high-dose
administration of neuroregenerative drugs, among all other attempts to
optimize the individual recovery of our patients: first, we did not
observe the development of critical brain oedema in these patients -
despite the extremely massive trauma in both cases - neither in the
early nor in the later stages. Stabilisation of damaged cell membranes,
reduction and/or acceleration of the absorption of brain oedema are well
described effects of Citicoline. The need for analgosedation and
vasopressors was consecutively moderate. This naturally has a positive
effect on gastrointestinal motility, which reduces the risk of
translocation and bacteraemia. Overall, this results in better stability
during the most critical phase of the first 10 days after the trauma.

Second, we observed a relatively good neurocognitive long-term outcome
in these patients with regard to GOSE and mRS, despite the diffuse
axonal trauma, typical for massive acceleration respectively
deceleration trauma in all two cases. After a phase of ``vegetative
storm'', typically a sign of diffuse axonal trauma, the patients
developed positive cognitive abilities over the next few weeks. Despite
the prolonged rehabilitation (especially in case 2), the patients
recovered much better than expected in terms of cognitive competence and
mood stability. The latter may be due in particular to the positive
effects of Cerebrolysin, as was shown in the meta-analysis by
Ghaffarpasand et al. and the recently published ``CAPTAIN'' trial.
Cerebrolysin may stimulate neurotrophic activity and improve
neuromodulation and metabolic regulation. Cerebrolysin as well as
Citicoline were safe in toxicological tests, showing no significant
systemic side effects. In rare cases (\textless{} 1/1000) agitation,
loss of appetite, dizziness or pruritus was observed in awake (stroke)
patients receiving Cerebrolysin. In a retrospective cohort study among
7,769 adult patients, Muresanu et al. did not find any difference in
adverse effects between Cerebrolysin and placebo controls. Side effects
of Citicoline are also very rare and of mild intensity; single cases
suffering from headache, diarrhoea, elevated liver enzymes and weight
loss were reported.

Limitations

Despite our experience with Citicoline for more than a decade, and about
4 years with Cerebrolysin, we are well aware of the limitations of these
exemplary observations and the ongoing discussion about the effectivity
of both drugs. Nevertheless, our data may be understood as a hint that
neuroprotective and neuoregenerative mechanisms may be supported by
these two externally supplied pharmacologic substances. The effects of
our multimodal treatment concept have yet to be demonstrated in a large,
prospective and randomized clinical trial.

Conclusions

Treatment of sTBI has to follow standardized protocols, essentially
based on the Brain Trauma Foundation guidelines. The complementary
medication with Citicoline and Cerebrolysin shall improve regeneration
of cell membranes, reduce cerebro-endothelial cell permeability,
neuroinflammation, neuronal degeneration and apoptosis. Additionally,
neurotrophic stimulation can increase survival of highly differentiated
neuronal cells; neuromodulation will amplify changes in neuronal and
synaptic plasticity. Both drugs should be administered as soon as
possible, intravenously and continuously for at least 21 days to cover
the acute phase as well as the early rehabilitation period. The efficacy
of this multimodal approach has to be proven in a multicentre,
prospective and randomized trial.

References

\textbf{Tables}

Table 1 -- Status and measures on scene

Table 2 -- Injury severity and prognosis scores

Table 3 -- Laboratory findings at 24 hours after admission in ICU

\textbf{Figures}

Figure 1a,b,c: MRT, Case 1

Legend:

(left) MRT of the 29-year-old male, 3 weeks after the accident.
Diffusion-weighted (DWI) sequences (b=1000) demonstrated multifocal
areas of abnormal bright signal along the corpus callosum and within the
left corona radiate and body of caudate nucleus corresponding to axonal
injuries after the trauma. (Middle) On T2*-sequences multifocal areas of
punctiform susceptibility artefacts (white arrow) at the grey-white
matter junction, more pronounced at the left parietal region, in the
corpus callosum and the temporal lobe (not shown) were visible,
indicating small foci of posttraumatic bleeding. (Right) Follow-up MR 18
months later showed that the oedematous areas on DWI-sequences and the
microbleeds had been resolved. The size of the ventricles and the sulci
seem to be a bit wider than right after the accident.

Figure 2a,b: CCT scan, Case 2

Legend:

Cranial CT of a 30-year-old male, 1 day after the accident (left image)
demonstrates extensive oedematous swelling within the anterior
cerebellar lobes as well as in both posterior temporal and occipital
lobes due to extensive hypoperfusion of the posterior circulation. The
cerebellar tentorium (right image) is slightly bowed upwards and a
slight compression of the basal cistern and the IV.ventricle is shown,
however liquor flow was patent.



\textbf{Abbreviations}

BTF -- Brain Trauma Foundation

CT -- Computer Tomography

CCT -- Cranial Computer Tomography

ED -- Emergency Department

EEG -- Electroencephalogram

EVD -- External Ventricular Drainage

GCS -- Glasgow Coma Score

GOSE -- Glasgow Outcome Score

HEMS -- Helicopter Emergency Service

ICP -- Intracranial Pressure

ICU -- Intensive Care Unit

L -- lumbar

LE -- Lower Extremities

mRS -- modified Rankin Scale

MRT -- Magnetic Resonance Tomography

RCT -- Randomized Control Trial

SSEPs -- Somatosensory Evoked Potentials

sTBI -- severe Traumatic Brain Injury

TH -- thoracic

UE - Upper Extremities

Funding:

Publication fees will be covered by Karl Landsteiner Institute for
Emergency Medicine.

Authors contribution:

HT and GH concepted and designed this paper; CD and IG contributed in
acquisition and analysis of data; JK is responsible for radiologic
examination and reporting. HT drafted the article; all authors revised
it critically for important intellectual content and approved this
version to be published.

I, Helmut TRIMMEL, as the corresponding author have the right to grant
on behalf of all authors, an exclusive licence for contributions from
all authors to permit this work if accepted, to be published.

Consent for publication

Written informed consent was obtained from the patients for publication
of these case reports and any accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of this journal.

Ethics approval

Since both patients gave their written consent, the institutional board
had no objection to the publication of the cases.

Acknowledgements

Not applicable

Availability of data and material

All data is available from the authors.

Competing interests

All authors confirm that they have no competing interests.\selectlanguage{english}
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