Introduction
At the beginning of the 20th century, Joseph Babinski had already shown interest in
understanding the injury mechanism of cerebral concussions in World War I soldiers.
Later, Derek Denny-Brown tried to describe the physiopathology of concussion.[1] The clinical scenario was uncertain, often coursing with transient symptoms, not
attributed to cerebral lesions. Currently, cerebral concussion is defined as a complex
physiopathological cerebral process induced by external biomechanical forces that
cause injuries. Originated by forces directed against the skull, face and/or neck,
concussion typically results in rapid and transient neurological dysfunction, which
resolves spontaneously and does not necessarily compromise the level of consciousness,
as believed in the past. The symptoms of cerebral concussion are directly related
to the intensity of the impact, reflecting functional and structural alterations.
Until recently, no neuroimaging modality could “see” the brain injury caused by concussion.
With the advent of tractography by magnetic resonance imaging, it was concluded that
cerebral concussion compromises the integrity of the white matter.[2]
[3] There are many symptoms of cerebral concussion, and they may compromise the level
of consciousness, motricity, somatic sensitivity, the vestibular system, the psychic
apparatus, oculomotricity and vegetative functions. The symptoms may present hours
or even weeks after the traumatic injury, which hinders the emergency room professionals
from defining its severity at the time the patients arrive at the hospital.[2]
[4]
Currently, cerebral concussion is classified as possible, probable and defined. The
lesion considered possible occurs when the patient has another clinical cause that
better explains the symptoms and cannot be attributed to concussion as it was classically
described. In this case, the injury mechanism cannot be clearly established. The symptoms
include headache and fatigue during physical activities, which can be attributed to
dehydration, migraine, hyperthermia or viral infections. In the lesions considered
probable, the symptoms are no longer well explained by other causes than cerebral
concussion, but there is presence of comorbidities, such as migraines, sleep disorders,
anxiety, mood disorders and attention deficit hyperactivity disorder (ADHD). Finally,
in the defined form, the symptoms can only be explained by cerebral concussion.[5]
Epidemiologically, over the last decades, there has been an increase in the prevalence
of concussions in emergency rooms. In the United States, the prevalence is around
128/100,000 people.[6] In the pediatric age group, the estimated incidence is around 304 cases for every
100,000 children, being higher in children between the ages of 5 and 9 years and in
males.[7] In the past 10 years, the incidence has increased by 200%, and this is largely attributed
to the concussions resulting from playing sports, including football, soccer, hockey,
martial-arts and general contact sports.[8]
[9]
Development
Injury Mechanism
Concussion is a brain injury triggered by a biomechanical mechanism described in the
20th century. The brain suffers a process of abrupt acceleration and deceleration,
in the anteroposterior plane, often associated with rotational movements, colliding
against the internal board of the skull, maintaining a relatively fixed point, the
brainstem. The most recent studies have observed that in this closed traumatic mechanism
there are electrophysiological alterations (compromising neuronal activity) in the
ascending reticular activating system (ARAS) and in the diencephalon ([Fig. 1]).[10]
Fig. 1 Injury mechanism attributed to cerebral concussion. Note that there is an acceleration
provided by an external force that closes instantaneously before a bulkhead (collision);
however, the nervous tissue remains accelerated, colliding against the inner board
of the skull, slowing abruptly, and performing a movement contrary to the initial
one. At this moment, the heavier gray matter performs its movement slower compared
with the white matter, promoting shearing, that is, the stretching of the nerve fibers.
Physiopathology: Neurometabolic Cascade
The animal models of moderate cranioencephalic trauma (CET) have revealed biochemical
alterations compatible with cerebral concussion. The elucidation of the neurometabolic
cascade involves cellular bioenergetic, cytoskeletal, and axonal alterations, neurotransmission
impairment, delayed cell death, and chronic functional impairment.
Physiopathology of Cerebral Concussion: Acute Stage
Ionic influx and excitotoxicity. In the acute stage of the lesion, there are neuronal influxes of glutamate, calcium
and sodium with potassium efflux, observed after the traumatic injury of the plasma
membrane. Postconcussion syndrome is marked by a wave of cellular depolarization followed
by a phenomenon similar to cortical spreading depression.
Alteration in cerebral blood flow self-regulation. Immediately after the concussion, there will be a reduction in cerebral blood flow,
which may take days to normalize. The relative hypoxia occasioned will initiate the
process of neuronal excitotoxic damage. The mechanism of reduction of blood flow comprises
the loss of brain self-regulation sensitive to trauma, compromising the hypothalamic
functions, leading to cellular energetic imbalance associated with sympathetic dysautonomia.
Energy crisis. In an extremely early postconcussion stage, there is an increase in energy consumption
by ionic pumps, with relative reduction in the cerebral blood flow, resulting in an
uncoupling of energy, that is, an imbalance between supply and cellular energy demand.
Calcium influx is the most common and lasting ionic disorder, and is attenuated by
mitochondrial calcium sequestration. However, this “blockade” will result in mitochondrial
impairment regarding its oxidative metabolism. After this stage of initial hyperglycolysis
with energy decoupling, the glycolytic metabolism will be compromised (hypometabolism)
for ∼ 7 to 10 days after the trauma.
Cytoskeletal injury. Biomechanical forces directed against neuronal and glial structures course with intra-axonal
calcium inflow, neurofilament collapse and axonal integrity loss, compromising the
anterograde and retrograde molecular flow.
Axonal dysfunction. The lesions to the microtubules and axonal neurofilaments can disrupt the cellular
connections, evolving with complete functional loss. Recent studies have shown that
non-myelinated axons are more susceptible to traumatic injuries, especially in the
corpus callosum region. In the brain still under development, repeated traumatic lesions
to the white matter often result in cognitive impairment.[11]
Neurotransmission impairment. After traumatic injuries, alterations are observed in the subunits of the N-methyl-D-aspartate
(NMDA) receptors, resulting in reduction in their electrophysiological, cognitive,
and memory consolidation capacity. In animal models, several patterns of calcium inflow
are observed, resulting in the activation of genes and phosphorylation that will modify
the calcium/calmodulin-dependent signal transductions of protein kinase II (CaMKII),
the extracellular signal-regulated kinase- (ERK), the cyclic adenosine monophosphate
response element binding (CREB) protein, and the brain-derived neurotrophic factor
(BDNF). The imbalance in the binomial excitation-inhibition is also associated with
the loss of gamma-aminobutyric acid (GABAergic) interneurons, reflected by the drop
in the glutamic acid decarboxylase (GAD67) marker (precursor of GABA synthesis) in
the region of the amygdaloidal complex. The postconcussion clinical manifestations
associated with anxiety and posttraumatic stress disorder seem to be able to reduce
this inhibition promoted by GABA.
Cerebral inflammation. After a moderate traumatic injury, there is activation of proinflammatory genes with
microglia infiltration. When analyzed microscopically, the black substance of the
mesencephalon has intense inflammatory activity, with excitotoxicity mediated by glutamate,
corroborating with the physiopathological mechanism of posttraumatic Parkinson disease.
The attenuation of the neuroinflammatory mechanism has been the target of several
therapeutic proposals, since there is an increase in proinflammatory interleukin (IL),
such as IL-6, tumor necrosis factor α (TNFα) and IL-1β, and several substances are
being tested, such as: lithium, N-acetylcysteine and minocycline, all with promising
results.[12]
[13]
[14]
Cell death. Cell death is a final phenomenon in the process of traumatic brain injury observed
in cerebral concussions, especially in recurrent lesions. It is not yet clear the
exact moment when acute concussion injuries become chronic: hippocampal atrophies
and loss of dopaminergic neurons, clinically manifested in the form of cognitive deficit,
persistent headache, sleep disorders and reduction in concentration are observed ([Fig. 2]).[15]
[16]
Fig. 2 Neurometabolic cascade associated with cerebral concussion. Note the temporal evolution
of ionic disarrangements compromising neuron neurophysiology, which is related to
the postconcussion clinical symptoms. Giza and Hovda[17] describe three stages of cerebral concussion, and in the first two, the patient
should stay at rest (absolute and relative respectively). However, the duration of
the clinical stages of cerebral concussion is individualized. The figure only provides
an approximate temporal mean for each of these phases, and clinical revaluation is
recommended. Chronically, cerebral concussions may lead to functional impairment,
including ADHD, depression, psychoses, chronic headache, and even suicide. Modified
from Giza and Hovda, 2014.[17]
Physiopathology of Cerebral Concussion: Chronic Stage
The aspects regarding the chronification of the lesions associated with cerebral concussion
are related to recurrent traumas. Studies with professionals who play contact sports
reveal that successive, recurrent traumas are responsible for neuronal degenerative
lesions, including the accumulation of tau protein. The early return to sports activities
after a cerebral concussion aggravates the aforementioned metabolic damage (acute
stage), inducing neuronal apoptosis. Studies with professional fighters demonstrated
that the repetition of trauma, with strokes directed to the skull, evolve with cortical
and hippocampal atrophy associated with ventriculomegaly. Animal studies reveal that
a single severe cerebral concussion can result in chronic evolution of brain damage,
with cell death and atrophy in one year.[17]
[18]
The physiological protein degradation depends on the ubiquitin-proteasome system for
its proper functioning, requiring energy in the form of adenosine triphosphate (ATP).
Since there is energy decoupling due to a cerebral concussion, there will be failure
of the ubiquitin-proteasome system, resulting in the accumulation of non-degradable
toxic material, which is currently considered the precursor mechanism of posttraumatic
neurodegeneration.[19]
[20] There are several reports of cerebrospinal fluid (CSF) and tissue deposition of
phosphorylated tau protein, in addition to extracellular amyloid and CSF deposits
after cerebral concussion.[21]
As described, the chronic mechanisms triggered by cerebral concussion will manifest
clinically in the form of a slowness in reasoning, loss of concentration, aggressiveness,
impulsiveness, cognitive dysfunction, sleep alteration and emotional lability, including
depression, which is a direct reflex of neurotransmission impairment. Tractography
neuroimages can detect, already in early stages, the white-fiber compromise resulting
from the concussion. It is not yet known to what extent an axonal injury can be repaired.
Myelinization seems to protect the axon against trauma; however, in repeated concussions,
with no time for axonal recovery, immature or even incomplete myelinization, it is
not possible to avoid the sequelae of the initial trauma.[22]
[23]
[24]
[25]
Symptomatology. Respecting the topography of the lesion. Any portion of the nervous system may be affected by cerebral concussion, leading
to its characteristic clinical presentation. Several regions are commonly affected
concomitantly, resulting in a wide variety of symptoms.
Cortical structures. Due to its anatomical location, the frontal lobe is frequently affected by concussion,
presenting cognitive dysfunction. The diagnosis is made through neurocognitive and
neuropsychological tests. The affected temporal lobe may present memory deficits with
anterograde amnesia and impairment of the consolidation of long-term memory. During
the verbal and visual memory tests, in more than 75% of the cases, positron emission
tomography (PET) and single-photon emission tomography (SPET) present alterations.
The lesions to the parietal lobe traditionally result in complex impairments, such
as: aphasia, apraxia, alexia, agraphia, dyscalculia and dysesthesia.[2]
[26]
Subcortical structures. The concussive lesions that affect the hypothalamus may be characterized by autonomic,
endocrine, sexual (erectile) dysfunctions, as well as analgesic and circadian rhythm
dysfunctions. Hypopituitarism is described as a lesion to the hypophysial stem, with
consequent hormonal deficit, involving the adenohypophysis and the neurohypophysis.
Damiani et al[27] describe that hypocortisolism may mimic postconcussion syndrome, and it should be
considered in the clinical investigation.[27] Milroy et al[28] describe changes in the sleep-wake cycle, often manifested in the form of dyssomnias
and/or parasomnias resulting from cerebral concussion.[28] After trauma, appetite alterations can also be observed, often leading to central
obesity due to hyperphagia and gastroparesis. Mortality increases significantly if
there is central diabetes insipidus, compromising electrolyte balance, which must
be controlled with desmopressin acetate (DDAVP, Ferring GmbH, Kiel, Germany).[2]
[27] Lesions to the base cores may course with choreoathetosis, dystonia, chorea, hypertonic-hypokinetic
movements, aphasia, hemiparesis and emotional lability.[29]
[30]
Trigeminal-facial structure. One of the main symptoms associated with cerebral concussion is the presence of recurrent
and persistent headache. The lesion often involves the trigeminal-vascular system,
with subcortical cellular alteration. Headache has several characteristics, and may
present in a migraine, tensional, cluster, occipital or supraorbital form. Commonly,
headache is accompanied by nausea and vomiting, malaise and abdominal pain. The physiopathology
of this type of headache involves injury to the trigeminal-vascular system associated
with the distension of the dural vessels, with the presence of spreading depression.
The treatment for postconcussion headache includes: biofeedback, psychotherapy, non-steroidal
anti-inflammatory drugs, triptans, ergotamine, opioids, muscle relaxants and selective
serotonin reuptake inhibitors.[31]
[32]
Cerebellar structure. Purkinje cells are especially susceptible to blow-counterblow lesions, with neuronal
loss in the first 24 hours after the trauma. The symptoms attributed to cerebellar
lesions include: dysdiadokokinesia, positive Romberg test, dysmetria, intention tremor,
dysphemia, motor incoordination and cognitive-affective dysfunction.[33]
Clinical Management in the Emergency Room
The diagnosis of cerebral concussion is clinical. It is a lesion of diffuse nature,
without focal manifestations upon clinical examination.[34] Loss of consciousness only occurs in ∼ 10% of the cases, while anterograde and/or
retrograde amnesia occurs in 30 to 50% of the cases. Headache occurs in most cases
(∼ 85%). It is noteworthy that the symptoms may not be present at the time of patient
admission; they may appear hours after the trauma, or only be diagnosed after neurocognitive
or neuropsychological tests.
In the emergency room, clinical measures should be established as a priority, according
to the treatment protocols recommended by Advanced Trauma Life Support (ATLS), following
this sequence: Ac (airway/cervical stabilization); B (respiration); C (circulation);
D (neurological status); E (exposure). Once diagnosed or suspected, concussion should
be handled with frequent clinical reassessments. Special attention should be given
to those patients with lowering levels of consciousness (or prolonged periods of unconsciousness
after head trauma), seizures, focal neurological signs and/or suspicion of cervical
injury.
Due to the impact, there is a risk of subdural and extradural hematomas, bone fractures
and/or cerebral contusion, with the need for neuroimaging exams, usually computed
tomography (CT) of the skull without contrast. Less than 10% of the patients present
bleeding in the neuroimaging exam, and less than 2% of them require neurosurgical
intervention.[5]
In the clinical practice, two scales are recommended to evaluate these patients in
the emergency room regarding the need for cranial CT: the New Orleans criteria and
the Canadian CT Head Rule, both validated in prospective studies. The presence of
at least one criterion in any of the scales is indicative of the need for a neuroimaging
exam ([Table 1]).[10]
[35]
[36]
[37]
Table 1
New Orleans and Canadian CT Head Rule criteria used as warning signs for indication
of cranial computed tomography in cases of cerebral concussion
|
NEW ORLEANS CRITERIA — GLASGOW COMA SCALE 15
|
|
Headache
|
|
Vomit
|
|
Age > 60 years
|
|
Alcohol or drug intoxication
|
|
Persistent anterograde amnesia
|
|
Convulsion
|
|
Traumatic lesion to the soft tissues or bone lesion above the clavicle
|
|
CANADIAN CT HEAD RULE CRITERIA — GLASGOW COMA SCALE 13–15 FOR PATIENTS AGED ≥ 16 YEARS
|
|
✓HIGH risk of neurosurgical intervention:
|
|
Glasgow coma scale < 15 2 h after the trauma
|
|
Open or sinking cranial fracture
|
|
Cranial base fracture: rhino/otorrhea; raccoon eye; Battle
|
|
Two or more vomit episodes
|
|
Age > 65 years old
|
|
✓MODERATE risk of neurosurgical intervention
|
|
Retrograde amnesia ≥ 30 minutes
|
|
Injury mechanism: collision; vehicle ejection; fall > 1 m high; fall > 5 steps
|
A useful tool developed for the diagnosis of cerebral concussion in sports is called
Sport Concussion Assessment Tool, Third edition (SCAT3). It is a list of 22 relevant
symptoms. In cases of suspicion of cerebral concussion, the presence of only one symptom
concludes the diagnosis. A new scale called childSCAT3 was developed for children
aged between 5 12 years with suspicion of cerebral concussion.[38]
Patients with cerebral concussion diagnosis should remain at rest to reduce the cerebral
metabolic demand, which could otherwise exacerbate cellular lesions.[39] The observation period will depend on the severity of the trauma, represented by
the symptomatology presented. Patients with a normal neurological examination should
be observed for ∼ 2 hours.[40] It is always useful to leave written guidance on warning signs for the presence
of intracranial lesions with later manifestations: intense headache, vomiting, dizziness,
postural instability, or loss of fluid through the nose or ear. It should also be
clear to the patient and caregivers that headache and irritability are absolutely
frequent for a few days after cerebral concussion, and may manifest over the subsequent
days, not being a cause for concern. Regarding the drowsiness that the patient may
present in the days after the trauma, it is also a common postconcussion sign, but
it is still unclear whether waking the patient overnight has any benefits. It is recommended
that patients do not return to their daily activities until the headache and malaise
have improved.[10]
In the presence of new symptoms, such as hemiplegia, dizziness and drowsiness, after
cerebral concussion, a clinical reassessment with neuroimaging is mandatory, to discard
subdural and/or extradural hematomas. With the hypothesis of axial collections discarded,
posttraumatic ischemic strokes should be considered, commonly due to traumatic injuries
of the carotid and/or vertebral arteries. Once the aforementioned lesions have been
discarded, the migraine-like phenomenon may be considered as an etiology for the new
signs and symptoms.[10]
[41]
[42]
Some neuroimaging findings may prolong the observation time, requiring the hospitalization
of the patient. The presence of a small cerebral contusion or even discrete subarachnoid
hemorrhage is observed in ∼ 5% of the cases. Generally, these lesions do not result
in functional impairment, only persistent headache, requiring that the patient be
observed for a longer period (∼ 12 hours on average). In the presence of intracranial
lesions such as those mentioned, a neuroimaging evaluation is indicated for the comparison
with the initial image.[10]
Management of postconcussion syndrome. This syndrome is characterized by a constellation of symptoms observed in victims
of cerebral concussions in the days following trauma. Headache and irritability occur
frequently, followed by dizziness, anterograde/retrograde amnesia and somnolence.
About 25% of these patients still present symptoms 1 year after the concussion.
Anxiety and depression are described by more than one third of the victims, and are
more intense in hypochondriac patients. Imbalance and dizziness reflect vestibular
concussion, which can be evidenced in the vestibulo-ocular reflex (VOR) test.
The pharmacotherapy indicated for the victims of cerebral concussion is poorly studied.
The use of medications that interfere little with the level of consciousness is recommended.
Common analgesics are used for headache, and non-hormonal anti-inflammatory drugs
should be avoided in the initial stage of the trauma, due to the potential risk of
hemorrhage. Opioids should not be used, since they impair neuronal regeneration and
are associated with chronic pain in patients. Labyrinth system depressants are used
(preferably those with an associated antiemetic effect): promethazine, betahistine
dihydrochloride, meclizine, diphenhydramine and flunarizine. Serotonin reuptake inhibitors
are also widely used, however, with poorly-studied results. For individuals who already
suffer from migraine and who develop chronic postconcussion headache, several drugs
are used: triptans, anticonvulsants, β-adrenergic blockers, steroids and calcium channel
blockers.[5]
[10]
[43] Neuropsychological and neurocognitive approaches should be performed after the first
week of trauma. Complaints of lack of attention, impulsiveness and hyperactivity are
often already observed in this stage. Suicidal ideation is a possible consequence
of cranial trauma, reinforcing the need for psychiatric follow-up.[44] Neuropsychological follow-up can be useful, as well as the prescription of psychostimulants.[5]
Temporal Classification of Concussions
Current studies classify cerebral concussions in stages (periods of time) of recovery
based on the physiopathological knowledge and the neurometabolic cascade described
before. However, the same authors consider that each individual has his/her own particularities,
and this subdivision is only a generalization. In this context, stage I comprises
a temporal variation of zero to 5 days, constituting a period in which the individual
is unfit to return to his/her daily activities, and is usually very symptomatic, requiring
analgesic medications. Stage II varies from 2 to 10 days, and the patient remains
symptomatic, limiting his/her daily activities, restricting the workload, but already
participating again in his/her routine. The return to studies should also be gradual,
and the resting time is considered relative. Medications should be removed gradually.
Ultimately, in stage III, which consists of a period ranging between 7 and 14 days,
the patient no longer has symptoms related to cerebral concussion, and should no longer
take medications. In those athletes who are victims of trauma, this is the ideal time
to return to sports. Special attention should be given to those athletes who experience
the symptoms of the concussion again when they return to their routines, and they
should be instructed to do so more gradually. It is recommended that these athletes
should initially be subjected to mild aerobic exercises, evolving to sport-specific
exercises that require balance and movement control, and training in the field of
play and without contact with opponents (minimizing possible new traumas), but, at
the same time, improving their agility and cognition. Finally, after this evolution,
and being asymptomatic, the athlete will be able to return to normal training and
competition ([Fig. 2]).[45]
[46]
[47]
Drugs with Neuroprotective Potential
Once the physiopathological mechanisms involved in cerebral concussion have been recognized,
several drugs become promising to interrupt the harmful neurometabolic cascade. The
therapeutic targets include: reduction of glutamatergic excitotoxicity, limitation
of the damage caused by the production of free radicals and lipid peroxidation, and,
finally, reduction of the permeability caused by the breakdown of the blood-brain
barrier. Since the 1980s, several studies have tested magnesium sulfate, calcium channel
blockers, bradykinin inhibitors, immunoreceptor blockers, vitamins, anti-inflammatories
and minerals, with frustrating results in humans.[48]
[49] Despite previous results, some pharmacoprotective possibilities continue to be investigated:
-
Magnesium sulfate. Its action mechanisms include the blockage of N-methyl-D-aspartate
(NMDA) glutamate receptors and calcium-dependent receptors, and reduction of the neuroinflammatory
cascade associated with cranioencephalic trauma. However, in human studies, there
was an increase in mortality.
-
Progesterone. This drug can reduce the oxidative stress to the cell membranes, with
decreased lipid peroxidation and blood-brain barrier breakage. Recent studies, however,
have shown no benefit of their administration in humans.
-
Erythropoietin. This hormone has potential neuroprotective activity by several mechanisms,
and continues to be investigated for its best form of administration in cases of CET.
-
Ziconotide (SNX-111; Prialt) is an atypical analgesic agent for the amelioration of
severe and chronic pain. These are drugs that act in the reduction of calcium accumulation
in the cerebral cortex and in the white matter, including the restoration of mitochondrial
function. However, clinical studies have been interrupted due to the increased mortality
in humans. Calcium antagonists with greater selectivity, such as SNX-185, continue
to be investigated.
-
Substance P and neurokinin A receptor antagonists. They are drugs with neuroprotective
potential, because they reduce cellular edema, as well as capillary permeability,
with improved motor and cognitive functions after CET. Clinical studies are still
underway.
-
Minocycline. An antibiotic with a post-CET immunomodulator effect, as well as antioxidant
and anti-inflammatory effects. Studies are underway to prove its efficacy in humans.
-
Ciclosporine. It is an immunosuppressant with neuroprotective effects, because it
stabilizes the mitochondrial function, reducing the production of free radicals and
preventing the cellular calcium inflow. In animal models, there are proven benefits
of ciclosporine in cases of CET; however, in humans, its benefits are still being
investigated.[48]
[50]
-
Toll-like receptors. They are receptors of the immunologic innate response that activate
the intracellular inflammatory cascade. The blockade of these receptors is being investigated
with potential benefits in cases of CET.[48]
[51]
-
Vitamins, minerals and antioxidant agents (omega-3). These drugs, including B-complex
vitamins and nicotinamide, showed benefits in animal models, reducing cortical lesion
and inflammation. They still need studies that prove their efficacy in humans.
-
Micronutrients (zinc and magnesium). Both zinc and magnesium are necessary for proper
cell functioning, and their neuroprotective effect after CET is still being investigated.[48]
