Cerebrospinal fluid analysis

Secondary injury:

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  Follows initial TBI mediated by an inflammatory and excitotoxic cascade leading to further neurological damage and clinical impairments

  
  
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  Efforts to better understand the mechanism and develop strategies to mitigate its destructive properties are ongoing

  
  
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  CSF has been used in monitoring inflammatory and cytotoxic mediators

Interleukins (ILs):

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  Disruption of the blood-brain barrier after TBI allows infiltration of inflammatory mediators into the brain parenchyma.

  
  
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  The IL-1 system of proteins have been shown to play an important role in inflammation after a TBI.

  
  
  
  
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    IL-1B in CSF in patients with severe TBI may have prognostic value and has been shown to be attenuated with hypothermia. ^,

    
    
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    One study showed IL-1 levels in CSF were elevated in patients with TBI and correlated with worse prognosis.

  
  
  
  
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  IL-8 levels were found to correlate with increased intracranial pressure (ICP) and decreased cerebral perfusion pressure (CPP) in severe TBI and thus is suggested to be predictive of impending secondary injury.

Metabolic:

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  Neuronal damage after TBI is mediated by excitatory amino acids such as glutamate.

  
  
  
  
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    Elevated CSF glutamate levels found in severe TBI, however, are not necessarily correlated with outcome.

  
  
  
  
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  Neuronal recovery after TBI is metabolically demanding.

  
  
  
  
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    Cerebral damage worsened by an uncoupling of cerebral blood flow with increased energy demand.

    
    
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    One study assessed glucose and lactate as a prognostic tool, finding that a low glucose:lactate ratio and high CSF lactate levels may be predictive of poorer outcome.

  
  

Neuroproteins

TBI is considered a risk factor for onset of Alzheimer’s type dementia with associated abnormal CSF amyloid-B and phosphorylated tau (p-tau).

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  Debatable clinical significance of this relationship

  
  
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  Possible benefit in preventing dementia with targeted immunotherapy

  
  
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  One study in chronic TBI patients with disorder of consciousness showed differential effect of amyloid-B and p-tau

  
  
  
  
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    Amyloid-B levels were low, and p-tau levels were normal, suggesting amyloid-B may be a better target of immunotherapy.

  
  

CSF neurofilament light (NF-L)chain protein:

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  Increased 10-fold at 2 weeks postconcussion and remained elevated at 28 weeks postinjury in a cohort of boxers

  
  
  
  
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    Subacute axonal injury in absence of overt symptoms, which likely would have cleared the athlete to return to their sport

  
  

Serum analysis

Specific serum biomarkers for TBI with preventative and prognostic value has been of interest given the ease of obtaining a sample, but there has been limited success.

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  Few biomarkers have been consistently elevated in the acute phase after TBI.

Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1):

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  The combination of GFAP, an astroglial biomarker, and UCH-L1, a neuron-specific biomarker, has been found to be elevated early after TBI and helps predict patients who will require neurosurgical intervention.

S100B:

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  An astroglial protein sensitive to brain injury but not specific to TBI

  
  
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  High levels correlated with injury severity and poor outcome

  
  
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  Normal S100B levels have been correlated with negative intracranial computed tomography findings; helpful in predicting which mild TBI (mTBI) patients may require CT

  
  
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  Inversely associated with return to work after mTBI

Tau:

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  A microtubule-associated protein abundant in neurons and other cells

  
  
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  Ultrasensitive Quanterix Simoa assay demonstrated acute increase in hockey players after a game than preseason levels

  
  
  
  
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    Highest levels immediately after a concussion

    
    
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    Duration of symptoms correlated with tau levels at 1 hour after concussion

    
    
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    Limitations: Assay doesn’t distinguish between CNS- and non–CNS-derived tau.

  
  

Spectrin N -terminal fragment (SNTF):

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  Marker for neurodegeneration prevalent after TBI or cerebral ischemia

  
  
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  Levels elevated in the serum of patients with severe TBI

  
  
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  Elevated levels after mTBI correlate with prolonged cognitive impairments

  
  
  
  
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    Predicted severity of mTBI and return to play in professional ice hockey players

  
  

Gait analysis

Balance impairments are common after TBI of all severities and are a routine component of the clinical assessment after a concussion.

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  Currently, balance assessments are limited to static control of posture.

  
  
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  Evidence is indicating dynamic balance testing, combining motor tasks with cognitive testing, in a dual task assessment is a better method of detecting more subtle cognitive impairments.

Gait characteristic derangements after a concussion in dual-tasking assessments include :

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  Slower walking speed

  
  
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  Shortened stride length

  
  
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  Longer period of double-leg stance phase of gait

  
  
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  Increased medial–lateral displacement of the patient’s center of mass (COM)

  
  
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  Faster velocity of side-to-side movement of the patient’s COM

Conventional electroencephalography

Electroencephalography (EEG) was the first clinical diagnostic tool to provide evidence of abnormal brain function after TBI.

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  Correlated with functional imaging to provide optimal, noninvasive, monitoring of brain activity

  
  
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  Portable and inexpensive; appealing diagnostic and prognostic tool

  
  
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  Common in the acute postinjury critical care setting

  
  
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  Limitation: need for clinicians skilled in the equipment and software

Nonconvulsive seizures occur in approximately 20% of TBI patients in critical care setting.

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  Deleterious impact on neurorecovery and would go undetected without continuous EEG monitoring

Common EEG findings in the early postinjury period after moderate or severe TBI :

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  Generalized or focal slowing

  
  
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  Attenuated posterior alpha

  
  
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  These findings usually resolve with recovery of consciousness

EEG abnormalities are rare in mTBI and when present are usually associated with loss of consciousness for greater than 2 minutes.

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  EEG is not recommended or clinically appropriate for assessment of mTBI.

  
  
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  EEG-based devices are being marketed as diagnostic tools in the acute setting of mTBI.

  
  
  
  
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    Food and Drug Administration approved only as adjunct tools in the assessment of mTBI.

  
  
  
  
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  EEG abnormalities in mTBI that are noted in the first 24 hours are usually associated with posttraumatic amnesia (PTA) of greater than 30 minutes’ duration.

  
  
  
  
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    Helpful prognostic tool as prolonged and incomplete recovery is more likely in such circumstances

  
  
  
  
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  EEG abnormalities in mTBI are likely to resolve completely within 3 months postinjury.

Factors that can influence the presence and persistence of EEG abnormalities include:

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  Early or advanced age

  
  
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  Comorbid pre- and postinjury conditions:

  
  
  
  
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    Illicit substance use, anxiety, pain, cooccurring neurological problems, time postinjury, and technical quality

  
  

One review showed most studies correlating conventional EEG with TBI were of poor quality and have several methodological limitations, including :

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  Inconsistency in clinical case definitions of TBI

  
  
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  Heterogenous TBI population with various comorbidities

  
  
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  Inconsistency in time postinjury

  
  
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  Broad range of recording and data assessment, limiting cross-sectional comparisons

  
  
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  Confounding effects of psychiatric, neurological, or substance abuse factors

Routine conventional EEG in evaluation of patients with TBI, other than in the neurocritical care setting, is not recommended over a thorough history and physical examination.

Quantitative electroencephalography

qEEG refers to computer-assisted analysis of EEG data.

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  Different methods include comparing frequency and amplitudes of signals to measure differences or changes in connectivity between different areas of the brain that are affected after TBI.

Information can be represented graphically by comparing electrodes in different areas of the scalp, known as brain electrical activity mapping (BEAM).

There are typical qEEG findings that are unique to patients with TBI :

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  Reduced mean alpha frequency

  
  
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  Increased theta activity

  
  
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  Increased theta:alpha ratios

Discriminant functions:

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  Refers to statistical functions that were developed by a combination of qEEG findings to probabilistically discriminate individuals with TBI from healthy controls solely with qEEG ^,

  
  
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  Clinical utility is controversial because the discrimination of a patient with TBI from a control is of limited clinical value

  
  
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  qEEG data rely on information derived from thorough history and physical examination, neuropsychological assessment, and neuroimaging

  
  
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  May have medico-legal and forensic implications

A qEEG-based TBI severity index was developed to characterize TBI severity retrospectively :

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  Overall classification accuracy of 96%

  
  
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  Retrospectively predicted initial Glasgow Coma Scale score, duration of posttraumatic coma, and post-TBI performance on a broad range of neuropsychological tests

  
  
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  Further studies to control for confounding variable are needed to validate this measure but is a promising tool with clinical utility

To date available evidence regarding the clinical usefulness of qEEG as a diagnostic tool is low, but it does represent a promising application of electrophysiological techniques to the care and treatment of patients recovering from TBI.

Evoked potentials

Evoked potentials (EPs) are scalp-recorded responses to external stimuli that reflect automatic preconscious information processing by the nervous system.

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  Sensory cortex readings are evident in 1 to 150 ms after stimulus

  
  
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  Cerebral information processing recordings occur 70 to 500 ms after stimulus

When paired with thorough history, physical, and cognitive evaluation, EPs may help identify neurobiological correlations with sequelae of a TBI and help target treatments.

Short-latency EPs:

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  Occur within the first 30 ms of stimulus

  
  
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  Brainstem auditory, pattern visual, brainstem trigeminal, motor, and somatosensory EPs

  
  
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  Delayed latency is the most common type of short-latency EP abnormality after mTBI

  
  
  
  
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    Development of the EP is after stimuli is abnormally delayed

  
  
  
  
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  Somatosensory EPs may be most prognostically useful in severe TBI

  
  
  
  
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    Assess perseveration of automatic preconscious information processing in patients with disorders of consciousness

    
    
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    Controversy regarding utility of their use in clinical decision making

  
  

Middle-latency EPs:

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  Middle-latency P50 evoked-response abnormalities are associated with impaired auditory processing and correlated with lower hippocampal volumes and may reflect posttraumatic cholinergic deficits.

  
  
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  Studies have looked at P50 evoked responses to paired auditory stimuli as a means of measuring processing speed among patients with persistent attention and memory impairments after TBI.

  
  
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  Findings suggest the potential utility of applying EPs to the study of neuropsychiatric symptoms

Long-latency EPs:

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  Occur 70 ms or greater after stimulus

  
  
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  Considered markers of cortically mediated stimulus detection and processing, specifically in cognitive tasks

  
  
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  Frequently used in the study of cognitive impairments after TBI of all severities

  
  
  
  
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    Most frequently studied long-latency EPs are auditory mismatch negativity (MMN), auditory N200 (N2), P300 (P300a and P300b), and Contingent Negative Variation, with many used in the study of patients with disorders of consciousness after TBI.

    
    
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    Reduced amplitudes or delayed latencies of N2, P300, and CNV have been correlated with reduced processing and attention in mTBI.

    
    
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    P300 abnormalities have been used to monitor recovery of function after a TBI because normalization of these abnormalities correlates with functional recovery after TBI.

    
    
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    Delayed latency suggests slowed detection of stimuli

    
    
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    Reduced amplitude suggests inattention

    
    
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    Exaggerated amplitude suggests distractibility.

    
    
    
    
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      Possible measure of posttraumatic cholinergic function

      
      
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      Reduced amplitude and prolonged latency have been correlated with cholinergic depletion.

      
      
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      Abnormalities may normalize with treatment of a cholinesterase inhibitor.