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10 Articles in Volume 13, Issue #4
Traumatic Brain Injury
US Service Members With Polytrauma
Cancer Patient: Controlling The Pain
Pharmaceutical Treatment of the Cancer Pain Patient
Drug Interactions in Cancer Patients Requiring Concomitant Chemotherapy and Analgesics
How Do We Get Enough Physicians to Medically Manage The Difficult (High-dose Opioid) Pain Patient?
Ultra-high Dose Opioid Therapy: Uncommon and Declining, But Still Needed
Head Trauma: More Than A Headache
Ask the Expert May 2013
Letters to the Editor May 2013

Traumatic Brain Injury

With millions of traumatic brain injuries occurring in the United States each year, it is becoming more crucial for pain practitioners to understand the biomechanics, pathophysiology, and symptomatology of these conditions.

Traumatic brain injuries (TBIs) are on the rise in the United States, and most TBIs (the mild form of which is also referred to as a concussion) are not treated in hospitals or emergency departments. According to the Centers for Disease Control and Prevention (CDC), approximately 1.4 million TBIs occur in the United States each year.1 For military personnel, TBIs also are an increasingly common injury, with blasts in combat zones being the most frequent causes for military service members.2 Added to this are the rising medical costs of treating TBIs, which the CDC estimates at $12 billion.2 Since more TBI patients are being seen by private practice clinicians, as opposed to hospital emergency departments, this article discusses the importance of clinicians understanding the biomechanics, pathophysiology, and symptomatology of these injuries, especially since highly variable symptom durations are such a common occurrence following TBIs. Part 2 of this article series will discuss treatments for TBI-related headaches. Part 3 discusses the evaluation, treatment and rehabilitation

Concussion Biomechanics

There are a number of variables to consider when a TBI occurs. The two main types of forces are inertial and contact. Inertial acceleration loading occurs without actual head contact.3 Contact loading may result in injuries directly at the site of impact, such as a skull fracture, as well as at distant areas in the brain. Milder TBI rarely results in linear or depressed fractures.

With milder TBI, the inertial forces (acceleration) are responsible for most of the symptoms. Acceleration forces are divided into two types: 1) rotational, and 2) linear.4 After a blow to the head, there is a temporary rise in pressure within the cranium. Neuronal injury somewhat correlates with the height of the peak pressure. Rotational forces produce more serious damage than do acceleration ones. When the head rapidly rotates, shear-induced damage to brain tissue ensues.5 Rotational impacts produce the unconsciousness associated with more severe concussions.

The important question in understanding the biomechanics of concussion is: How does energy from a blow to the head get transferred into the brain? Brain tissue is soft, consisting mostly of water. If a shearing force hits the skull, the brain is easily deformed. Models have been able to predict how much pressure is generated in the brain by various forces.6 Pressure gradients lead to deformation of the cerebrum and brainstem. Rotational accelerations produce much more profound effects than do linear accelerations.

Experiments have proven that coronal (lateral) rotational accelerations produce the most profound effects deep within the brain. These coronal accelerations often produce loss of consciousness.7 Other factors enter into the effects of head trauma, such as the ventricular system, which may dampen the effect of the trauma. Detailed 3-D computerized modeling of different rotational forces will help to predict the extent of neural and vascular deformations from various blows.

Concussion Pathophysiology

A complex series of neurometabolic and neurochemical changes occur immediately following a concussion. Axons are stretched and cell membranes disrupted. This results in ionic flow that is largely unregulated. The result is a release of various neurotransmitters, in particular the excitatory amino acids (EAAs).8 The ATP-dependent pump works overtime to restore sodium (Na+) and potassium (K+) balance, all of which take a tremendous amount of energy. With most concussions, these molecular changes are short lived, but they can be permanent, particularly in the setting of multiple head traumas.

After the concussion, K+ flows out of the neuron, along with EAAs such as glutamate. N-methyl-D-aspartate (NMDA) receptors are activated, and calcium ions rush into the neuron.9 Neurons are suppressed, similar to the situation we encounter with spreading depression. Spreading depression (originally described by Leao) is important in epilepsy and migraine.

The Na+ and K+ pumps kick into high gear, which requires increased glucose metabolism. Oxidative metabolism is compromised, and lactate accumulates. Lactate adds to local acidosis, and contributes to cerebral edema.

Directly following a concussion, hyperglycolysis is observed, followed by a glucose hypometabolism. This glucose hypometabolism may last weeks or months (after a severe TBI). The influx of calcium (Ca++) into mitochondria leads to glucose oxidative dysfunction.10

All of the above problems set the brain up for the deadly or disabling second impact syndrome. The exact reasons why second impact syndrome occurs are not clear. Second impact syndrome involves cerebral edema after a second concussion, and often is catastrophic.11 The first concussion leaves the brain in a vulnerable state, with depleted energy stores, activation of neurotransmitters, and altered ionic balance. Dysfunction in the mitochondria adds to the increased vulnerability. With repeated blows to the head, axonal disruption may be permanent.

After a severe TBI, the effect on cerebral blood flow has been described in 3 phases. Initially there is a cerebral hypoperfusion, followed by hyperemia, and finally a cerebral vasospasm. Edema may occur. The axons are stretched during a blow to the head, resulting in depolarization, mitochondrial dysfunction, calcium influx, and flux of other ions.12

Axonal injury occurs even after a milder TBI. The myelin and cell bodies are relatively untouched after milder injuries. Diffusion tensor imaging (DTI) has been able to detect subtle axonal changes after mild TBI.13> In addition to DTI, functional MRI may become clinically useful in helping to predict recovery time.

With repeated concussions and subconcussive hits, the dreaded progression in chronic traumatic encephalopathy (CTE) may occur. Tau and amyloid deposition occurs.14 CTE has previously been a post-mortem diagnosis, but a PET study in 2012 was able to detect signs of CTE in living individuals.15 To prevent tauopathy and CTE, it is crucial to limit the total hits, concussive and lesser, in the young athletes.

Post-concussion Syndrome

Mild and so-called minor TBIs produce well-documented post-concussion symptoms, including migraines and other headaches. These individual symptoms are quite treatable, and should be documented and worked up objectively using an interdisciplinary approach.16

Post-concussion syndrome is when a set of symptoms occurs following an initial concussion and lasts for extended periods of time. The symptoms can occur for weeks, months, or years; are quite frequent; and are seen in the majority of patients with so-called mild or minor brain trauma. Often, these TBIs are of the whiplash type, without contact of the head against a solid and immovable object. Frequently, no loss of consciousness is reported by the patient, but many will speak about being dazed or “dinged” at the time of the injury. Table 1 outlines the symptoms commonly exhibited following a TBI.

The good news, however, is that most, if not all, of these symptoms can be approached from a treatment standpoint. First, the patient needs to have a proper evaluation and workup to get an objective look at what kinds of problems are present. Treatment will be further discussed in Part 2.

Evaluation and Testing
A proper evaluation consists of a neurologic examination by a neurologist experienced in evaluating mild TBI. Unfortunately, the majority of post-concussion syndromes are not evaluated as thoroughly as might be wished for, and symptoms often are presented to the doctor but are disregarded and remain undertreated. By our estimate, minor brain trauma occurs several million times per year. In children and adolescents in particular, the sudden onset of headaches in a headache-free individual is, in these authors’ experiences, a sign of post-concussion syndrome. If there is a change in attitude, behavior, participation in school, sleep patterns, and some of the other symptoms outlined, very often the history of a mild TBI can be obtained, although children and adolescents will rarely volunteer this information for fear of parental retribution.

Once there is a hint of neurologic abnormality on examination, the single most sensitive test that can show objective evidence of trauma to the brain is a high-grade electroencephalogram (EEG). This is a brain wave test, and when high-grade data (28 or more channels) are obtained and interpreted, a large percentage (30%-60%) of studies—at least in our laboratory in Dallas, Texas—will show abnormalities when read correctly. The test is noninvasive and has to be performed using high-grade equipment, by properly certified technicians, and preferably interpreted by a neurologist who is board certified in EEGs. Many 8- and 12-channel studies miss subtle abnormalities. Often, tests are performed by relatively untrained technicians using older equipment, and are interpreted by poor-quality readers. The data often are contaminated by a lot of eye- and muscle-movement artifacts, and, unfortunately, good quality EEG data are not generated in every laboratory.

In some cases, quantitative EEG can be performed, which gives a mathematical look at certain aspects of the EEG. This equipment is not widely available, and only a small proportion of neurologists are trained to use quantitative EEG technology as part of their practices.

Balance systems can be tested electrically using evoked potentials. Brainstem auditory evoked potentials, visual evoked potentials, and somatosensory evoked potentials, as well as P50 and P300 studies, can yield data regarding transmission of signals to and within the brain. They often can yield subtle abnormalities, which are then correlated with the clinical findings. In all cases, EEG and evoked-potential data have to be correlated with the patient’s clinical state because they are not diagnostic by themselves, just as the brain MRI would not necessarily be diagnostic of TBI. A very high-grade (3 Tesla) brain MRI with DTI sequencing can yield structural evidence of brain damage, especially in tracts coming from the corpus callosum. Detailed neuro-otologic evaluation can reveal middle ear, inner ear, or brainstem difficulties. Functional MRI is a promising technique for studying functional brain activity.

The most detailed aspects of brain functioning (ie, attention, memory, cognition, concentration) are evaluated via a detailed neuropsychological evaluation. This has to be performed by a neuropsychologist (preferably board certified) who is properly trained to evaluate various areas of brain functioning in detail, and who has experience in TBI evaluations.

Not all neuropsychological testing is created equal. The gold standard is the Halstead-Reitan Battery, which, with modifications, has been used for many years and yields precise data regarding cognitive brain dysfunction after TBI. Newer neuropsychological batteries, such as the Neuropsychological Assessment Battery (NAB) or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), offer powerful means of evaluating frontal lobe dysfunction after TBI.

If the EEG and neuropsychological testing agree in terms of the locations of problems, then clinicians can undertake attempts at cognitive rehabilitation, which aims to ameliorate problems with memory, attention, and cognitive processing. Often, the frontal lobes, which are the most developed portion of the human brain, are affected in TBI. The frontal lobes perform many of the executive functions of planning and coordination of activity, and cognitive rehabilitation attempts to remediate defective processing. Note that we will not use the term “cure” in this or any other article, since we are trying to improve symptoms. The brain trauma often leaves a person with relatively longstanding or even permanent changes in the way they perform cognitively. Many people, however, will recover over time from their brain trauma. In general, the age of the person who has the brain injury will go a long way in determining the rate, extent, and recovery of various post-concussion symptoms.

Post-traumatic Headache

Post-traumatic headache (PTHA) is a common symptom following TBI. A study by Walker et al measured data on headache frequency, type, location, and incapacitation levels of Veterans Affairs (VA) patients undergoing acute rehabilitation.17 The investigators demonstrated that 41 out of 109 (38%) VA patients with moderate or severe TBI also had acute PTHA. Of those 41 patients, 20 (49%) experienced PTHA in a frontal location, and 31 out of 41 (76%) experienced it daily. Post-hospitalization, PTHA symptom severity declined and better individual improvement was associated with less anxiety and depression at 6-month follow up. Almost all subjects with PTHA symptoms that persisted at the 6-month follow up (21 of 22; 95%) continued to report symptoms at 12-month follow up.

PTHA is one of several symptoms of both post-traumatic syndrome and TBIs and it may be accompanied by somatic, psychological, or cognitive disturbances. The etiologies of symptoms between PTHA and TBI/whiplash injury vary slightly, however. PTHA can resemble a tension-type, migrainous, or cervicogenic headache. Post-whiplash headache typically is a pain radiating from the neck to the forehead with a prolonged course. The pathogenesis of PTHA still is not well known, but it might share some common headache pathways with primary headaches, such as migraines.18

German investigators have suggested that TBI and whiplash injury are followed by a PTHA in approximately 90% of patients.19 They found that PTHA due to common whiplash is located occipitally (67%); is of dull, pressing, or dragging character (77%); and lasts 3 weeks on average. Tension-type headache is the most frequent type of PTHA (85%). Besides post-traumatic cervicogenic headache, migraine- or cluster-like headache may be observed in rare cases.

The relationship of PTHA to cognitive dysfunction after sports-
related TBI is poorly understood. A study by Collins et al examined high school athletes who reported headaches approximately 1 week after injury. Investigators found that the athletes reporting headaches had significantly more non–headache-related concussion symptoms, such as slower reaction time and impaired memory, according to on-field markers of concussion severity at the time of injury. Symptoms and neurocognitive test results collected via ImPACT, a computerized neuropsychological test battery and post-concussion symptom scale, found symptoms a mean of 6.8 days after injury. The athletes reporting PTHA performed more poorly on neuropsychological tests than athletes not experiencing headache.20 Study participants included 109 athletes who had sustained concussion; they were divided into 2 groups: those reporting headache 7 days after injury and those reporting no headaches. The authors concluded that any degree of post-concussion headache in athletes after brain injury (7 days after injury) is likely to be associated with an incomplete recovery after concussion.

Another report by the same authors further enforced the prevalence of incomplete recovery following a concussion in patients exhibiting post-concussion headache.21 The authors studied a larger cohort of high school and college-aged athletes who had sustained concussive injuries with and without headaches and post-traumatic migraine (PTM). In this study, 261 high school and college athletes were divided into 3 groups: the PTM group (74 athletes with a mean age of 16.39 ± 3.06 years), the headache group (124 athletes with a mean age of 16.44 ± 2.51 years), and the non-headache group (63 patients with a mean age of l6.14 ± 2.18 years). Symptom scores were collected using ImPACT to assess sports-related concussion. Significant differences existed among the 3 groups for all outcome measures. The PTM group demonstrated, once again, significantly greater neurocognitive deficits when compared with the headache and non-headache groups. The authors concluded that athletes suffering a concussion accompanied by PTM should have symptom status assessed and neurocognitive testing performed to address their recovery more fully. We would add that a high-grade EEG study (26 channels or more) would add further information on the injured player’s status.

As an aside, the ImPACT battery is rather cursory for evaluating post-TBI functioning. Currently, RBANS and NAB test protocols are considered more accurate and complete for testing frontal lobe functioning after TBI.

There are also telltale risk factors that may identify TBI patients who are at increased risk for developing post-concussion symptoms A Finnish study evaluated patients with mild head injury (MHI) in a series of 172 consecutive MHI patients admitted into the emergency room of a general hospital and who subsequently developed post-concussion symptoms.22 One month after the injury, the investigators used a modified Rivermead Post­Concussion Symptoms Questionnaire to identify the patients with and without post-concussion symptoms. They identified 37 patients with MHI who developed post-concussion symptoms (22%). Risk factors for post-concussion symptoms in the MHI patients were skull fracture (OR, 8.0; 95% CI 2.6-24.6), serum protein S-100B >0.50 mcg/L (OR, 5.5; 95% CI, 1.6-18.6), dizziness (OR, 3.1; 95% CI, 1.2-8.0), and headache (OR, 2.6; 95% CI, 1.0-6.5). The presence of skull fracture, dizziness, and headache may help physicians identify patients at risk for post-concussion symptoms. Serum protein S-100B proved to be a specific but not a sensitive predictor of post-concussion symptoms.

Chronic PTHA

Traditionally, chronic PTHA lasts longer than 3 months. With PTHA resulting from TBI, 80% of patients show remission within 6 months, but chronic PTHA lasting at least 4 years occurs in 20% of TBI patients. Unfavorable prognostic factors include age more than 40 years; a low intellectual, educational, and socioeconomic level; previous head trauma; or history of alcohol abuse. Patients with initially severe headache after whiplash are likely to have a prolonged PTHA lasting years as well as an extensive decrease of mobility of the cervical spine and other associated risk factors.19

Chronic PTHA is a common condition that often is seen as part of the post-concussion syndrome.23 The pathophysiology is not well understood but includes biological, psychological, and social factors. Tension-type headache is the most common manifestation of chronic PTHA, but exacerbations of migraine-like headaches often occur.

De Benedittis et al examined the epidemiological and clinical profile of chronic PTHA in 57 out of 130 consecutive patients hospitalized following closed head injuries at the Institute of Neurosurgery of the University of Milan.24 The incidence of chronic PTHA was 44%. Patient ages ranged between 4 and 69 years. Head injury severity varied from mild to moderate to severe. Chronic muscle contraction headache was the most common clinical picture, followed by migraine. Following the head trauma, moderate correlations were found between the severity of chronic PTHA, disturbance of consciousness, and positive findings at computed tomography (CT) scan. Using the Minnesota Multiphasic Personality Inventory to assess personality profiles, the investigators compared 26 chronic PTHA patients with 17 patients in a post-traumatic control group without headache. Higher scores were seen on hypochondriasis, depression, hysteria, and schizophrenia scales only in the severe chronic PTHA group.24 Patient ages, duration of unconsciousness, neurologic deficits, course length, and pending litigation or compensations were unrelated to the occurrence and outcome of chronic PTHA. The authors suggested that both physical and psychological determinants (social or emotional maladjustment) are important to the pathogenesis of chronic PTHA.

TBI and Migraine

Although very early studies spoke to the possibility of migraine headaches occurring after TBI, several more recent studies have speculated on the similarity or overlap of post-concussion headaches with traditional migraine presentations.25-28 Margulies concluded that patients suffering recurrent PTHA or other elements of the post-concussion syndrome should be treated for migraine.25 Other authors concluded that the most common symptom in mild head injury or TBI is headache that resembles migraine with unknown pathophysiology. Biochemical mechanisms believed to be similar in both conditions include: increased extracellular K+ and intracellular Na+, Ca++, and chloride; excessive release of excitatory amino acids; alterations in serotonin; abnormalities in catecholamines and endogenous opioids; decline in magnesium levels and increase in intracellular calcium; impaired glucose utilization; abnormalities in nitric oxide formation and function; and alterations in neuropeptides.27 A very early paper alluded to cortical spreading depression to account for transient neurological disorders that resulted from rather mild head injuries. These events, which appeared after a lucid interval, included headache, nausea, vomiting, pallor, somnolence, irritability and restlessness, stupor, hemiparesis and aphasia.28 The symptoms were not attributable to cerebral compression.

TBI in Children And Adolescents

While headaches and migraines after TBI are very prominent in adults, there is also a corollary body of data in children and adolescents who developed these disorders following TBI. (For more on headaches in adolescents, see the April 2013 issue of Practical Pain Management.) Haas et al grouped attacks of hemiparesis, somnolence, irritability, vomiting, blindness, and brainstem signs that occurred following TBI in 25 juvenile patients and related them to the head trauma.29 The authors concluded that there may be a common underlying process of these attacks that is related to migraines.

Another early study examined when the diagnosis of migraine should be considered in children who have experienced head trauma. Guthkelch evaluated 13 children and adolescents who developed transient nonconvulsive neurologic symptoms within a few hours of trivial head injury.30 It’s important to note that some of these patients were known to have migraines before and/or after these episodes. In all but one, a family history of migraine was elicited. The authors concluded that a diagnosis of migraine should be considered in children who develop delayed impairment of consciousness after head trauma, with or without convulsive phenomena or focal neurological deficits. A Polish researcher re-evaluated the characteristics and persistence of PTHA 90 days after brain concussion and 10 days after contusion in 100 children (29 girls and 71 boys), aged 3 to 14 years old; 83% of the children experienced headache after brain concussion and contusion.31 The majority (56%) experienced acute PTHA, but 27% of the children complained of chronic—mainly tension-type—headache.

Regional cerebral blood flow (rCBF) evaluations can demonstrate the presence and extent of nerve tissue damage caused by head trauma. Polish researchers demonstrated that rCBF measurements using single-photon emission computerized tomography in children with post TBI headaches showed persistent differences over time and can be a valuable tool in the assessment of head trauma consequences and post-traumatic symptoms in children.32 In the study, rCBF was assessed in 32 children, ages 6 to 16, 10 to 15 days after trauma, and in cases of brain concussion, 3 months and 1 year. In all children, no changes were found in CT and MRI examinations. In the early period after trauma, the investigators found blood flow impairment, mostly in frontal areas, in 21 of the children. One year after trauma, the rCBF improved in 11 children and exhibited a normal pattern in the remaining 10 cases. In 3 of the 4 children who still had headache 1 year after brain concussion, there was persistent impairment of blood flow.

Another evaluation of children who experienced TBI in France showed that 11 of 51 children developed common migraine.33 The study retrospectively evaluated 51 children who experienced TBI. The dominant symptoms seen following the TBI included: syncope-like loss of consciousness (11), seizures (6), severe headaches with neurologic signs (15), confusion (8), visual disorders (6), and amnesia (5). The long-lasting episodes suggested a migrainous pathogenesis, perhaps at a stage where the trigger of migrainous mechanism is at a low level in the brain.

We would pose one criticism of many of the studies reviewed here: EEG data were not examined as part of the work up. We believe this to be far more sensitive in the TBI setting for documenting electrographic abnormalities that may accompany headaches, migraines, and behavioral and cognitive changes. Additionally, Joseph C. Marcus, MBBCH, FCP (SA), and his colleagues measured serum ionized magnesium and ionized calcium/ionized magnesium ratios in 135 children with primary complaints of headaches. Out of those patients, 9 were given a diagnosis of PTHA. The children with PTHA also demonstrated abnormalities in serum ionized magnesium concentrations and ionized calcium/ionized magnesium ratios.34

Clinical Observations

My own (JCK) anecdotal evidence, based on clinical experience treating patients with post-concussion headaches and migraines, is quite concordant with the literature reviewed. Although not formally published, my clinical observations and evaluations include more than 2,850 patients with TBI. The vast majority (94%) of patients we’ve evaluated have suffered so-called minor or mild TBI, with most of the remaining patients diagnosed as moderately severe TBI. Table 2 outlines the different severity levels for TBIs based on generally agreed-upon parameters.35

Overwhelmingly, more than 90% of my clinic patients with PTHA and migraines fulfilled International Headache Classification (IHC) criteria for migraine or migrainous headache, well described in the latest International Classification of Headache Disorders.36 I have summarized data from more than 20 years of evaluation and treatment of PTHA and migraines in Table 3. Accumulated personal clinical experience shows that patients without any headache features whatsoever are extremely rare. For example, only 10 of 2,850 patients did not complain of any kind of headache, either tension-type, migrainous, or migraine. The vast majority (94%) had either migraines or migrainous headaches, as defined by the IHC criteria.36 Of my patients, 5.6% had primarily tension-type headaches without migrainous features, and there was an overlap in virtually all patients with features of tension-type headache mixed with migrainous or migraine headaches. Complaints of nausea and/or vomiting were made in 85% of my patients with migraines, 77% complained of light or smell sensitivity accompanying their migraines and 71% complained of dizziness or vertigo accompanying the headaches.


TBIs produce well-documented post-concussion symptoms, including migraines and other headaches. Thorough and proper testing and evaluation is crucial for clinicians to achieve a better look at the problems the patient may be experiencing. Proper evaluation consists of a neurologic examination. Additionally, high-grade EEG is a valuable tool for clinicians treating TBI patients and can show objective evidence of trauma.

Part 2 of this article series will focus on treatments of post-TBI migraines and other headaches.

Last updated on: April 15, 2015

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