Postconcussion syndrome

Handbook of Clinical Neurology, Vol. 158 (3rd series) Sports Neurology B. Hainline and R.A. Stern, Editors https://doi.org/10.1016/B978-0-444-63954-7.00017-3 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 17

Postconcussion syndrome BRIGID DWYER AND DOUGLAS I. KATZ* Department of Neurology, Boston University School of Medicine, Boston, MA, United States

Abstract Postconcussion syndrome (PCS) is a heterogeneous condition comprised of a set of signs and symptoms in somatic, cognitive, and emotional domains. PCS is a controversial concept because of differing consensus criteria, variability in presentation, and lack of specificity to concussion. Whereas symptoms of concussion resolve in most individuals over days to weeks, a minority of individuals experience symptoms persisting months to years. The clinical consequences of concussion may be best conceptualized as two multidimensional disorders: (1) a constellation of acute symptoms termed early-phase posttraumatic disorder (commonly headache, dizziness, imbalance, fatigue, sleep disruption, impaired cognition, photo- and phonophobia); and (2) late-phase posttraumatic disorder, consisting of somatic, emotional, and cognitive symptoms. This phase is highly influenced by various psychosocial factors and is much less specific to the brain injury itself. Risk factors for development of a late-phase disorder include a high early symptom burden (e.g., headache, fatigue), a history of multiple concussions, psychiatric conditions (anxiety, depression), longer duration of unconsciousness or amnesia, and younger age. Successful treatment requires thoughtful differential diagnosis, including consideration of comorbid and premorbid conditions and other possible contributing factors. Treatment should include a hierarchic, sequential approach to management of treatable symptoms that impact functioning, such as depression, anxiety, insomnia, headache, musculoskeletal pain, and vertigo. A guided prescription of aerobic exercise is beneficial for early- and late-phase disorders after concussion.

INTRODUCTION Postconcussion syndrome (PCS) has been the subject of extensive study but there remain controversy and debate regarding its definition, etiology, pathophysiology, and prognosis. Multiple signs or symptoms are required to meet criteria for most consensus definitions of PCS, but the presenting constellation of symptoms may differ significantly among individuals. The lack of specificity of symptoms to brain injury is also problematic. Identical symptom profiles can occur among different disorders and, to a large extent, even in the normal population (Iverson et al., 2015; Hunt et al., 2016b). Diagnosis of mild traumatic brain injury (mTBI) or concussion (used synonymously here) still lacks established objective biomarkers so the diagnosis is based on clinical examination of early signs and symptoms or unreliable retrospective

reports. So fallacious retrospective diagnosis of concussion or mTBI based on the nonspecific symptom profile of PCS is a common clinical pitfall. This chapter addresses aspects of definition and diagnosis, clinical features, expected clinical course, and variability in prognosis of PCS. The review concludes with a brief discussion on treatment and future directions.

DEFINITIONS Several definitions of PCS, including those focused on sports concussion, have been used for both clinical management and research, but there remains lack of consensus on a precise definition (Table 17.1). Reliance on one or another definition can lead to wide variations in diagnosis and inclusion criteria for epidemiologic and other research, as well as clinical decision making.

*Correspondence to: Douglas I. Katz, MD, Department of Neurology, Boston University School of Medicine, 72 E Concord St C3, Boston MA 02118, United States. Tel: +1-781-348-2500, E-mail: [email protected]

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Table 17.1 Definitions for postconcussion syndrome and related disorders

ICD-10

DSM-IV

DSM-V

5th International Consensus Conference on Concussion in Sport

Terminology

Postconcussion syndrome

Postconcussional disorder

Trauma

History of head trauma

History of head injury

Loss of consciousness (LOC)

“Usually sufficiently severe to result in loss of consciousness” Yes

Suggested criterion: > 5 minutes

Major or mild neurocognitive disorder: traumatic brain injury Impact to head or rapid movement/displacement of brain Not required

Sports-related concussion: symptoms and signs Impulsive force transmitted to the head Not required

Yes, or (+) imaging/ neurologic exam

“Impairment of neurologic functioning”

Immediate or when conscious

Minutes to hours

Adults: 10–14 days Children: 4 weeks Not required

Maximum symptom delay for attribution to trauma Minimum duration

4 weeks

Relative attention or memory impairment on neuropsychologic testing N/A

N/A

3 months

“Past the acute injury phase”

Objective evidence

Not required

Required

Not required

Altered consciousness / cognitive impairment

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, fifth edition; ICD-10, International Statistical Classification of Diseases and Related Health Problems, 10th revision.

The International Statistical Classification of Diseases and Related Health Problems (ICD-10) clinical criteria for postconcussional syndrome proposed in 1992 (World Health Organization, 1992) require that a head trauma is sufficiently severe to cause loss of consciousness, and is followed within 4 weeks by at least three of the following features: (1) complaints of unpleasant sensation and pains such as headache, dizziness, general malaise and excessive fatigue, or noise intolerance; (2) emotional changes such as irritability, emotional lability, or some degree of depression and/or anxiety; (3) subjective complaints of difficulty in concentration and in performing mental tasks, and of memory problems without clear objective evidence; (4) insomnia; (5) reduced tolerance to alcohol; and (6) preoccupation with the above symptoms and fear of permanent brain damage, to the extent of hypochondria and adoption of a sick role. The lack of specificity of these symptoms to TBI is problematic, and the vague requirement of loss of consciousness challenges inclusion of the large majority of mild brain injuries without complete unconsciousness. Objective evidence of cognitive deficits is not included

in this definition, as it is for the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV definition (American Psychiatric Association, 2000). The DSM-IV criteria for PCS also require a history of head injury and stipulate: that relative attention or memory impairment be present on neuropsychologic testing; that symptoms cause clinically significant impairment in social or occupational functioning; and that the duration of these symptoms exceeds 3 months. At least three of the following must be present, either as new-onset symptoms or as a substantial clinical worsening following head injury (although no maximum delay in onset is stipulated): becoming fatigued easily; disordered sleep; headache; vertigo or dizziness; irritability or aggression with little or no provocation; anxiety, depression, or affective lability; changes in personality (e.g., social or sexual inappropriateness); and apathy or lack of spontaneity (American Psychiatric Association, 2000). The definition of head injury is more detailed than in the ICD-10, and is described as “significant cerebral concussion.” Although it is pointed out that there is insufficient evidence to establish a definitive threshold,

POSTCONCUSSION SYNDROME suggested criteria are loss of consciousness greater than 5 minutes, posttraumatic amnesia greater than 12 hours, or posttraumatic onset of seizures. As with ICD-10, this definition excludes the majority of concussed patients for whom there is no loss of consciousness. ICD-10 criteria have been criticized for their focus on the presence of symptoms independent of cause, possibly resulting in misdiagnosis of PCS in patients without a TBI-related disorder. The DSM-IV criteria are similarly criticized, although estimated rates of PCS in TBI populations according to this definition are much lower. The 3-month minimum time threshold of the DSM-IV criteria excludes many individuals with similar symptoms that resolve more quickly. Boake and colleagues (2004) applied diagnostic criteria to147 patients with mild or moderate TBI; 64% were diagnosed with PCS according to ICD-10 criteria, versus 11% according to DSM-IV criteria. Forty percent of controls with extracranial trauma but no TBI also met ICD-10 criteria for PCS. At 6 months postinjury, no significant differences were found between ICD-10 and DSM-IV definitions (McCauley et al., 2005). A World Health Organization task force review found no empiric support for either set of criteria due to their lack of specificity (Carroll et al., 2004). A recent study of nonconcussed college athletes demonstrated that 16.3% had baseline symptoms meeting criteria for the ICD-10 definition of PCS, further demonstrating the lack of specificity of these criteria (Asken et al., 2017). The latest version of the DSM (DSM-V), published in 2013, abandons the label “postconcussion syndrome” and instead refers to “major or mild neurocognitive disorder due to traumatic brain injury” within the spectrum of other neurocognitive disorders (American Psychiatric Association, 2013). This definition requires evidence of TBI, described as an “impact to the head or other mechanisms of rapid movement or displacement of the brain within the skull.” One or more associated findings are also necessary, including loss of consciousness, posttraumatic amnesia, “disorientation and confusion,” or neurologic signs either detected clinically (“new onset of seizures; a marked worsening of a preexisting seizure disorder; visual field cuts; anosmia; hemiparesis”) or evident on neuroimaging. The disorder must develop immediately after injury or upon recovery of consciousness and should “persist past the acute post-injury period.” These criteria are more in keeping with other widely used clinical and research concepts of the spectrum of neurocognitive problems across the range of severity of TBI from mild to severe. The criteria specify immediate onset of neurocognitive disorder immediately after injury or recovery of consciousness with postacute time durations that more clearly depict the expected recovery after different severities of TBI, usually up to 3 months after mTBI.

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The consensus statement from the 5th International Conference on Concussion in Sport (McCrory et al., 2017) describes the symptoms and signs after sportsrelated concussion (SRC) that “evolve over minutes to hours” and “may or may not involve loss of consciousness.” Symptoms are described among somatic, cognitive, and/or emotional categories. Problems in other clinical domains may include physical signs (e.g., loss of consciousness, amnesia, neurologic deficit), balance impairment, behavioral changes, cognitive impairment, and sleep/wake disturbance. The statement describes resolution of clinical and cognitive problems that “typically follows a sequential course” but “in some cases symptoms may be prolonged.” The statement also emphasizes that the term “persistent symptoms” should only be used clinically when an individual does not recover within the usual recovery time of 10–14 days for adults and 4 weeks for children. There is a caveat that a “single physiologic time window for SRC recovery” is not established. Persistent postconcussive symptoms are described as a “constellation of non-specific post-traumatic symptoms.” It is not required that these symptoms share a common cause, and the consensus statement encourages consideration of confounding factors. These criteria are still in the early stages of being applied to clinical and research settings. Not surprisingly, a notable lack of consensus remains among practicing clinicians regarding the numbers of symptoms and their duration required to define PCS. In 2015, Rose et al. surveyed 597 physicians regarding the minimum duration of symptoms needed to diagnose PCS; 26.6% of responders indicated that less than 2 weeks was required, 20.4% required 2 weeks to 1 month, 33% required 1–3 months, and 11.1% required more than 3 months. Those seeing more patients with concussion in their practice, or for whom over 50% of their concussion patients were pediatric, were more likely to require at least a month of symptoms ( p < 0.001). Regarding the number of symptoms required, 55.9% required only one symptom, 17.6% required two, 14.6% required three, and 3.2% required at least four symptoms. It should be noted that this survey took place prior to the 5th International Conference on Concussion in Sport (McCrory et al., 2017), and so it is unknown if similar findings would still occur. One of the main ambiguities among these definitions and in clinical use is when to apply the term PCS after mTBI. Does it cover the immediate symptoms after mTBI? Should it be reserved for symptoms that are present after the acute period? Should there be a minimal time threshold such as included in the DSM-IV definition? The term persistent PCS is often used for those with

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longer-lasting symptoms, although there is no consensus of when to apply the term – 3 months, 6 months, 1 year. Symptom profiles usually vary over time as recovery evolves. Although most persons experiencing PCS after SRC and other causes of injury recover fully, persistent and sometimes severe residual symptoms occur in a minority of individuals after mTBI. The causes of symptoms may be more or less directly related to the brain injury or may be a consequence of other associated injuries and conditions. Further, the causes of symptoms may vary over time. Thus, it may be more meaningful to consider PCS as having two phases: an early-phase posttraumatic disorder, occurring in the days to weeks after injury, which may be more closely linked to the brain injury and associated injuries; and a less common latephase posttraumatic disorder, which may persist months or more, and likely has a more complex etiology of multiple interacting factors (Katz et al., 2015). It might be argued that we should abandon the term PCS entirely, because of the ambiguities of symptom profile, etiology, and time duration in the use of this diagnostic label.

CLINICAL FEATURES The most common symptoms of PCS are headache, dizziness, fatigue, irritability, anxiety, sleep disorder, impaired attention and memory, and sensitivity to noise and light. Symptoms associated with PCS in both earlyand late-phase disorders are often divided into somatic, cognitive, and emotional domains, mostly for convenience. Symptoms in each domain may overlap and have multiple interacting etiologies that can change over time. After confusion clears, the early phase may include headache, dizziness, nausea, sleep disruption, mental fogginess, anxiety, light sensitivity, noise sensitivity, fatigue, emotional lability, and irritability. At least 80% of those with mTBI report one or more symptoms in this early phase, but there is no pathognomonic or mandatory set of symptoms. Up to 20% of those with mTBI report no symptoms after a brief period of altered consciousness (Levin et al., 1987; Dikmen et al., 2010). Symptoms improve in the vast majority of patients within 1–3 weeks after SRC and 1–3 months after other causes of mTBI (Levin et al., 1987; Ponsford et al., 2000; McCrea et al., 2003; Bleiberg et al., 2004).

Somatic symptoms of mTBI Somatic symptoms after mTBI include headache, dizziness, fatigue, insomnia, photophobia, phonophobia, and tinnitus. Headache and dizziness are the most common – headache may occur in up to 90% of those with mTBI (Guskiewicz et al., 2000; Kraus et al., 2005; Faux and Sheedy, 2008). Headache types include, most commonly, tension and migraine-type headache (Haas,

1996; Lew et al., 2006, Lucas and Blume, 2017). Other headache types may be related to musculoskeletal injuries, such as cervical whiplash and craniomandibular injury (Horn et al., 2013); some patients may have a mix of headache types (Couch and Bearss, 2001). Other posttraumatic headache syndromes include: localized pain at the site of scalp trauma or laceration that may persist for months; occipital neuralgia from direct occipital nerve injury or entrapment with pain from the nuchal-occipital area radiating to parietal, temporal and frontal, periorbital areas; and trigeminal nerve injury with constant or paroxysmal facial pain in one or more of the trigeminal nerve distributions. Other headache types are less common after trauma. These include trigeminal autonomic cephalalgias, such as cluster headache, hemicrania continua, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, short-lasting unilateral headache, and paroxysmal hemicrania (Matharu and Goadsby, 2001; Putzki et al., 2005; Jacob et al., 2008). Additional uncommon posttraumatic causes of headache include traumatic dissection of carotid or vertebral arteries and low cerebrospinal fluid pressure. These are characterized by prominent exacerbation with upright position, usually caused by cribiform plate fracture or dural root sleeve tear (Siavoshi et al., 2016). Common cervical injuries accompanying mTBI include myofascial pain in the cervical musculature following whiplash injury; associated symptoms can include vertigo, tinnitus, a sense of fullness in the ear, and even external ear pain (Horn et al., 2013). It is thought that the proximity of sensory afferents from cranial nerves V, VII, IX, and X may play a role in this connection, referred to as the convergence projection theory (Arendt-Nielsen et al., 2000). Cervical afferents also contribute to vestibular integrations of head, neck, and eye movement, further adding to the plausibility of whiplash-induced symptoms (including dizziness), separate from those more directly related to TBI. Temporomandibular joint disorder is another possible contributor that should be assessed. Dizziness occurs in about half of individuals with mTBI; it may result from a variety of injuries affecting vestibular function, or may have a nonvestibular etiology. Some complaints of dizziness are nonspecific and difficult to characterize clinically. Dizziness after sports injury may be a predictor of more prolonged recovery (De Kruiijk et al., 2002; Lau et al., 2011). Some individuals with mTBI report true vertigo, which may be caused by benign paroxysmal positional vertigo (BPPV), labyrinthine concussion, perilymphatic fistula, or migraines (Swartz and Longwell, 2005). Labyrinthine concussion can cause both auditory and vestibular symptoms. BPPV, caused by otolith displacement

POSTCONCUSSION SYNDROME into the semicircular canals, is associated with episodic vestibular symptoms maximal in particular positions and triggered by movement. Posttraumatic endolymphatic hydrops (or Menière syndrome) presents with vertigo, a sense of aural fullness, unilateral low-frequency hearing loss, and tinnitus. BPPV is the most common of these complications after concussion (Shepard et al., 2013). Autonomic nervous system dysfunction has also been suggested as a contributor to PCS pathophysiology in cases where somatic symptoms are exacerbated by exercise (Ellis et al., 2016). For example, patients with PCS have higher resting heart rates (King et al., 1997; Gall et al., 2004; Leddy et al., 2007) and abnormal cerebral blood flow regulation (Clausen et al., 2016) during exercise. In cases of PCS associated with cervicogenic complaints, the sympathetic nervous system also has a proposed role via multiple mechanisms, including modulation of the contractility of muscle fibers and of both proprioceptive and nociceptive inputs (Passatore and Roatta, 2006).

Cognitive symptoms of mTBI Cognitive symptoms include difficulty with concentration, decreased attention, impaired memory, and reduced processing speed. In the early phase after concussion, typical complaints are feelings of fogginess, losing track of thoughts and conversations, slowed thinking, forgetfulness, word-finding problems, and distractibility. In SRC, a number of tools and measures are used to characterize impairments and track recovery, such as the Immediate Post-concussion Assessment and Cognitive Test (ImPACT: Lovell and Maroon, 2000). Studies using this tool show recovery of cognitive signs (including verbal and visual memory, visual motor processing speed, and reaction times) in most athletes within 4 weeks after injury (Henry et al., 2016). However, early ImPACT scores (24–48 hours after injury) do not necessarily predict scores at a week postinjury (Sufrinko et al., 2017). A recent systematic review of ImPACT showed that reliability for most ImPACT composite scores was poor to moderate, and might therefore be of limited utility in concussion assessment and management. In individuals without a history of concussion, 22–46% experienced what was considered a reliable change on at least one ImPACT subscore on serial assessments, and 40–80% of all participants were misclassified on at least two of three serial ImPACT testings for any given ImPACT composite. ImPACT should not be used as a stand-alone tool in assessing postconcussive status (Alsalaheen et al., 2016). Neuropsychologic testing may not correlate well with self-reported cognitive symptoms after concussion.

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At 5 days postinjury, neuropsychologic testing results were similar after concussion in persons with or without cognitive complaints (Meares et al., 2006). In a metaanalysis of several studies of cognitive dysfunction after mTBI, the effect size of neuropsychologic test scores diminished to very small levels, below one standard deviation after 24 hours and well below a half standard deviation compared to controls after 6 days postinjury (Iverson et al., 2013). Dikmen and colleagues (2017) reported on 421 adults followed prospectively, divided into groups based on initial Glasgow Coma Scale score between 13 and 15 or positive computed tomography (CT) findings, and compared them to non-TBI trauma controls. They demonstrated differences on a neuropsychologic battery only in those with positive CT findings at 1 month postinjury, and no differences at 1 year in any group with mTBI.

Emotional symptoms of mTBI Emotional symptoms after mTBI include irritability, anxiety, depression, or emotional lability. Irritability and anxiety may be early-phase symptoms, but depression tends to occur later. In all cases of mTBI, rates of depression are between 11% and 44% within the first 3 months postinjury (Mooney and Speed, 2001; Levin et al., 2005). In a retrospective review of pediatric patients referred to a sports concussion program, half the group reported at least one emotional symptom and 11.5% were diagnosed with a psychiatric disorder, either new since injury or exacerbation of a premorbid condition (Ellis et al., 2015). Female sex, a higher initial concussion symptom score, a higher emotional early postconcussion symptom subscore, presence of a preinjury psychiatric history, and presence of a family history of psychiatric illness were significantly associated with psychiatric outcomes. There is substantial overlap between common symptoms of depression, such as fatigue, insomnia, and cognitive complaints, and symptoms attributed to PCS. Over 85% of patients with depression without a history of head trauma endorse postconcussion-like symptoms (Iverson, 2006). Depression also has a significant effect on PCS symptom reporting, as demonstrated in a study comparing patients with or without depression after mTBI and a group with depression without trauma (Suhr and Gunstad, 2002; Lange et al., 2011). There is also considerable overlap of symptoms of PCS and posttraumatic stress disorder (Lagarde et al, 2014). Although posttraumatic stress disorder occurs in mTBI not caused by sports, especially in the military (Gil et al., 2005; Hoge et al., 2008), it is probably very uncommon after sports concussion.

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CLINICAL ASSESSMENT Clinical evaluation of mTBI and PCS in sports is increasingly occurring earlier at the sidelines (see Chapter 8), immediately following injury, but often occurs later in emergency rooms (see Chapter 9), primary care offices, or specialty clinics (see Chapters 10 and 11). Early identification of concussion and proper protocol-driven management, including clearance to return to sports and other activities, increases the likelihood of a more rapid, uncomplicated recovery (Paniak et al., 2000; Mittenberg et al., 2001; Lane and Arciniegas, 2002; Ponsford et al., 2002; Willer and Leddy, 2006; Leddy et al., 2012). Those with delayed diagnosis, inadequate management, and associated comorbidities make up a significant proportion of the group with more prolonged symptoms who present for later clinical evaluation. Accurate evaluation and effective management of this late-phase posttraumatic disorder can be a more complex, multidisciplinary process. The first challenge in evaluating symptomatic patients is determining the nature and severity of concussion or brain injury, if one occurred at all. Subconcussive head injuries or other soft-tissue injuries, such as cranial impact injuries and cervical injuries after whiplash, can produce similar symptoms without brain injury (Horn et al., 2013). A history of the injury, obtained not only from the patient but also from available bystanders, emergency responders, and other acute care providers, is important. If available, videos of the event can be useful in characterizing the injury and early consequences.

Screening tools An increasing number of screening and diagnostic tools are available for sideline and office assessment of postconcussive symptoms. These tests are described and reviewed in greater detail in Chapters 10 and 11. Some of the tools that are utilized in the assessment of uncomplicated mTBI without PCS are also used for patients with presumed PCS. The acute diagnostic tests identified by the American Academy of Neurology (AAN) in its guidelines on the evaluation and management of concussion in sports include the Post-Concussion Symptom Scale (PCSS) and Graded Symptom Checklist, Standardized Assessment of Concussion (SAC), the Balance Error Scoring System (BESS), and the Sensory Organization Test (SOT) and formal neuropsychologic testing. Both the BESS and SOT have low to moderate sensitivity for concussion, while the remainder have better sensitivity and specificity (Giza et al., 2013). These assessments have been studied in the early phase of recovery, but their validity as clinical monitoring tools is more questionable. For example, McCrea and colleagues (2003, 2005) concluded that performance on

the SAC does not differ between concussed and nonconcussed athletes at 1 week postinjury. The BESS has been a popular clinical tool for measuring recovery after SRC, but it has shown poor sensitivity after 3 days postinjury (Finnoff et al., 2009; King et al., 2014; Murray et al., 2014). The PCSS is often used in serial assessments. It is a 22-item tool reflecting commonly encountered cognitive, physical, and affective symptoms in PCS, rated on a seven-point Likert scale (Pardini et al., 2004). This instrument is part of the ImPACT test mentioned above (Lovell and Maroon, 2000). In 2013 Meehan et al. demonstrated that total PCSS score was independently associated with symptoms persisting at least 28 days after concussion in 182 pediatric sports concussion patients of mean age 15.2  3.04 years. A 2014 study by Meehan et al. showed that the majority of pediatric SRC patients (86%; 95% confidence interval 80–90%) with an initial PCSS score of <13 experienced resolution of their symptoms within 28 days of injury. The Rivermead Post-Concussion Symptom Questionnaire (Crawford et al., 1996) has also been widely used; if administered in the acute period, it can predict endorsement of at least one PCS symptom in early follow-up at 3–15 days (Ganti et al., 2016). The Pediatric Quality of Life Inventory and PedsQL Cognitive Functioning scale were recently studied in adolescent athletes with concussion. Those who developed PCS had significantly worse physical and cognitive performance at initial consultation (median of 6.5 days postinjury) and a slower rate of recovery in these domains, compared with those who recovered in less than 30 days (Russell et al., 2017). Saccadic eye movements, vergence, and smooth pursuit are commonly negatively affected after mTBI, but methods of assessment and clinical management have not yet been established (Hunt et al, 2016a). There is no widely accepted test that can universally identify all concussion-related vestibulo-ocular or related impairments (Heinmiller and Gunton, 2016). Aerobic treadmill testing, usually administered during physical therapy evaluation, can also be incorporated into clinical assessment of PCS symptom thresholds and recovery. It may play a role in classifying sports-related PCS into operational subtypes, as proposed by Ellis and colleagues (2016).

Clinical assessment and pathophysiologic subtypes of PCS In the approach described by Ellis et al. (2016), clinical history, a systematic neurologic examination and aerobic treadmill testing suggest pathophysiologic underpinnings of persisting PCS symptoms defined in three or

POSTCONCUSSION SYNDROME more postconcussion disorders. Diagnosis of these subtypes of PCS can inform clinical management of patients with a late-phase disorder. This conceptualization is largely empiric and the authors suggest a research agenda to evaluate this diagnostic schema. The physiologic postconcussion disorder includes symptoms characteristic of acute concussion and is worsened by physical or cognitive activity. It may be mediated by a mismatch between the brain’s metabolic needs and energy delivery capacity. In this group, a submaximal exercise program could help to improve symptoms. Those with the physiologic subtype of mTBI demonstrated worsened symptoms on graded exercise assessments such as the Buffalo Concussion Treadmill Test usually within 5–15 minutes of initial testing (Leddy et al., 2013, 2015, 2016; Ellis et al., 2016). Those with persisting PCS symptoms who are not symptomatic with treadmill testing are assessed for vestibulo-ocular or cervicogenic disorders. The vestibulo-ocular postconcussion disorder may represent pathologic functioning of both the vestibular and oculomotor systems for maintenance of balance, postural control, and gaze stability. There may be objective evidence of dysfunction in convergence, accommodation, smooth pursuits, saccades or vestubulo-ocular reflexes, and BPPV. Patients may complain of dizziness, gait instability, headaches triggered or worsened by visually challenging activities, difficulty focusing, and intermittent blurred vision or diplopia. Vestibular or vision-based physical therapy may be of benefit depending on the underlying etiology (Ellis et al., 2016). The cervicogenic postconcussion disorder may derive from dysfunction of the complex sensory and autonomic interconnections between the spinal cord, brainstem, and cerebellum as they mediate dynamic head, neck, and eye positions. Cervical muscle spasm may also play a role in symptoms such as cervicogenic headaches and occipital neuralgia. Associated symptoms include neck pain, neck stiffness, dizziness with activity, occipital headaches (even occipital neuralgia), and fatigue or fogginess. Evaluation of paraspinal and suboccipital muscles, cervical range of motion, cervical dizziness, and palpation of the greater and lesser occipital nerves should be incorporated into the examiner’s assessment. Cervical spine rehabilitation is recommended for this group (Ellis et al., 2016). New-onset or worsened migraine headaches after concussion characterize a fourth group, which may benefit from a submaximal exercise regimen and traditional pharmacologic treatments for migraine. Among members of this subgroup, both graded aerobic treadmill testing and formal neuropsychologic testing were recommended by Ellis et al. (2016) in determining medical clearance.

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Although this approach will need further validation and support with diagnostic biomarkers and outcome research, it represents a principled clinical protocol that may be useful for differential diagnosis and treatment.

NATURAL HISTORY AND PROGNOSIS Following a brief period of unconsciousness or, at least, partially altered awareness, early-phase postinjury disorder symptoms usually arise immediately or within hours. In a 2016 study by Henry and colleagues of 66 adolescents and young adults with SRC (age range 14–23 years; 64% male), most postconcussion symptoms improved in the 2 weeks postinjury but in some cases took up to 28 days to resolve fully as measured by ImPACT testing, PCSS, a modified Dizziness Handicap Inventory, and vestibulo-ocular examination and were slower to improve after week 2. Males were morelikely than females to be symptom-free by 4 weeks postinjury. The population studied was notable in that all pre-existing neurologic or psychiatric diagnoses except migraine served as exclusion criteria. In a study by Iverson and colleagues (2015), adolescent athletes reported symptoms of PCS at substantial rates, even without a history of recent concussion. Gender and pre-existing conditions predicted PCS symptoms in these uninjured high school athletes. Symptoms associated with PCS were reported in 19% of boys and 28% of girls in the absence of concussion, with much higher rates in those with pre-existing conditions – 60–82% of boys and 73–97% of girls – including depression, preinjury migraines, substance use, and attention deficit-hyperactivity disorder (Iverson et al., 2015). The usual trajectory of recovery of symptoms after mTBI evolves over days to weeks and the vast majority recover from the early-phase postinjury disorder by 3 months (Kashluba et al., 2004). A small subset have persisting symptoms and a late-phase postinjury disorder (Ruff, 2011). One often-cited prospective study by Rutherford et al. (1979) reported that 15% of patients hospitalized with mTBI had persisting PCS symptoms at 1 year or more. Although 15% had one symptom or more at 1 year, the percentage dropped to less than 5% in those with multiple (four or more) symptoms. A recent study by Dikmen and colleagues (2017) reported three or more symptoms at 1 year in 53–55% of 336 patients with mTBI of all etiologies, compared to 27% in non-TBI trauma controls. However, inclusion criteria requiring a period of loss of consciousness, posttraumatic amnesia over 1 hour, or CT abnormalities describe more severe injuries than is typical among those with SRC. In a series of 64 adults with sports concussion followed prospectively, the mean duration of symptoms

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was 32 days ( 48 days) and early PCSS score predicted more prolonged symptoms (Meehan et al., 2016). Overall, the proportion with persistent PCS symptoms and a late-phase posttraumatic disorder after sports concussion is probably very low, but further prospective studies are necessary to clarify the risk. In general, SRC confers a better outcome than mTBI associated with motor vehicle accidents or other mechanisms (Ponsford et al., 2000). This may relate to a number of factors. including younger age, better conditioning, better health status and, perhaps, more incentive to achieve baseline functional status. SRC is less likely associated with multiple concomitant orthopedic, skin, and soft-tissue injuries predisposing to chronic pain and loss of physical functioning. SRCs also tend to lack the life-threatening aspects of injury causes such as combat, assault, or motor vehicle accidents that predispose to posttraumatic stress disorder and other psychologic traumas (Carroll et al., 2004; Stulemeijer et al., 2006, 2008; Jacobs et al., 2010).

Transition from early- to late-phase posttraumatic disorder The transition from early- to late-phase posttraumatic disorder is not clearly defined in timing or symptom profiles (Katz et al., 2015). Although there is considerable overlap, early- and late-phase symptom profiles after mTBI probably have different characteristics (Rees, 2003). Physical symptoms, most commonly headache and dizziness, are predominant in the early phase (1–2 weeks) and emotional disturbances are more likely in the later phase (4–8 weeks) (Yang et al., 2007). Dischinger et al. (2009) evaluated mTBI admissions to a trauma service at 3–10 days and at 90 days after injury; prevalence of physical symptoms declined more rapidly than emotional and cognitive symptoms. Symptoms associated with a late-phase posttraumatic disorder should evolve from an early-phase postinjury disorder to be considered related at all to the injury. It is a common diagnostic pitfall to misattribute symptoms after injury to PCS even if symptom onset occurs after a considerable gap in time postinjury. As the Berlin and Zurich consensus conferences emphasize, PCS after sports injury is a graded set of clinical symptoms following a “sequential course,” prolonged in a small percentage (McCrory et al., 2017), not a course associated with late onset of symptoms. Although the early-phase symptoms after concussion have a closer link to the injury, the later-phase symptoms are less clearly directly associated with the concussion and concomitant injuries. The concussion itself may no longer be a factor causing the prolongation of PCS symptoms. Other comorbid and premorbid factors tend to be

more important than the brain injury in explaining the clinical symptoms as they extend from days and weeks to months and years postinjury. The lack of specificity of concussion to persisting symptoms of PCS has been reported in a number of studies, including some demonstrating that late symptoms attributed to PCS are similarly prevalent after mTBI and trauma without brain injury (such as mild orthopedic injuries), especially when eliminating other confounds such as litigation (Mickeviciene et al., 2004).

Differential diagnosis and factors contributing to late-phase posttraumatic disorder For any set of ongoing late-phase symptoms and loss of function, the clinician should assess for multiple potential etiologies, including contributions from coexisting mood disorders, chronic pain syndromes, vestibular dysfunction, musculoskeletal injuries, psychosocial stressors, and personality factors such as resilience. A comprehensive medical, surgical, family, and social history, including a detailed description of preinjury social, occupational, and academic functioning, is critical to account for multiple potential contributing factors. Mood and anxiety disorders are among the most common contributors to late-phase symptoms. Any history of depressed mood, anxiety, irritability, attention or concentration difficulties, fatigue, and sleep disturbance should be explored. These could all indicate a diagnosis of depression, anxiety disorder, adjustment disorder, posttraumatic stress disorder, or other psychiatric disorders. A history of mood disturbance may precede the injury, or emerge as a consequence. Athletes can have particular psychosocial stressors during concussion recovery, such as alienation from desired social experiences, interruption of roles as player and teammate, and deterioration in academic performance. Prolonged disability after concussion can lead to adjustment difficulties and mood disorder associated with a diminished sense of self and identity (Charmaz, 2002; Fenech, 2013). Depression can influence multiple symptoms attributed to PCS (Trahan et al., 2001; Suhr and Gunstad, 2002; Garden and Sullivan, 2010), including deficits on neuropsychologic testing (Zakzanis et al., 1998; Austin et al., 1999; McDermott and Ebmeier, 2009). Symptoms and neuropsychologic impairments can be clinically indistinguishable between depression and mTBI. Factitious disorder and malingering should be considered with any neurologic complaints that may lack objective signs or atypical symptoms, and in persons who display exaggeration of symptoms, inconsistent neurologic examination findings, and a discrepancy between

POSTCONCUSSION SYNDROME reported distress and objective findings. Factitious disorders involve the deliberate reporting of false symptoms, exaggeration of minor symptoms, or even the surreptitious induction of self-harm (“making oneself sick”). There is little or no reward other than the attention and sympathy of others and administration of symptomrelevant treatment. Malingering involves similar behaviors, but the reward is not intrinsic to having an ill or injured status and instead relates to rewards such as monetary gain and freedom from work, school, or financial responsibilities. The DSM-IV (American Psychiatric Association, 2000) describes the distinction as follows: “Malingering differs from factitious disorder [by proxy] in that motivation for the symptom production in Malingering is an external incentive, whereas in Factitious Disorder external incentives are absent.” The risk of encountering a malingering patient is increased in a medicolegal context, poor compliance with evaluation and treatment, or a history of antisocial personality disorder (Guilmette, 2013). Efforts are currently underway to efficiently identify patients who are manipulating symptom reporting, especially in military populations (Dretsch et al., 2017; Lippa et al., 2017). As baseline neurocognitive testing becomes more routine within athletic programs, clinicians and researchers have also examined the notion that athletes could paradoxically attempt to underperform on baseline testing for the purposes of being cleared to return to play sooner, despite the presence of ongoing postconcussive signs and symptoms. Systems can be developed to detect such purposeful underperformance. A study by Siedlik et al. in 2016 examined the performance of 20 male collegiate rugby players who were instructed to intentionally underperform on ImPACT without making their attempts to score poorly obvious. ImPACT detected 70% of malingering attempts using internal validation measures, and clinician reviewers identified 80% of malingering attempts. Underreporting of concussive events or symptoms after concussion is another problem that defies detection in athletes. McCrea et al. (2004) studied a group of Wisconsin varsity high school football players who reported concussions only 47.3% of the time. A significant proportion (41%) with identified concussion failed to report symptoms in an effort to avoid being withheld from competition. Differential diagnosis of the clinical features associated with PCS should include a number of considerations. Headache is a common symptom and a primary headache disorder is a possibility, both as a premorbid condition, exacerbated by injury, and as a headache condition of new onset. New onset of migraine and other primary headache disorders is particularly common among adolescents and young adults, and may or may

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not be directly related to the injury. The timing of early-phase symptoms should be considered in attributing etiology. Chronic pain from musculoskeletal injuries or other disorders is a common factor that may prolong other PCS symptoms such as insomnia, irritability, fatigue, and cognitive disturbance. Vestibular symptoms, potentially from disorders of the inner ear, cervical injuries, or migraines, may also worsen and prolong late symptoms. Endocrine disorders such as hypothyroidism can mimic many of the somatic, mood, and cognitive symptoms of both TBI and depression (Davis and Tremont, 2007). Concurrent use of illicit substances or alcohol abuse can mimic and exacerbate the cognitive, mood, and behavioral disturbances attributed to PCS. Undiagnosed structural lesions, or a more severe brain injury than initially diagnosed, are possible considerations in those with prolonged symptoms. Structural lesions on routine neuroimaging are uncommon after concussion. Focal findings on examination and persistent symptoms such as headache are a frequent justification for brain imaging such as magnetic resonance imaging (MRI) in the postacute setting, but reveal a very low incidence of abnormalities and an even lower incidence of abnormalities for which an intervention would be indicated (Morgan et al., 2015). Brain MRI should be considered in PCS patients who present with a history of abnormal CT findings, focal neurologic deficits, or seizures. Other brain imaging techniques such as diffusion tensor imaging, functional MRI, quantitative cerebral blood flow sequences, and cerebrovascular reactivity mapping are important research tools, but currently are not a part of routine clinical management of PCS (Ellis et al., 2016).

Risk factors for developing a late-phase disorder A number of risk factors may prolong PCS symptoms, including: older age of injury (King, 2014), high school age of play or younger, female sex, attention deficithyperactivity disorder, learning disabilities, and specific symptoms such as cognitive deficits, headaches, dizziness and disequilibrium, mood disorders, and disturbances of oculomotor functioning (Table 17.2). GRIN2A promotor polymorphisms (McDevitt et al., 2015), and SLC17A7 promotor variations (Madura et al., 2016) have been shown in prospective cohort studies to be associated with longer recovery times after SRC. ApoE4 genotype (Merritt et al., 2016) has been associated with more severe symptom reporting after SRC. Early headache and dizziness increased the chance of symptoms at 1 month postinjury in a general mTBI sample (Savola and Hillbom, 2003). Significant symptoms at 6 months postinjury correlated with

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B. DWYER AND D.I. KATZ Table 17.2 Factors mediating risk of posttraumatic disorder (early and late phase) Pre-existing factors

Injury characteristics

Postinjury factors

Prior traumatic brain injury Psychiatric disease Personality disorder Headache disorder Attention deficit-hyperactivity disorder Genetics Younger age Female gender

Early symptom burden Nonsports-related context

Adjustment (psychosocial, personality factors) Malingering Factitious disorder Treatment compliance Litigation Employment status

complaints of headache, dizziness, and nausea in the emergency room following an mTBI of all causes (De Kruijk et al., 2002). A multivariate analysis identified postinjury anxiety, noise sensitivity, and female gender as a cluster of predictors with the highest probability of later symptoms (Dischinger et al., 2009). The 5th International Conference of Concussion in Sport concluded that the severity of symptoms in the first or initial few days after SRC is the “strongest and most consistent predictor” of slowed recovery, while minimal symptoms on the first day conferred a favorable prognosis (McCrory et al., 2017). In line with this statement, several studies of athletes presenting to sports concussion clinics found that early symptom burden predicted more prolonged symptoms after SRC (Lau et al., 2009; Meehan et al., 2014). Lau et al. (2009), using computerized cognitive testing in male high school football players, also found that those with symptoms lasting over 10 days were more likely to show relative deficits with visual memory and processing speed. In a later study, longer recovery occurred in those with primarily migrainous complaints associated with slowed reaction times and increased visual and/or verbal memory impairment (Lau et al., 2011). Risk factors for more prolonged symptoms included unconsciousness, posttraumatic amnesia, and more severe acute symptoms in a prospectively studied group of 570 high school and college athletes, who experienced concussion and took longer to recover (10% of the group) (McCrea et al., 2013). The AAN guidelines on the evaluation and management of concussion in sports concluded that a prior history of concussion is likely associated with more severe and longer-lasting symptoms (Giza et al., 2013). The AAN guidelines identified probable risk factors for prolonged recovery, including younger age of play, early posttraumatic headache, fatigue, early amnesia, alteration in mental status, and disorientation. Possible risk factors included dizziness, playing the position of quarterback in American football, and wearing a halfface shield in ice hockey.

Although a history of prior mTBI was a risk factor for longer PCS in some studies, the extent of the influence of prior injury is unclear among athletes and in the general population. Apart from the risk of so-called secondimpact syndrome, the occurrence of a repeat concussion shortly after a previous concussion may be particularly problematic in worsening and extending symptoms (Guskiewicz et al., 2000, 2003; Giza et al., 2013). The recent 5th International Conference acknowledged that multiple past mTBIs are associated with increased “physical, cognitive and emotional symptoms” before participation in a sporting season, although the specific symptoms most suggestive of poor outcome or prolonged recovery are still a subject of debate (McCrory et al., 2017). Pre-existing and postinjury psychiatric conditions are associated with a higher risk of prolonged PCS symptoms (Greiffenstein and Baker, 2001; Mooney and Speed, 2001; Evered et al., 2003; Meares et al., 2006). Anxiety in particular may increase the likelihood of reporting of PCS symptoms (Ponsford et al., 2000; Mooney and Speed, 2001; Snell et al., 2010; Cooper et al., 2011; King and Kirwilliam, 2011), which may in turn increase an individual’s degree of anxiety (Kay et al., 1992; Bay and de-Leon, 2011). A history of psychiatric conditions or headaches is an important risk factor for >1 month of symptoms among youth with SRC (McCrory et al., 2017). Personality features such as histrionic, narcissistic, and compulsive personality disorders appear to increase the risk (Evered et al., 2003). Psychosocial stress factors also play an important role in symptom prolongation (Kay et al., 1992; Ruff et al., 1996; Evered et al., 2003; Wood, 2004). Those with symptoms lasting beyond 3 months are more likely to plateau in their trajectory of improvement (Kashluba et al., 2008; McLean et al., 2009; Snell et al., 2010). Although patients may demonstrate recovery in the 3–12-month postinjury period, if symptoms persist beyond 1 year, total remission is much less likely among patients who continue to present for care, even when confounding factors such as litigation are no longer

POSTCONCUSSION SYNDROME involved (Fee and Rutherford, 1988; Packard, 1992). Tiersky et al. (2005) reported that clinical improvement with cognitive behavioral therapy was less significant between 3 and 6 months than between 1 and 3 months on a prospectively followed group of 20 adults with mTBI; however, only one member of this group had an SRC. In 2010 Barlow et al. prospectively followed 670 children (mean ages 7.62 and 9.44 years) in a consecutive controlled cohort study of patients presenting to an emergency department with concussion or extracranial injury. Approximately 25% of the mTBI group was injured while playing sports. Nine percent of children with mTBI met ICD criteria for PCS at 3 months; approximately 21% remained symptomatic at 1 year.

TREATMENT Successful treatment of PCS involves early postconcussion management and includes assessment, recognition of early complications, education about symptoms and expectations for recovery, recommendations for activity modifications, and follow-up assessment. These interventions are key to successful recovery and minimizing the risk of early-phase symptoms evolving to a late-phase disorder with more prolonged symptoms. Treatment of persisting symptoms in a late-phase disorder involves thoughtful differential diagnosis, consideration of comorbid and premorbid conditions, and other factors that may impact symptoms. A hierarchic, sequential approach to symptom management should be undertaken, emphasizing problems with a significant impact on the late-phase symptom profile and those with available, effective treatments (e.g., depression, anxiety, insomnia, headache, and vertigo). A program of exercise, avoiding levels above the symptom threshold, is of benefit for those with both early- and late-phase disorders after concussion (Willer and Leddy, 2006; Leddy et al., 2010, 2013; Baker et al., 2012). Recent literature reviews examining interventions for PCS meant to speed recovery or ameliorate prolonged PCS symptoms concluded that there is no evidence to support the use of any particular treatment (Burke et al., 2015). However, the recent consensus statement on concussion in sport (McCrory et al., 2017) describes a clinical approach capturing emerging, evidence-based support for multimodal, symptom-guided plans of care. Recognizing that SRC can cause a number of symptoms and problems, including injury to the cervical spine and vestibular system, they argue that existing data provide support for specific interventions, including cervical and vestibular rehabilitation, as well as psychologic treatment. In contrast to previous statements, the authors now report that data indicate that controlled, subsymptom-threshold, submaximal exercise programs

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can facilitate recovery. For patients with persistent symptoms, the consensus statement recommends a “detailed, multimodal clinical assessment” aimed at the identification of both primary and secondary pathologies that may be underlying the persisting symptoms. There is early evidence to support the use of several therapies, including aerobic exercise in patients with persistent PCS who are thought to have clinically significant deconditioning or autonomic instability. If there is cervical spine pathology or vestibular dysfunction, physical therapy targeting these specific pathologies may be of benefit. Finally, if mood or behavioral issues are prominent, psychotherapy, particularly cognitive behavioral therapy, may be beneficial (Al-Sayegh et al., 2010; McCrory et al., 2017). However, the statement underscores that there is limited evidence to support use of pharmacotherapy and warns that pharmacotherapy should be considered carefully in athletes who are returning to play.

CONCLUSIONS PCS remains controversial because of its lack of specificity to concussion, particularly at times more remote from the injury. There is no consensus for its definition, and limited understanding of its epidemiology, pathophysiology, time course, and prognosis. It may be more useful to divide postconcussion symptoms into early- and latephase posttraumatic disorders. The early-phase disorder is more clearly causally linked to TBI, whereas latephase symptoms lack specificity and are often driven by comorbid or noninjury conditions. Early-phase symptoms are more commonly somatic or cognitive and include dizziness, headache, imbalance, fatigue, sleep disruption, impaired cognition, photophobia, and phonophobia. Autonomic dysfunction likely contributes to early-phase symptoms and exacerbations with activity and exertion. Late-phase symptoms feature a greater impact of emotional factors on the symptom profile, but chronic headaches, other pain problems, vestibular problems, and disequilibrium are also common factors. Cognitive problems more likely emerge as a result of these other factors in the late-phase disorder. The transition between early- and late-phase disorders is not well defined temporally or symptomatically. Risk factors for developing a late-phase disorder include elevated early symptom burden, a history of multiple concussions, comorbid or premorbid psychiatric conditions, longer duration of unconsciousness or amnesia, and younger age of play. Treating providers should construct a thoughtful differential diagnosis, mindful of potentially coexisting mood, sleep, and primary headache disorders; musculoskeletal injuries, vestibular pathology; undiagnosed structural lesions; and other complications, especially when evaluating individuals with a late-phase disorder.

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Successful early-phase treatment should include education about symptoms and recovery, recommendations for activity modifications, graded return to activities (including a program of subsymptom threshold exercise), and follow-up assessment. In those with late-phase disorder, clinicians should institute a hierarchic, sequential approach to symptom management, emphasizing problems with a significant functional impact and available, effective treatments. Further research focusing on biomarkers, epidemiology, symptom profiles, natural history, prognosis, and treatment will need to clarify the disorders now referred to as PCS, and to elucidate the distinctions and transition between the early- and late-phase posttraumatic disorders. Protein biomarkers such as MAP-2 (as a marker of axonal damage) and CNPase (as a marker of oligodendrocyte activity) show promise as correlates of chronic postconcussive symptomatology (Broglio et al., 2017). Another protein biomarker study that merits further study is neurofilament light protein that has been demonstrated to correlate with a late-phase posttraumatic disorder in athletes with symptoms more than 1 year after injury, as well as with a greater number of lifetime concussions (Shahim et al., 2016). Significantly lower cerebrospinal fluid beta-amyloid levels were also seen in this population. Multimodal neuroimaging, using structural and functional imaging tools, is also potentially important as a biomarker to improve detection and understanding of early and late symptoms after concussion (Broglio et al., 2017). Further study is necessary to develop more sensitive, reliable concussion assessment tools to track natural history, trajectory of recovery and response to treatment, such as the efforts underway by the National Collegiate Athletic Association–Department of Defense Concussion Assessment, Research and Educatio consortium (McCrea et al., 2005; Broglio et al., 2017) Assessments should involve more than symptom reporting and objectively reflect clinical features such as cognitive impairment, postural stability, and oculovestibular functioning. Further research is also needed to clarify the individual and interacting contributions of risk factors for the development of late-phase posttraumatic disorders after concussion and interventions that may modify these risks and improve outcomes.

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