Reframing Postconcussional Syndrome as an Interface Disorder of Neurology, Psychiatry and Psychology

Camilla N. Clark; Mark J. Edwards; Bee Eng Ong; Luke Goodliffe; Hena Ahmad; Michael D. Dilley; Shai Betteridge; Colette Griffin; Peter O. Jenkins

Disclosures

Brain. 2022;145(6):1906-1915.

Approaching Mild Traumatic Brain Injury as an Interface Disorder

The syndrome of persistent symptoms following mTBI rests at the interface between neurology, neurosurgery, psychiatry and psychology. Far from being a 'one-size fits all' condition, mTBI is a complex condition with multiple potential underlying pathophysiological and psychopathological processes, requiring a range of interventions across numerous specialties. A novel approach focusing on pathology and impairment-based diagnostics would allow accurate and timely diagnosis of the often complex symptoms occurring after mTBI.^[20]

Preinjury Factors

Pre-injury depressive or anxiety disorder are the strongest predictors of persistent symptoms after mTBI.^[21,22] Additional factors that influence recovery include pre-injury life events, social circumstances, personality traits including neuroticism and memory perfectionism, illness expectation and beliefs.^[23–25] Expectations relevant for outcome include beliefs about symptom duration, the strength of identity and the emotional impact of the TBI.^[26–28] Pre-existing anxiety and anxiety sensitivity are associated with more severe and prolonged symptom reporting, potentially related to negative illness beliefs.^[29,30]

Pre-injury neurodegeneration or even healthy ageing affect the outcome of the injury regardless of its severity.^[31,32] In addition, it is likely that pre-existing neurodevelopmental disorders would have an impact on outcome after mTBI. Premorbid psychiatric illnesses including attention deficit hyperactivity disorder are seen in a higher proportion of those with mTBI than would otherwise be expected.^[33–35] This may relate to impulse control behaviours, including alcohol and substance misuse, which can predispose an individual to sustaining a TBI. These examples indicate that the neural substrate on which the injury occurs interacts with the effect of the injury itself.

The Injury: To What Extent has Persistent Damage Occurred?

A TBI results from an external mechanical force which is hypothesized to cause a primary injury. However, the mTBI group comprises a huge range of injury severity. Within this same category might be a person who sustained a very minor blow to the head resulting in symptoms such as dizziness, headache and nausea and a person who, following a blow to the head, had 29 min of loss of consciousness, 23 h of post-traumatic amnesia and a non-displaced skull fracture. It seems logical that the physical consequences to the brain are likely to differ across this spectrum.

Despite this complexity, there often appears to be an assumption in the literature that symptoms after mTBI are always caused by the same basic process of brain injury at a cellular and structural level and, therefore, that experimental studies at a group level are a reasonable way to investigate the nature of these injuries.^[36] This fails to recognize the heterogeneity of likely physical injury within the broad mTBI category and also, crucially, that other disorders can cause persistent symptoms after mTBI (e.g. functional neurological disorder, depression, migraine) which are themselves associated with abnormalities on experimental measures such as functional MRI.^[37–39]

Post-mortem studies of patients with a history of mTBI, but who died of other reasons, have found evidence in some of white matter injury and persistent inflammation months after the injury.^[40,41] Secondary injury could therefore develop in minutes, hours or months, with possible long-term effects on symptoms and function.^[42] However, caution must be applied, because these phenomena are likely to affect only a proportion of people with mTBI. There is also a tendency to extrapolate in an unrestrained way the results of animal studies to humans, even though the vast range of injury severities in humans with mTBI do not map well onto the carefully controlled experimentally-induced injuries in animal studies.

Use of Brain Imaging to Define Extent of Brain Damage After Mild Traumatic Brain Injury

Advances in brain imaging techniques have allowed the possibility of examining the presence of post-TBI pathophysiological changes in vivo. However, several potential pitfalls exist in the interpretation of neuroimaging results in people with persistent symptoms after mTBI. These include (i) the sensitivity of routine clinical and advanced imaging techniques for detecting injury after mTBI; (ii) the specificity of any abnormalities detected; (iii) their role in prognostication; and (iv) their relationship to persistent post-trauma symptoms. Over (or under) interpretation of imaging findings can lead to misdiagnosis in an individual and consequently inappropriate treatment and prognostication. At a research level, insufficiently powered studies or incorrect extrapolation of imaging findings to underlying pathophysiology can also lead to inappropriate conclusions being formed.

A variety of imaging methods are sensitive to changes in brain structure (e.g. volumetric and diffusion tensor imaging), functioning (e.g. functional MRI and magnetoencephalography) and alterations in cellular and biochemical milieu, including evidence of persistent inflammation (e.g. PET).^[43–45] Using these methods, numerous studies have identified imaging changes at a group level in those with persistent symptoms after mTBI.^[1] However, these changes are inconsistent and cannot easily be extrapolated to single cases of mTBI.^[46–48]

It is also important to recognize that potential imaging changes may not necessarily be a direct consequence of the mTBI itself. Co-morbid conditions which might be relevant for causing persistent symptoms after mTBI, but not via structural damage, can also cause detectable changes using these neuroimaging techniques. For example, diffusion tensor imaging metrics have been shown to be altered in migraine,^[49,50] depression^[51] and post-traumatic stress disorder.^[52] Equally, functional neuroimaging changes have been reported in the same conditions and in functional neurological disorder, irrespective of the presence of a TBI.^[37–39] This complexity is not reliably accounted for in imaging studies of mTBI.

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Next Section

Abstract and Introduction
Current Terminology and its Weaknesses
Approaching Mild Traumatic Brain Injury as an Interface Disorder
Diagnoses That may Underpin Persistent Symptoms After Mild Traumatic Brain Injury
Recommendations on how to Implement Assessment and Treatment
Conclusions
References

Table 1. Key definitions of mTBI and concussion
Criteria (year)	Definition of head injury	Factors related to injury can include
Centers for Disease Control and Prevention (2003)⁷	Blunt trauma to head or acceleration/deceleration forces results in a brief alteration of mental status or brief loss of consciousness	GCS 13–15, LOC < 30 min; PTA ≤ 24 h; non-penetrating cranio-cerebral injury.
WHO (2005)⁶	Acute brain injury resulting from mechanical energy to the head from external physical forces.	GCS 13–15^a, LOC ≤ 30 min; PTA < 24 h; and/or other transient neurological abnormalities,^b,c and intracranial lesion not requiring surgery.
Mayo (2007): mild (probable) TBI¹²	Traumatically induced injury that contributed to physiological disruption of brain function	GCS 13–15 (≥13 at 30 min); LOC momentary to 30 min; PTA momentary to 24 h; skull fracture with intact dura; EXCLUSION if death due to TBI, worst GCS in first 24 h < 13^c, abnormal head CT.
Mayo (2007): symptomatic (possible) TBI¹²	Traumatically induced injury that contributed to physiological disruption of brain function	Symptoms only^d. Symptoms must not be attributable to pre-existing or co-morbid diagnoses. EXCLUSION if criteria met for mild probable TBI.
Department of Veterans Affairs/Department of Defense (2009)⁸	A traumatically induced structural injury and/or physiological disruption of brain function as a result of an external force	GCS 13–15^e; LOC momentary to 30 min; alteration of consciousness/mental state (AOC) momentary up to 24 h; PTA < 24 h; neurological deficits^f that may or may not be transient; normal structural imaging.
Ontario neurotrauma (2018)^11,g	Concussion/mTBI denotes the acute neurophysiological event related to blunt impact or other mechanical energy applied to the head, neck or body (with transmitting forces to the brain), such as from sudden acceleration, deceleration or rotational forces	LOC < 30 min; any AOC at the time of the injury; PTA ≤ 24 h; physical symptoms^h; normal standard imaging.
American congress of rehabilitation medicine (2021)⁴	A traumatically induced physiological disruption of brain function	Symptoms following a head impact, without associated observable signs (in some instances), Recommendation (i) consider a probabilistic framework that weighs observable signs more than subjective symptoms and (ii) incorporate objective cognitive, balance and vestibular-oculomotor test findings. 1993 criteria^c: initial GCS 13–15; any LOC; any AOC at the time of the injury and focal neurologic deficit(s) that may or may not be transient; any PTA.
1st International conference of concussion in sport (2002)¹³	A complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces.	(i) Direct blow to the head, face, neck or elsewhere on the body with an 'impulsive' force transmitted to the head. (ii) Rapid onset of short-lived impairment of neurological function that resolves spontaneously. (iii) May result in neuropathological changes, but the acute clinical symptoms largely reflect a functional disturbance versus structural injury. (iv) Results in a graded set of clinical syndromes that may or may not involve LOC. Resolution of the clinical and cognitive symptoms typically follows a sequential course. (v) Typically grossly normal structural neuroimaging studies.
5th International conference of concussion in sport (2017)⁵	Sports-related concussion is a TBI induced by biomechanical forces	Modifications to the above: (i) In some cases, signs and symptoms evolve over a number of minutes to hours. (ii) No abnormality is seen on standard structural neuroimaging (iii) Sports-related concussion results in a range of clinical signs and symptoms.^c In some cases symptoms may be prolonged.

AOC = alteration of consciousness; GCS = Glasgow coma scale; LOC = loss or decrease of consciousness; PTA = post traumatic amnesia, any loss of memory for events immediately before or after the accident.
^aIdeally at 30 min post injury or first opportunity presented to healthcare.
^bSuch as focal signs or seizure.
^cThe clinical signs and symptoms cannot be explained by alternate cause, e.g. drugs or other comorbidities (e.g. psychological factors or coexisting medical conditions).
^dBlurred vision, confusion (mental state changes), dazed, dizziness, focal neurologic symptoms, headache or nausea.
^eBest available score <24 h.
^fWeakness, loss of balance, change in vision, praxis, paresis/plegia, sensory loss or aphasia, etc.
^gStratified into high and low risk mTBI.
^hVestibular, headache, weakness, loss of balance, change in vision, auditory sensitivity or dizziness.

Table 2. Current definitions of persistent symptoms post head injury
	Timing	Trigger	General	Physical	Emotional	Cognition
Postconcussional syndrome (ICD-10)	Chronic, permanent or late emerging.	Head injury usually with loss of consciousness.	Not explicitly specified.	Headache, dizziness, fatigue, insomnia.	Irritability, reduced tolerance to stress, emotional excitement and alcohol.	Difficulties with concentration, memory and mental tasks.^a
Mild neurocognitive disorder (ICD-11)	<1 month between head injury and symptom onset.	Head injury with loss of consciousness or aetiology may be undetermined.	Not sufficiently severe to significantly interfere with independence or activities of daily living.	Headache, dizziness, fatigue, insomnia, noise intolerance.	Irritability, reduced alcohol tolerance, depression, anxiety, emotional lability, preoccupation with symptoms.	Subjective decline in concentration, memory, or intellectual difficulties.
Major/mild neurocognitive disorders due to TBI (DSM-5)	From injury or when consciousness recovers. Persists beyond acute period. Resolution: usually complete and <3 months.	Head injury.	Severe versus modest interference with ability to be independent in functions of daily living.	Headache, vertigo, sleep disorder, tinnitus, hyperacusis, photosensitivity, anosmia, hemiparesis, seizures, visual disturbance, orthopaedic injury, cranial nerve or neuromotor deficits.	Irritability, reduced tolerance to psychotropic medication, loss of emotional control (e.g. aggression), inappropriate affect, apathy, anxiety, depressed mood,^b altered personality and/or social cognition.	Difficulty concentrating, learning and memory, executive function, slowed processing speed, reduced cognitive efficiency, decline in language, neglect, constructional dyspraxia.

^aPersistent disorientation and confusion (compare post-traumatic stress disorder with specific triggers).
^bDepressive and anxiety symptoms amplify cognitive complaints and worsen functional outcome.

Table 3. Diagnoses and important differentials for persistent symptoms post head injury from DSM-5
	Timing	Trigger	General	Physical	Emotional	Cognition
PTSD^a	>1 month of persistent symptoms With delayed expression: Full symptom expression >6 months after event.	Actual/threatened harm including head injury.	Impaired social, occupational and other aspects of functioning.	Disturbed sleep (e.g. recurrent distressing dreams related to trauma), change in arousal, hypervigilance for potential threats, episodic physical symptoms can act as trigger for PTSD symptoms.^b	Irritability, outbursts, recklessness, flashbacks, intense/prolonged distress related to cues with/without avoidance, persistent negative emotional state.	Difficulty concentrating, inability to remember important aspects of event (not due to head injury), recurrent distressing memories (consider obsessive compulsive disorder criteria for obsession if unrelated to trauma).
Generalized anxiety disorder	Persistent symptoms for more than 50% of the time for >6 months.		Impaired social, occupational and other aspects of functioning.	Disturbed sleep, fatigue, exaggerated startle, muscle tension or soreness, change in arousal including panic attacks, somatic symptoms e.g. sweating, diarrhoea.	Irritability, anxiety/fear not related to traumatic event or specific triggers, overestimate dangers/future threat with avoidance, worry about multiple events, situations or activities.	Difficulty concentrating owing to worrisome thoughts, mind going blank.
Major depressive disorder	>2 weeks duration of new or clearly worsened symptoms, can be discrete episodes.	Can be traumatic/stressful event, often on a background of adverse childhood experiences.	Impaired social, occupational and other aspects of functioning.	Sleep disturbance, fatigue, weight change, loss of libido, general heaviness of limbs,^c somatic symptoms especially pain,^d psychomotor agitation or retardation.	Irritation, ^e outbursts, excessive guilt/worthlessness , low/dysphoric mood or anhedonia , diminished interest, suicidal thoughts, anxiety, phobias, excessive worry.	Difficulty concentrating, thinking, distractibility, indecisiveness, obsessive rumination (compare PTSD where related to a specific event).
Functional neurological disorder	Acute: <6 months duration (may have similar previous episodes). Persistent: >6 months.	Onset may be preceded by injury (physical/psychological).	Impaired social, occupational and other aspects of functioning.	Disturbance of any neurological system, internal inconsistency on examination.	Can be associated with dissociative symptoms at onset or during attacks, distress associated with loss of function.	Absent from definition.
Somatic symptom disorder	Any one symptom may not be persistent but state of being symptomatic >6 months.	Can be precipitated by stressful life events	Symptoms are distressing or result in significant disruption of daily life.	May represent normal bodily sensations/discomfort, may be specific (e.g. localized pain) or generalized (e.g. fatigue).	Persistently high levels of anxiety related to symptom and/or family history of disease, appraise bodily symptoms as threatening.^f	Excessive thoughts related to somatic symptom (thoughts are less intrusive than obsessive compulsive disorder).

PTSD = post-traumatic stress disorder.
Within symptom columns: bold denotes useful differentiating features; italics denotes shared symptoms across more than one category.
^aMore than 80% likely to have symptoms that meet diagnostic criteria for another mental disorder eg depression, bipolar disorder, anxiety, substance use compared to those without PTSD.
^bNew onset of somatic symptoms within the context of posttraumatic distress may indicate PTSD rather than a functional neurological disorder.
^cVersus focal and more prominent in functional neurological disorder.
^dDepression single diagnosis if somatic symptoms and related thoughts, feelings or behaviours occur only during major depressive episodes.
^eIf mood disturbance characterized by irritability alone in the absence of sadness/anhedonia consider alternative diagnoses, e.g. attention deficit hyperactivity disorder.
^fAnxiety is focused on symptoms and distress caused by the symptoms (cf. generalized anxiety disorder). Absence of repetitive behaviours aimed to reduce anxiety that occur in obsessive compulsive disorder.