C. Alan Anderson, M.D.
David B. Arciniegas, M.D.
Christopher M. Filley, M.D.
The medical management of patients with hypoxic-ischemic brain injury has improved substantially over the last 25 years. Although advances in prehospital care and critical care management of the conditions causing hypoxic-ischemic brain injury (e.g., cardiac arrest, carbon monoxide poisoning, respiratory failure) have improved overall survival rates and long-term outcomes, these remain conditions that present substantial clinical challenges and entail substantial neuropsychiatric morbidity (Betterman and Patel 2014; Elmer and Callaway 2017; Howard et al. 2011; Sadaka 2013). Cognitive impairment, parkinsonism, seizures, and other neurobehavioral sequelae are among the most common consequences of hypoxic-ischemic brain injury, and their occurrence is associated with postinjury disability and reduced quality of life for affected persons and their families (Arciniegas 2010). In this chapter, we review the neurophysiology of some of the different mechanisms of hypoxic-ischemic brain injury, the neuropsychiatric sequelae of hypoxic-ischemic brain injury, and diagnostic and treatment options.
Hypoxic-ischemic brain injury is an umbrella term that includes injury to the brain resulting from hypoxia, ischemia, and cytotoxicity, alone or in combination and across a broad range of severity (Busl and Greer 2010). It is important to recognize that hypoxic-ischemic brain injury is a clinical category with several subtypes: hypotonic (or hypoxic) hypoxia; anemic (or hypemic) hypoxia; ischemic (or stagnant) hypoxia; histotoxic hypoxia (Table 13–1). Hypotonic (or hypoxic) hypoxia describes a state in which low partial pressure of oxygen (Pa02) in the blood compromises oxygen delivery to tissues. Anemic (or hypemic) hypoxia is a state in which low blood oxygen-binding capacity compromises oxygen delivery to tissues. Ischemic (or stagnant) hypoxia refers to a condition in which inadequate delivery of blood compromises delivery of oxygen and other essential factors for cell metabolism and may occur with normal or low Pa02. Histotoxic hypoxia is the result of insufficient oxygen extraction from blood into tissues.
Injury type |
Characteristics |
Contexts |
Examples |
Hypotonic (hypoxic) hypoxia |
Low Pa02 Normal blood oxygen-binding capacity Normal perfusion Normal end-tissue oxygen extraction capacity |
Low O2 tension in inspired air |
High-altitude location Near-suffocation in enclosed space Choking on foreign object Tracheal collapse |
Diffusion impairment |
Inhalation of water (near drowning) Severe pulmonary edema |
||
Alveolar ventilation-perfusion mismatch |
Pulmonary embolism Chronic obstructive pulmonary disease |
||
Venous-to-arterial shunts |
Vessel-to-vessel or intracardiac shunts |
||
Anemic (hypemic) hypoxia |
Normal Pa02 Reduced blood oxygen-binding capacity |
Reduced hemoglobin or blood cells |
Bone marrow failure Hemorrhage |
Normal perfusion Normal end-tissue oxygen extraction capacity |
Interference with the binding of oxygen to hemoglobin |
Methemoglobinemia due to carbon monoxide poisoning, including cigarette smoking |
|
Ischemic (stagnant) hypoxia |
Normal or low Pa02 Normal blood oxygen-binding capacity Reduced perfusion Normal end-tissue oxygen extraction capacity |
Insufficient blood flow Normal Pa02 |
Severe hypotension Focal ischemia Global ischemia due to near-strangulation Low cardiac output |
Low Pa02 |
Cardiopulmonary arrest |
||
Histotoxic hypoxia |
Normal Pa02 Reduced blood oxygen-binding capacity Normal perfusion Reduced end-tissue oxygen extraction capacity |
Blockade of mitochondrial metabolism |
Cyanide poisoning |
Although the concept of hypoxic-ischemic brain injury and these subtypes are well established in the basic neurosciences and in many areas in clinical medicine, this condition is often referred to by the historical terms anoxic brain injury, anoxic brain damage, or anoxic encephalopathy, especially in neurorehabilitation settings. It is important to note that these terms are misleading with regard to the mechanism of injury and the severity of oxygen deprivation required to produce it. As described in more detail below, pure hypoxia—even when relatively prolonged and/or severe—produces functional changes within neurons without necessarily inducing cell death, provided the systemic circulation is adequately preserved. Accordingly, pure hypoxia is better tolerated than is ischemia or combined hypoxia-ischemia (Busl and Greer 2010; Greer 2006).
True anoxia (i.e., complete absence of oxygen in the blood) is a relatively rare event in clinical contexts given the affinity of hemoglobin for oxygen and the sigmoidal nature of the relationship between oxygen saturation and the partial pressure of oxygen in the blood-hemoglobin dissociation. Although complete cessation of respiratory function eliminates introduction of new oxygen into the circulatory system, oxygen remains available, albeit in rapidly diminishing quantities, in the blood for extraction and use by brain tissue for at least several minutes thereafter. Indeed, the point when true anoxia occurs is one after which survival is unlikely.
Anoxic brain injury and related terms therefore are problematic in that they unduly emphasize oxygen deprivation and overstate its severity in relation to this type of brain injury while simultaneously directing attention away from the more injurious process of ischemia—and thereby generating confusion about this condition and its implications when these terms are used in research, education, and/or clinical practice. Accordingly, anoxic brain injury and related terms are eschewed in this chapter, as in similar works (Busl and Greer 2010; Greer 2006; Ropper et al. 2014), and the problem of interest is referred to as hypoxic-ischemic brain injury.
The high metabolic demands of the brain render it susceptible to injury from prolonged periods of hypoxia as well as relatively brief periods of combined hypoxia and ischemia. Hypotonic (hypoxic) hypoxia, anemic hypoxia, ischemic hypoxia, and histotoxic hypoxia are all potentially injurious to the brain. Conditions that lower the oxygen blood levels deprive the brain of oxygen; such deprivation produces changes in cellular energetics and metabolism that may render neurons (and, by extension, the circuits and networks in which they participate) dysfunctional without necessarily inducing cell death—provided that systemic circulation is preserved (Busl and Greer 2010).
Conditions that concurrently reduce brain oxygenation and perfusion also deprive it of glucose and all other nutrients and impair the nutrient-waste exchange process required to support brain metabolism. Interruption of these processes is immediately followed by cellular energy failure, membrane depolarization, brain edema, excess neurotransmitter release (particularly the excitatory amino acid neurotransmitters), and neurotransmitter uptake inhibition. These processes result in N-methyl-D-aspartate receptor–mediated increases in intracellular calcium, production of oxygen-free radicals, lipid peroxidation, and disturbances in autoregulation of cerebral blood flow at the microscopic and macroscopic levels (Busl and Greer 2010; Calvert and Zhang 2005; Greer 2006). The collective effects of these processes render brain tissues dysfunctional and incite processes that lead to cell death.
The pathophysiology of hypoxic-ischemic brain injury is characteristic of the nonhemorrhagic forms of stroke and more like this category of brain injury than it is like traumatic brain injury (Arciniegas 2010; Smania et al. 2013). The principal difference between hypoxic-ischemic brain injury and stroke is the use of the latter term to denote injury resulting from focal or multifocal ischemia (i.e., that occurring in one or a few specific vascular territories), whereas the former denotes injurious exposure to global (i.e., whole brain) hypoxia and/or hypoxia-ischemia.
Carbon monoxide poisoning (the prototypic histotoxic hypoxic injury and most common example of this injury type in clinical practice) may produce a pattern of brain injury comparable to that associated with pure (hypotonic) hypoxia. If the severity and duration of carbon monoxide poisoning engender systemic hypotension, however, the effects become increasingly similar to those of ischemic-hypoxic injury.
The pathophysiology of hypoxic-ischemic brain injury therefore is influenced both by the severity and duration of the hypoxia and the presence or absence of concurrent ischemia. The short- and long-term effects of hypoxia or hypoxia-ischemia are modified further by a host of additional factors including, but not limited to, patient age, comorbid medical and neurological conditions, individual differences in susceptibility to the effects of hypoxia and ischemia, and the provision (or not) of acute and chronic medical and rehabilitative interventions (Greer 2006). If sufficiently severe and/or prolonged, both hypoxic and hypoxic-ischemic states produce neuronal death and irreversible brain injury, although this endpoint is reached more rapidly during ischemic hypoxia. As Busl and Greer (2010) note, 15 minutes of global ischemia (e.g., during cardiac arrest) damages up to 95% of brain tissue (Busl and Greer 2010).
Although exposure to hypoxia and/or hypoxia-ischemia is global, not all areas of the brain are equally vulnerable to the injurious effects of such exposures. Structures with higher metabolic rates have greater oxygen nutrient demands, making them vulnerable to injury by hypoxia or ischemic hypoxia (Cervós-Navarro and Diemer 1991). Injury resulting from these processes tends to be most pronounced in the following: upper brain stem and lower diencephalon (i.e., ascending reticular activating system); cerebellum; CA1 region of the hippocampus; medium-size neurons of the striatum (particularly dorsal striatum); and neocortical layers 3, 5, and 6 (injury to which produces laminar cortical necrosis, referring to the death of cells in these layers, or lamina, in the cortex) (Anderson and Arciniegas 2010; Arbelaez et al. 1999; Busl and Greer 2010; Chalela et al. 2001; Jang et al. 2014). Neurons in the CA1 region of the hippocampus and the dorsal striatum are adversely affected by short periods of ischemia, which renders them dysfunctional rapidly and initiates a cascade of cellular responses that lead to delayed neuronal death (Busl and Greer 2010; Greer 2006). By contrast, glial cells and vascular cells in these regions are less susceptible to comparable degrees and durations of ischemic hypoxia.
The gradient of vulnerability to hypoxic-ischemic injury based on the anatomy of the vascular supply of the brain diminishes with proximity to the medulla oblongata (Busl and Greer 2010). Tissues in the border zones between cerebral vascular territories (also described as “watershed areas”) are anatomically susceptible to ischemia (Cervós-Navarro and Diemer 1991). The watershed areas include an anterior border zone between the anterior cerebral artery (ACA) and middle cerebral artery (MCA); a posterior border zone between the MCA and posterior cerebral artery; and an internal border zone between the superficial branches of the MCA and the deep branches of the MCA or ACA. Prolonged periods of ischemia produce wedge-shaped lesions at the border zones between the cerebral artery territories that are appreciable macroscopically and on cerebral neuroimaging (particularly magnetic resonance imaging [MRI]); these lesions have their bases at the pial surface and their apices near the lateral ventricles. The vasculature of the deep white matter of the cerebral hemispheres comprises linear arterioles with few anastomoses, making the deep white matter particularly vulnerable to hypoxic ischemic injury. Tissues in which perfusion relies on small perforating arteries (e.g., lenticulostriate arteries) also are vulnerable to the effects of ischemic hypoxia; these tissues include the pallidum, in particular, as well as the capsular white matter (Okeda 2003).
Clinical guidelines for assessing prognosis, which are still widely used, derive mainly from neurological evaluation observations that are found to predict a low likelihood of meaningful neurological recovery. Examples include the presence or absence of pupillary responses, motor response to noxious stimuli, and diagnostic studies including the absence of somatosensory evoked potentials and elevated neuron-specific enolase levels. In the setting of hypoxic-ischemic brain injury after cardiac arrest, the advent of treatment with therapeutic cooling has improved survival and outcomes and called into question the validity and timing for many of these clinical markers (Greer et al. 2013; Scirica 2013; Stevens and Sutter 2013). Studies performed in the hypothermia era suggest that serial multimodal clinical and imaging assessments (including evoked potential, electroencephalogram [EEG], and MRI) are likely to yield more robust predictors of long-term recovery after hypoxic-ischemic brain injury (Estraneo et al. 2013; Heinz and Rollnik 2015; Rothstein 2014).
The neurological and neuropsychiatric sequelae of hypoxic-ischemic brain injury follow the patterns of metabolic and anatomic susceptibility to hypoxia and ischemic hypoxia. Consequences of hypoxic-ischemic brain injury commonly include seizures (event related and recurrent), disturbances of sensorimotor function, and a broad array of cognitive, emotional, and behavioral disturbances (Anderson and Arciniegas 2010; Lu-Emerson and Khot 2010).
Seizures develop in as many as 35% of patients with hypoxic-ischemic brain injury during the immediate postinjury period, usually beginning within 24 hours of injury but occurring or recurring over the first 2 weeks thereafter. Event-related seizures may be generalized, reflecting the excitotoxic consequences of global hypoxia and/or ischemic hypoxia. After the immediate postinjury period, most posthypoxic seizures are of focal onset; some may secondarily generalize. Seizures in patients in coma or with other disturbances of consciousness can be difficult to recognize. As continuous EEG monitoring has become more common, it is clear that subclinical seizures or subtle clinical manifestations of either partial or generalized seizures may be overlooked.
The occurrence of immediate postinjury seizure does not necessarily portend the development of posthypoxic epilepsy and does necessarily predict poor neurological or functional outcome. However, the development of posthypoxic status epilepticus (SE) is associated with almost invariably fatal outcome after hypoxic-ischemic brain injury (Rossetti et al. 2010). Whether the high rates of mortality associated with posthypoxic SE merely reflect the severity of injury or are the aggravating effects of SE, or both, remains uncertain. The frequency of late seizures—posthypoxic epilepsy—is not well established, although common clinical experience suggests that a substantial minority of persons with hypoxic-ischemic brain injuries develop this problem.
Myoclonus following hypoxic-ischemic brain injury is a syndrome characterized by multifocal high-velocity muscle contractions often brought on by action or volitional movements. In some cases, the myoclonic jerks are elicited by environmental stimuli such as loud noises, touch, pain, or procedures including phlebotomy, intubation, and intravenous line placement. An analogous phenomenon known as negative myoclonus, in which there is an abrupt loss of muscle tone sometimes associated with contraction in antagonist muscle groups, can also be seen. When negative myoclonus occurs in the upper extremities, it leads to dropping objects, and in the lower extremities falls can result. Myoclonus following hypoxic-ischemic brain injury can originate in either cortical or subcortical structures. Typically, cortical myoclonus involves the limbs or face and is brought on by intentional movements. Subcortical myoclonus is thought to originate in the brain stem and is more often associated with proximal limb and axial generalized contractions that are often triggered by environmental stimuli (Lu-Emerson and Khot 2010). Myoclonus after hypoxic-ischemic brain injury sometimes progresses to posthypoxic myoclonic status, the prognostic implications of which are similar to those associated with posthypoxic SE.
While the presence of seizures or myoclonus is not necessarily a poor prognostic sign, SE and ongoing myoclonus are both associated with higher morbidity and mortality. At present, however, seizure prophylaxis has not been demonstrated to prevent the development of posthypoxic seizures, myoclonus, SE, or myoclonic status. Applying current guidelines for seizure prophylaxis after traumatic brain injury (i.e., 1 week of prophylaxis postinjury, after which anticonvulsants are provided only if seizures develop) (Chang and Lowenstein 2003) therefore remains standard practice (Turnbull et al. 2016). However, the development of seizures, myoclonus, SE, or myoclonic status therefore should prompt aggressive treatment with anticonvulsants. The treatment of posthypoxic seizures and/or myoclonus follows that of other secondary epilepsies and myoclonus and appears to be similarly effective as the treatment of these conditions after other severe neurological injuries.
A variety of disorders of movement have been described following hypoxic-ischemic brain injury, including parkinsonism, tremor, dystonia, chorea, and athetosis (Lu-Emerson and Khot 2010). Neuroimaging and postmortem studies consistently associate basal ganglia, thalamic, midbrain, and cerebellar injury with these abnormal motor phenomena. Posthypoxic parkinsonism is generally symmetric and predominantly akinetic-rigid (i.e., not tremor predominant) but may sometimes include resting or postural tremor as well. The development of posthypoxic akinetic-rigid parkinsonism is most closely associated with injury to the globus pallidus. Posthypoxic dystonia is often asymmetric initially but over time may progress to a more symmetric and generalized form; it is generally taken as an indication of injury to the putamen (Venkatesan and Frucht 2006).
These motor abnormalities may develop early after hypoxic-ischemic brain injury, but more commonly, they become apparent weeks to many months after injury. A variety of mechanisms for this delayed onset have been proposed, including demyelination, oxidative changes, synaptic reorganization, and inflammatory changes (Lu-Emerson and Khot 2010; Venkatesan and Frucht 2006).
Treatment of dystonia and parkinsonian states following hypoxic-ischemic brain injury is similar to that used in other settings. Response to treatment can vary significantly, with some patients showing dramatic response to medications. In general, however, these conditions appear less responsive to pharmacologic treatment and interventional therapies (i.e., deep brain stimulation) than primary parkinsonism (i.e., Parkinson’s disease) and idiopathic dystonia, perhaps reflecting hypoxic-ischemic-induced damage and/or destruction of the neurons in these structures that ordinarily are the targets of these pharmacotherapies (Lu-Emerson and Khot 2010; Venkatesan and Frucht 2006).
As noted earlier, watershed areas are particularly vulnerable to the effects of reduced perfusion. When the injury occurs in anterior frontal white matter and involves the zone between the anterior and middle cerebral artery territories, patients may present with bilateral arm weakness (brachial diplegia) and relatively preserved lower extremity function. This condition is commonly referred to in neurological practices as the “man-in-the-barrel syndrome.” Involvement of parieto-occipital structures in the watershed zone between the vascular territories of the middle cerebral and posterior cerebral arteries is associated with the development of cortical blindness or, more rarely, Balint’s syndrome (i.e., optic ataxia, oculomotor apraxia, and simultanagnosia).
Pharmacotherapeutic and rehabilitative interventions for these problems and their complications (e.g., spasticity, contractures, gait and mobility impairments) are modeled on those applied for similar motor impairments due to other acquired brain injuries. The effectiveness of these motor-specific rehabilitative interventions in this population is not well established, but common clinical experience and several rehabilitation outcome studies suggest that these interventions may improve the functional status of persons with hypoxic-ischemic brain injuries (Burke et al. 2005; Shah et al. 2004, 2007).
Following initial resuscitation efforts, abnormalities of wakefulness and awareness of self and environment are common (Table 13–2). The duration of these disturbances varies with the degree and duration of hypoxia and/or ischemic hypoxia. Patients typically progress from coma through the states of diminished arousal and awareness—i.e., the disorders of consciousness, including vegetative state (VS, also known as the unresponsive wakefulness syndrome) and minimally conscious state (MCS)—albeit to varying endpoints (Giacino and Kalmar 2005; Giacino et al. 2002; van Erp et al. 2015; Whyte et al. 2009).
Brain stem function |
Wakefulness |
Awareness |
|
Minimally conscious state |
Present |
Present |
Present |
Vegetative state |
Present |
Present |
Absent |
Coma |
Present |
Absent |
Absent |
Brain death |
Absent |
Absent |
Absent |
Coma represents a spectrum of reduced arousal and awareness and results from severe injury or depressed function of bilateral cerebral hemispheres, bilateral thalami, or brain stem arousal systems (Posner and Plum 2007). Typically, patients in coma have their eyes closed and do not respond to external stimuli. They demonstrate no purposeful motor activity, and their sleep-wake cycles are abolished, but they may have occasional purposeless movements and reflex motor activity. After hypoxic-ischemic brain injury, coma may be very brief in duration or last days to weeks (or longer). Emergence from coma after this type of injury typically means transitioning into either the VS or MCS (Bodart et al. 2013; Giacino and Kalmar 2005).
Emergence from coma into the VS represents the recovery of arousal mechanisms in the absence of any recovery within cerebral networks subserving the content of consciousness. VS is characterized by the presence of wakefulness (i.e., spontaneous eye opening, sleep-wake cycles) but no evidence of awareness of the environment or the self (i.e., no observable responses to verbal, visual, or external physical stimuli or to internal sensations) (Giacino and Kalmar 2005; Giacino et al. 2002). There is sufficient autonomic function to permit survival with medical and nursing care and preserved brain stem function.
Depending on the severity of the injury, some patients may emerge from the VS to MCS higher levels of function. While there are exceptions, the likelihood of emerging from VS markedly decreases after 3 months in adults with hypoxic-ischemic brain injury. When patients do not emerge from VS, terms like “persistent” or “permanent” VS are sometimes employed to describe them. The recommendation of the Aspen Neurobehavior Conference Working Group was to limit the diagnosis to the indefinite term “vegetative state” and include the cause of the injury (i.e., hypoxic-ischemic brain injury versus traumatic brain injury or other) and the length of time that the patient had been in VS (Giacino et al. 2002). The descriptor “vegetative” is also controversial because of the implication that patients in this condition are “vegetables,” and an alternative term—unresponsive wakefulness syndrome—has been proposed (Laureys et al. 2010).
Because VS is diagnosed on the basis of observable behavior, there is a risk of mistaking other states for VS—in particular, the locked-in syndrome (in which consciousness is preserved but motor output is interrupted at the level of the pons), particularly when the anatomy of this syndrome extends rostrally and interferes with eye movements. Indeed, the clinical diagnosis when made without the benefit of structured clinical examination using validated metrics designed for this purpose and performed serially may be wrong as much as 40% of the time (Schnakers et al. 2009). The potential liability of relying entirely on behavioral criteria for VS is highlighted by functional MRI and EEG studies demonstrating preserved consciousness in a small subset of patients who would otherwise have been described as in VS (Fernández-Espejo and Owen 2013; Owen and Coleman 2007; Sitt et al. 2014). Although the subset of patients retaining consciousness that is amenable to detection with advanced imaging have been survivors of traumatic brain injury rather than hypoxic-ischemic brain injury, these studies, nonetheless, suggest the need to maintain vigilance for such exceptions and to remain open to the application of such technologies that may improve diagnostic confidence as such become feasible, valid, and reliable at the individual patient (rather than group) level.
The inherent complexity of these low-level states also naturally leads to the potential for substantial misunderstanding among many clinicians, family members, and others who are uneducated about these conditions. For example, media reports of patients emerging from the VS months or years following injury make for sensational news stories; however, their exceptional nature is often not understood clearly and creates unrealistic expectations with respect to the likelihood, course, and completeness of recovery from prolonged VS (or MCS) (Estraneo et al. 2013, 2014). It is worth bearing in mind as a clinician and communicating empathically but clearly that most patients with hypoxic-ischemic brain injuries who remain in VS and MCS for extended periods continue to experience functionally important cognitive impairments, motor impairments, and functional limitations if they emerge from these states (Estraneo et al. 2014).
The diagnosis of VS has many other significant implications, including medicolegal issues such as the consideration of life-sustaining interventions and decisions regarding end-of-life care. Given potential errors in diagnosis, the uncertainty of prognosis, and the many medical, ethical, legal, and moral implications of these cases, it is important that the diagnosis be made as precisely as possible and that care be used in selecting terminology in the process of communicating with family members, caregivers, and other interested third parties.
MCS is defined by the presence of wakefulness with at least minimal and intermittent capacity for awareness of self or interaction with the environment (Giacino and Kalmar 2005; Giacino et al. 2002). These latter features distinguish MCS from VS. Diagnosing the MCS requires careful serial examination and observation and consideration of potential confounds including medication effects and focal disturbances such as aphasia, apraxia, sensory deficits, and elemental motor impairments. MCS must also be distinguished from akinetic mutism and the locked-in syndrome, a distinction that is complicated by the occasional overlap between MCS and these states. While the construct of the VS is based on an absolute criterion—the absence of any awareness of self and interaction with the environment—the MCS represents a spectrum of function ranging from minimal and inconsistent interaction to a much higher level with more consistent functional interaction.
As patients progress through posthypoxic MCS toward higher states of cognitive and functional abilities, their awareness of self and environment increases, and they regain the capacity for at least intermittent functional communication and functional object use. Defining emergence from the MCS to higher-level functioning remains difficult. The Aspen Neurobehavioral Conference Working Group recommended that the upper boundary of the MCS be contingent on the patient demonstrating a consistent ability for functional interactive communication, the functional use of objects, or both (Giacino et al. 2002).
The prognosis for patients who recover rapidly to MCS after hypoxic-ischemic brain injury is more favorable than for those who do so after a protracted period in VS. The importance of the prognostic difference between the VS and the MCS cannot be overstated. Distinguishing between the two states carries important considerations not only for judging prognosis but also for decision making regarding continued supportive care and nutritional support and the management of associated conditions.
While treatment of patients with any of the disorders of consciousness remains an understudied area, there are interventions of potential benefit. The first steps in the care of these patients are 1) recognizing and treating any comorbid medical or neurologic problems; 2) limiting the use of medications with the potential to negatively affect arousal and cognition; and 3) providing adequate supportive care including hydration, oxygenation, and nutrition. As patients are stabilized, efforts to help normalize their sleep-wake cycles with active engagement and stimulation during daytime hours and limitation of environmental stimulation during nighttime hours are crucial (Anderson and Arciniegas 2010). Because the U.S. Food and Drug Administration (FDA) has not approved any medications for the treatment of disorders of consciousness due to any cause, all pharmacotherapies for posthypoxic disorders of consciousness must be regarded as off-label. Although there is emerging evidence for the use of amantadine (Giacino et al. 2012) and zolpidem (Whyte and Myers 2009; Whyte et al. 2014) to treat these disorders after traumatic brain injury, the evidence base for pharmacological treatment of posthypoxic disorders of consciousness is limited, but it includes amantadine, baclofen, bromocriptine, levodopa, pramipexole, methylphenidate, lamotrigine, modafinil, tricyclic antidepressants, and zolpidem (Ciurleo et al. 2013). Empiric treatment with these drugs may be considered and undertaken with caution; in general, beginning with low doses and carefully monitoring patients for efficacy and adverse effects is recommended. Transcranial direct current stimulation (Naro et al. 2016) and other neurostimulation interventions also may emerge to play a role in the treatment of patients with posthypoxic disorders of consciousness.
The most extensively studied neuropsychiatric sequelae of hypoxic-ischemic brain injury are cognitive impairments. In addition to the disorders of arousal and awareness (i.e., the disorders of consciousness discussed in the preceding sections of this chapter), impairments of attention and processing speed, memory impairment, and executive dysfunction are common short- and long-term consequences of hypoxic-ischemic brain injury (Anderson and Arciniegas 2010). Less commonly, aphasia (often motor, sensory, or mixed transcortical in character), apraxia (particularly ideational or conceptual apraxia), agnosias, visuospatial dysfunction, Balint’s syndrome (optic ataxia, oculomotor apraxia, simultanagnosia), and/or Anton’s syndrome (anosognosia for visual impairment) occurs.
This broad array of posthypoxic cognitive impairments follows on the vulnerability of many cognitively salient areas to the adverse effects of global hypoxia and/or ischemia. In brief summary, these include upper brain stem and thalamus (arousal and basic aspects of attention); deep white matter of the cerebral hemispheres (processing speed); CA1 region of the hippocampus (episodic memory); basal ganglia, anterior watershed area, and frontal cortex (executive function and executive control of attention, memory, language, and other cognitive function); and cortical layers 3, 5, and 6 (potential widespread effects on cognition depending on the area injured).
Cognitive recovery is both common and remarkably robust in many cases, with the most robust recovery occurring within the first 3 months after injury, and much of that occurring within the first 45 days postinjury (Lim et al. 2004; Lundgren-Nilsson et al. 2005). The level of recovery reached by the end of the first year is generally quite stable (Harve et al. 2007). Nonetheless, more than half of those recovering to that postinjury point in time do so fully—or at least well enough that their residual cognitive impairments are not obvious using the bedside cognitive assessments employed in most clinical practices, and the majority are not limited by cognitive impairments in their daily activities (van Alem et al. 2004). Among those who experience clinically important cognitive impairments, comorbidity with motor impairment is not infrequent (Anderson and Arciniegas 2010). Predictors of long-term cognitive impairment include the duration of impaired consciousness following the injury, shorter times to defibrillation, access to advanced life support, and the time to restoration of functional circulation.
When interventions for posthypoxic cognitive impairments and their functional consequences are required, nonpharmacologic and pharmacotherapeutic approaches are generally modeled after those provided to persons with posttraumatic cognitive impairments. The effectiveness of these interventions for patients with hypoxic-ischemic brain injury is not well established, but common clinical experience suggests that they may be of benefit to some persons with these kinds of injuries.
Nonpharmacologic interventions are used in an attempt to improve functional performance in real-world settings. The goal of these interventions is to develop compensatory strategies that capitalize on remaining cognitive strengths, enhance self-regulation, establish environmental and behavioral performance supports (and reduce sources of distraction and interference), and thereby improve everyday function (Cicerone et al. 2000, 2005, 2011). Examples include the use of daily planners, reminder lists, assistive devices (i.e., alarms, notebooks, communication boards and devices), and routines to encourage independence. Formal cognitive rehabilitation targeting specific cognitive impairments is typically provided by neuropsychologists, occupational therapists, and speech-language pathologists and can be helpful in developing a plan for therapy that includes the development of compensatory strategies. These interventions are typically employed in persons with hypoxic-ischemic brain injury who have mild to moderate impairments and sufficient functional independence and motivation to participate in the process and make use of compensatory strategies. In most cases, these interventions are most helpful when provided in the subacute or postacute rehabilitation period, rather than in the acute phase of care immediately following the injury.
Studies of pharmacologic interventions are typically limited to case reports or small case series, and there is no FDA-approved therapy for posthypoxic cognitive disturbances. Accordingly, the use of medications for this purpose is considered off-label. The two principal approaches are augmentation of catecholaminergic function or cholinergic function (Anderson and Arciniegas 2010). When slow processing speed and sustained attention are the predominant cognitive impairments, agents that augment catecholaminergic function (e.g., methylphenidate, amantadine, levodopa, bromocriptine) may be useful. When episodic memory impairments are the most salient and functionally limiting cognitive impairment, cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine) may be useful. In some cases, combinations of these agents may be required and, in general, are well tolerated by most patients. Much like the effects of pharmacotherapy on the motor complications of hypoxic-ischemic brain injury, common clinical experience suggests that these agents tend not to be as effective as when they are used to treat posttraumatic cognitive impairments. Although individual patient experiences will vary, providing realistic, and relatively modest, treatment response expectations to patients and their caregivers is prudent.
Emotional and other behavioral disturbances are common after hypoxic-ischemic brain injury. However, the literature on this topic focuses predominantly on survivors of out-of-hospital cardiac arrest rather than hypoxic-ischemic brain injuries more specifically. The observations offered in these studies need to incorporate psychological, medical (especially cardiac), and other influences on the development of postevent emotional and behavioral issues and to avoid narrowly focused attribution of emotional and behavioral disturbances in this population to hypoxic-ischemic brain injury alone.
That said, survivors of out-of-hospital cardiac arrest report high rates of persistent anxiety (up to 60%), depression (more than 40%), and posttraumatic stress (nearly 30%). Comorbid cognitive impairments and fatigue also are commonly reported long-term outcomes in this population, and these symptoms in combination with emotional and behavioral symptoms negatively affect long-term quality of life for persons with hypoxic-ischemic brain injuries (Green et al. 2015; Moulaert et al. 2010; Wilson et al. 2014). Caregivers of survivors of out-of-hospital cardiac arrest also report high rates of depression, anxiety, and posttraumatic stress, with insufficient social and financial support (Green et al. 2015; Moulaert et al. 2010).
The treatment of the emotional and behavioral sequelae of hypoxic-ischemic brain injury remains understudied. Treatment by analogy to other conditions, especially the neuropsychiatric sequelae of traumatic brain injury, is common practice. Whether there are substantive differences between these groups with respect to treatment response remains uncertain. Providing psychotherapy and support group and therapeutic activities during rehabilitation after hypoxic-ischemic brain injury improves quality of life and social participation (Tazopoulou et al. 2016) and therefore is encouraged pending additional research with which to clarify this recommendation.
A rare but noteworthy consequence of hypoxic-ischemic brain injury is delayed posthypoxic leukoencephalopathy, a severe demyelinating syndrome that occurs a few days to a few weeks after an early and complete (or near complete) initial recovery. This delayed demyelinating syndrome is characterized by acute or subacute onset of severe and progressive neuropsychiatric problems such as delirium, psychosis, parkinsonism, akinetic mutism, and/or quadriparesis, among others. Although this condition was first described as a delayed sequela of carbon monoxide–induced hypoxic-ischemic brain injury, it has been described subsequently in association with nearly all causes of hypoxic-ischemic brain injury (Arciniegas et al. 2004; Shprecher and Mehta 2010). The pathophysiological mechanism(s) of delayed posthypoxic leukoencephalopathy are established definitively. However, combinations of toxic exposure (e.g., carbon monoxide, inhaled heroin), genetic factors (e.g., pseudodeficiency of arylsulfatase A, abnormalities of other genes regulating myelin turnover), and age-associated vascular risk factors have been suggested as possible contributors to this unusual demyelinating syndrome. Regardless of mechanism, this syndrome is characterized neuropathologically by diffuse bihemispheric demyelination that generally spares the cerebellum and brain stem.
Neurological and neurobehavioral improvement over the first 3–12 months following onset of this syndrome is typical, but many survivors experience persistent cognitive impairments (particularly impairments of attention, processing speed, and/or executive function), parkinsonism, and/or corticospinal tract signs. There are case reports describing symptomatic and functional improvement of the cognitive and parkinsonian sequelae of delayed posthypoxic leukoencephalopathy during treatment with stimulants, amantadine, or levodopa. The observation that these agents offer some benefit in this context despite their lack of efficacy for the same sequelae of hypoxic-ischemic brain injury itself may reflect differences in the anatomy of these conditions. Hypoxic-ischemic brain injury entails widespread neuronal injury and, in severe cases, death in anatomically and metabolically vulnerable brain areas. Recovering early from this injury suggests relative preservation of those tissues. The development of delayed posthypoxic leukoencephalopathy selectively affects white, rather than gray, matter, creating anatomic targets for drug action that may be less available in those with similar clinical problems due to hypoxic-ischemic brain injury alone.
Advances in prehospital care, emergency resuscitation techniques, therapeutic cooling, critical care, and rehabilitative techniques have improved survival rates for patients with hypoxic-ischemic brain injury and, in some cases, cognitive and functional outcomes. Unfortunately, a substantial proportion of survivors of hypoxic-ischemic brain injury will experience early and late neurological and neuropsychiatric disturbances. These may include seizures, myoclonus, movement disorders, motor weakness, the disorders of consciousness (coma, VS, and MCS), cognitive impairments, and emotional and behavioral disturbances. While the outcomes after hypoxic-ischemic brain injury are highly variable, a clear understanding of regional vulnerability to hypoxia and ischemic hypoxia reveals an anatomy of injury that predicts all of these neurological and neuropsychiatric sequelae. As new approaches for prevention of hypoxic-ischemic brain injury, acute resuscitation and critical care management, pharmacotherapy, and rehabilitation emerge, improved outcomes from hypoxic-ischemic brain injuries seem likely to follow as well.
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