Chapter 1 Hypoxic-Ischemic Brain Damage

The brain is our most essential organ but also the most sensitive to oxygen deprivation. Diffuse hypoxia and ischemia result in global cerebral damage that follows a typical pattern defined by the selective vulnerability of brain regions. Irreversible injury occurs when systemic blood pressure drops below the minimal levels required for sustaining effective brain metabolism and energy production. Physiologically, this occurs when mean arterial pressure falls below the lower limit of cerebral autoregulation. Whereas moderately severe reductions in cerebral blood flow and oxygen supply result in depression or suppression of brain tissue metabolism, critically severe reductions cause irreversible disruption of cellular membranes (responsible for the development of cytotoxic edema) and cell death.

The most characteristic example of hypoxic-ischemic brain damage is produced by cardiac arrest. Attempts to prognosticate outcome accurately after cardiac arrest have generated abundant research. Although clinical examination remains the preeminent tool to predict the chances of recovery after cardiac resuscitation, a number of electrophysiological and neuroimaging techniques provide valuable aid.^1,2 This chapter summarizes the most important and useful features of neuroimaging in the diagnosis and prognosis of patients with global hypoxic-ischemic brain damage.

Computed tomography (CT) scan has limited sensitivity to diagnose the extent of brain damage after a diffuse hypoxic insult. Loss of the normal differentiation between cortical gray matter and subcortical white matter and effacement of the delineation of deep gray matter structures are the best known signs of global hypoxia on CT scan. They represent early stages of brain swelling, mostly due to cytotoxic edema. However, these findings may be subtle and difficult to recognize. Additionally, CT scans can be deceiving, showing little change in patients with severe hypoxic damage or presenting signs that may be confused with other conditions (i.e., pseudo-subarachnoid hemorrhage).^3–5 In patients who develop areas of infarction, CT scans may fail to reveal any focal hypodensities until 24 to 48 hours after the episode.

In contrast, magnetic resonance imaging (MRI) scans are extremely useful to recognize the severity of structural damage even very shortly after a hypoxic-ischemic event. The prognostic usefulness of MRI scans is becoming increasingly well established. The advent of diffusion-weighted imaging (DWI) has added a new dimension to the role of MRI in the workup of patients with acute global brain hypoxia-ischemia. This sequence allows good visualization of laminar necrosis and other characteristic signs of hypoxic injury, and it offers reliable information of prognostic importance with unsurpassed promptness.^5–11.

Figure 1-1 summarizes the main radiological findings encountered in patients with severe hypoxic-ischemic brain damage.

Figure 1-1 Imaging findings in patients with hypoxic-ischemic brain damage affecting the basal ganglia and cerebral cortex. First row: Axial computed tomography (CT) of the basal ganglia showing symmetrical hypodensity in the caudate nuclei (left). Axial CT scans of the brain without contrast revealing linear hyperdensity outlining the cortex (right). Second row: Axial diffusion-weighted imagery (DWI) magnetic resonance imaging (MRI) scan demonstrates bilateral symmetrical hyperintensity within the stratiocapsular regions (left). Axial DWI MRIs show diffuse hyperintense signal change in the cerebral cortex indicating laminar necrosis (right). Third row: Axial T1-weighted MRI shows bilateral symmetrical hyperintense signals within the putamen bilaterally (left). Axial T1-weighted MRIs show bilateral areas of cortical hyperintensity representing laminar necrosis (right). Fourth row: Axial T1-weighted MRI with contrast discloses bilateral symmetrical enhancement in the external putamen bilaterally (left). Axial and sagittal T1-weighted MRI with contrast show linear enhancement outlining the cortex, predominantly located in the occipital lobes (right). Fifth row: Axial fluid-attenuated inversion recovery (FLAIR) MRI denoting bilateral symmetrical hyperintense signals in the lenticular nuclei (left). Examples of axial FLAIR MRI showing diffuse and focal cortical hyperintensities distributed throughout the cerebral cortex or preferentially in the medial occipital cortex (right).

Case Vignette

A 29-year-old, previously healthy man collapsed after a lightning strike. A bystander at the scene noted absence of pulse and audible heartbeat and performed basic cardiopulmonary resuscitation for nearly 15 minutes. On arrival, paramedics confirmed the diagnosis of cardiac arrest and initiated full advanced cardiac life support. Electrical defibrillation resulted in return of spontaneous circulation. Initial neurological examination at the hospital revealed that the patient was comatose but with intact brainstem reflexes. He had a Glasgow coma scale sum score of 4 and exhibited frequent myoclonic jerks (myoclonic status). He subsequently failed to regain consciousness. Five days later, he was transferred to a tertiary care center. That day, an electroencephalogram (EEG) showed a very low-amplitude, slow (delta, occasional theta) background. A brain CT scan disclosed severe diffuse edema (Figure 1-2, upper row). A brain MRI performed 13 days after the insult displayed signs of extensive laminar necrosis (Figure 1-2, lower row). A second EEG was essentially unchanged almost 1 month after the arrest. He remained in vegetative state 2 months later.

Figure 1-2 Computed tomography (CT) scan of the brain showing effacement of the perimesencephalic cisterns (thin arrows) and areas of parenchymal low attenuation (thick arrows, upper left). Lower cut of the same CT scan reveals diffuse sulcal effacement with decreased differentiation between gray and white matter (upper right). T1-weighted magnetic resonance imaging scan showing high-intensity signals in the lenticular nuclei (arrows, lower left). Fluid-attenuated inversion recovery sequence disclosing hyperintense signal in the medial occipital cortices indicative of laminar necrosis (arrows, lower right).

Figure 1-3 Additional case illustrating the changes of severe of anoxic brain injury on computedtomography (CT) scan. A 55-year-old man had a cardiac arrest after surgery. CT scan 12 hours after the arrest shows effacement of the cortical sulci, loss of distinction of gray white matter junction, and slit-like lateral ventricles suggestive of diffuse cerebral edema (left). Higher cut displays multiple areas of decreased attenuation due to diffuse cerebral edema in a gyriform distribution over the hemispheric convexities (right).

ADDITIONAL EXAMPLES OF GLOBAL BRAIN EDEMA

Cortical Laminar Necrosis

♦ Cortical laminar necrosis occurs because of the selective vulnerability of cortical layers 3, 4, and 5 to anoxia and ischemia. In addition to neurons, glial cells and blood are also damaged, resulting in a pan-necrosis. The selective vulnerability of gray matter may be due to higher metabolic demand and denser concentration of receptors for excitatory amino acids that are released after the anoxic-ischemic event, precipitating the mechanism of excitotoxicity.

♦ Early cytotoxic edema in these injured cells is responsible for the bright signals seen on DWI and the corresponding low apparent diffusion coefficient (ADC) values^7,10,11 (Figures 1-4 and 1-5).

♦ The hyperintense signal observed on T1-weighted sequences is believed to be caused by the accumulation of denatured proteins in dying cells and does not represent presence of hemorrhage^14,15(Figure 1-6).

♦ Laminar necrosis may be identified within hours of the anoxic-ischemic event. In this acute phase (particularly the first 24 hours), DWI is far superior to conventional MRI sequences in its ability to distinguish cortical changes.^6,7,11 ADC values are typically decreased to values ranging from 60% to 80% of normal.¹¹ Cortical diffusion abnormalities are associated with poor outcome after cardiac arrest.¹⁶

♦ T1 hyperintensities signaling laminar necrosis become evident after 2 weeks, peak at 1 to 3 months, and then fade slowly but can still be visible as late as 2 years after the insult.

♦ On fluid-attenuated inversion recovery (FLAIR), injured cortical areas are more prominently hyperintense between 1 month and 1 year after the event.^14,15 However, we have observed cortical changes on FLAIR within a few days of the anoxic insult (Figure 1-7).

♦ Affected cortex tends to appear isointense to slightly hyperintense on T2-weighted sequence. In our experience, this sequence offers limited value for the accurate diagnosis of laminar necrosis.

♦ Cortical enhancement is first seen after 2 weeks, peaks after 1 to 2 months, and is usually resolved after 6 months^14,15 (Figure 1-8).

♦ Very severe cases of cortical necrosis can be visualized on CT scan, either in the form of gyriform high attenuation (likely caused by local hemorrhage) (Figure 1-9) or areas of cortical hypoattenuation (Figure 1-10).

Figure 1-4 Diffusion-weighted imaging sequence (left) and corresponding apparent diffusion coefficient maps (right) of a brain magnetic resonance image from a 51-year-old woman obtained 16 hours after resuscitation from prolonged cardiac arrest. Note restricted diffusion in the lenticular nuclei and throughout the cortex of both cerebral hemispheres. The patient remained comatose and expired 3 days later after withdrawal of life support.

Figure 1-5 Additional example of restricted diffusion affecting extensively the cortex of both cerebral hemispheres in a 58-year-old patient who underwent cardiopulmonary resuscitation after out-of hospital ventricular fibrillation. Images shown are diffusion-weighted imaging sequence (left) and apparent diffusion coefficient map (right) from a brain magnetic resonance image performed 46 hours after the cardiac arrest.

Figure 1-6 T1-weighted magnetic resonance imaging (MRI) scan showing patchy areas of cortical hyperintensity representing laminar necrosis (thin arrows). Also notice hyperintense signal in the putamen (thick arrows). This MRI scan was performed nearly 3 weeks after a cardiac arrest,

Figure 1-7 Two cases of anoxic brain injury depicted on fluid-attenuated inversion recovery (FLAIR) sequences. Upper row: FLAIR sequence of a brain magnetic resonance imaging (MRI) scan of a patient with persistent coma 6 days after being resuscitated from a cardiac arrest. It shows diffusely increased signal intensity in the insular, high frontal, parietal, and occipital cortex. The cortex also appears swollen in this relatively early stage. Lower row: Another example of cortical changes on FLAIR but in a later stage. This MRI was obtained 12 days after cardiac arrest. In addition to the high-intensity signal changes in the cortex, the lenticular nuclei also appear hyperintense bilaterally.

Figure 1-8 Magnetic resonance imaging scan of the brain with gadolinium performed for prognostic purposes 1 month after cardiac arrest in a 45-year-old woman with limited recovery. She was fully incapacitated and was suspected to be cortically blind. Notice diffuse cortical enhancement predominantly involving the occipital and perirolandic cortical areas. The figure shows enhanced T1-weighted sequences with axial cuts (upper row), sagittal cut (lower left), and coronal cut (lower right).

Figure 1-9 This figure illustrates the changes caused by cortical laminar necrosis on computed tomography scan. Cortical edema (low attenuation) can be combined with small areas of hyperdensity (likely caused by hemorrhage or vascular congestion). These changes can be rather subtle as seen in the upper left (with magnified view on the upper right) or, less commonly, more manifest as shown in the lower row (arrowheads).

Figure 1-10 Computed tomography scan of the brain shows multifocal areas of severe cortical edema 3 days after cardiac arrest in a patient with persistent coma and myoclonic status. Basal ganglia also exhibit low attenuation.

Basal Ganglia Involvement

♦ Changes in the deep gray nuclei are seen in most cases of anoxic-ischemic brain damage.

♦ Bilateral thalami, lenticular nuclei, and caudate nuclei may be involved. As exhibited by the illustrations, the distribution of lesions is not uniform across patients and may change over time in each patient (Figures 1-11 and 1-12).

♦ Lesions may be seen in association with cortical laminar changes or in isolation.

♦ Although signal changes are often present early, the time of appearance varies. The factors determining the timing and extent of these lesions remain to be established.

♦ Basal ganglia injury may be the anatomical substrate that accounts for the various adventitious movements frequently seen in survivors of cardiac arrest and other severe hypoxic-ischemic events.

Figure 1-11 Magnetic resonance imaging (MRI) scans showing evidence of basal ganglia involvement after anoxic insults. Upper row: Diffusion-weighted imagery sequence revealing restricted diffusion on bilateral putamen and caudate nuclei (left) and in the caudate nuclei and cortical areas (right). Lower row: T1-weighted sequence showing high-intensity signal in the putamen bilaterally (axial view on the left and coronal on the right). Note associated medial occipital changes on the axial cut.

Figure 1-12 Magnetic resonance imaging (MRI) scans showing evidence of basal ganglia involvement after cardiac arrest. Upper row: T2-weighted sequence displaying increased signal in lenticular nuclei, caudate nuclei, and throughout the cortical layer. Lower two rows: Various examples of anoxic changes affecting the basal ganglia on FLAIR. Notice that these changes may occur only in the deep structures (middle row) or may also involve cortical areas (lower row). The distribution of lesions in the basal ganglia may vary. See predominant putaminal involvement in the middle and lower images of the left column, combined caudate and lenticular involvement on the middle right, and predominant thalamic lesions in the lower right.

Watershed Infarctions

♦ Watershed infarctions caused by a diffuse anoxic-ischemic insult appear to be more common in neonates and children.

♦ In adults, we have observed these lesions more often in patients who survive the event. In addition, watershed infarcts are not typically seen in conjunction with extensive laminar necrosis (Figure 1-13).

♦ It is tempting to hypothesize that watershed infarcts occur in cases of severe hypoperfusion without anoxia (as happens when they are caused by carotid occlusion or critical stenosis with systemic hypotension), whereas laminar necrosis results from anoxic injury.

Figure 1-13 Images demonstrate watershed infarctions after cardiac arrest. Upper row: Diffusion-weighted imaging sequence showing restricted diffusion in internal and external watershed distributions 4 days after cardiac arrest in a pediatric patient. Lower row: Early changes already observed in the fluid-attenuated inversion recovery sequence. Notice that the changes extend beyond typical watershed territory to affect larger areas of the frontal cortex on the right hemisphere.

Vulnerable Cortical Areas: Perirolandic and Occipital Cortex

♦ The perirolandic (Figure 1-14) and occipital cortex (Figure 1-15) are often involved to a greater extent than other cortical areas. In our experience, the medial occipital cortex is the area most commonly affected after anoxic-ischemic brain injury.

♦ The intense baseline metabolic demand of these regions may explain their selective vulnerability.

♦ Although it is commonly held that the hippocampi in the mesial temporal lobes are the cortical areas most susceptible to anoxia, radiological evidence of damage to these structures is seen much less commonly after cardiac arrest than are lesions in the medial occipital lobes and perirolandic regions. However, it has been suggested that the damage to the hippocampus (along with the corpus callosum and white matter) may occur as a delayed manifestation of brain anoxia.¹⁷

♦ Presence of diffusion abnormalities or T1 hyperintensity in these cortical areas in a patient with coma of unclear cause should be considered strongly supportive of the diagnosis of hypoxic-ischemic brain damage.

♦ Cerebellar lesions may be prominent in certain severe cases, and cerebellar ischemia is probably an extremely poor prognostic indicator (Figure 1-16).

Figure 1-14 This figure illustrates predominant anoxic changes in the perirolandic regions after cardiac arrest. Upper row: Restricted diffusion on diffusion-weighted imaging (left) and corresponding dark signal on the apparent diffusion coefficient map (right) in a 56-year-old man who sustained prolonged ventricular fibrillation-arrest 5 days before. Lower row: FLAIR sequence shows high-intensity signal outlining the perirolandic cortex (normal view on the left and magnified view on the right).

Figure 1-15 Figure demonstrating predominant involvement of changes indicative of laminar necrosis in the occipital cortex (arrows). Diffusion-weighted imaging sequence is shown in the upper left and FLAIR sequence in the rest of the images. Notice selective involvement of medial occipital cortex and relative sparing of mesial temporal structures.

Figure 1-16 Evidence of cerebellar lesions after brain anoxia is seen in this magnetic resonance image of an 84-year-old woman who had prolonged respiratory arrest. Diffusion-weighted image showing extensive areas of restricted diffusion in both cerebellar hemispheres (left). T2-weighted sequence also shows high signal intensity in these regions (right).

False Radiological Signs: Pseudo-Subarachnoid Hemorrhage and False Middle Cerebral Artery Sign

♦ False appearance of subarachnoid hemorrhage (SAH), or pseudo-SAH, may be seen in cases of advanced diffuse cerebral edema,³ including that caused by anoxia-ischemia⁴ (Figure 1-17, upper row).

♦ The most plausible explanation for the occurrence of this phenomenon is a combination of displacement of hypoattenuated cerebrospinal fluid, engorgement of pial compliance vessels, and edema in the adjacent cortex.³

♦ As displayed in our cases, increased attenuation within the falx, tentorium, and, most remarkably, the basal cisterns is responsible for the possible misdiagnosis of SAH. This appearance may be particularly deceptive in patients with coma of unclear etiology; in these patients, it may result in unnecessary testing.

♦ The pitfall of mistakenly diagnosing SAH in patients with global edema may be avoided by being aware of this possibility. When in doubt, it is useful to pay special attention to the attenuation values in the basal cisterns, because they are much lower in these false cases than those observed in true cases of SAH.³

♦ As clearly shown by the images in Figure 1-17, patients with severe brain edema may also exhibit the false appearance of unilateral or, most often, bilateral middle cerebral artery (MCA) signs, which would suggest bilateral stroke rather than diffuse anoxia-ischemia. Close attention to the presence of signs of diffuse swelling beyond the boundaries of restricted arterial vascular territories helps avoid this misdiagnosis.

Figure 1-17 False radiological signs in computed tomography scans after severe brain anoxia: pseudo-subarachnoid hemorrhage and false hyperdense middle cerebral artery sign. Pseudo-subarachnoid hemorrhage thick arrows in the tentorium and sulci in the upper left panel and in the perimesencephalic cisterns in the upper right panel. Thin arrows mark examples of false hyperdense middle cerebral artery signs. Notice extensive brain swelling in all cases.

Early and Delayed White Matter Changes: Anoxic Leukoencephalopathy

♦ White matter lesions typically become visible in the late subacute or chronic phase of evolution of anoxic-ischemic brain damage and worsen over time.^6,18 (Figure 1-18).

♦ It has been suggested that this delayed leukoencephalopathy may be more common after prolonged hypoxemia combined with hypotension and acidosis,¹⁹ yet surprisingly little research addressing this form of leukoencephalopathy has been reported in the literature.

♦ Early white matter changes have been observed in some patients.²⁰ The actual prevalence of this finding is unclear, but from our experience, it is probably quite low.

Figure 1-18 Seventy-year-old man with poor recovery 2 weeks after prolonged cardiorespiratory arrest complicated with renal failure and associated with severe acidosis. Mild initial improvement in alertness was followed by irreversible decline. Upper row: Axial diffusion-weighted imaging sequence shows patchy areas of bright signal within the white matter suggestive of anoxic leukoencephalopathy. These bright spots matched with low apparent diffusion coefficient (ADC) on the ADC map (not shown). Lower row: Axial FLAIR shows extensive white matter changes in the same patient.