Anoxic brain injury (ABI) is a condition in which reduced oxygen supply to brain tissue causes damage or impairment of brain function. It can cause permanent damage to the visual system (optic nerve, optic chiasm, optic tract, optic radiation, and visual cortex), and ophthalmic sequelae become a problem.
In adults, the main causes are cardiac arrest, respiratory arrest, trauma (strangulation, head injury), acute vascular disorders, and poisoning (carbon monoxide poisoning, drug overdose). In children, causes include prenatal, perinatal, and postnatal complications, cardiovascular and respiratory problems, congenital infections, genetic factors, as well as dehydration and abusive head trauma. The prevalence is increasing with improved survival rates of preterm infants.
Epidemiologically, out-of-hospital cardiac arrest occurs in approximately 80 per 100,000 people annually, with survival to discharge reported at about 10% and complete neurological recovery at about 5% 1). Severe hypoxic-ischemic encephalopathy (HIE) is found in 61% of brain autopsies of post-cardiac arrest patients 1). Among cardiac arrest survivors, 50–83% experience clinically significant cognitive symptoms, with visual impairments including cortical visual impairment in up to 50–70% and oculomotor dysfunction in 60–85%.
In children, CVI (Cerebral/Cortical Visual Impairment) is the most common cause of visual impairment in developed countries, and the most common underlying etiology is hypoxic-ischemic encephalopathy. Other causes include epilepsy, hydrocephalus, trauma, and infection.
QHow often does visual impairment occur due to anoxic brain injury?
A
Among cardiac arrest survivors, cortical visual impairment occurs in up to 50–70% and oculomotor dysfunction in 60–85%. In children, hypoxic-ischemic encephalopathy is the most common cause of cerebral/cortical visual impairment (CVI) and is also the leading cause of childhood visual impairment in developed countries.
Some visual function may recover within months after injury. In children with CVI, variability in visual function (temporary decline due to seizures or illness, increased difficulty in complex visual environments) is characteristic.
Homonymous hemianopia: with or without macular sparing. Upper occipital lobe damage → inferior quadrantanopia, lower occipital lobe damage → superior quadrantanopia.
Congruous homonymous hemianopia: Bilateral congruous homonymous hemianopia involving both upper and lower quadrants may appear several months after the initial injury. Similar to horizontal hemianopia or checkerboard visual field defects.
Cortical blindness: Occurs due to extensive bilateral occipital lobe damage. The pupillary light reflex remains intact. May be accompanied by Anton syndrome (denial of blindness and behaving as if seeing).
Riddoch syndrome / blindsight: Inability to recognize stationary objects but ability to perceive moving objects. Suggests involvement of visual pathways other than LGB-V1.
Eye movement and other disorders
Ocular dipping: Slow downward deviation followed by rapid upward return. Associated with hypoxic-ischemic brain injury, suggesting suppression of cortical function with relatively preserved brainstem reflexes.
Ocular bobbing: rapid downward jerk → slow upward drift. Associated with structural pontine lesions. Inverse ocular bobbing is associated with metabolic encephalopathy.
Conjugate gaze deviation: Frontal eye field (Brodmann area 8) lesion → conjugate gaze deviation toward the side of the lesion.
Optic atrophy: Due to anoxic ischemic optic neuropathy secondary to ABI.
Balint syndrome: bilateral parieto-occipital lesions. Triad of psychic gaze paralysis, optic ataxia, and visual attention disorder.
In pediatric CVI, characteristic findings include crowding effect/simultanagnosia, preference for near vision, relative preservation of color vision (due to bilateral representation of color), reduced contrast sensitivity, photophobia, and paradoxical gaze.
In severe ABI, brainstem reflexes are absent. Cases have been reported with fixed dilated pupils, absent corneal reflex, absent oculocephalic reflex, and absent cough/gag reflex 2). Basal ganglia damage causes hypertonia and rigidity, which worsen with stress and anxiety 1).
QIs the pupillary light reflex preserved in cortical blindness?
A
Cortical blindness results from bilateral occipital lobe damage, so the pupillary reflex pathway (hypothalamus and midbrain) is spared. Thus, the light reflex remains normal. This is an important finding for differentiating from psychogenic visual disturbance. In cases with Anton syndrome, the patient may be unaware of vision loss.
A special cause in adults is BRASH syndrome (a vicious cycle of bradycardia, renal failure, AV nodal blockers, shock, and hyperkalemia). Cases have been reported where this syndrome developed during hyperkalemia (7.9 mmol/L) and metoprolol use, leading to PEA arrest and then ABI 3).
Diagnosis of visual impairment due to ABI requires a combination of neuro-ophthalmic examination and multiple imaging and electrophysiological tests. In patients with brain disorders, visual symptoms may go unnoticed due to concurrent dementia or decreased attention. It is important to perform tests specific to the symptoms predicted by the lesion location.
Brainstem reflex assessment: Systematically check pupillary light reflex, corneal reflex, oculocephalic reflex, and cough/gag reflex. These findings are important for prognosis 2).
Differential diagnosis: Cortical blindness due to bilateral occipital lobe damage presents with normal pupillary light reflex and no abnormal eye findings, so differentiation from psychogenic visual disturbance is necessary.
Ischemic changes in the cortex and deep gray matter (within 6 days of injury), basal ganglia T2/FLAIR signal abnormalities, DWI diffusion restriction
Encephalomalacia and atrophy develop over time1)
CT
Loss of gray-white matter differentiation, reversal sign, white cerebellum sign
Complete obliteration of sulci and cisterns in diffuse ABI3)
PET
Can detect hypoperfusion/hypometabolism even when structural imaging is normal
ABI cannot be ruled out even if initial CT/MRI is normal
CT perfusion imaging can evaluate post-ischemic hyperperfusion (increased CBF and CBV, shortened MTT and TTP) and ischemic penumbra (decreased CBF, increased CBV, prolonged MTT and TTP)5).
In delayed posthypoxic leukoencephalopathy (DPHL/DTHL), MRI shows diffuse white matter hyperintensity (sparing U-fibers, corpus callosum, brainstem, and cerebellum) and scattered diffusion restriction 4).
As an ancillary test for brain death determination, the three methods recommended by the AAN (conventional angiography, transcranial Doppler ultrasound, and 99mTc scintigraphy) are used2).
QCan anoxic brain injury be ruled out even if initial CT/MRI are normal?
A
Cannot be denied. Early structural imaging may be normal to nearly normal. PET can sometimes detect hypometabolism. In DPHL, acute exacerbation occurs after a lucid interval of 2–5 weeks following a hypoxic event, so evaluation with serial MRI over time is important4).
There is no proven effective treatment for vision loss after ABI. The goals of treatment are prevention of secondary brain damage in the acute phase and functional compensation and life support in the recovery phase.
Acute Phase Management
Maintenance of cerebral perfusion and oxygenation: The highest priority to prevent secondary brain injury.
Targeted temperature management (TTM): For perinatal HIE, whole-body or selective head cooling is standard treatment. After cardiac arrest, maintain body temperature at 33°C for 24 hours, followed by gradual rewarming 3).
Seizure prevention and management: Actively manage epileptic seizures as they worsen secondary brain injury.
When cerebral infarction is complicated: In the very early stage, consider t-PA thrombolytic therapy or endovascular treatment. For recurrence prevention, use antiplatelet drugs such as aspirin 75–150 mg/day, clopidogrel 75 mg/day (grade A), or cilostazol 200 mg/day (grade B), or anticoagulants. For severe internal carotid artery stenosis, consider carotid endarterectomy or stenting.
Rehabilitation
Occupational therapy (OT) / Physical therapy (PT): Aimed at functional recovery and acquisition of compensatory techniques.
Low vision care: Maximizing residual visual function and introducing assistive devices.
Vision therapy (VT): Expected to improve function through learning alternative strategies.
Optimization of the visual environment: For pediatric CVI, adjustment of visual stimuli and multidisciplinary care (ophthalmology and systemic comorbidities) are recommended.
Prognosis of homonymous hemianopia: Recovery of visual field defects after cerebral infarction is poor in elderly patients, but may be possible in younger patients.
The use of antipsychotics (e.g., haloperidol) in patients presenting with agitation after ABI requires caution because dopamine blockade increases the risk of neuroleptic malignant syndrome (NMS)6). The following alternatives are recommended.
Amantadine: Promotes indirect dopamine release and inhibits reuptake. Level 1a evidence in traumatic brain injury patients. Doses over 200 mg carry risks of rigidity, depression, and seizures.
Beta-blockers: Pindolol reduces the number of agitation episodes, and propranolol reduces severity (class 1b recommendation)6).
Treatment of Delayed Post-Hypoxic Leukoencephalopathy (DPHL)
A case report showed improvement with a combination of methylprednisolone 1000 mg IV once daily for 5 days and amantadine 100 mg twice daily4). However, evidence is limited, and complete to near-complete recovery with appropriate supportive care is common.
6. Pathophysiology and Detailed Mechanism of Onset
After cerebral perfusion ceases, oxygen stores are depleted within seconds, leading to loss of consciousness. Within 5 minutes, glucose and oxygen are exhausted, ATP production is impaired, and ATP-dependent membrane pump dysfunction occurs.
Shift to anaerobic metabolism → lactate accumulation → membrane potential breakdown → intracellular accumulation of Na⁺/Ca²⁺ → K⁺ loss5). Furthermore, loss of cell membrane integrity → Ca²⁺ influx → glutamate release → NMDA receptor binding → high intracellular Ca²⁺ → electron transport chain disruption → free radical formation → leading to necrosis and apoptosis5).
After blood flow is restored, reactive oxygen species (ROS) and immune cells enter the vulnerable brain tissue, causing reperfusion injury. Excessive hyperperfusion poses a risk of hemorrhagic transformation5).
Selective vulnerability of the primary visual cortex is due to two factors: (1) blood supply from the terminal portion of the posterior cerebral artery, which is prone to hypoperfusion during hypotension; and (2) the granule cells of the primary visual cortex have low tolerance to hypoxia.
Selective vulnerability of the basal ganglia is due to high metabolic demand, dense glutamatergic input, and limited collateral perfusion1). Basal ganglia damage leads to motor control disorders such as hypertonia and rigidity. It has been reported that 75% of patients with bilateral basal ganglia hypoattenuation have a poor prognosis (Barthel Index less than 50).
After ischemia, dopamine signaling initially increases in the striatum and then subsides after 72 hours as basal ganglia lesions progress. Dopamine-producing neuron death leads to a permanent decrease in dopamine levels. D2 receptors are highly sensitive to hypoxic-ischemic conditions6). This mechanism underlies the increased risk of NMS due to antipsychotics after ABI.
Mechanism of delayed post-hypoxic leukoencephalopathy (DPHL)
Extensive white matter disease acutely appears after a lucid interval of 2–5 weeks following a hypoxic event. The half-life of the fast component of the myelin basic protein pool (19–22 days) matches the length of the lucid interval.
It has been proposed that the initial toxic hypoxic event impairs oligodendrocyte myelin protein synthesis → during the lucid interval, function is maintained by existing myelin → acute functional failure occurs due to failure of myelin replacement 4). Deep white matter is vulnerable to hypoxic-ischemia because it is perfused by widely spaced arterioles with few anastomoses.
The ventral pathway (“what” pathway) involves the V4 area in form and color vision; damage leads to visual agnosia, prosopagnosia, cerebral color blindness, and topographic agnosia. The dorsal pathway (“where” pathway) involves the V5/MT area in spatial location and motion vision; damage leads to spatial perception deficits. Higher-order visual cortical areas are classified into 10 regions: V1 to V8, V3A, V3B, V7, MT+, and LO.
Regarding the effect on the optic nerve, a pathway has been shown in which hypoxia increases the endoplasmic reticulum stress marker CHOP → increased expression of GFAP in the retina and optic nerve → death of oligodendrocytes → optic atrophy.
QWhy is the visual cortex particularly vulnerable to hypoxia?
A
There are two factors. First, the primary visual cortex receives blood supply from the terminal branches of the posterior cerebral artery, making it prone to hypoperfusion during systemic hypotension. Second, the granular cells of the primary visual cortex have lower tolerance to hypoxia compared to other regions.
7. Latest Research and Future Perspectives (Research-stage Reports)
The American Heart Association (AHA) recommends that neurological prognosis prediction for comatose patients after cardiac arrest should be performed at least 72 hours after ROSC (return of spontaneous circulation)5). In cases where TTM (targeted temperature management) and sedation are used, observation for at least one week after completion of TTM/cessation of sedation is recommended. Prognostic uncertainty may persist for days to weeks to months, and attention should be paid to delayed recovery.
Diagnostic Significance of Postischemic Hyperperfusion
Postischemic hyperperfusion (luxury perfusion) can be detected on CT perfusion imaging and may be beneficial as a compensatory mechanism. However, excessive hyperperfusion can be a precursor to reperfusion injury or hemorrhagic transformation 5). Delayed hyperperfusion requires particular attention. Systematic evaluation of CT perfusion parameters (CBF, CBV, MTT, TTP) has been shown to contribute to acute-phase management.
Visual stimulation programs and stem cell therapy have been proposed, but sufficient evidence is currently lacking. Advances in preterm infant care and HIE management may reduce the incidence of CVI in the future.
DTHL typically results in complete or near-complete recovery with appropriate supportive care, but misdiagnosis as other white matter diseases is a concern. It differs from multiple sclerosis, osmotic demyelination syndrome, and progressive multifocal leukoencephalopathy in clinical, imaging, and pathological features. The clinical course (presence of a lucid interval) and history of a hypoxic event are key to differentiation 4).
Chachkhiani et al. (2021) reported a case of a 46-year-old man who developed DTHL after opioid overdose 4). He was discharged 8 days after the hypoxic event → a 19-day lucid interval → readmitted on Day 27 with mutism and psychomotor slowing → MRI showed diffuse white matter hyperintensity (sparing U-fibers, corpus callosum, brainstem, and cerebellum) → methylprednisolone 1000 mg IV for 5 days + amantadine 100 mg twice daily → discharged on Day 48 → nearly normal by Day 62 → MRI white matter hyperintensity nearly resolved by Day 138.
Further research is needed on the dosage and indications of amantadine (level 1a evidence in TBI patients) and beta-blockers (class 1b recommendation) for ABI patients. Careful use of antipsychotics in brain injury patients is required, and establishing protocols for alternative medications remains a challenge 6).
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Abdelrehim A, Landau D, Gaukler C, Brundavanam H. Interdisciplinary approach in post-cardiac arrest anoxic brain injury with unconfirmed brain death. BMC Palliat Care. 2025;24:251.
Ghumman GM, Kumar A. BRASH Syndrome Leading to Cardiac Arrest and Diffuse Anoxic Brain Injury: An Underdiagnosed Entity. Cureus. 2021;13(10):e18628.
Chachkhiani D, Chimakurthy AK, Verdecie O, Goyne CT, Mader EC Jr. Delayed Toxic-Hypoxic Leukoencephalopathy As Sequela of Opioid Overdose and Cerebral Hypoxia-Ischemia. Cureus. 2021;13(12):e20271.
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