Neuroimaging Patterns in Patients with COVID-19-Associated Neurological Complications: A Review
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.314531
Source of Support: None, Conflict of Interest: None
Keywords: Acute disseminated encephalomyelitis, encephalitis, encephalopathy, leukoencephalopathy, SARS-COV-2Key Message: A variety of neuroimaging abnormalities in COVID-19 have been described. Neuroimaging abnormalities are often vascular in origin. None of the neuroimaging abnormality is specific for COVID-19. Hypoxic-ischemic encephalopathy, on neuroimaging, manifests as diffuse leukoencephalopathy, widespread microbleeds and subcortical white matter hyperintensities.
COVID-19 is caused by a novel coronavirus named severe acute respiratory syndrome corona virus-2 (SARS-COV-2). The SARS-COV-2 virus is a positive-stranded RNA virus that belongs to the family Coronaviridae. World Health Organization reports that, currently, there are more than 36.7 million confirmed COVID-19 cases world-wide. So far, across the world, 1064838 COVID-19 related deaths have been reported. COVID-19 pandemic is active in 235 countries. Approximately 20% of COVID-19 patients have severe disease and 5% of them eventually become critically ill. A critical illness is characterized by dysfunction of multiple body organs including, respiratory functions, neurological dysfunction, cardiac dysfunction, shock, renal failure, liver damage, and metabolic derangements. The mortality is higher in older age groups and in those with comorbidities.
Increasing number of reports are now demonstrating neuroimaging abnormalities in COVID-19-associated encephalopathy/encephalitis.,,,,,,,,,,,,,,,,,,,,, [Table 1] and [Table 2] In this article, we have reviewed the neuroimaging pattern, diagnostic utility, and possible pathogenic mechanisms of COVID-19-associated neuroimaging abnormalities.
Analysis of TriNetX database comprising of data of 40,469 COVID-19 patients noted that 9086 (22.5%) patients had some kind of neuropsychiatric complications. The frequently encountered neurological complications were headache, sleep disorders, encephalopathy, myalgia, pain, loss of taste and smell, cerebrovascular disease, dizziness, extrapyramidal and movement disorders, seizures, polyneuropathy, and radiculopathy and plexopathy. Mao and colleagues, in a retrospective study from China, noted neurological complications in 36.4% (78/214) of indoor patients with laboratory-confirmed COVID-19. Among severe central nervous system complications, altered consciousness was noted in 16 (7.5%) patients. Stroke was the next serious complication noted in 6 (2.8%) patients. Five patients had ischemic stroke and one had intracerebral hemorrhage. Patients with stroke had severe COVID-19. Of note, neurological complications are generally more common in older age groups and patients with pre-existing comorbidities.
Search strategy for Neuroimaging patterns in COVID-19
For this review, we searched all publications regarding neuroimaging aspects of COVID-19-associated encephalitis and encephalopathy. We searched PubMed, Google Scholar, Scopus, preprint databases (medRxiv and bioRxiv). We reviewed all kinds of published articles including case reports, case series, cohort studies, and review articles. The search terms used were “COVID -19 and encephalitis, encephalopathy, neuroimaging or neuroradiology” and “SARS-CoV-2 and encephalitis, encephalopathy, neuroimaging or neuroradiology”. Relevant full-text articles from journals' websites were reviewed. We analyzed the neuroimaging characteristics of COVID-19-associated neurological complications. The last search was performed on September 27, 2020.
Large vessel occlusion
Many reports have described cases of large cerebral vessel occlusion in COVID-19 patients. For example, in a retrospective study, conducted in 56 hospitals of China and enrolled 917 confirmed COVID-19 patients, revealed neurological complications in 32 (3.5%) patients. Altered consciousness (n = 25) and stroke (n = 10) were the most frequent neurological complications. The majority had either infarct in the region of a large cerebral vessel territory or the water-shed region., Similar observations were recorded in a large study that included data from Europe and America. The study focussed on large cerebral vessel occlusions. In this study 88 (1.3%) patients with acute ischemic strokes were included, 66 patients had a large cerebral vessel occlusion. In majority, the middle cerebral artery and internal carotid artery were occluded. Oxley described 5 young patients of COVID-19-associated ischemic strokes; in 4 patients, infarcts were in the territory of the middle cerebral artery and internal carotid artery. In one patient, posterior cerebral circulation was involved.
Infrequently, infarcts in multiple brain territory has been described. Guillan and colleagues described a 67-year-old COVID-19 affected man, who presented with altered mental status and acute cortical vision loss. MRI brain noted infarcts in the territories of the middle cerebral artery, the left posterior cerebral artery, and the right superior cerebellar artery. Large vessel occlusion strokes in patients with COVID-19 is associated with severe disease, multivessel involvement and enhanced mortality than patients without COVID-19.
Cerebral venous thrombosis
Neuroimaging in patients with cerebral venous thrombosis demonstrates brain infarction, edema, or hemorrhage and the thrombosed sinus. Cerebral infarct does not correspond to any arterial territory and has hemorrhagic components. Lately, many reports have described cerebral venous thrombosis in COVID-19. In COVID-19 patients, both superficial and deep cerebral venous systems are likely to be affected. In COVID-19-associated cerebral venous thrombosis, multiple superficial venous sinuses (superior sagittal sinus, lateral sinus, and sigmoid sinus) are typically involved, however, thrombosis of the superior sagittal sinus involvement is the more frequent.,
Thrombosis affecting the deep venous system (straight sinus, internal cerebral veins, vein of Galen, the vein of Rosenthal) can present with unusual neuroimaging findings. Chougar and colleagues described COVID-19 patients who had deep cerebral vein thrombosis with hemorrhagic venous infarction with several unusual imaging features. There was a large necrotic infarction in right thalamus and basal ganglion extending up to the right cerebral peduncle and the pons. There were hemorrhagic changes in the lateral ventricle too.
Cavalcanti and co-workers described neuroimaging in 3 patients with COVID-19-associated cerebral venous thrombosis. One patient had thrombosis in both the superficial and deep cerebral venous systems. Another patient had thrombosis of the straight sinus, the vein of Galen, and internal cerebral veins. In the third patient, venography demonstrated thrombosis of the deep medullary veins. These patients either had hemorrhagic infarcts and/or hydrocephalus. All patients clinically had acute encephalopathy. In two patients, chest imaging revealed characteristic ground-glass lung abnormalities.
COVID-19-associated intracerebral hemorrhage on neuroimaging resembles anticoagulant associated intracerebral hemorrhage. COVID-19-associated intracerebral hemorrhage are frequently a lobar in location. These hemorrhages are often multiple, irregular in shape, and may have intraventricular extension.,, The fluid-blood levels within the intracranial hematoma, akin to that seen in anticoagulant-associated hematoma, is a characteristic finding of COVID-19 intracranial hemorrhage [Figure 1].,
In COVID-19, heparin therapy can precipitate massive multifocal intraparenchymal hemorrhage with intraventricular extension and can lead to rapid deterioration and death. In a retrospective study of 33 COVID-19 patients with neuroimaging-documented intracerebral hemorrhage, five catastrophic large hemorrhages with herniation were observed while in others hemorrhages were small. Ghani and colleagues described three cases of intracranial hemorrhage in critically ill patients because of anticoagulation therapy.
Nicholson and co-workers described the neuroimaging pattern in 4 patients with encephalopathy. MRI demonstrated varied picture like subcortical or cortical petechial multiple hemorrhages, subarachnoid bleed, parenchymal hematoma with fluid level, and intraventricular hemorrhage. Susceptibility-weighted imaging showed much more extensive abnormality consistent with thrombotic microangiopathy. All 4 patients had markedly elevated D-dimer levels. In a retrospective cohort study, authors noted that anticoagulation use was associated with a five-fold increased risk of intracerebral hemorrhage and COVID-19-associated intracerebral hemorrhage , in turn, was associated with increased mortality.
Neuropathological examination of the brain corroborated the frequent cerebrovascular complications in COVID-19. In an autopsy study, the most notable finding was widespread microthrombi and acute infarction. Acute parenchymal micro-hemorrhages, especially within the necrotic infarct were noted. Hemorrhagic transformation of infarct indicated vessel damage and reperfusion injury.
Small vessel disease
Cerebral small vessel disease refers to involvement of vessels of small caliber, including smaller arteries, arterioles, capillaries, and small veins. Small vessel disease is, otherwise, common in aging adults. Small subcortical infarcts, lacunar infarcts, cerebral microbleeds, cortical microinfarcts, and white matter hyperintensity of presumed vascular origin represent the major neuroimaging markers of small vessel disease [Figure 2].
Coolen and co-workers performed an MRI evaluation in 19 critically ill patients of COVID-19 immediately after death (within 24 hours). MRI abnormalities were observed in 4 patients. Brain MRI abnormalities were consistent with cerebral small vessel disease. Abnormalities were diffuse microbleeds and macrobleeds, and marked deep white matter changes. In one patient imaging abnormality was consistent with posterior reversible encephalopathy syndrome.
Hyperintense T2/FLAIR white matter abnormalities a common neuroimaging abnormality in COVID-19-associated encephalopathy. These white matter hyperintensities generally indicate cerebral microangiopathy. Damage to the deep perforating cerebral vessels is held responsible for white matter abnormalities of the brain. The deep perforating cerebral vessels lack anastomotic system, hence white matter becomes vulnerable to cerebral ischemia.
Leukoencephalopathy is a term that refers to an extensive subcortical white-matter tract involvement. In COVID-19 subcortical white-matter is particularly vulnerable because hypoxic injury inflicts additional damage to the deep penetrating cerebral vessels.,, In a series described by Radmanesh and co-workers, out of 11 patients that were evaluated, 10 had leukoencephalopathy. T2/FLAIR MRI hyperintense lesions were symmetric and confluent and involved bilateral deep and subcortical white matter. These lesions also demonstrated mild restricted diffusion. All 11 patients of this series were critically ill and were on mechanical ventilation [Figure 2].
Histopathology of the brain of patients, who died of critical illness, demonstrated hypoxic damage of cerebrum and cerebellum. Loss of neurons was recorded in the cerebral cortex, hippocampus, and cerebellar Purkinje cell layer. However, there was no evidence of the presence of cerebral thrombi or vasculitis. Damage to cerebral neurons possibly resulted in diffuse or focal cerebral leukoencephalopathy.
White matter microbleeds are common neuroimaging abnormalities in patients with COVID-19-associated encephalopathy. White matter microbleeds are small, bilateral, symmetrically distributed, round foci of low signal intensity with the predominant location in juxta-cortical white matter and corpus callosum. White matter microbleeds are best visualized in magnetic resonance imaging gradient echo (GRE) or susceptibility-weighted angiography sequences. White matter microbleeds are considered indicative of cerebral microangiopathy [Table 1] and [Figure 2].,,
The presence of extensive white matter microbleeds has also been demonstrated on autopsy. von Weyhern and colleagues performed autopsy in six patients, who died from severe COVID-19. In younger patients, autopsy revealed the presence of diffuse cerebral petechial hemorrhage. Besides, there were extensive involvement of brain, meninges, and brainstem as well.
Acute necrotizing encephalitis
Acute necrotizing encephalopathy is unusual devastating complication described in many viral infections. Acute necrotizing encephalopathy has also been described in severe COVID-19. Characteristically, in acute necrotizing encephalopathy imaging shows symmetric, multifocal lesions with predominant bilateral thalamic and brainstem involvement. Other commonly involved structures are brain stem, cerebral white matter, and cerebellum. T2/FLAIR images reveal hyperintense lesions with hemorrhage. Postcontrast images may show a ring enhancement. Intense inflammatory reaction resulting in cytokine storm is held responsible for acute necrotizing encephalopathy in COVID-19., Histopathology of autopsied affected brain tissue may reveal the perivascular lymphocytic infiltration and neuronal necrosis. Virhammar and colleagues, in a similar case, demonstrated SARS-CoV-2 viral RNA in CSF.
Delamarre and colleagues in a recently published case report demonstrated that clinical syndrome and neuroimaging lesions of acute necrotizing encephalopathy showed significant improvement following methylprednisolone and intravenous immunoglobulin treatment.
Acute disseminated encephalomyelitis
There are reports where a neuroimaging picture like acute disseminated encephalomyelitis (ADEM) has been described following the SARS-COV-2 infection. These patients clinically present with acute encephalopathy and imaging lesions are characterized by bilateral, asymmetrically distributed white matter T2/FLAIR hyperintensity. Patients of COVID-19-associated ADEM show improvement following methylprednisolone therapy [Figure 3].,
An autopsy study confirmed demyelinating changes in the brain, in a patient who died of COVID-19. The authors demonstrated hemorrhagic white matter demyelinating lesions throughout the brain. Histopathology revealed scattered clusters of macrophages, associated axonal injury, and a perivascular ADEM-like change in the subcortical white matter.
Cortical gray matter hyperintensity
In COVID-19-associated encephalitis, neuroimaging demonstrated orbitofrontal cortex and hippocampal and mesial temporal hyperintensity akin to that seen in autoimmune encephalitis.,, Moriguchi and colleagues described a case of COVID-19-associated encephalitis; FLAIR images, in this case, demonstrated hyperintense signal abnormalities in the right mesial temporal lobe and hippocampus. Besides, DWI images demonstrated hyperintensity along the wall of the inferior horn of the right lateral ventricle. The CSF in this patient was positive for the SARS-CoV-2. In another similar case, Efe and colleagues described an unusual case of COVID-19-associated encephalitis. MRI demonstrated marked T2/FLAIR hyperintensity in the left temporal lobe. The patient had uncontrolled seizures so anterior temporal lobectomy was done. Histopathological examination of resected brain tissue demonstrated inflammatory changes consistent with encephalitis. Human brain gene-expression recently suggested that the hypothalamus and other structures of limbic system express ACE 2 receptor and transmembrane proteinase, serine 2. Both these receptors mediate SARS-CoV-2 entry in neurons.
Cytotoxic lesions of the corpus callosum
Rasmussen and colleagues described dominant corpus callosum involvement in a 66-year-old patient with multiple comorbidities. MRI signal changes were dominantly present in the splenium. Patient was having encephalopathy and was admitted in intensive care unit. Cytokine storm was considered responsible for clinical manifestations and imaging changes.
Hayashi and colleagues described a 75-year-old man with COVID-19-associated encephalopathy. MRI of the brain, on DWI sequences, revealed a reversible abnormal hyperintensity in the splenium of corpus callosum.
Splenium signal changes were noted in four severely ill pediatric patients having the pediatric multisystem inflammatory syndrome. All these patients had encephalopathy. Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to severe disease characterized by dysregulated immune response and extensive tissue damage.
Cortical laminar lesions
Cortical laminar necrosis is a condition that indicates a state of hypoxia and brain energy depletion. Anzalone and colleagues reported four cases with COVID-19-associated subacute encephalopathy, neuroimaging in these patients revealed multiple areas of T2/FLAIR cortical laminar hyperintensity in the parietal, occipital and frontal lobes. In cortical laminar necrosis, T2/FLAIR hyperintensity followed the gyral pattern. After one month, all lesions had completely disappeared.
Posterior reversible encephalopathy syndrome
Posterior reversible encephalopathy syndrome (PRES) refers to a disorder with reversible posterior cortical white matter T2/FLAIR hyperintensity. MRI lesions predominantly involve bilateral parieto-occipital regions. In COVID-19-associated PRES, hemorrhage in demyelinating lesions are common., PRES in COVID-19 possibly caused because of blood pressure fluctuations indicating that manifestations of hypertensive encephalopathy may occur at lower blood pressure thresholds due to endothelial dysfunction [Figure 4].,,
Diffuse cerebral oedema
Fulminant diffuse cerebral oedema with chinked ventricles, effaced sulci, obliterated basal cisterns and herniated brain has been described in a severely ill patient of COVID-19.
In many patients, contrast-enhanced MRI revealed cerebral and spinal leptomeningeal enhancement. The precise reason for meningeal enhancement may be a not clear but either a direct viral meningeal invasion or an autoimmune meningeal inflammation may be a likely pathogenic mechanism.
Olfactory tract changes
Anosmia is a common symptom of COVID-19. Frequently, anosmia is a heralding manifestation. Smell sensations are transmitted to the limbic system of the brain via olfactory nerve and olfactory bulb across the cribriform plate. Neuroimaging in a patient with COVID-19 and anosmia revealed a cortical hyperintensity in the right gyrus rectus in the olfactory bulbs. In another patient, Laurendon and colleagues demonstrated olfactory bulb edema. Olfactory clefts showed mild hyperintensity. Rest of the olfactory pathway was normal.
Miller Fisher syndrome
Miller Fisher syndrome is a post-infectious autoimmune disorder. Lately, several cases of Miller Fisher syndrome have been described in association with COVID-19. Miller Fisher syndrome is clinically characterized by ophthalmoplegia, ataxia, and areflexia. In a recent report, neuroimaging demonstrated enlargement, T2 hyperintensity, and enhancement of third cranial nerve throughout its course from the cavernous sinus to the orbit.
In many reports of isolated cases, imaging abnormalities of the spinal cord have been described. In COVID-19, spinal cord can be affected by several pathogenic processes viz., acute inflammatory transverse myelitis, acute disseminated encephalomyelitis, and acute flaccid myelitis [Figure 3]. MRI of spinal cord in COVID-19-associated myelitis often demonstrates longitudinally extensive transverse myelitis. Acute flaccid myelitis is a polio-like illness, that is characterized by acute flaccid paraparesis and long T2/FLAIR hyperintensity of the gray matter of the spinal cord.,,
Incidental MRI findings
Imaging of spine and CT angiography performed for non-pulmonary indications may occasionally demonstrate unsuspected lung findings, consistent with the COVID-19. Now experts recommend that routine lung imaging should be included the neuroimaging protocol.
Incidental gadolinium enhancement of bilateral abducens and right ophthalmic veins were noticed along with bilateral facial nerve enhancement in a patient with bifacial weakness in a variant of Guillain-Barrè syndrome. Another case presenting with ophthalmoparesis demonstrated enhancement of multiple cranial nerves.
Siddiqui and co-workers noted that assessment of apical portion of lungs, while performing carotid computed tomography angiography in patients of stroke, can help in detecting unsuspected COVID-19. Apical ground-glass shadows were observed in 22.2% (50/225) patients.
The sudden unexpected massive influx of proinflammatory cytokines is the hallmark feature of severe COVID-19 infection. High plasma levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β have been observed in critically ill patients leading to vascular hyperpermeability, multiorgan failure, and death. Cytokine storm disrupts blood-brain barrier leading to brain injury and neuroimaging abnormalities.,
Cytokine storms can induce coagulopathy. COVID-19-associated coagulopathy is often held responsible for cerebral vascular complications, like large vessel occlusion, cerebral venous thrombosis, and intracerebral hemorrhage. Elevated levels of fibrinogen, D-dimer, and C-reactive protein are common in patients with COVID-19 related strokes.,
The characteristic feature of COVID-19-associated coagulopathy is markedly elevated D-dimer and fibrin degradation product levels. A D-dimer level of more than 1000 ng/mL is a strong predictor of death. In COVID-19, prothrombin time (PT) is mildly prolonged. while the activated partial thromboplastin time (aPTT) is either normal or less. Platelet count usually remains unaffected. In severe cases, the course of illness may be complicated by disseminated intravascular coagulation (DIC). DIC is characterized by thrombocytopenia, prolonged prothrombin time, and increased D-dimer. DIC is generally associated with multiple organ dysfunction. Zayet and colleagues described 2 cases of ischemic stroke with infarcts in multiple arterial territories. where laboratory investigations demonstrated increased antiphospholipid antibodies in blood.
Vascular injury, in the form of endotheliitis, endothelial cell damage, and dysfunction is a key element in the pathogenesis of SARS-CoV-2 induced organ injury. Endothelial cells profusely express the ACE2 receptor, the target receptor for SARS-CoV-2 cell entry. Endothelial injury damage facilitates the cerebral vascular thrombosis and injury to the blood-brain barrier, resulting in either brain edema or microhemorrhages.
The SARS-CoV-2 has capability to infect brain cells, especially the brain microvascular endothelial cells of the blood–brain barrier. Blood–brain barrier damage by SARS-CoV-2 usually occurs in combination with neuronal cell damage, edema, glial proliferation, and inflammatory cell infiltration of the vascular walls and neuronal tissue. In a recent investigation, high-tites of anti-SARS-CoV-2 antibodies were observed in the CSF of patients with encephalopathy indicating blood–brain barrier damage as well as intrathecal synthesis of antiviral antibodies. A disrupted blood–brain barrier allows the entry of inflammatory mediators inside the brain with potential to harm the brain by process of neuroinflammation and neuronal cell damage.
In COVID-19, majority of neurological complications happened in older age groups or the elderly with various comorbidities like diabetes mellitus and chronic hypertension. Cerebral microvasculature (both arterioles and venules) in the elderly population is commonly associated with cerebral amyloid angiopathy leading to microangiopathy. Hypoxic brain damage in severe COVID-19 can further damage small vessels resulting in white matter microhemorrhages or periventricular neuronal demyelination. Prolonged hypoxia results in widespread small vessel thrombosis and tissue damage.,
The SARS-CoV-2 can invade the brain through several mechanisms. ACE2 receptors in humans are expressed in the lung, kidney, intestine, and vascular endothelium. The SARS-CoV-2 can reach the brain either transsynaptically or through blood vessels. Transsynaptically virus can travel to the brain via the olfactory nerve across the cribriform plate. Parts of the limbic system, basal ganglia and the midbrain have a direct neuronal link with the olfactory nerve. In many cases, imaging abnormalities in the hypothalamus and other related structures have also been noted. Viruses can also spread to the brain via a hematogenous route. The hematogenous spread can occur through infected endothelial cells or migration of infected leukocytes across the blood-brain barrier.
Post-infectious immune-mediated complications like ADEM are considered to be caused by an autoimmune mechanism. Molecular mimicry between neuronal and viral proteins directs an inadvertent immune reaction towards host cells.
The ε2/ε4 alleles of the apolipoprotein E gene, because of greater amyloid deposition, is one of the potential risk factors for recurrent intracerebral hemorrhage. A recent investigation noted that apolipoprotein e4e4 allele increases risks of severe COVID-19 infection.
Neuroimaging findings in patients having COVID-19-associated neurological complications are now increasingly being reported. Neuroimaging abnormalities are common in old age and patients with comorbidities. None of the neuroimaging abnormality is peculiar for COVID-19 encephalopathy. Periventricular white-matter MR hyperintensity, microbleeds, arterial and venous infarcts, and hemorrhages are apparently distinctive abnormalities.
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There are no conflicts of interest.
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[Table 1], [Table 2]