Beneath the tip of the COVID-19 iceberg

To date, COVID-19 has infected more than 160 million people and caused more than 3 million deaths across the globe. Although most patients predominantly present with respiratory illness, researchers uncovered evidence that COVID-19 is a multisystemic disease, including renal failure, cardiac dysfunction, and various neurological manifestations (1). Neurologic complications are common and present to a higher extent in severe COVID-19 patients. This article compiles an overview of reported links between COVID-19 and neurological symptoms and discusses the role of neuroimaging in the detection and management thereof.

Neuro-clinical Manifestations

Early reports from Wuhan, China, revealed that neurological complications in COVID-19 are frequent, occurring in more than 30% of hospitalized patients, which were confirmed in recent systematic reviews  (2). Neurological complications included headaches, dizziness, seizures, dysgeusia, anosmia, dysphagia, muscle pain, and impaired levels of consciousness (2,3). In an effort to determine the neurological impact of COVID-19, researchers compiled these findings from COVID-19 patients across the globe. 

Many neurological symptoms occur early after infection, even in the absence of pulmonary symptoms, indicating that the virus might directly affect the central nervous system as well as the peripheral nervous system (4,5). Furthermore, recent systematic reviews from neuroimaging findings among patients with COVID-19 indicated life-threatening complications such as encephalopathy and cerebrovascular abnormalities (mostly ischemic but also hemorrhagic) in 27-37% of the patients (6-9). 

It has also been reported that SARS-CoV-2 might trigger hyperstimulation of the immune system, potentially leading to encephalitis and acute disseminated encephalomyelitis (ADEM)-like cases as well as the exacerbation of demyelinating disease and nonspecific, but likely chronic, white matter disease (8-10). Furthermore, it needs to be determined whether the incidence of Guillain-Barré syndrome is increased in COVID-19 patients (8,10). Currently, it is unclear whether these complications are arising because of critical illness or whether SARS-CoV-2 is directly invading the central nervous system (11,12).

Stroke, COVID’s deadly payload 

Notably, stroke is one of the most common neuroimaging findings in patients with COVID-19  (13, 17). In this context, it has been demonstrated that the mortality of hospitalized COVID-19 patients who presented neuroimaging findings for acute stroke is 50% (13). (Figure 1)

Figure. 1. Acute or subacute infarct in patients with COVID-19. (A) A 62-year-old man with COVID-19, intubated for acute hypoxic respiratory failure, initially presented with left MCA syndrome. Noncontrast head CT showed a dense left MCA sign suggesting a left MCA occlusion, later confirmed on CT angiography and catheter angiography (not shown here). (B) A 77-year-old woman with COVID-19 presented with left-sided weakness. Noncontrast CT showed an acute/subacute right MCA territory infarct. (C) A 63-year-old COVID-19 patient with ataxia. Brain MRI revealed a patchy acute infarct in the left cerebellar hemisphere. (D) A 78-year-old man with COVID-19 presented following an unwitnessed fall. Brain MRI showed left more than right cingulate gyrus and callosal body acute infarct. (Figure from Radmanesh et al. 2020)

Recent publications repeatedly reported the possibility that COVID-19 might increase the risk of ischemic stroke, similar to other respiratory tract infections (14,15). Approximately 5% of hospitalized COVID-19 patients suffer from stroke, with over 80% of those cases being ischemic. These COVID-19 patients exhibited a higher mortality rate compared to stroke patients without COVID-19 infection (16). According to a retrospective cohort study conducted in 1,916 adults with confirmed COVID-19, patients with COVID-19 are at 8.1 times higher risk of ischemic stroke than patients with other viral respiratory infections like influenza (14).

On the lookout for long-haulers

Though only accounting for 1% of COVID-19 patients, most research has focussed on the acute phase of COVID-19 in hospitalized patients. Emerging data suggests that a significant proportion of COVID-19 patients experience persistent symptoms of five main types: chest pain and cough, difficulty breathing and cough, anxiety and irregular heartbeat, abdominal pain and nausea, and lower back pain and joint pain (18). Such patients presenting with ‘long COVID-19’ are often referred to as ‘long-haulers’. 

Recent evidence suggests that the majority of hospitalized patients (19), and 27% of all COVID-19 patients (18), will become long-haulers. What’s more, one out of three patients suffering from long COVID-19 did not present with initial symptoms (18). This urges the need to examine the long-term outcomes of “mild” COVID-19 infections to better understand both the pathophysiology and the public health impact of COVID-19. 

Based on data from more than 200.000 patients diagnosed with COVID-19, over 34% of them suffered from neurological or psychiatric outcomes in the following 6 months, emphasizing the need to monitor these carefully. This risk increased with the severity of COVID-19 (increasing up to 46% in patients admitted to an intensive therapy unit) (23). Amongst others, concerns are arising around the potential increased risk of developing dementia following SARS-CoV-2 infection, because of frequently observed brain inflammation and blood vessel damage (20). To investigate such potential long-term complications, more than 40.000 patients aged 50 and above, will be tracked globally in a study performed by The Alzheimer's Association (20).

Neuroimaging to the rescue?

Considering the incidence of neurological symptoms in COVID-19 patients, neuroimaging can play an important role in the diagnosis and treatment planning. Magnetic resonance imaging (MRI) might be useful to confirm rare cases of encephalitis and ADEM. A recent case report states that in suspected encephalitis cases, a combination of brain MRI, EEG monitoring, and lumbar puncture can be performed to rule out encephalitis (21). Although encephalopathies have been frequently reported in COVID-19 patients, evidence of distinct brain volume change patterns is lacking. 

The management and treatment of complex procedures such as stroke during COVID-19 create several challenges: 

1. The ability to conduct neurological and neuroimaging exams is limited by patient isolation.
2. There is a need for strict precautions.
3. Disinfection and intubated patients are difficult to transport. 

Next to this, potential complications associated with COVID-19, such as acute renal injury, are essential factors when considering CT angiography and perfusion to triage for mechanical thrombectomy. A detailed report by an international panel of experts regarding the management of stroke in COVID-19 patients was recently published (16). The report indicates that with the high rate of renal insufficiency in COVID-19, CT angiography and perfusion images should be avoided if neuro-interventional procedures are not possible due to poor patient conditions. 

Based on the incidence of neurological symptoms, other complications, and the risk of contamination, there is no indication to routinely apply neuroimaging in every COVID-19 patient. However, a recent study identified a correlation between CT lung severity scores and the occurrence of acute neuro-related abnormalities. (22) On average, lung severity scores of patients with neurologic symptoms and acute abnormalities on neuroimaging were significantly higher than those without. Similar to previous studies, neuroimaging features were predominantly acute ischemic infarcts (28%), intracranial hemorrhages (10%), and white matter disease (36%). Ground glass opacities and consolidations were the most dominant CT chest findings and should therefore be objectively assessed. (Figure 2) Overall, these findings indicate that assessing the CT severity score can be a potential predictive tool for patient management and could prompt the use of neuroimaging in patients with severe lung involvement.

Figure 2. LEFT: Acute leukoencephalopathy. A 48-year-old man without a history of seizures presented with convulsions and altered mental status. Extensive and confluent symmetric deep and subcortical white matter FLAIR hyperintensities in the bilateral centra semiovale (A) and periventricular frontal and parietal regions (B) with associated mild restricted diffusion on DWI/ADC images, most prominent in the centra semiovale (C and D) and peritrigonal regions (E and F). No associated enhancement or microbleed was seen on the T1 post-contrast and SWI (not shown). Coronal MPR and axial non-contrast images in lung windows demonstrate mixed ground-glass and consolidative opacities in all lobes with a lower lung and peripheral predominance (G–J). The CT lung severity score was 16 (right upper lobe, right lower lobe, left upper lobe, left lower lobe, 25%–49%, and right middle lobe 50%–75%). The chest CT scan was obtained 8 days after the initial onset of respiratory symptoms. (Figure from Mahammedi et al. 2021)  RIGHT: Automated quantification of lung involvement provided by icolung. 

Melissa Verheijen

About icolung

icolung is the first CE-labelled CT solution to arise from a COVID-19 collaboration, icovid.ai .[LINK TO http://icovid.ai/ ] By quantifying lung involvement in COVID-19 patients, icolung helps with the assessment of the pulmonary status and consequential triage and resource allocation. The newest icolung version, including image classification, can help differentiate COVID-19 from similar diseases as seen on CT and assist in screening COVID-19. Learn more about our icolung solution, currently offered pro bono in Europe, here.

About icobrain portfolio and icobrain cva

The icobrain portfolio leverages artificial intelligence to provide measurably better volumetric quantification of brain structures on MRI and CT in patients with neurological conditions. Its automated and robust quantification allows for the precise and fast assessment of brain abnormalities and brain volume change patterns in individual patients. Learn more about the icobrain portfolio here.

icobrain cva is an automated CE-marked and FDA-cleared software solution for the quantitative assessment of tissue perfusion on CT. Learn more about icobrain cva here.

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