INTRODUCTION
There is growing evidence of neurological involvement associated with SARS-CoV-2 infection[1],[2]. Immune-mediated neurological manifestations have been reported, including Guillain-Barré
and Miller-Fisher syndromes, polyneuritis cranialis and acute demyelinating encephalomyelitis[1],[2],[3],[4]. In addition, central nervous system (CNS) lesions and brain magnetic resonance
imaging (MRI) abnormalities in COVID-19 patients are being increasingly recognized.
Arterial occlusion and venous thrombosis related to a prothrombotic state have been
reported[1],[2]. Small case series have also described cortical signal abnormalities on fluid-attenuated
inversion recovery (FLAIR) images, cortical diffusion restriction, leptomeningeal
enhancement, cortical blooming artifact, and diffuse white matter abnormalities[5],[6].
We describe two patients that presented white matter lesions, suggestive of an inflammatory-demyelinating
process associated with a prolonged hypoactive encephalopathy related to severe COVID-19
infection and long intensive care unit (ICU) stay.
PATIENT 1
A 59-year-old woman with controlled mild arterial hypertension was admitted with a
three-day history of cough, fever and dyspnea, progressing to respiratory failure
requiring mechanical ventilation. Oropharyngeal swab polymerase chain reaction (PCR)
was positive for SARS-CoV-2, and negative for influenza (H1N1). The patient received
hydroxychloroquine and broad-spectrum antibiotics for ventilator-associated pneumonia.
After sedation discontinuation, the patient remained in an unconscious state. Neurological
evaluation disclosed a patient in coma with asymmetric flexor motor responses (left
more than right). Pupils were symmetric and reactive. Extraocular movements were normal.
Deep tendon reflexes were hypoactive, with bilateral extensor plantar responses.
A non-contrast head computed tomography (CT) and magnetic resonance imaging (MRI)
are shown in [Figure 1]. Cerebrospinal fluid (CSF) analysis was normal, oligoclonal bands and cultures were
negative. PCR for SARS-CoV-2 in the CSF was negative. Electroencephalography (EEG)
revealed diffuse slowing, without epileptiform discharges.
Figure 1 Multiple bilateral focal areas of signal abnormalities in the cerebral and cerebellar
white matter, including corpus callosum (not shown). Axial computed tomography (CT)
shows round foci of hypoattenuation in the centrum semiovale bilaterally (a), that
also demonstrate high signal on diffusion-weighted imaging (DWI) (b) with areas of
restricted diffusion on apparent diffusion coefficient (ADC) (c), and hyperintensity
on axial T2-weighted images (d). Some of these lesions appear to have a perivenular
dissemination on sagittal T2-weighted (e,f) and coronal fluid-attenuated inversion
recovery (FLAIR) (g,h) images. There appears to be a “target” sign, with a low signal
dot in the center of the lesion. There are also some lesions in the cerebellar white
matter (e,h) and globus pallidus.
The patient's clinical condition worsened and she died of systemic complications associated
with COVID-19.
PATIENT 2
A 41-year-old man presented to the emergency service with a six-day history of fever,
rhinorrhea, progressive dyspnea, and was intubated due to respiratory failure. Medical
history was remarkable for hypertension, diabetes, obesity and smoking. SARS-CoV-2
PCR was positive in tracheal aspirate specimens. After respiratory improvement, sedation
and neuromuscular blocking, agents were weaned. Prolonged difficulty in awakening
was attributed to acute renal failure. Renal replacement therapy was instituted. After
ICU discharge (day 14), a neurology consult was required due to persistent decreased
level of consciousness and four-limb weakness.
On neurological evaluation, the patient was awake, with spontaneous eye opening, but
displayed blunted affect and poor verbal interaction with the examiner. Motor examination
showed decreased spontaneous movement of the four limbs, with normal withdrawal response
to pain, preserved deep tendon reflexes, and bilateral flexor plantar responses. Pupils
were reactive to light, extraocular motor movements were normal, and the face was
symmetrical.
Brain CT and MRI are depicted in [Figure 2]. Spinal cord MRI did not show abnormalities. CSF was normal, with negative microbiologic
analysis and absent oligoclonal bands. CSF PCR for SARS-CoV-2 was negative. EEG showed
diffuse slowing, without epileptiform abnormalities. Nerve conduction and needle studies
showed a moderate subacute sensorimotor polyneuropathy.
Figure 2 Focal lesions located in the centrum semiovale, bilaterally (a,b,c,d,e), right thalamus
(f,h), globus pallidus bilaterally (g), and anterior limb of internal capsule (f,g,h),
characterized by hyperintensity on axial fluid-attenuated inversion recovery (FLAIR)
images (d,e,f,g), high signal on diffusion-weighted imaging (DWI) (c) and apparent
diffusion coefficient (ADC) (b), representing diffusion facilitation. Noncontrast
CT demonstrates hypoattenuating areas (a). Only one lesion, located in the anterior
limb of the internal capsule, was hypointense on susceptibility-weighted angiography
(SWAN) (h), suggestive of a hemorrhagic focus. Another lesion in the left centrum
semiovale shows perivascular topography (c,d).
After two weeks, mental status evaluation disclosed a fully alert and cooperative
patient, with mild attentional and executive dysfunction.
DISCUSSION
We describe two cases of severe COVID-19 with prolonged ICU stay and delayed awakening
that presented with neurological impairment and bilateral multifocal white matter
lesions on MRI.
The neurotrophic potential of the coronaviruses has been widely recognized since the
original descriptions[7]. SARS-CoV-2 potential to cause neurological damage has been rapidly recognized as
the present epidemic unfolded. SARS-CoV-2 may reach the brain via bloodstream or transcribriform
route along the olfactory nerve[1],[8]. The virus invades neurons through angiotensin-converting enzyme-2 (ACE-2) receptors.
Most of SARS-CoV-2 neurological manifestations are thought to occur in late stages
of the infection, possibly associated with immune response[8].
Neurological manifestations and neuroimaging findings in our cases could be caused
by ischemic injuries, by a direct encephalitic viral effect, by toxic-metabolic insults
or by an acute demyelination process. MRI diffusion images did not display diffusion
restriction that resembles a vascular pattern, rendering ischemia unlikely. Additionally,
CSF analysis was not suggestive of an infectious process, neurological impairment
was not present in the acute phase of the infection, and neuroimaging findings were
not characteristic of classical toxic and metabolic disorders, making the first three
elicited mechanisms unlikely. The finding of bilateral periventricular relatively
asymmetrical lesions associated with deep white matter involvement is suggestive of
an acute demyelination process.
We considered both cases compatible with the diagnosis of acute disseminated encephalomyelitis
(ADEM) related to COVID-19 disease, since the clinical presentation was encephalopathy
and neuroimaging displayed multifocal white matter abnormalities. Other clinical clues
favoring this diagnosis are: prior confirmed acute viral infection, unremarkable CSF
study excluding CNS infection, negative oligoclonal bands and lack of previous history
of demyelinating diseases, such as multiple sclerosis, in both patients.
ADEM is an acute inflammatory CNS demyelinating condition precipitated by viral infection
or, more rarely, vaccination, and is characterized by encephalopathy and multifocal
neurologic deficits[9],[10]. Given the lack of specific biomarkers or confirmatory tests, the diagnosis of ADEM
is based on combined clinical and radiological features and exclusion of other possible
similar conditions[9],[10]. In children, in whom ADEM is more frequently encountered, current diagnosis criteria
require the presence of encephalopathy, multifocal CNS events, and acute MRI abnormalities[10],[11]. Specific criteria for ADEM in adults have not been established. Due to lower incidence
in adults, ADEM is less studied in this population. The largest study comparing ADEM
in different age groups showed that, in adults, disease course was more aggressive,
and outcomes were poorer than in children[12].
MRI is the preferred neuroimaging modality in patients with suspected ADEM, since
head CT can be normal or display non-diagnostic features. In these cases, brain MRI
typically displays bilateral and asymmetric T2/FLAIR hyperintensities in central and
subcortical white matter[9],[10], that may also be present in cortical gray-white matter junction, thalami, basal
ganglia, cerebellum, and brainstem. Heterogeneous findings are frequently encountered.
Up to one third of patients may present gadolinium-enhancing lesions, and up to one
third may present spinal cord involvement[9]. Restricted diffusion in diffusion-weighted imaging (DWI) sequences can be present
in acute settings, and has been associated with a more aggressive disease course[13].
ADEM has already been reported in endemic coronavirus subtypes, in previous coronavirus
outbreaks[14],[15]. In 2004, a 15-year-old boy presented cerebellar and spinal cord demyelinating lesions,
with a preceding history of upper respiratory tract illness. Coronavirus OC43 was
detected by CSF PCR and in nasopharyngeal secretions[14]. In 2015, a case report described a patient with slow awakening after prolonged
ICU stay due to MERS-CoV infection, in whom brain MRI identified bilateral multifocal
white matter lesions. The authors related those findings to ADEM, rather than to encephalitis,
due to direct viral neuroinvasion, since CSF analysis disclosed negative PCR for MERS-CoV[15].
Demyelinating lesions after viral infection can be caused by cross-reaction between
immune response and host cell components, as well as by lymphocyte and macrophage
reaction and lymphokine-mediated damage, and immune cell protease release[16]. Pro-inflammatory state in COVID-19 is associated with increased cytokines (“cytokine
storm”) that may activate glial cells, leading to demyelination[17],[18]. Additionally, viral infection can trigger the production of antibodies targeted
against glial cells[18]. In primates, murine coronavirus can acutely replicate and cause oligodendrocyte
lysis and demyelination[19].
Perivenular sleeves of demyelination associated with inflammatory infiltrates are
the hallmark of ADEM pathology[9]. Eventually, larger areas of demyelination may occur secondary to coalescence of
perivenous demyelinating lesions. Post-mortem neuropathological findings in one COVID-19
patient revealed features suggestive of combined demyelinating and vascular mechanisms.
Additionally, hemorrhagic white matter lesions, clusters of macrophages associated
with axonal injury and ADEM-like appearance were also found in subcortical white matter[20].
We found three single case reports of suspected COVID-19 infection related to ADEM[3],[21]. The first described case reports a woman in the forties presenting with encephalopathy
and bulbar involvement nine days after exhibiting COVID-19 symptoms, in whom MRI revealed
white matter lesions suggestive of a demyelinating process[3]. The second case describes a 64-year-old woman with optic neuritis and myelitis
with corresponding enhancing lesions on MRI three weeks after an influenza-like syndrome.
The patient had positive serum IgG for SARS-CoV-2, and negative anti-AQ4 and anti-MOG
antibodies[21]. Both of these cases occurred in outpatients with mild COVID-19 presentation, contrary
to what we have reported in our two cases. Despite the differences in clinical presentation,
MRI findings in the first case are similar to those in our patients.
The third case report[22] describes a 51-year-old woman with severe COVID-19 who remained in coma after sedation
withdrawal, with impaired oculocephalic response to the left. Brain MRI showed bilateral
deep hemispheric and juxtacortical white matter lesions, with restricted diffusion.
CSF analysis was normal, with negative PCR for SARS-CoV-2. Subsequent MRIs obtained
during hospitalization showed increasing lesions associated with decreased restricted
diffusion. The patient was treated with methylprednisolone and intravenous immunoglobulin
(IgIV), and gradually improved.
In a case series[23], ADEM was related to severe COVID-19 infection requiring long ICU stay in three
patients. Two of these presented with post-extubation encephalopathy characterized
by unresponsiveness. Brain MRI in the three cases showed multifocal lesions predominantly
distributed in the white matter, many of which displayed diffusion restriction. CSF
showed only mild protein elevation, and CSF PCR for SARS-CoV-2 was negative in all
cases. COVID-19 infection severity in this case series is similar to that found in
our cases, with prolonged mechanical ventilation and ICU stay[23].
The largest COVID-19-associated ADEM series to date describes 43 patients with COVID-19-related
neurological disorders, nine of whom were classified within the ADEM spectrum, with
a broad range of clinical and radiological presentations[4]. None of the five tested patients presented positive for SARS-CoV-2 in the CSF.
Four of the nine patients presented with critical or severe COVID-19 infection; in
three the initial neurological symptom was slow awakening in the ICU; eight underwent
immunotherapies. Only one patient presented a complete recovery, seven were showing
improvement by the time the article was published, and one died. A neuropathological
specimen obtained in a patient that underwent hemicraniectomy revealed findings supportive
of ADEM; SARS-CoV-2 was not identified in brain tissue. All patients presented multifocal
supratentorial white matter lesions, and two also disclosed intraspinal lesions[4].
The main characteristics of the three patients with slow awakening in ICU in that
series[4] resemble those of the two patients presented here. These patients had more than
two weeks of ICU stay, presented with severe respiratory distress due to confirmed
COVID-19 infection, PCR for SARS-CoV-2 in CSF was negative in the tested ones, and
MRI depicted multifocal areas of white matter lesions, some with hemorrhagic features.
Additionally, one of these patients showed ongoing improvement with supportive treatment
alone, similarly to patient 2.
Treatment of ADEM consists of immunotherapies, such as intravenous pulse methylprednisolone,
plasma exchange and IgIV. There are no randomized controlled trials related to ADEM.
Use of high-dose intravenous corticosteroids is widely accepted as first-line therapy,
and was associated with substantial clinical improvement in adults in uncontrolled
observational studies[9],[10]. In patients who fail to respond to corticosteroids, IgIV and, less commonly, plasma
exchange are considered second-line options[24]. In COVID-19 patients immunotherapy should be individualized, taking into account
concerns about safety of these treatments.
COVID-19 infection-related ADEM described in the current literature presents heterogeneous
clinical and neuroimaging findings. We have encountered reports that point to increasing
ADEM diagnoses in a subgroup of patients that present with marked encephalopathy and
disorders of consciousness after prolonged mechanical ventilation and ICU stay due
to severe COVID-19 infection. The pathophysiology of this pattern of CNS lesions related
to these conditions remains incompletely understood. An attractive explanation would
be of an immune-mediated inflammatory reaction associated with the viral infection.
Further studies should help elucidate the role of the viral infection, and of COVID-19-associated
inflammatory states in the pathogenesis of brain lesions in this clinical setting.
These two reported cases highlight the importance of a careful neurological evaluation,
followed by adequate neuroimaging, preferably MRI, in SARS-CoV-2 patients with delayed
awakening after ICU stay. Disorders of consciousness are frequently attributed to
toxic-metabolic encephalopathy. In this setting, brain lesions can be missed, unless
patients undergo brain imaging studies.
The neurological impairment caused by ADEM may have a negative impact on long-term
neurologic deficits, functional outcomes and mortality of patients with severe COVID-19
infections. Health professionals should be trained to promptly recognize neurologic
manifestation in COVID-19 patients, allowing an early diagnosis of potentially treatable
conditions, and possibly minimizing neurological sequelae of COVID-19 infection.
