Demyelinating Disease after COVID-19 Infection

SARS-COV-2 is a neurotropic virus that can trigger a large-scale outbreak of neurological complications in the future. SARS-COV-2 virus has neuroinvasive and neurotropic properties that allow it to enter the central nervous system (CNS) and infect neurons, accumulate in nervous tissue and promote the development of delayed neurodegenerative processes. Among the neurological complications of SARS-CoV-2 to date, we can distinguish a group of demyelinating lesions of the CNS. The paper describes two cases of severe COVID-19, which were accompanied by neurological disorders and multifocal white matter lesions on MRI, which may correspond to demyelinating CNS disease. Both cases may be a manifestation of an acute infectious demyelinating process associated with COVID-19, as the clinical picture was appropriate, and neuroimaging showed multifocal lesions of the white matter. Other clinical signs con ﬁ rming this diagnosis were previously con ﬁ rmed acute viral COVID-19 infection and the absence of a history of demyelinating diseases such as multiple sclerosis in both patients. Monitoring such patients can help to understand better and identify factors in the early stages of the disease and to predict its progression. In the future, it will also allow the development of e ﬀ ective treatment strategies and the ability to reduce the risk of demyelinating process or its progression during SARS-CoV-2 infection.

COVID-19 is a polyhedral and unpredictable syndrome with its consequences primarily determined by the immune response.Compared to other respiratory viruses, SARS-CoV-2 causes a stronger, longer-lasting, autoimmune infl ammatory response [1], fueled by massive cytokine release, leading to coagulation dysfunction and multiple organ failure in severe cases [2].
Initially, the focus was on severe acute coronavirus 2 (SARS-CoV-2), which was the most common and life-threatening, but there are now increasingly more reports of damage to the central and peripheral nervous system [23,24].Neurological symptoms are observed in more than 80% of cases with a history of the disease and, in contrast to respiratory distress syndrome, are more common in young people [3].Neurological disorders in the case of COVID-19 were fi rst described by Chinese experts L. Mao et al [4].Almost 40.0% of patients with COVID-19 were found to suff er damage to the central and peripheral nervous system in 2020.The most common and severe neurological complications of COVID-19 include cerebrovascular disease, acute necrotic encephalopathy, encephalitis, encephalomyelitis, hypoxic encephalopathy, and Guillain-Barré syndrome.Descriptions of demyelinating damage to the brain and spinal cord are much less common [5].
The review of Ismail Ibrahim, Sara Salama allows considering a probable causal relationship due to parainfectious or postinfectious immune-mediated pathology in patients with COVID-19 [6].Overall, the fi nal analysis of this systematic review included 60 articles covering 102 patients: 52 (51%) men and 50 (49%) women, a mean age of 46.5.Demyelination simulated a variety of conditions, with encephalitis/encephalomyelitis being the most common.At the same time, other models such as multiple sclerosis (MS), transverse myelitis (TM), neuromyelitis, optic spectrum disorders (NMOSD) and even myelin oligodendrocyte glycoprotein antibodies (MOGAD) have been reported less frequently.
The virus enters the nervous system and reaches the central brain structures due to direct infectious damage through the infection of neurons and glial cells by hematogenous and transneuronal pathways [7,8,9,10].There is a known and indirect eff ect of infection on the nervous system through hypoxia, systemic infl ammatory response, hypercoagulation and endothelial damage [11].It has been suggested that SARS-CoV-2 may leverage the expression of angiotensin-converting enzyme-2 (ACE2) in the nerve tissue to penetrate neurons and glial cells [9,11].Underlying mechanisms of various neurological syndromes include, both individually and in combination, direct viral neuronal damage (Zubair et al., 2020), secondary hyperinfl ammatory syndrome (Mehta et al., 2020), para-and post-infectious infl ammatory and immune-mediated disorders or consequences of a severe systemic disorder with neurological eff ects of sepsis, hyperpyrexia, hypoxia, hypercoagulation, and other mechanisms [9,11].
Recent studies have shown that SARS-CoV-2 can cross the blood-brain barrier and lead to acute or delayed CNS demyelination [12].Various mechanisms have been proposed, including virus-induced hypercoagulable or proinfl ammatory conditions, direct viral invasion of the CNS, and post-infectious immune-mediated processes [8].
The question remains whether demyelination is a manifestation of direct viral invasion of the CNS, or whether it is an immune-mediated process causing other conditions, or, in some cases, simply the continuation of hypoxia, which aff ects the CNS as a direct result of respiratory damage [2].
Some recent studies assessed possible mechanisms of demyelination associated with COVID-19 [6].Viral infection has been shown to induce an infl ammatory response by triggering myelin-specifi c T cells, which may accelerate the development of early or delayed virus-induced demyelination [13].A similar mechanism has been described in cases of multiple sclerosis (MS), where activated vascular epithelium acts as a gateway for pathogenic B and T lymphocytes in response to peripheral infl ammation [14,15,16].Cross-links between cytotoxic lymphocytes and microglia cells reach a peak in the formation of microanatomical niches, so-called "microglial nodules", which have a common pro-infl ammatory eff ect that spreads throughout the brain.
Based on the principle that genetic data inform of the multifactorial disease process, a study of systemic biology revealed a signifi cant interaction of SARS-CoV-2 with genes associated with autoimmune diseases and comorbidities that cause severe COVID-19.A strong association with autoimmunity was characteristic of SARS-CoV-2 over other coronaviruses and respiratory viruses following powerful and autoimmune response causing COVID-19.Interestingly, genes associated with MS were most enriched by interactions of SARS-CoV-2 host, which suggests pathophysiological similarities that should be investigated [17].In particular, there are three key intersections of the MS and COVID-19 immunological substrates: IFN-1 response (IFN-I), TH-17 axis, and the infl ammatory pathway.
In patients with MS, impaired IFN-I response has been widely described at the genetic and transcriptional levels and is confi rmed by three decades of successful treatment with IFN-1B [18,19].Studies of patients with severe COVID-19 have shown defective IFN-I production with adequately delayed and uncontrolled T cell response, which enhances both viral spreading and cytokine release, leading to multiorgan failure [20,21].These data may suggest that people at risk of MS may be more susceptible to virus-induced dysimmune eff ects.
The interaction between SARS-CoV-2 and Epstein-Barr virus (EBV) may go beyond the acute phase and play a role in the pathogenesis of ongoing symptomatic COVID-19 or post-COVID-19 syndrome.It is manifested by pro-longed symptoms and/or delayed or long-term complications after 4 weeks of the acute phase.
At present, the exact mechanism of viral spread to the CNS has not been established, but two possible explanations are 1) hematogenous spread from the systemic circulation to the CNS; 2) trans-neuronal spread through the olfactory tract.In addition, the CNS may be potentially compromised by the hypoxic-ischemic injury resulting from severe damage to respiratory tracts or by latent immune-mediated mechanisms [6].
SARS-CoV-2 has neurotropic and neuroinvasive properties and can cause direct neurological damage by binding to angiotensin-converting enzyme-2 (ACE-2) receptors, which are expressed everywhere, including in the CNS [8].Delayed CNS damage is mediated by an adverse immune response after acute infection, leading to CNS demyelination [22].
In addition, autopsy data from deceased patients showed the activation of astrocytes and microglia with infi ltration of cytotoxic T cells, particularly in the brainstem, in patients with COVID-19 [23].The main receptors used to recognize substances expressed by CNS cells play a signifi cant role in MS pathogenesis [24,25].TLRs (Toll-like receptors) are also deemed to play an important role in the pathogenesis of COVID-19, mainly through recognizing viral particles, activation of the innate immune system, and proinfl ammatory cytokine secretion [25].
The production of antibodies against virus-associated myelin may serve as another possible explanation.SARS-CoV-2 may play a role in the emergence of MS, similar to the documented role of the Epstein-Barr virus [26].
These key aspects represent a maladaptive immune response to SARS-CoV-2, which is characterized by hyperactivity.
Given the relevance of the issue under research, our work was aimed at studying the peculiarities of the clinical course, diagnosis, and treatment of demyelinating CNS damage associated with SARS-CoV-2.Results and discussion.Two patients with white matter lesions have been reported, which indicates an infl ammatory demyelinating process associated with SARS-CoV-2 infection.

Clinical case 1
Patient B., born in 1964, consulted a doctor on December 21, 2020, with complaints of burning headache, localized mostly in the frontotemporal area, pain in shoulder joints, numbness on the left side of the body, deteriorated vision, memory impairment, dizziness, shaking while walking.
Life history: neurosurgeon's patient due to a small meningioma of the falx.
Disease history: in September 2020, she was conservatively treated for COVID-19 at home under the supervision of a family doctor, the disease was complicated by bilateral segmental pneumonia, verifi ed by the CT of thoracic cavity performed on September 23, 2020 (CT imaging is characteristic of bilateral segmental (in S10) pneumonia probably of viral etiology, CO-RADS3, involving less than 5% of the lung parenchyma, CT1, signs of interstitial changes at the apex of both lungs, right-sided scoliosis and degenerative changes of the thoracic spine, such as osteochondrosis and spondylosis).She took antiviral drugs, antibiotics, vitamin D, zinc, painkillers.The patient suff ered from severe headache, a feeling of cold in the extrem-ities, general weakness, dizziness.Blood pressure was increased occasionally.After the treatment with antivirals, antibiotics, painkillers, vitamin D, fatigue and dizziness lowered, however, severe headache in the frontotemporal area of the head stayed, gait instability, motor dysfunction and dizziness and numbness and numbness of the left side of the body.
Objectively: at the time of admission, the condition is moderately severe.Somatically: blood pressure 135/80 mm Hg, rhythmic heart tones, heart rate 72/min, respiratory rate 16/min, vesicular breathing at auscultation, body temperature 36.6° C. The abdomen is soft and painless during palpation.
Neurological status: clear consciousness.Contact is diffi cult due to dysphonia and dysarthria.The patient complied with the instructions.The orientation in time, location, self-identifi cation are preserved.Speech and higher mental functions are not impaired.The assessment of cranial nerves revealed bilateral horizontal nystagmus, slight asymmetry of nasolabial folds.Movements in the extremities are preserved in full, muscle strength is reduced in the left extremities.Deep tendon refl exes were intensifi ed in the left extremities.Babinski refl ex was observed on the left.Left hemihyperesthesia.During coordinating tests, slight intentional tremor and dysdiadochokinesia on the left side were observed.Shaking is observed in Romberg's stance.The gait is ataxic.
MRI of the brain dated October 13, 2020: hyperintense area in the left frontal lobe of the brain with a transition to the mesolobus.This MR image may correspond to the demyelinating process, requires MRI control in the dynamics in 2-3 months.Diagnosis: disseminated encephalomyelitis (DEM)?, the manifestation of the glial neoplastic process?) (Figure 1).MRI of the brain dated December 1, 2020: Multiple hyperintense lesions of the white matter, covering the juxtacortical and periventricular areas in both hemispheres of the brain.MR image may correspond to the eff ects of encephalitis, DEM (F igure 2).As see n in Figure 2, there are multiple hyperintense lesions of the white matter covering the juxtacortical and periventricular regions in both brain hemispheres, which corresponds to the criteria of spatial spreading.
Laboratory tests showed normal blood formula, kidney and liver function; serum electrolytes; creatine kinase; markers of infl ammation (erythrocyte sedimentation rate, C-reactive protein).
The patient was consulted by a cardiologist who diagnosed hypertension, 2nd degree, moderate cardiovascular risk.
The patient met the diagnostic criteria for the infectious demyelinating disease.
The treatment was started per international guidelines for the treatment of demyelinating process.The patient underwent pulse therapy with Dexamethasone 12 mg for 5 days, with a gradual lowering of the dose over 5 days.The patient was also prescribed Pregabalin at a dose of 75 mg per day to reduce neuropathic pain, and B gro up vitamins.The gait improved and the weakness of extremities reduced.

Clinical case 2
Patient P. On November 30, 2020, a previously healthy 30-year-old woman without a family history of neurological problems complained of blurred vision, spotting in the right eye, swaying during walking, the feeling of weakness and numbness in the right extremities, fatigue.The disease history shows that on October 14, 2020, a severe headache started, as well as low-grade fever, severe weakness.The patient consulted a family doctor who diagnosed COVID-19 (PCR date: October 17, 2020).The s ubsequent symptoms included blurred vision and eye twitching.Subsequently, the patient developed anosmia, paresthesia, and weakness in the right extremities and a feeling of shaking when walking.Magnetic resonance imaging of the brain dated October 28, 2020: periventricular -in the white matter of the frontoparietal area, there are 3 polymorphic foci on the right with increased vT2 and FLAIR 33 without signs of limited diff usion of the signal sized 5*4.5*3.3*2 and there is a similar focus subcortically in the right parietal lobe, and presumably, foci of demyelination (Figure 3).IgG antibodies to SARS-CoV-2 were determined using enzyme-linked immunosorbent assay (ELISA) on October 31, 2020, -↑ 8.89.
Thus, the article describes two clinical cases of severe COVID-19, which were accompanied by lesions of the white matter on MRI, which may correspond to demyelinating CNS disease.
Diagnostic search: neurological manifestations and results of neuroimaging in our cases could be caused by ischemic damage, direct encephalitic viral eff ect, toxic-metabolic lesions or acute demyelination.Diff usion MRI images did not show a diff usion restriction that resembles a vascular picture, which makes ischemia unlikely.In addition, neuroimaging data were not characteristic of classical toxic and metabolic disorders, making the fi rst three possible mechanisms unlikely.
The identifi cation of periventricular relatively asymmetric lesions associated with deep white matter lesions indicates an acute demyelination process.

Fig. 1 .Fig. 2 .
Fig. 1.MRI of the brain of Patient B. dated October 13, 2020 (areas of hyperintensity are marked by red arrows) Ophthalmologist -initial atrophy of the optic nerve disk on the right.Laboratory tests (blood formula, kidney and liver function; serum electrolytes; creatine kinase; markers of infl ammation: erythrocyte sedimentation rate, C-reactive protein) showed normal values.According to the clinical manifestations of the disease in the patient and changes shown on the MRI, a post-infectious demyelinating disease caused by COVID-19 was suspected (based on McDonald criteria, 2017).5-day therapy with 12 mg Dexamethasone was started with a gradual lowering of the dose over 5 days, B group vitamins, nucleotides, anticholinesterase drugs.After the treatment of paresthesia, weakness in the extremities and ataxia decreased without the disappearing of anosmia.
acute viral COVID-19 and no history of demyelinating diseases, such as multiple sclerosis, in both patients.2. MRI is the best method of neuroimaging in patients with suspected infectious demyelinating disease because CT of the head can't show such changes.In these cases, MRI of the brain usually refl ects bilateral and asymmetric hyperintensity in T2/FLAIR in the central and subcortical white matter, thalamus, basal ganglia, cerebellum, and brainstem.3. Demyelinating lesions after viral COVID-19 (according to the literature) may be caused by a cross-reaction between the immune response and cell components, as well as the response of lymphocytes and macrophages and lymphokine-mediated damage and release of immune cell protease.The proinfl ammatory state in the case of COVID-19 is associated with increased levels of cytokines ("cytokine storm"), which can activate glial cells, leading to demyelination.In addition, viral infection may cause the generation of antibodies directed against glial cells.4.There are no randomized controlled trials associated with the diagnosis of the acute infectious demyelinating process.The use of high doses of intravenous corticosteroids is widely accepted as fi rst-line therapy and has been associated with signifi cant clinical improvement in adults in uncontrolled observational studies.In patients who do not respond to corticosteroids, immunoglobulins and, less commonly, plasmapheresis, are considered second-line options.CoV-2.Healthcare professionals should be trained to quickly recognize neurological manifestations in patients with COVID-19, which will allow early diagnosis and proper treatment of these conditions and help minimize the neurological consequences of COVID-19.6.Further research in this area is needed to determine whether demyelination is the result of direct viral activity in the central nervous system, the immune response, or possibly the result of hypoxia associated with lung damage.