Although the most common presentation of SARS-Cov2 infection is respiratory illness, recent data reports an increasing number of neurological conditions. There appears to be a combination of nonspecific complications from the systemic effects of direct viral infection or inflammation of the nervous and vascular systems, which may be parainfectious or postinfectious.
Four of the 6 coronaviruses with the capacity to infect humans, identified before SARS-CoV-2, cause seasonal disease, particularly mild airway disease, and have a high incidence worldwide (15-30% of cases). upper respiratory tract infections).
Both the more harmless coronaviruses and the epidemic strains have been associated with conditions of the central (CNS) and peripheral (PNS) nervous systems. After SARS, 2 of 3 cases of encephalopathy with seizures, CNS and PNS disease were reported, with SARS-CoV detected in the CSF, by RT-PCR (Reverse Transcription-Polymerase Chain Reaction).
Culture of brain tissue obtained from the autopsy of the third patient tested positive for SARS-CoV. Four patients with severe SARS developed neuromuscular disease, predominantly motor neuropathy, myopathy, or both, which could have been specific to SARS or secondary to critical illness.
CNS involvement was found in 5 adult patients with MERS (Middle East Respiratory Syndrome); 2 of the patients had acute disseminated encephalomyelitis, 2 had cerebrovascular disease, and 1 had Bickerstaff brainstem encephalitis. Three patients had neuropathy.
Human coronavirus OC43, a seasonal coronavirus, caused encephalitis in an infant with severe combined immunodeficiency. In an immunocompetent older child it caused acute disseminated encephalomyelitis. In 22 children (0.8 to 72 months) with suspected CNS infection or with anti-coronavirus IgM antibodies in serum, CSF or both, headache, neck stiffness and seizures were found. Ten of these children had pleiocytosis and 8 had abnormal brain imaging. All 22 made a full recovery .
Neurological complications have also been described by other respiratory viruses, particularly seasonal ones, such as pandemic influenza. These complications include acute necrotizing encephalopathy (associated with RANBP2 gene mutations), acute infantile encephalopathy, and acute hemorrhagic leukoencephalopathy and myelopathy in adults.
The estimated incidence of neurological disorders during the 2009 influenza A H1N1 pandemic was 1.2/100,000, with a predominance of affected children. The 1918 H1N1 influenza pandemic has been associated with lethargic postinfectious encephalitis, although a causal link has not been demonstrated.
| Projected epidemiology of COVID-19 associated with neurological disease |
Although neurological complications are rare in SARS, MERS and COVID-19, the scale of the current pandemic means that even a small proportion could comprise a large number of cases.
The minimum prevalence of CNS complications varies from 0.04% for SARS to 0.20% for MERS. PNS complications vary between 0.05% for SARS and 0.16% for MERS. The calculation of the number of cases with neurological complications of COVID-19 arose from extrapolation from these data, the result being: 1,805–9,671 patients with CNS complications and 2,407–7,737 with PNS complications. These numbers do not include strokes, which are becoming more common.
| Clinical characteristics of COVID-19 associated with neurological disease |
As the COVID-19 pandemic progresses, reports of neurological illnesses are increasing. To date, 901 patients have been reported. The manifestations can be considered direct, immune-mediated effects of the virus on the nervous system, and parainfectious neurological complications or the systemic effects of COVID-19.
In a UK registry, of 125 patients with COVID-19 and neurological or psychiatric disease reported over a 3-week period, 39 (31%) patients had altered mental status, 16 (13%) of them with encephalopathy and 23 (18%) had a neuropsychiatric diagnosis, including 10 (8%) with psychosis, 6 (5%) with dementia-like neurocognitive disorder, and 4 (3%) had an affective disorder.
In particular, 77 (62%) patients had a cerebrovascular disease event, of which 57 (46%) were ischemic strokes, 9 (7%) were intracerebral hemorrhages, 1 (<1%) were CNS vasculitis, and 10 ( 8%) events in other cerebrovascular vessels.
The challenges in managing patients with a highly contagious infection, and the overwhelming number of cases, resulted in many of the early reports being insufficiently detailed, with little complete description of CSF analysis, imaging or follow-up, and often , appear on peer-reviewed websites. The data obtained by most trials have not used standard definitions.
> Encephalitis
Encephalitis is inflammation of the brain parenchyma, usually caused by infection or immune system defenses. Although the diagnosis of encephalitis is strictly histopathological, for practical purposes it is accepted that it involves inflammation of the brain, with pleiocytosis in the CSF, imaging changes, or focal abnormalities on the electroencephalogram (EEG).
Detection of the virus in CSF, per se , does not provide the diagnosis of encephalitis if there is no evidence of brain inflammation.
As of May 19, 2020, 8 adults aged 24–78 years, including 4 women, had been described with COVID-19-associated encephalitis, mostly diagnosed by nasal or nasopharyngeal swab. At 17 days, the majority began with a neurological condition, simultaneously with the appearance of respiratory symptoms. In a 60-year-old man, confusion preceded cough and fever by 2 days. Two patients had only fever, without respiratory symptoms or signs.
Neurological manifestations were typical of encephalitis, with irritability, confusion and reduced consciousness, sometimes associated with seizures. Three patients also had neck stiffness, and another had psychotic symptoms.
A 40-year-old man developed ataxia, oscillopsia, hiccups, and bilateral facial weakness. In 5 of 6 patients, CSF analysis showed pleiocytosis, mostly lymphocytic; In the remaining patient the CSF was normal. PCR for SARS-CoV-2 was performed on the CSF of 4 patients; in 2 of them, the result was positive. One of them, a 24-year-old man with encephalitis, had minor respiratory symptoms and ground-glass images on the chest CT scan. The PCR of the respiratory sample was negative. Few publications have reported exhaustive investigation of other causes of encephalitis.
Brain images were normal or showed no acute alterations in all 6 patients; In 2 patients, the signals were of high intensity, 1 patient had alterations in the temporal lobe. The patient with ataxia had a cerebellar lesion extending into the spinal cord.
EEG was performed in 5 patients. Two patients had generalized slowing abnormalities; 2 patients had focal abnormalities and 1 presented psychotic symptoms followed by a seizure. These patients were in nonconvulsive status epilepticus.
One patient responded quickly to high doses of steroids, but the other 7 patients had no specific treatment except anticonvulsants, antivirals, and antibiotics. There is no specific treatment for SARS-CoV-2 encephalitis.
As for other forms of encephalitis, there are still unanswered questions about the relative contributions of viral damage and the host inflammatory response, and whether corticosteroids might be helpful. Clinical trials seem unlikely, given the current low number of cases.
> Other encephalopathies
Encephalopathy is a phytopathological process, which usually develops over hours or days, and is manifested by changes in personality, behavior, cognition or consciousness (there may be delirium or coma).
In patients with encephalopathy and COVID-19, whose brain inflammation has not been proven, there are a wide variety of other causes, such as hypoxia, drugs, toxins and metabolic alterations.
The largest study to date, from Wuhan, China, retrospectively described 214 patients with COVID-19, of whom 53 (25%) had CNS symptoms (17%) such as headache (13%) and impaired consciousness (16 [7%]). Twenty-seven (51%) of the CNS patients had severe respiratory disease, but there were very few other details.
In a French series of 58 intensive care patients with COVID-19, 49 (84%) had neurological complications, including 40 (69%) with encephalopathy and 39 (67%) with corticospinal tract signs. Magnetic resonance imaging (MRI) in 13 patients showed leptomeningeal enhancement (8 patients) and acute ischemic changes in 2 patients.
In the CSF examination of 7 patients, no pleiocytosis was found. Fifteen (33%) of 45 patients who had been discharged presented with dysexecutive syndrome. Furthermore, a few case reports have appeared, including a woman with encephalopathy, with imaging abnormalities consistent with acute necrotizing encephalopathy. 1 fatal case was also reported with the finding of viral particles in endothelial cells and neural tissue, although without indications of being associated with inflammation.
Several reports have described seizures in children with SARS-CoV-2 infection. In 2 infants without respiratory symptoms, with SARS-CoV-2 in the nasopharyngeal swab, paroxysmal convulsive episodes were described, with complete recovery.
In a series of 168 children hospitalized with COVID-19, 82 seizures were described in 5 (3%) children, of whom 3 had preexisting epilepsy. One child had previous febrile seizures.
> Encephalomyelitis and acute disseminated myelitis
Acute disseminated encephalomyelitis is a multifocal demyelination syndrome, which usually occurs weeks after an infection. It generally presents with multifocal neurological symptoms, often with encephalopathy.
Two case reports describe middle-aged women with acute disseminated encephalomyelitis and SARS-CoV-2 detected in respiratory swabs. One developed dysphagia, dysarthria and encephalopathy, 9 days after the onset of headache, and myalgia.
The other had seizures and decreased consciousness, and required intubation due to respiratory failure. Both patients had normal CSF and elevated signal intensities on MRI, typical of acute disseminated encephalomyelitis. Both improved after treatment, one with intravenous immunoglobulin and the other with steroids. To date, there is only one report of COVID-19-associated myelitis. A 66-year-old man from Wuhan, China, developed fever, fatigue, and subsequently acute flaccid paraparesis with incontinence.
The physical examination showed hyporeflexia and a sensory level at the level of the 10th dorsal vertebra. He was treated with dexamethasone and intravenous immunoglobulin, and discharged to rehabilitation. Encephalomyelitis and acute disseminated myelitis are usually considered post-infectious diseases.
They are generally treated with corticosteroids or other immunotherapies. In parainfectious cases of SARS-CoV-2 detectable at presentation, more caution may be required, especially if the virus is detected in the CSF, because such treatment could diminish the immune response to the virus.
> Disease of the peripheral nervous system and muscles
Guillain-Barré syndrome is an acute polyradiculopathy characterized by symmetrical and rapidly progressive weakness of the extremities, areflexia, sensory symptoms and, in some patients, facial weakness, although variants exist. To date, 19 patients (including 6 women) with Guillain-Barré syndrome (or its variants) and COVID-19 have been reported, with a median age of 23 to 77 years. Given the number of SARS-CoV-2 infections worldwide, the incidence is not particularly higher than might be expected.
Neurological symptoms began a median of 7 days after systemic or respiratory symptoms, although 2 patients developed febrile illness 7 days after the onset of Guillain-Barré syndrome; during hospitalization. One had a positive swab for SARSCoV-2 and the other had lymphopenia and thrombocytopenia, characteristics of SARS-CoV-2 infection. Three patients had diarrhea before the onset of neurological disease. Three of the patients diagnosed with Guillain-Barré syndrome who had weakness of all 4 extremities, with or without sensory loss, had a paraparetic variant, only with weakness in the legs, and another had paresthesia of the lower extremities. Four of these patients had facial nerve involvement; 5 had dysphagia and 8 developed respiratory failure. Three had autonomic complications, one with hypertension and 2 with sphincter dysfunction.
Electrophysiological studies were performed in 12 patients, which showed demyelination (n = 8) and axonal disease (n = 4). Two patients had the Miller Fisher variant of Guillain-Barré syndrome, with ophthalmoplegia, ataxia, and areflexia. One patient reported loss of smell and taste, and was positive for anti-GD1b-IgG. One patient was recorded as having bilateral paralysis and another with unilateral abductor paralysis. Acute vestibular syndrome with horizontal nystagmus and oscillopsia was diagnosed in 1 patient.
SARS-CoV-2 was detected in respiratory swab material from 16 patients. In 2 cases the sample was not specified. One patient was also positive for rhinovirus and in another, it was done through a blood antibody test. On the other hand, in 11 of the 13 patients who underwent CSF analysis, no albuminocytological dissociation was found.
SARS-CoV-2 was detected in none of the CSF samples. Only 4 patients were tested to detect other pathogens commonly associated with Guillain-Barré syndrome, and they were treated with intravenous immunoglobulin; 8 patients (all with Guillain-Barré syndrome) were admitted to intensive care for ventilatory support, of whom 2 died, 2 improved, and 5 remained with continuous disability at the time of discharge. In the Wuhan series of 214 patients, 23 of them (11%) had muscle injury associated with elevated creatine kinase. There are also reports of rhabdomyolysis from COVID-19.
Anosmia and ageusia emerged as common symptoms of COVID-19, with other features or in isolation, suggesting they could be useful diagnostic markers. A study of 259 patients, including 68 who were SARS-CoV-2 positive, found that abnormal smell and taste had a strong association with COVID-19.
In a European study, 50 olfactory dysfunctions were reported in 357 (86%) of 417 patients with COVID-19; 342 (82%) reported taste disorders. The frequency of these symptoms in COVID-19 exceeds the frequency with which they appear in those affected by influenza. Subclinical deficits in smell, taste, or both have also been detected. Although these symptoms can occur in any respiratory infection as a consequence of coryza, in COVI-19 they occur without being accompanied by other symptoms, suggesting involvement of the olfactory nerve.
> Cerebrovascular manifestations
As COVID-19 spreads around the world, evidence shows an association with cerebrovascular disease, and other forms of vascular disease. In an early retrospective case series from Wuhan, cerebrovascular manifestations were reported in 13 (6%) of 221 patients with COVID-19; 11 (5%) patients developed ischemic stroke, 1 (<1%) developed intracerebral hemorrhage, and 1 (<1%) suffered cerebral venous sinus thrombosis.
In Milan, Italy, 9 (2%) of 388 hospitalized patients, retrospectively identified with COVID-19, suffered a stroke. Another Italian center reported that 43 (77%) of 56 SARS-CoV-2 positive patients, admitted to a neurology unit, had cerebrovascular disease and suffered an ischemic stroke; 3 had hemorrhagic stroke and another 5 had transient ischemic attacks. In the Netherlands, 3 (2%) of 184 intensive care patients with COVID-19 had ischemic stroke.
In total, 88 patients had ischemic stroke and 8 had hemorrhagic stroke (19%), of which 2 died. Most patients were older than 60 years and many had risk factors for cerebrovascular disease. Known Younger patients also suffered strokes. In New York, USA, 5 patients < 50 years of age with stroke and SARSCoV2 were identified. Two patients had no symptoms of COVID-19. In all, the stroke was ischemic.
Cerebrovascular symptoms began a median of 10 days after the onset of respiratory disease, although in one patient, the stroke preceded airway disease and 5 others had only cerebrovascular symptoms. In 2 patients, ischemic stroke was associated with aortic thrombi, and multiple infarcts have been reported in these and other patients, sometimes associated with arterial thrombosis and limb ischemia.
In other stroke patients, concurrent deep vein thrombosis and pulmonary embolism have been found. It is very important to have arterial and venous images of patients with COVID-19 and cerebrovascular events. Small asymptomatic infarcts have also been described, only on MRI. D-dimer concentration increased in many COVID-19 patients, consistent with a pro-inflammatory, coagulopathic state in the context of critical illness.
There are reports of lupus anticoagulant, anticardiolipin, and anti-β2 antibodies. Antibodies against glycoprotein-1 were also found in stroke associated with COVID-19, although they may appear in other critical diseases, such as infections.
Low molecular weight heparin has been recommended for patients with COVID-19 to reduce the risk of thrombotic disease and stroke ischemia associated with COVID-19, but must be balanced with the risk of intracranial hemorrhage, hemorrhagic transformation of a heart attack. sharp.
| Disease mechanisms |
> Infection and inflammation of the central and peripheral nervous systems
As with other neurotropic viruses, the key questions for SARS-CoV-2 infection concern the routes of entry into the nervous system and the relative contribution of the viral infection versus the host response to subsequent damage. A possible entry route for SARS-Cov2 to the brain is the olfactory bulb, which is a part of the CNS not protected by the dura mater, and in COVID-19 anosmia is very common.
This seems to be the case with the herpes simplex virus, the most common cause of sporadic encephalitis. Other entries could be through the blood-brain barrier, after viremia, or through infected leukocytes.
The angiotensin-converting enzyme 2 receptor, to which SARS-CoV-2 binds to enter cells, is located in the endothelium of cerebral vessels and smooth muscle. SARS-CoV-2 replicates in neuronal cells in vitro.
The CNS and PNS can be damaged directly by the virus or by innate and adaptive immune responses to infection.
The data so far do not indicate that SARS-CoV-2 or related coronaviruses are highly neurovirulent. Autopsy material from a patient who developed encephalopathy weeks after presenting with SARS showed edema, neuronal necrosis, and gliocyte hyperplasia. It is possible that virus entry into the CNS is accompanied by the infiltration of immune cells and the release of cytokines and chemokines, which contribute to tissue damage.
> Cerebrovascular disease
Cerebrovascular disease in COVID-19 could be due to coagulopathy. SARS-CoV-2 can cause damage to endothelial cells, activating inflammatory and thrombotic pathways. Infection of endothelial cells or activation of monocytes upregulates tissue factors, and the release of microparticles, which activate the thrombotic pathway and cause microangiopathy , which could occur in cases of SARS-CoV-2 or other viruses.
Monocyte activation is believed to be part of the hemophagocytic lymphohistiocytosis described in severe cases of COVID-19. The presence of thrombocytopenia with elevated D-dimer and C-reactive protein in severe COVID-19 and stroke is consistent with a microangiopathy associated with the viral process.
Endothelial dysfunction can lead to microvascular and macrovascular complications in the brain. It is also possible that in acute ischemic stroke an early inflammatory process occurs after an acute infection, with destabilization of a carotid plaque or the appearance of atrial fibrillation.
It is important to consider that a patient with a neurological disease may also be infected with SARS.Cov-2, coincidentally, especially if they are hospitalized. It is also crucial to distinguish nosopharyngeal infection by SARS-CoV-2 from infection of the nervous system. All causes of encephalopathy should be considered in patients with altered consciousness or agitation.
In patients with possible PNS disease, clinicians should aim to examine CSF, looking for evidence of albuminocytologic dissociation. Likewise, request nerve conduction studies and electromyogram during recovery, even if they cannot be done acutely.
In patients with neuropathy, cerebrovascular disease, acute disseminated encephalomyelitis, in which the damage is likely caused by the host response to the viral infection, establishing causality is even more difficult, especially if patients present after the virus has has been cleared in the nasopharynx.
Clinical case definitions for COVID-19, based on history and typical findings on chest imaging, and blood investigations are helpful. In stroke patients, cerebral angiography is useful to evaluate intracranial vessels and, if necessary, perform a brain biopsy to rule out vasculitis.
The high prevalence of the virus during the pandemic, and the fact that most stroke patients have other risk factors, make it difficult to ensure causality.
The link to SARS-CoV-2 will ultimately need to be proven by careful case-control studies. In the investigation of patients with limb weakness and sensory disturbances, it is crucial to distinguish between disease of the peripheral nerves (e.g., Guillain-Barré syndrome) and inflammation of the spinal cord, which can present with flaccid paralysis, if the cells of the anterior horn are affected.
CSF examination , neurophysiological studies, and spinal imaging are essential. For patients in intensive care, it is necessary to establish whether the nonspecific manifestations of neuropathy, myopathy, encephalopathy or cerebrovascular disease are specific to the virus, which can be very difficult; There are no reliable markers for neurological disease caused by critical illness, although it tends to occur after several weeks. Up to 70% of patients with sepsis may develop encephalopathy or polyneuropathy.
In the Wuhan series, neurological complications were more common in those with severe illness, suggesting that some of the neurological manifestations were related to critical illness.
| Conclusion and future directions |
As is already known, there are coronaviruses and respiratory viruses that cause a wide range of CNS and PNS conditions, so the association with COVID-19 is not surprising. Some recent case reports and series describe a wide range of neurological manifestations, but many lack important details, making diagnosis difficult.
Encephalopathy has been found in 93 patients in total, including 16 (7%) of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 intensive care patients with COVID-19 in France. To date, 8 patients with encephalitis have been reported, and 19 patients with Guillain-Barré syndrome. SARS-CoV-2 was detected in the CSF of some patients.
Anosmia and ageusia are common and can occur in the absence of other clinical manifestations. An emerging pathology is acute cerebrovascular disease, which appears as an important complication (2-6% of patients hospitalized with COVID-19).
To date, 96 patients with stroke associated with COVID-19 have been described. It frequently occurs in the presence of a proinflammatory hypercoagulable state, accompanied by elevated C-reactive protein, D-dimer, and ferritin. It is also likely that neurological disease will be increasingly seen in patients who are SARS-CoV-2 positive, but with little or no manifestation of COVID-19.
Further case-control studies will be needed to help establish whether in these patients, SARS-CoV-2 is causative or coincidental.
The hypercoagulable state and cerebrovascular disease, rarely observed in some acute viral infections, are an important neurological complication of COVID-19.
In general, the proportion of patients with manifestations of neurological diseases is small compared to that of the disease. However, the continuity of the pandemic and the expectation that 50-80% of the world’s population will be infected before herd immunity develops, indicates that the total number of patients with neurological disease could become large.
Neurological complications, particularly encephalitis and stroke, can cause permanent disability, generating the need for long-term care, with potentially high health, social and economic costs.
Health care planners and policymakers must be aware of the increasing burden of this viral disease complication.
