Neurological Involvement of Coronavirus Disease 2019: A Systematic Review

Abstract

Background: In December 2019, unexplained cases of pneumonia emerged in Wuhan, China, which were found to be secondary to the novel coronavirus SARS-CoV-2. On March 11, 2020, the WHO declared the Coronavirus Disease 2019 (COVID-2019) outbreak, a pandemic. Although the most common presentations of COVID-19 are fever, cough and shortness of breath, several clinical observations indicate that COVID-19 does affect the central and peripheral nervous system.  

Methods: We conducted a systematic literature search from December 01, 2019 to May 14, 2020 using multiple combinations of keywords from PubMed and Ovid Medline databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included articles with cases of COVID-19 that were evident for neurological involvement.  

Results: We were able to identify 82 cases of COVID-19 with neurological complications. The mean age was 62.28 years. 37.8% of the patients were women (n = 31). 48.8% of the patients (n=40) had cerebrovascular insults, 28% (n=23) had neuromuscular disorders, 18.3% of the patients (n=15) had encephalitis or encephalopathy, and 2.4% (n=2) presented with status epilepticus. 

Conclusions: Neurological manifestations of COVID-19 infection are not rare, especially large vessel stroke, Guillain barre syndrome and meningoencephalitis. Moving forward, further studies are needed to clarify the prevalence of the neurological complications of COVID-19, investigate their biological backgrounds, and test treatment options. Physicians should be cautious not to overlook other neurological diagnoses that can mimic COVID-19 during the pandemic.

Introduction

Coronaviruses (CoV) are a family of enveloped, positive-sense, single-stranded RNA viruses that have been described for more than 50 years. Some strains are found to be zoonotic, whereas others may infect humans and transmit from human-to-human (HCoV). [1] Multiple strains of Coronavirus are associated with human disease, causing mainly respiratory infections. [2] Of these, SARS-CoV-1, MERS-CoV, HCoV-OC43, and HCoV-229E are associated with neurological complications. [3] Large territory stroke, polyneuropathy, myopathy, seizures and status epilepticus were reported in patients with SARS CoV-1 outbreak in 2002/2003. [4, 5] In-vivo, intranasal inoculation of the SARS-CoV-1 led to severe neuronal loss at the brainstem and specifically the respiratory center at the medulla. This was postulated to contribute to the respiratory failure seen in the most severe cases of coronavirus infections, in addition to the primary lung pathology. [6] The full spectrum of COVID-19 infection is not fully described yet. Some patients may have no clinical symptoms, [7, 8] while others might suffer from severe disease and die. The most commonly recognized symptoms are cough, fever, fatigue, shortness of breath, myalgia, anosmia, and sputum production. Other less-reported symptoms include diarrhea, hemoptysis, and nasal congestion. [7, 9] During the current uncertain times, growing evidence suggests that SARS-CoV-2 virus has neuroinvasive potential, like other coronaviruses. Hence, it was only a matter of time before neurological complications were reported, especially stroke, neuromuscular disorders and meningoencephalitis. The goal of this review is to outline the broad spectrum of the neurological consequences of COVID-19 infection.

Methods

We conducted a systematic literature search from December 01, 2019 to May 14, 2020 from PubMed and Ovid Medline databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following search strategy was implemented and these keywords and their synonyms (in the all fields) were combined in each database as follows: (“COVID 19" OR "coronavirus") AND ("brain" OR "CNS" OR “spinal cord” OR “nerve” OR "neurologic” OR “stroke” OR “cerebrovascular” OR “cerebral vein thrombosis” OR “sinus thrombosis” OR “Intracerebral hemorrhage” OR “hemorrhage” OR “myelitis” OR “GBS” OR “Guillain barre syndrome” OR “neuropathy” OR “radiculopathy” OR “cranial neuropathy” OR “myopathy” OR “myositis” OR “rhabdomyolysis” OR  “encephalitis” OR “encephalopathy” OR “meningitis” OR “meningoencephalitis” OR “seizure” OR “convulsion” OR “epilepsy”) [Figure 1]. We included case series and case reports of COVID-19 that were evident for neurological involvement. After exclusion of duplicates, all articles were evaluated through title and abstract screening by three independent reviewers (M.G., QA., GM.). The same three reviewers performed an accurate reading of all full-text articles assessed for eligibility and performed a collection of data to minimize the risk of bias. In case of disagreement among the investigators regarding the inclusion and exclusion criteria, the senior investigator (GM.) made the final decision. Articles were included if they met the following inclusion criteria: (i) described patients with neurological signs or symptoms attributed to COVID-19 (e.g.focal neurological deficit  or impairment of consciousness); (ii) written in English language; and (iii) published in a peer-reviewed journal. The exclusion criteria were: (i) studies conducted in animals or in vitro models or basic science studies; (ii) patients age less than 18-year old; and (iii) conference proceedings, pooled analysis, clinical trials, case control studies, case reports or case series of anosmia or mental health problems in COVID-19 patients, reviews and books. 

For each study, the following descriptive, microbiological, and clinical information were extracted: patient demographic data, SARS-CoV-2 testing from nasal swab and CSF, neurological symptoms and signs and their onset in relation to respiratory or gastrointestinal (GI) symptoms or anosmia or dysgeusia, any neurological investigations and CSF or any other relevant laboratory testing (such as CK, LDH, CRP, D-dimer, lupus anticoagulant, fibrinogen, ganglioside antibodies), neurological diagnosis, occurrence of respiratory failure (defined as need for intubation, abnormal PO2 in blood gas, or Glasgow Coma Scale score less than or equal 8), treatments administered for the neurological diagnosis, and final outcome. We studied the following outcomes: good, recovering, poor, and deceased. Good outcome was defined as discharge of the patient to home or a quarantine facility, or the use of the following descriptive terms in the study: “no morbidity”, “no worsening” or “discharged well” or “good recovery”. Recovering outcome was defined as discharge of the patient to a rehabilitation facility or use of the following descriptive terms: “began to improve”, “recovering”, or “stayed in the floor”. Poor outcome was defined as continuing deterioration of the patient’s clinical status, need for ICU admission, continued intubation, or use of the following descriptive terms: “poor” or “no improvement after certain time of treatment”, at the time of submitting the manuscript. Deceased was defined as reported death within 30 days of COVID-19 diagnosis.

Results

Through the search strategy, we could identify 42 articles about neurological involvement by COVID-19. We were able to identify 82 cases of COVID-19 with neurological complications. The mean age was 62.28 years (22-91). 37.8% of the patients were women (n = 31). All patients except 2 had positive nasopharyngeal (NP) or oropharyngeal (OP) SARS-CoV-2 RT-PCR swabs. Only 2 patients had positive CSF SARS-CoV-2 RT-PCR, one of which showed negative NP swab testing. 48.8 % of patients (n=40) had cerebrovascular insults (CVIs), 28% (n=23) had neuromuscular disorders (NMDs), 18.3 % (n=15) developed CNS complications related to infection or inflammation, 2.4% (n=2) presented with status epilepticus and 1.2 % (n=1) had CNS demyelinating lesions. 32.9% of patients (n=27) were recovering, 18.3% (n=15) had good outcome, 25.6 % (n=21) had poor outcome and 18.3% (n=15) died. One patient showed postmortem evidence of the presence of viral particles in the neurons and capillary endothelial cells in the frontal lobe (Table 1). In 23.2 % of patients (n=19), the neurologic syndrome was the initial presentation of COVID-19. Four of which, they developed respiratory symptoms 2-8 days after the onset of neurologic syndrome. In 2 patients the neurologic syndrome proceeded by 2-3 days of GI symptoms, while in 2 other patients, it was proceeded only by anosmia and dysgeusia. [Figure 2].

5% (n=2) of the CVIs were cerebral vein thrombosis (CVT), 5% (n=2) were intracerebral hemorrhage (ICH), 2.5% (n=1) were aneurysmal subarachnoid hemorrhage & ICH, and 87.5% (n=35) were ischemic stroke. 3 out of the 35 patients were cardioembolic stroke, 5 were small vessel disease stroke, and 27 were large vessel occlusion (LVO) stroke. 25.7% (n=9) of the ischemic stroke patients had significant elevation of D-dimer level (>7000 ng/ml), 28.6 % (n=10) had significant elevation of C-reactive protein (>100mg/L), 22.8% (n=8) had elevated fibrinogen (> 500 mg/dl), and 14.3% (n=5) were tested positive for lupus anticoagulant antibodies. Out of the 27 LVO stroke patients, 7 were under the age of 50, 6 underwent thrombectomy, 4 were given IV tPA, 6 were given therapeutic low molecular weight heparin (LMWH), 3 were given apixaban, 4 were given dual antiplatelets (DAPs), and one was given rivaroxaban and DAPs, and 6 died. One of the ischemic stroke patients developed hemorrhagic conversion after thrombectomy. The LVO stroke were distributed in the following territories: left middle cerebral artery territory (MCA) (n=6), right MCA (n=6), left internal carotid artery (ICA) (n=2), right ICA (n=2), left common carotid artery (n=1), basilar artery (n=1), left vertebral artery (n=1), left posterior cerebral artery (PCA) (n=1), right PCA (n=1), bilateral multiple vascular territory infarcts (n=2), and unspecified (n=4). Stroke with LVO was the presenting manifestation of COVID-19 infection in 8 patients, 3 of which were under the age of 45 [Figure 3]. 

17.4% (n=4) of the NMDs patients had rhabdomyolysis, 4.3 % (n=1) had polyneuritis cranialis, 4.3% (n=1) had oculomotor nerve palsy, and 73.9% (n=17) had Guillain Barre syndrome (GBS). 7 out of the 17 GBS cases had facial weakness. One of which had solely facial diplegia as a neurologic syndrome. In 2 cases, GBS was the first presentation of SARS-CoV-2 infection. While in 14 other patients, GBS developed 3-24 days after the onset of flu-like symptoms. One patient presented 2 weeks after anosmia and ageusia without respiratory or GI symptoms. Electrophysiologic studies showed evidence of acute motor and sensory axonal variant (AMSAN) in 5 patients, mixed axonal and demyelinating pattern in 2 patients, and demyelinating patterns in 6 patients. EMG was not performed in 4 patients, one of which was diagnosed with Miller Fisher syndrome with positive serum GD1b-IgG antibody. CSF studies revealed albuminocytologic dissociation in 10 patients, were normal in 3 patients (protein <45 mg/dl, WBCs 0-5 cells/μ). In one patient CSF protein and WBCs were 54 mg/dl and 9 cells/μL respectively. 14 out of 17 patients received IVIG, one patient received IVIG and plasmapheresis, 1 patient showed spontaneous recovery and one patient received prednisone. 6 out of the 17 patients developed respiratory failure, one of which died (Table 2).

80% (n=12) of the CNS infection related complications were meningoencephalitis, 6.6 % (n=1) had rhombencephalitis, 6.6% (n=1) had acute necrotizing hemorrhagic encephalopathy, and 6.6 % (n=1) had encephalopathy. In the 12 meningoencephalitis cases, only 4 CSFs revealed lymphocytic pleocytosis, two of which had positive CSF SARS-CoV-2 RT-PCR. 9 patients developed respiratory failure, 6 of which received plasmapheresis and one died. Furthermore, one of the status epilepticus patients was focal status epilepticus. Finally, The CSF of the patient with CNS demyelinating lesions was normal and oligoclonal bands were not sent (Table 3).

Discussion

It became clear that the respiratory tract is not the sole target of SARS-CoV-2 virus. In an analysis of 214 cases of COVID-19 in Wuhan, China, 78 (36.4%) had neurological complications. Patients with severe infection were more likely to have neurological manifestations like alteration in sensorium and muscle weakness (45.5% Vs 30.2% in non-severe). The manifestations involved both the central and peripheral nervous system. The severity of these manifestations ranged from acute cerebrovascular disease and impaired consciousness to dizziness and headache. [53] Our systematic review confirms that neurological complications are not uncommon. Therefore, physicians should be attentive to such conditions like ischemic and non-ischemic stroke, Guillain Barre syndrome and its variants, CNS infection and seizure.

In our review, ischemic stroke was the most common neurological manifestation, occurring in 42.7% of the subjects. More than 75% of which was LVO stroke. According to a series of 388 COVID-19 patients from Italy, thromboembolic events occurred in 21% of the patients. Including venous thromboembolism, ischemic stroke, and acute coronary syndrome. [54] The exact mechanism of the hypercoagulable state is not well understood. D-dimers might play a major prothrombotic role in COVID-19 patients. In this review, more than 25% of the ischemic stroke patients had significant elevation of D-dimer level (>7000 ng/ml). High D-dimer levels are independently associated with poor outcome in SARS-CoV-2 infection. [55]. Severe COVID-19 respiratory infection often leads to sepsis induced hypercoagulability. Which is evident by increased D-dimer levels, increased intravascular platelet activation, increased fibrinogen, and mild prolongation of PT and aPTT. [56] Indeed, a study in Wuhan, China, showed that 71.4% of patients who died of COVID-19 had disseminated intravascular coagulation (DIC) with significant D dimer elevation. [55] Moreover, SARS-CoV-2 virus is known to bind angiotensin converting enzyme 2 (ACE2) receptor on endothelial cells which promotes a proinflammatory and vasoconstrictive state of endothelial dysfunction leading to end organ damage, including stroke. ACE2 recombinant therapy, therefore, may be a promising targeted therapy for COVID-19 related stroke. [57] Transient production of antiphospholipid antibodies may also play a role. In a study by Harzallah et al, 25 out of 56 patients with confirmed or suspected SARS-CoV-2 infection were positive for lupus anticoagulants, and 5 patients had either anticardiolipin or anti–β2-glycoprotein I antibodies. [58] Zhang et al detected antiphospholipid antibodies in 3 COVID-19 patients, all of them had multiple cerebral infarcts. [59] in this review, 5 of the LVO stroke were tested positive for lupus anticoagulant.

When presenting in the appropriate time window, thrombolytic treatment of COVID-19 patients with ischemic stroke is reasonable. While the role of anticoagulation, like LMWH, in this clinical context is still unclear. [57] Harzallah et al recommended early anticoagulation therapy for individuals with COVID-19 infection and positive lupus anticoagulant. [58] Previous investigations suggested that COVID-19 is associated with both platelet and clotting cascade activation. [60] In our review, 6 patients were given therapeutic LMWH, 3 were given apixaban, 4 were given dual antiplatelets (DAPs), 1 was given rivaroxaban and DAPs.  Along those lines, further clinical trials are necessary to determine the role of antiplatelets and/or anticoagulation for the treatment and prevention of thrombotic events in COVID-19 infection, including milder cases. 

Previously identified coronaviruses, including SARS-CoV1 and MERS, were associated with GBS. [61] In our review, neuromuscular disorders are the second most commonly encountered neurological complication of COVID-19 infection (28%), especially GBS. The mechanisms of GBS related to SARS-CoV-2 are still incompletely understood. Both para- and post-infectious mechanisms were proposed. [18 & 24] Two of the GBS patients in our review did not experience preceding respiratory or GI symptoms or fever and GBS was the initial presentation. This suggests para-infectious process, as has been reported recently with other viral infections like Zika virus. [62] COVID-19 infection is associated with macrophage activating syndrome, cytokine storm (IL-1β, IL-2, IL-6, IL-17, IL-8, TNF and CCL2) [63], immune system dysregulation, and lymphocyte alterations [64], all of which could induce an autoimmune damage to the peripheral nervous system. Expectantly, each molecule in this cascade might represent a future therapeutic target. With the emergence of more cases of acute neuropathies temporally linked to COVID-19 infection, we should gain better understanding of the underlying pathophysiology. Since these neuropathies are treatable and they pose increased morbidity and mortality, neurologists, intensivists and internists working with COVID-19 patients must be vigilant of this association.

The potential of the virus for direct invasion of the CNS has now been convincingly demonstrated by CSF analysis and postmortem examination. Two patients in our review have positive CSF SARS-CoV-2 RT-PCR. In one of which, the infection was entirely confined to the CNS and no other organs were affected. The other patient has negative NP swab testing while having positive CSF PCR. On postmortem examination, Paniz‐Mondolfi et al documented evidence of viral particles in the neurons and capillary endothelial cells of the frontal lobe. They concluded that there was an active viral entry across the brain microvasculature into the neurons, as there was blebbing of viral particles coming in and out of the endothelial membrane. [35] Mechanistically, SARS-CoV2 virus may enter the CNS through hematogenous route or retrograde synaptic transmission. ACE 2 receptors, which are abundantly expressed in the endothelial cells, supporting glia and neurons, might be the binding site facilitating hematogenous entry. The systemic hyper-inflammation increases the permeability of the blood-brain and blood-CSF barriers, which might facilitate CNS entry as well. [63] Retrograde synaptic transmission is probably associated with the olfactory nerve. [65] This possibility is supported by the fact that anosmia is a frequent early sign of COVID-19 infection. [66] It has been proposed that SARS-CoV-2 neurotropism may explain not only the common symptoms of encephalitis, but also the respiratory failure, by involvement of the medullary respiratory centers. This mechanism has been demonstrated in animal models, but not yet in humans. [67] Detailed investigations, including CSF studies, imaging, and when possible, autopsy, are required to better elucidate those mechanisms.

Although two COVID-19 patients in our review presented with status epilepticus, one of them had an established history of epilepsy from another cause. Lu et al studied 304 COVID-19 patients and concluded that none of these patients had acute symptomatic seizures or status epilepticus. [68] The current data are too limited to make any conclusions about the effects of COVID-19 on developing seizures.

Finally, Lovati et al reported a case of HSV-1 encephalitis, where the diagnosis and treatment were delayed because of anchoring on COVID-19 and its neurological complications. [69] Despite all the reports of COVID-19 neurological complications, other pathologies are still more common. Ignoring this would result in significant delays in diagnosing and treating neurological patients.

Our study has some limitations. First, most of the used evidence is based on single case reports or small series, which limits its generalizability. Second, some case reports did not complete or report the full workup required to exclude alternative causes of the neurological syndrome presented. Third, many cases are reported from specific ethnic populations, and hence, a number of demographics, genetic, or microbiologic variables, might preclude the applicability of the conclusions in different populations. Fourth, we have not studied the severity of COVID-19 infection and how it correlates with different neurological complications. Last, but not least, several stroke patients had multiple comorbidities and potentially causative vascular risk factors, that we did not include in our analysis.

Conclusions

Neurological manifestations of COVID-19 infection are not rare, especially large vessel stroke, Guillain barre syndrome and meningoencephalitis. They could be related to the direct cytopathic effect of the virus, the inflammatory response, hypercoagulable state, or complications of treatment and ICU stay. Moving forward, further studies are needed to clarify the prevalence of the neurological complications of COVID-19, investigate their biological background, and treatment options. Physicians should be cautious not to overlook other neurological diagnoses that can mimic COVID-19 during the pandemic.

Declarations

Conflict of Interest

The authors declare that they have no competing interests

Acknowledgements

Not Applicable

Authors Contributions

Dr. Ghannam and Dr. Manousakis planned the search strategy, made the inclusion and exclusion criteria and built the key words for the systematic review. Dr. Ghannam, Dr. Alshaer and Dr. Manousakis participated in articles screening and assessing their eligibility to the study. Both Dr. Ghannam and Dr. Manousakis completed the final form of PRISMA flowchart of the selection of the studies for this review. Dr. Ghannam, Dr. Alshaer, Dr. Al-Chalabi and Dr. Zakarna were responsible for drafting and editing of the manuscript. Dr. Ghannam and Dr. Robertson were responsible of making the tables and the figures. Dr. Manousakis participated in critical revision of the manuscript for intellectual content. All authors read and approved the final manuscript.

Funding

No funding was obtained for this study

Ethical Approval Information

There was no ethics committee approval as the data has been analyzed in a retrospective manner and has no effect on treatment of the patient

Data Sharing Statement

All the data supporting our findings is contained within manuscript

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