A more recent study underscored the high incidence of ischemic stroke due to large vessel occlusion in patients younger than 50 years old. More importantly, all of those patients (n=5) had confirmed SARS-CoV-2 infection but were not critically ill until the stroke occurrence. Two of them did not have any known risk factors for stroke.
More case reports of neurological manifestations have also followed (Table 2). A patient with COVID-19 developed decreased consciousness during hospitalization in the intensive care unit and tested positive for SARS-CoV-2 by RT-PCR in the CSF. The authors diagnosed this patient as a case of SARS-CoV-2 encephalitis. However, caution is highly suggested since positive RT-PCR in the CSF is not necessarily equivalent to CNS infection. A traumatic lumbar puncture with contamination of the CSF sample by the patient's blood or other biological secretions that contained the genetic material of SARS-CoV-2, cannot be entirely excluded. One more patient with COVID-19 presented with altered mental status and possible encephalopathy and underwent electroencephalogram (EEG), which showed bilateral slowing and focal slowing in the left temporal region with sharply countered waves. However, the patient had suffered a stroke in the past and had an underlying left temporal lesion of encephalomalacia, that could have contributed to the abnormal EEG. CSF analysis was also not indicative of CNS infection. More conclusive evidence of SARS-CoV-2 associated meningitis/encephalitis are presented by a case report of a comatose patient with positive RT-PCR for SARS-CoV-2 in the CSF and neuroimaging features indicative of right lateral ventriculitis and encephalitis mainly on right mesial lobe and hippocampus. Surprisingly, no genetic material of SARS-CoV-2 was detected during nasopharyngeal swab testing raising the question of primary seeding of the CNS versus residual CNS infection after viral clearance from other sites, a feature observed in other viral infections like Ebola and human immunodeficiency virus. A case of acute haemorrhagic necrotizing encephalopathy in a patient with COVID-19 has also been described as a result of an intracranial cytokine storm, similar to the one occurring in the lungs during severe COVID-19, leading to respiratory failure. Large trials have been looking into therapeutic countermeasures that include immune modulation like IL-6 inhibition in an attempt to fight this inflammatory cascade. Another case involved the peripheral nervous system with the development of para-infectious Guillain-Barre syndrome. However, the authors acknowledge the fact that SARS-CoV2 infection in their case might as well be a coincidence rather than causality. Five more patients developed Guillain-Barre syndrome 5 to 10 days after the onset of COVID-19 symptoms. Severe deficits, axonal involvement and respiratory failure with subsequent need for mechanical ventilation were reported among those patients. PNS involvement has also been documented in two patients who were diagnosed with Miller-Fisher syndrome and polyneuritis cranialis at 3 to 5 days after exhibiting COVID-19-related symptoms.
Another recent study reported the neurological features in a case series of 58 patients hospitalized in intensive care unit because of acute respiratory distress syndrome due to COVID-19. Agitation, confusion and abnormal corticospinal tract signs were commonly documented in those critically ill patients and 33% of those discharged had a persistent dysexecutive syndrome. Further diagnostic evaluation was also performed in a subset of patients, consisting of magnetic resonance imaging, electroencephalography and CSF examination. Among neuroimaging features, leptomeningeal enhancement in eight patients, frontotemporal hypoperfusion in 11 patients and cerebral ischemic stroke in three patients were reported. CSF examination was performed in seven patients and was abnormal in three of them, presenting positive oligoclonal bands with an identical electrophoretic pattern in serum or elevated protein and IgG levels. However, RT-PCR testing for SARS-CoV-2 was negative in all examined CSF samples.
The distinction between true causality and non-etiological concomitance may pose a real challenge in some instances, but its importance is unquestionable when presenting case-reports with neurological manifestations attributable to COVID-19. Microbiological assays and temporal association can contribute to one or the other direction. We present the case reports of two stroke patients with clearly identified underlying aetiopathogenic stroke mechanisms, who also suffered from COVID-19 manifestations (Figures 1 and 2). These cases highlight the potential of comorbidity between COVID-19 and stroke. In fact, COVID-19 and stroke share some common risk factors (Table 3) such as age, cardiovascular disease, diabetes mellitus, smoking, cardiac arrhythmia, coronary artery disease and others. Consequently, COVID-19 and stroke may coexist without any causal association. The CASCADE (Call to Action: SARS-Cov-2 and CerebrovAscular DisordErs) study is a worldwide, multicentre hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. The main aim of this study is to enable the understanding of the changes in models of stroke care, differential hospitalization rate, and stroke severity, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that treating cerebrovascular comorbidities is appropriately prioritized during the global crisis.
In the spectrum of PNS involvement in COVID-19, we present the case report of a patient with confirmed SARS-CoV-2 infection who developed facial nerve palsy during hospitalization (Figure 3). Despite that, RT-PCR in the CSF was negative for SARS-CoV-2 and direct infection of the nervous system could not be established, the temporal association between COVID-19 and facial nerve palsy is highly suspicious for an indirect, possibly immune-mediated mechanism.
Regardless of any direct or indirect neurological manifestations related to SARS-CoV-2, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. Normal neurological medical care, as we know it, has been seriously impaired worldwide. Many neurological wards, among other general medical wards, have been converted into quarantine wards for the treatment of infected patients. Routine neurological outpatient visits are delayed or suspended, and treatment remains available only for emergency conditions and highly selective cases. Even in the emergency setting, neurological departments may be forced to function with fewer staff, either due to staff redeployment to COVID services, prophylactic quarantine or direct illness. The remaining healthy personnel are at high risk of burn-out, due to long shifts, sleep deprivation, psychological distress, shortages of medicine and supplies and discomfort associated with personal protective equipment (PPE) use. Characteristically, PPE use has recently been associated with the development of de novo headaches and aggravation of pre-existing headaches among frontline healthcare personnel and these factors can interfere with compliance and workplace safety and productivity. Despite those unprecedented conditions, quality of care in neurology should be maintained.
Stroke, as the cornerstone of neurological emergency and a major cause of mortality and disability, should not be neglected at the expense of extreme community and health-care COVID-19-measures. However, published and anecdotal reports of declining stroke admission volumes are accumulating. Stroke patients with mostly mild symptoms, and for that reason with better chances of recovery if appropriately treated, may be unwilling to seek medical help due to their fear of the virus. Such a practice can significantly narrow down the time-window for available acute treatments and can lead to neurological deterioration, early recurrent stroke and permanent disability. In light of those data, several stroke centres have come together to design a study protocol with the aim to investigate the worldwide burden of cerebrovascular disease before, during and after SARS-CoV-2 pandemic (CASCADE study).
In addition, stroke centres have been guided to implement a 'protected code stroke' for the management of acute stroke patients. 'Protected code stroke' actually originates from the acknowledgment that every stroke patient is potentially infected and should be treated accordingly. However, maintaining the high standards of stroke care is of utmost importance. For example, early cerebral imaging should be preserved in order to avoid unnecessary delays, noted in our patient presented in the case report (Figure 1). During stroke patient presentation, doctors should ask patients and their companions whether they have symptoms indicative of COVID-19. If so, they might consider ordering a chest CT-scan, which can be performed at the same time as the brain CT-scan. Return visits to the imaging departments run the risk of exposing and being exposed and should be avoided. As early as at the admission process, doctors should establish a discharge plan and perform in-hospital only the most essential diagnostic tests, in order to shorten the duration of hospitalization. Finally, early consultation should be asked from an infectious disease specialist in cases of suspected SARS-CoV-2 infection or from an intensive care unit physician, if the patient requires high fractions of inspired oxygen. Stroke patients with confirmed SARS-CoV-2 infection should be transferred to dedicated COVID-19 wards. The need for a multidisciplinary team approach and vigorous inter-specialist cooperation is essential.
Notably, the European Stroke Organization (ESO) has recently announced a press release, cautioning for a potential increase in the risk of death or disability from stroke during the COVID-19 pandemic (https://eso-stroke.org/news/). In a survey of 426 stroke care providers from 55 countries, only one in five reported that stroke patients are currently receiving the usual acute and post-acute care at their hospital. This press release concluded that the lack of optimal care is likely to lead to a greater risk of death and a smaller chance of a good recovery (https://eso-stroke.org/news/). The ESO has also emphasized that patients with stroke symptoms should still present to the hospital as soon as possible and that efforts should be made to maintain the usual level of stroke care, including intravenous and endovascular reperfusion strategies, irrespective of the patient's COVID-19 status, to avoid unnecessary 'collateral damage' through the inadequate treatment of this often disabling or life-threatening condition (https://eso-stroke.org/news/).
Other fields of neurology are less obviously, albeit still affected, by the COVID-19 pandemic. Many neurological patients with multiple sclerosis and autoimmune syndromes such as myasthenia gravis, neuromyelitis optica, angiitis and inflammatory polyneuropathies are on a wide variety of immunosuppressive therapies. Whether those therapies can impair the immune response to SARS-CoV-2 infection is a matter of great concern, but few data are currently available. However, not only should the disease-modifying therapies not be discontinued, but also neurologists have to ensure that the patients can present safely for their regular treatment appointments. Such patients may need to take extra precautions to prevent exposure to the virus during their hospital visits but also in the community. Any follow-up visits which are unrelated to treatment can be postponed or completed through tele-neurology programs. Once a patient is confirmed with SARS-CoV-2 infection, the physician might consider postponing any second-line immunomodulating (fingolimod, ocrelizumab or natalizumab in particular) or immunosuppressive therapies, especially if the patient is of higher risk for severe COVID-19 disease. Treatment should be restarted when symptoms have fully resolved and the repeat testing is negative. When feasible, prompt treatment re-initiation is particularly important in the cases of fingolimod and natalizumab, in order to minimize the risk of the rebound effect that has been associated with the discontinuation of these agents. In the case of a clinical relapse of COVID-19 patients, treatment with intravenous pulse steroids should be carefully considered and potentially avoided, in view of the recent multiple sclerosis scientific organizations' statements, cautioning against the use of corticosteroids in patients with viral infections and COVID-19. Fever in the case of a multiple sclerosis patient with COVID-19 can further deteriorate pre-existing symptoms (Uhthoff phenomenon) and this should be differentiated from a 'true' clinical relapse. Respectively, in patients with myasthenia gravis, an infection can also induce a myasthenic crisis. Those patients are generally at high risk for developing various in-hospital complications and the treating physicians should be extremely vigilant.
Patients with neurodegenerative diseases also belong to a more vulnerable subset of the general population. Patients with dementia, which are generally older and therefore at high mortality risk due to COVID-19, can hardly follow protective measures or use telecommunication when needed. Lock-down can also trigger or worsen behavioural symptoms in such patients and their caregivers should be appropriately prepared. In addition, if such patients need prolonged hospitalization or deal with hypoxia, they will be in immediate risk of developing delirium and deteriorate permanently. Patients with extrapyramidal disorders are not immunocompromised, however COVID-19 may be particular challenging for those with significant movement restrictions. In fact, patients with Parkinson's disease are more prone to lower respiratory tract infections and, in turn, pneumonia is the leading cause of death in Parkinson patients. The association of COVID-19 and neurodegenerative diseases is even more complex since a significant proportion of such patients live in nursing homes and are at particular risk of developing the disease or infecting others with SARS-CoV-2. Healthcare- and community-based approaches are urgently needed to minimize the bilateral impact between COVID-19 and neurodegenerative diseases.
During their clinical practice, neurologists should also be prepared to confront neurological adverse effects and drug interactions related to the use of anti-viral agents and other medications that may be tested and used against SARS-CoV-2. For example, hydroxychloroquine sulphate has been associated with headache, dizziness and extrapyramidal disorders, such as dystonia, dyskinesia and tremor. In addition, it interacts with a variety of antiepileptic drugs and can potentially lower the convulsive threshold. Caution is also required when patients with disorders of the neuromuscular junction are prescribed hydroxychloroquine sulphate, especially with co-administration of aminoglycoside antibiotics. Certain drug databases report additional minor interactions of chloroquine with anti-Xa inhibitors, resulting in a decrease of their excretion rate and potentially in higher bleeding risk. All direct oral anticoagulants also interact with the antiviral agent ritonavir (a protease inhibitor used in conjunction with another PI lopinavir, as the lopinavir/ritonavir combination for COVID-19), which is a strong inhibitor of both cytochrome P450 3A4 and P-glycoprotein transporter and therefore may increase their plasma concentrations to a clinically relevant degree. Remdesivir, a promising nucleoside analogue currently tested for its efficacy in COVID-19, may be associated with delirium. In addition, colchicine that is currently being investigated as a potential therapy for cardiac complications of COVID-19 (ClinicalTrials.gov identifier: NCT04326790), presents with substantial neuromuscular complications that may exacerbate myalgias, weakness and other muscle symptoms of COVID-19. Massive, inconsiderate or over-the-counter administration of such drugs may pose a significant morbidity risk for the neurological patient. Since more than 100 trials currently evaluate anti-SARS-CoV-2 agents, we should be aware for potential drug-drug interactions affecting commonly prescribed neurological agents.
The healthcare of neurosurgical patients is also affected by the COVID-19 pandemic. Intensive care units are being overcrowded by COVID-19 patients, and post-operative neurosurgical patients cannot be admitted for monitoring. The less emergent surgeries are being postponed. Patients are being triaged according to case severity and are transported to a limited number of designated neurosurgical centres, since the majority have been transformed to COVID-19 wards. Fortunately, but not surprisingly, cases with traumatic brain lesions, which require urgent surgery, are being reduced in number due to the public lockdown and social distancing measures.
Drastic times call for drastic measures and the safety of neuroscience specialists should be preserved. Neurologists are first responders to stroke and other neurological emergencies and have to be protected. One management approach could be that only neurology subspecialists who do procedures or surgeries should be going to the emergency room, stroke units and neuro-intensive care units (i.e. neuro-intensivists and neuro-endovascular specialists, vascular neurologists). Other non-urgent neurological evaluations may be performed remotely. Tele-neurology has emerged as a fundamental component of solutions to sustain neurological healthcare quality. Its expanding use ranges from the simplest drug prescriptions to the more complicated tele-triage of patients before they get admitted to an emergency department. It has already been implemented with success in stroke care over the past decade and in pilot projects for epilepsy care but can also be applied to other neurological fields. We expect that information technology experts would scientifically support this endeavour and that authorities would reimburse it appropriately. More optimistically, after the management of the SARS-CoV-2 outbreak and the recovery of global health, the COVID-19 pandemic may act as a stimulus for a new era of tele-neurology to be established. Finally, medical education for neurological residents and the younger generation of neurologists needs to adapt to e-learning activities in these times of extraordinary needs.