The COVID–19 pandemic is one of the biggest medical challenges of this century. The wealth of medical data generated is contrasted by the dearth of data on the frequency of neurological symptoms and occurrence of (rare) neurological complications.
As summarized above, headache, dizziness, and impaired consciousness are neurological symptoms frequently observed in patients with COVID–19. Such symptoms are not specific for infection with SARS-CoV–2 and may also be found in other viral infections. These symptoms do not necessarily postulate an infection of underlying neurological structures, but could also occur via indirect mechanisms of neuropathogenicity, e.g., as a consequence of respiratory distress, hypoxia, or due to hypotonia, dehydration, and fever during sepsis. Indirect mechanisms of neuropathogenicity may be sufficient to explain headache and dizziness as frequent non-specific symptoms in mild or moderate, as well as impaired consciousness in severe or critical COVID–19 patients. The latter might be confounded by the fact that impaired consciousness is frequently noted in hospitalized elderly patients.
Interestingly, a high frequency of olfactory and gustatory dysfunction in COVID–19 patients has been noted. A loss of olfactory function in viral infections is well known in otolaryngology. Viruses such as rhinovirus, parainfluenza, Epstein–Barr virus, and some other CoVs may cause olfactory dysfunction through an inflammatory reaction within the nasal mucosa and the occurrence of rhinorrhea [51,52]. Data published by Lechien and colleagues suggest, however, that olfactory dysfunction associated with COVID–19 infection may appear in the absence of rhinorrhea . Therefore, nasal inflammation and related obstruction may not be the only etiological factors underlying the frequent observation of smell and taste dysfunctions in patients with COVID–19. Indeed, the transcribial route has been suggested as one possible route of SARS-CoV–2 to the brain and its direct infection.
Yet, data on direct brain infection by SARS-CoV–2 is very limited. Moriguchi et al. and Poyiadji et al. described the most compelling cases of encephalitis with the detection of SARS-CoV–2 RNA in CSF, constituting strong evidence for neurotropism . Notwithstanding, in most reports on encephalitis and related disorders, SARS-CoV–2 RNA was neither detected in CSF, nor relevant further examinations such as CSF analyses and cerebral MRI scans were performed. Therefore, these reports are unable to support the described single observations further.
Seizures in patients with COVID–19 might occur in consequence of direct brain infection, but only single reports of patients with seizures exist so far. Thus, current evidence does not suggest an additional risk of seizures in COVID–19 .
Encephalopathy, rather than encephalitis, may occur due to indirect mechanism of neuropathogenicity, such as hypoxic encephalopathy found in deceased COVID–19 patients . In these cases, ARDS may act synergistically with intracranial hypertension, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage . Hyper-inflammatory systemic responses may further contribute to neurological symptoms and rare, but severe neurological complications. An activated systemic immune response might ultimately also lead to fatal encephalopathy or chronic CNS demyelination associated with long-term sequelae, depending on viral and host factors that may influence disease severity.  T-helper 1 cells producing IFN-γ and GM-CSF, previously reported in CNS neuroinflammation , have also been found in COVID–19 patients in intensive care units . Furthermore, accumulating evidence suggests that severely affected COVID–19 patients might suffer from a cytokine storm syndrome, which has been implicated as the putative mechanism underlying a case of COVID–19 associated with acute necrotizing encephalopathy .
Concerning peripheral neurological immune mediated complications, Gutiérrez-Ortiz et al. reported two patients with Miller-Fisher syndrome and polyneuritis cranialis in patients infected with SARS-CoV–2 . Miller-Fisher syndrome, a variant of Guillain-Barré syndrome, is an autoimmune disease that can manifest a few days to weeks following a viral upper respiratory or gastrointestinal infection. These reports may suggest that neurological complications of COVID–19 could occur as para-infectious autoimmune-mediated complications. Such complications are not specific for SARS-CoV–2, and currently available single reports do not suggest that the frequency is exceptionally high in COVID–19 patients.
Acute cerebrovascular events have been mostly observed in patients with severe or critical COVID–19 disease course . Nevertheless, such associations are based on a limited number of cases and are irresolute, because patients with severe or complicated disease courses are more likely to suffer from relevant comorbidities, such as diabetes and hypertension. These factors portray independent risk factors for cerebrovascular diseases and connote a strong association bias. Moreover, glucose imbalances, believed to impact on the homeostasis of the brain, have been described in SARS-CoV–2-infected patients with diabetes . Infection with SARS-CoV–2 might further drive dyslipidemia, which might associate with disease progression from mild to critical.  In severe or fatal COVID–19 cases, coagulopathy, including elevated D-dimer levels, prolonged prothrombin time, and decreased platelet counts have been highlighted in a recent meta-analysis . Interestingly, hyper-fibrinolysis, as reflected by elevated serum D-dimer, was present in 97% of COVID–19 non-survivors at admission  and 71.4% of non-survivors met the criteria for disseminated intravascular coagulation . For this reason, severely affected patients might also be more susceptible to cerebrovascular disease . The other way round, patients with pre-existing cerebrovascular conditions, are more likely to have worse clinical outcomes after SARS-CoV–2 infection, possibly due to plasmin, a key player in fibrinolysis, contributing to enhanced virulence and pathogenicity of SARS-CoV–2 .
With this review, we sought to identify the neurological features of a SARS-CoV–2 infection and COVID–19. We found that frequently reported neurological symptoms comprise headache, dizziness, taste and smell dysfunctions, or impaired consciousness. These symptoms, however, are non-specific for infection with SARS-CoV–2. Taste and smell dysfunction may indicate neurotropism. However, reports on direct brain infection remain scarce. Risks for other more severe neurological complications, such as cerebrovascular disease including ischemic strokes, might be increased; systematic analysis so far is hindered by the low number of associated cases reported and known interactions of vascular risk factors with a severe or critical COVID–19 disease course.
Further studies will be needed to address whether neurological symptoms manifest due to direct infection of structures of the nervous system, constitute a reflection of a systemic inflammatory syndrome, or occur as a consequence of the higher prevalence of cardiovascular comorbidities. This could be achieved through the early involvement of neurologists in the treatment of patients with COVID–19, and standardized international registries, such as the Lean European Open Survey for SARS-CoV–2 Infected Patients (LEOSS) with neurological items already integrated. Even though reports of anosmia and few cases of encephalitis suggest a neurotropic potential of SARS-CoV–2, additional experimental studies are mandatory to confirm the pathophysiological mechanisms.