Typical symptoms of COVID-19 primarily involve the low respiratory tract and range from mild disease to acute respiratory symptoms and severe pneumonia, with respiratory failure and septic shock. However, increasing evidence shows that coronaviruses are not always confined to the respiratory tract, but may also invade the central nervous system inducing neurological diseases. Several reports suggest that COVID-19 patients commonly have neurological symptoms (Filatov 2020, Mattiuzzi 2020).

A growing body of evidence highlights neurological involvement during SARS-CoV-2 infection and that neurotropism and neuroinvasion are a common characteristic of coronaviruses. In fact, coronaviruses were extensively reported to cause central nervous system infection, as well as presumed para-infectious disorders (Arabi 2015, Desforges 2020, Morfopoulou 2016, Turgay 2015).  Animal studies have also shown that SARS‐CoV and MERS-CoV possibly enter the brain via the olfactory nerves, rapidly spreading to specific brain areas including the thalamus and brainstem. This might explain the complaints of anosmia of many patients infected by SARS-Cov-2. Furthermore, the massive inflammation, caused by an excess of cytokines production, may affect the taste buds and cause ageusia - another frequent early symptom of COVID-19 (Li YC. 2020, Wang 2009).

Clinical data from the current pandemic shows that COVID-19 patients present both mild and severe neurologic manifestations. Headache and decreased responsiveness are considered initial indicators of potential neurological involvement and, together with anosmia and ageusia, are the most frequent symptoms observed. Among 2,000 patients tested in South Korea, 30% presented these signs, thus doctors are advising patients to self-isolate if they experience these symptoms, as they could be an early sign of infection (Russel 2020).

Evidence of more severe neurologic symptoms was described in a cohort of 214 hospitalized patients with COVID-19, in Wuhan (China). Overall, neurological manifestations were found in 36.4% of patients, among these, 6% manifested acute ischemic stroke, 15% had consciousness impairment and 19% displayed skeletal muscle injury (Mao 2020).

Consistently, neurological symptoms were observed in a retrospective study on 221 patients admitted with COVID-19 symptoms; 25% of all patients manifested a neurological disease, 5% had acute ischemic stroke, 0.5% developed cerebral venous sinus thrombosis, and 0.5% had cerebral hemorrhage (Li Y. 2020).

In all cases, neurological manifestations, such as acute cerebrovascular disease and impaired consciousness, were found mainly in patients with severe infection.

Significant observations of neurological disease in COVID-19 patients also derive from several case report studies.

Gutiérrez-Ortiz and colleagues described the occurrence of the Miller-Fisher syndrome and polyneuritis cranialis in 2 patients with SARS-CoV-2 infection. Both patients also presented anosmia and ageusia at the onset and, after 2 weeks, fully recovered from neurological disease, except for residual anosmia and ageusia in the patient with Miller-Fisher syndrome. The RT-PCR analysis for SARS-CoV-2 was negative in the cerebrospinal fluid of both patients (Gutiérrez-Ortiz 2020).

A case of Guillain-Barré syndrome (GBS), in a patient returning from Wuhan, was also reported on Lancet. GBS is an acute areflexic paralytic state that most commonly presents with progressive symmetric weakness. The woman, 61 years, presented with acute weakness in both legs and severe fatigue, that rapidly progressed within 3 days, without the typical symptoms of COVID-19. Fever and respiratory symptoms developed only 7 days after the onset of GBS signs. This single case report suggests a possible association between GBS and SARS-CoV-2 infection, although epidemiological data would be necessary to confirm a causal relationship. Supporting this hypothesis, several viral infections have already been associated with the onset of GBS, such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus and most recently Zika virus (Zhao 2020).

A similar case was reported by a hospital in Pennsylvania (USA). The patient, male-54 years, presented with complaints of numbness and weakness in his lower extremities. The weakness, typical of GBS early symptoms, rapidly progressed, together with the appearance of the COVID-19 respiratory syndrome. GBS symptoms generally develop 3 days to 6 weeks following an upper respiratory infection or diarrheal type illness. Given this data, a deeper comprehension of the relationship between SARS-CoV-2 infection, and development of GBS, is needed (Virani 2020).

Neurological symptoms should be considered more systematically in the clinical practice, as they could represent a possible COVID-19 alarm bell, appearing several days before the typical respiratory syndrome – e.g. anosmia, ageusia, weakness and numbness typical of GBS. Moreover, patients should be investigated thoroughly for CNS involvement as  some neurological signs - such as an altered sense of smell or hyposmia, in an uncomplicated early stage COVID-19 patient - could progress to severe neurological complications, such as acute ischemic stroke or cerebral thrombosis and hemorrhage, with serious or fatal consequences for the patient (Román 2020).

In light of these findings, a more precise understanding of the neurotropic potential of SARS-CoV-2 is urgently needed, in order to promptly address neurological implications in COVID-19 patients. This will enable clinicians to prioritize and tailor individual treatments on the basis of early symptoms, severity of the disease and predominant organ involvement.