**3. Neurological presentations of COVID-19: the polyform entity of neurocovid**

Psychiatric and neurological complications were reported during the SARS epidemic in 2003 [11].

Apart from depression, anxiety disorders and suicidal ideations, fear for survival, and fear of infecting others; across all timeframes, stigmatization, reduced quality of life, psychological distress, and posttraumatic stress symptoms were reported [11]. Moreover, cases of organic hallucinosis (visual and auditory hallucinations), deliriums of persecution, temporo-spatial disorientation and hypomanic disorder were reported. In some cases, these manifestations have been classified as secondary to steroid therapy. Isolated cases of fatal Coronavirus OC43 encephalomyelitis in the face of little pulmonary involvement [12] and generalized tonic–clonic convulsion in patients with infection and cerebrospinal fluid positivity for SARS-CoV [13] have also been described.

Recent data suggesting that the COVID-19 virus also reaches the central nervous system [7, 8, 14]. It has been shown that (like SARS-CoV) COVID-19 virus exploits the receptor for the angiotensin converting enzyme 2 (ACE2) to enter cells. This discovery made it possible to investigate the expression of ACE2 in the neurological tissue and to determine the possible contribution of neurological tissue damage to morbidity and mortality caused by COVID-19 [7, 14].

The neuroinvasiveness, neurotropism and neurovirulence of the COVID-19 has been demonstrated [7]. Pathological studies suggest a direct route of neuroinvasion via haematogenous diffusion and retrograde transport by the olfactory nerve. Retrograde transport via the vagus and olfactory nerves remains hypothetical [7].

In most cases, COVID-19 would not make a direct attack on vulnerable structures. This would explain why various manifestations of the nervous system are favorable to immune suppression or immune modulation [8].

Direct affection of the central nervous system is uncommon and may result in meningitis/encephalitis [8, 15, 16], manifesting as headache, seizures, confusion, ataxia, pyramidal signs, or impaired consciousness. Direct affection of the peripheral nervous system includes hyposmia or hypogeusia [8].

Neurological disease due to the immune reaction against the COVID-19 embraces acute disseminated encephalomyelitis; acute, haemorrhagic, myoclonus; necrotizing encephalopathy [17, 18]; cytokine release syndrome (a new nosographic entity characterized by aphasia, behavioral alterations, central hypothyroidism, cerebellar ataxia, coma, confusion, cranial nerve palsy, dysautonomia, pyramidal signs, and tremor) and mononeuritis [19]; myositis [20]; cerebral vasculitis; delirium; psychosis; transverse myelitis [21]; cranial nerve palsy; Guillain-Barre syndrome [22]. Neurological long-term complications may be also secondary to affection of the heart or the kidneys [8]. Cardiac involvement may be responsible for cardioembolic, ischemic stroke, or ischemic stroke due to hypotension [8].

The COVID-19 pandemic continues to affect millions of people globally, with increasing reports of neurological manifestations but limited data on their incidence and associations with outcome. Two recent papers report the presence of neurological symptoms in 36.2% [23] and 80% [24] of patients hospitalized with COVID-19. Neurocovid is a polymorphic entity [25]. More than seventy different symptom combinations have been reported in the literature. Symptoms of a general nature seem to be present in almost all patients, often with abnormal laboratory tests [25]. The timing of symptoms varies from early states (anosmia, headache, myalgia) to later stages (altered mental status, neuromuscular disorders, seizures, stroke) [25]. Some neurological symptoms may persist (such as anosmia or headache), while others may cause persistent disability (such as stroke or polyneuropathy) [25].

## **4. Brain imaging findings and new classification system**

The existence of alterations in brain structure as a result of SARS-CoV-2 infection appears to be well established [26, 27], even in subjects whose only symptom was anosmia [28]. Post-mortem structural MRI examinations revealed brain parenchymal abnormalities, subcortical micro and macro hemorrhages, cortico-subcortical oedema, non-specific deep white matter changes and asymmetrical olfactory bulbs [29]. Similar evidence is also found in hospitalized patients [30–33]. The most common neuroimaging findings include cortical signal abnormalities on fluid-attenuated inversion recovery images, associated with leptomeningeal enhancement or cortical diffusion restriction [26], which may reflect autoimmune or infectious encephalitis, hypoglycaemia, hypoxia, or seizures [34]. Acute demyelinating lesions have also been depicted [35–38].

Starting from the observation that different neurobiological processes and mechanisms may lie behind the onset of neurocovid, a three-stage MRI classification system to categorize patients has been recently proposed [39]:

