Early neurological symptoms include the loss of sense of smell and taste and also body aches, headache and myalgia.
Anosmia/ageusia, fever, and myalgia are considered the strongest independent predictors of positive SARS-CoV-2 assays. Rapidly developing neurological complications manifesting usually at the beginning of the infection include dizziness, headache, ataxia, seizures. Three recent case reports describe the development of acute parkinsonism following coronavirus disease 2019 (COVID-19) and this has generated concern on the possible induction of PD by SARS-CoV-2 [105
]. This case and previous evidence of possible link between coronaviruses and PD is alarming the scientific community of a potential role of COVID-19 in the potential emergence of Parkinsonism as a third wave of consequences of the SARS-CoV-2 pandemic [106
Some Controversies about the Clinical Manifestations of Neuro-COVID
During the ongoing COVID-19 pandemic, patients have experienced different and less frequent symptoms including headache (6.5%), dizziness (9.4%), nausea (10.1%), vomiting (3.6%), abdominal pain (2.2%), and shock (8.7%), in addition to the characteristic symptoms such as fever (98.6%), fatigue (69.6%), dry cough (59.4%), anorexia (39.9%) myalgia (34.8%), dyspnea (31.2%), arrhythmia (16.7%), and acute cardiac injury (7.2%) [90
]. Some patients have also reported difficulty breathing as well as gait alterations [68
] (Table 1
Although the involvement of both the CNS and PNS is now well documented, the percentage of patients suffering from these complications varies widely across different studies, assessment time-points as well as geographical location [86
]. For example, the incidence of neurological symptoms in patients in France was 14% at the time of admission in hospitals and 69% after the discontinuation/completion of the therapeutic course [93
]. Various neurological symptoms [68
] were reported for 36.4% of the patients in Wuhan, China. CNS complications include dizziness (16.8%), headache (13.1%), altered consciousness (7.5%), stroke (2.8%), ataxia and seizures (0.5%); reported complications related to autonomic nervous system were impaired sense of smell (5.6%) and taste (5.1%) as well as visual disturbances (1.4%). Musculoskeletal complications accounted for 10.7% of all cases with neurological complications, and neuralgia was reported by 2.3% of patients (Table 1
Data generated in the UK indicate that some patients with COVID-19 may suffer from encephalopathies accompanied by delirium/psychosis while others develop inflammatory CNS syndromes including encephalitis, acute disseminated encephalomyelitis and peripheral neurological disorders like GBS, while a few have life-threatening ischemic strokes [88
Varatharaj et al. [96
] reported neurological/psychiatric illnesses in 125 patients with COVID-19 for 3 weeks. One third of the patients (31%) had altered mental status, including 13% with encephalopathy and 18% with neuropsychiatric diagnosis entailing psychosis (8%), neuro-cognitive syndrome (5%), and affective disorder (3%). The authors state that 62% of the observed patients suffered cerebrovascular events, 74% of which were ischemic strokes, 12% intracerebral hemorrhages, and 1% CNS vasculitis.
Although some authors consider that established neurological complications are most often associated with a severe clinical picture of the viral infection or with concomitant diabetes or hypertension [68
] (Table 1
) contradictory data have been generated in this regard. In patients with moderate symptoms of viral infection or even during recovery, COVID-19 may cause fatal brain and neurological damage of immune–inflammatory origin that leads to destructive changes of the myelin sheath of neurons in the brain and spinal cord leading to paralysis [84
CNS damage in the absence of lung symptoms has also been reported [81
] in young patients (below 50 years of age) developing hemiplegia and impaired consciousness without other symptoms at the same time, and brain MRIs have demonstrated evidences of cerebral artery occlusion.
It is also of interest, in this regard, that the findings of a recent meta-analysis reporting abnormal EEG findings in patients with COVID-19-related encephalopathies included altered mental status, seizure-like events, and cardiac arrest. Abnormal EEG findings were observed in 88.0% of the 543 patients and were sub-classified into three groups including background abnormalities, periodic and rhythmic EEG patterns, and epileptiform changes. It was also shown that approximately a third of all findings consisted of frontal EEG patterns. In studies that utilized continuous EEG, 96.8% of the 251 patients were reported to have abnormalities compared to 85.0% of the patients who did not undergo continuous EEG. Frontal findings were therefore frequent during Neuro-COVID and can be proposed as a marker for its development [111
]. These data highlight the potential utility of using EEG for patients with COVID-19 infection exhibiting signs of CNS involvement.
Many authors suggest that the neurotoxic effects of coronaviruses leading to life-threatening neurological conditions are not necessarily linked to the manifestation of severe respiratory symptoms [65
As regards peripheral neurological symptoms, a recent study showed that the most common peripheral COVID-19-related symptoms of infection in China included the loss of the sense of taste and smell (5%), visual disturbances (1.4%) and neuralgia (2.3%) [68
] (Table 1
In Italy [97
], different degrees of ageusia and anosmia have been reported in 10.2% and 5% of the patients, respectively, while 18.6% of patients complained of both. These symptoms were more common in young patients and in women.
Other studies conducted in 12 European clinics showed that cases of mild to moderate disease were accompanied by olfactory (85.6%) and taste (88%) alterations with a high degree of correlation between them and also predominant in females [101
]. For most patients, the recovery of sensitivity took several weeks and 44% of the patients recovered earlier (Table 1
Musculoskeletal injuries are 10.7% prevalent, mainly in patients with liver and kidney problems, according to Mao et al. [68
]. Another study, involving 1099 patients from 550 hospitals in China, reported the occurrence of myalgia (14.9%). The severity of the observed symptoms correlated with the severity of the disease [112
]. Rhabdomyolysis was observed in 0.2% of cases (Table 1
Based on the available information, Sheraton et al. (2020) [87
] suggested that CNS symptoms mainly occur in connection with virus-induced inflammation. The PNS complications are secondary to immune-mediated processes, whereas musculoskeletal involvements are the result of the direct damaging effects of the virus [87
Cerebrovascular accidents usually occur in severe cases of the disease, affecting predominantly elderly patients with cardiovascular and cerebrovascular comorbidities and diabetes.
However, new data indicate that coronavirus-related ischemic strokes may not necessarily be age-related. In New York, five coronavirus patients in their 30s and 40s, most of whom had no past medical history, experienced life-threatening ischemic strokes. These cases may be multifactorial, on the one hand being related to the affinity of SARS-CoV-2 to endothelial cells, which leads to endothelial damage and the formation of blood clots even in individuals with no history or risk of coagulation disorders [103
], and on the other to the formation of antiphospholipid (anti-PL) autoantibodies [36
We already discussed that cerebrovascular events may be due to the presence of antiphospholipid (anti-PL) autoantibodies and that the presence of these autoantibodies should be tested in patients with coagulopathy and the elevation of d-dimer and lupus-like anticoagulant [36
], which may be secondary to the upregulated activation of B lymphocytes [113