A total of 353 studies initially matched the keywords (“Long COVID”, “Post-COVID 19”, “Neurological” and “Symptoms”), 73 of which were duplicates. A total of 229 articles were excluded, resulting in 51 articles after the initial screening. Within the data extraction process, 9 articles were excluded, resulting in 42 studies. We included 7 cohort studies (8, 9, 10,11, 12, 13, 14), 6 cross-sectional studies (15, 16, 17, 18, 19, 20), 3 retrospective studies (21, 22, 23), 2 follow-ups (24, 25), 1 case-control study (26), 6 case series (27, 28, 29, 30, 31, 32) and 17 case reports (33, 34, 35 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48,49), adding a total of 5888 patients. Unfortunately, 10 (15, 9,28, 17, 43, 45, 46, 47, 11, 26) studies did not specify symptom onset in their description of long COVID-19; that is, no clear distinction was evident regarding whether the symptoms had persisted from the acute phase or began to manifest after the acute phase.
The main neurological symptoms described were lower motor neuron-related disturbances (weakness, loss of strength, hypotonia, hyporeflexia), which were reported 26 times, followed by taste or smell disturbances (anosmia, ageusia, hyposmia, dysgeusia) and cognition-related disturbances (brain fog, attention difficulties, memory deficits, cognitive decline, cognitive impairment), which were cited 23 times each. Neuropsychiatric symptoms, such as depression, anhedonia, drowsiness, irritability and low mood, were also quoted 20 times. Other important manifestations included pain or aches, fatigue, movement disorders, anxiety symptoms, sleep disturbances and myalgia.
Among relevant patients, the mean age was 51.5 years old; the sample was 49.9% male and 50.1% female. A total of 806 patients (13.6%) required an ICU stay, with stays lasting from 1 to 73 days (some studies did not detail the need for and duration of ICU stay). The main comorbidities, when listed, were hypertension and diabetes, followed by depression and cardiovascular diseases.
We define long COVID-19 syndrome as the occurrence of residual symptoms after the acute COVID-19 infection, defined by a negative SARS-CoV-2 PCR test. In some isolated cases, the long symptoms started during the acute infection but persisted after the resolution of the respiratory tract infection.
Frequency of persistent neurological symptoms
A very important symptom observed was fatigue (including easy fatigue, extreme fatigue, easy fatigability and asthenia), which was reported in 15 articles 8 24 15 16 38 25 17 21 43 22 10 18 23 48 13. Most studies describe fatigue as a self-assessed symptom, with no clinical evaluation of differential diagnosis. One particular study reporting a high rate of fatigue-related manifestations, found an 85% prevalence and noted that most patients reported impaired quality of life due to persistent fatigue16. Furthermore, prospective research focusing on neurologic findings pointed out that that fatigue symptoms starting in the acute phase that persist through the “long COVID” phase suggests direct peripheral nervous system involvement25. Moreover, a follow-up study from England with a total n > 100 patients found correlations between both female sex and higher body mass index (BMI) and higher rates of fatigue22.
Pain or aches
In this section, we included symptoms described as: aches, pain or discomfort, headaches and retrosternal discomfort which were reported in 13 studies 8 24 16 38 25 17 21 43 18
46 23 48 13. With a total “n” of 588 patients, “pain or discomfort” was reported by 26% of patients in a cohort from China8 (n = 1733) and by 90% of patients in a retrospective analysis from the USA23 (n = 42) along with a case series type study with 6 patients46. Headaches were reported in 12 studies but were not specified in detail in terms of their type or location and were noted in more than two hundred patients across the analyzed studies. Retrosternal discomfort was reported in one study43.
Taste and smell disturbances
In this section, were gathered: taste disorders, ageusia, anosmia, dysgeusia, loss or distortion of sense of taste or smell, loss of smell, residual smell disorder, hyposmia and hypogeusia. A total of 14 studies8 24 35 9 16 38 30 25 21 22 18 47 48 14 reported some sort of alteration in the perception of smell or taste, and one particular study47 illustrated by two case reports documented that the loss of smell and taste had little to no correlation with nasal obstruction and rhinorrhea as it is common in other respiratory conditions such as upper airway viral infections and it seems to have higher prevalence among the female population. Furthermore, a larger cohort study8 documented that approximately 10% of its patients (approximately 176 individuals) had anosmia persisting for months after the acute phase.
Five articles24 25 42 21 31 reported the occurrence of movement disturbances in a total of 33 patients. Described symptoms included dystonia, tremors, tremulousness, myoclonus, opsoclonus and ataxia. Curiously, two patients presented with Myoclonus-Ataxia Syndrome (MAS)42 31 and one presented with Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS)31, suggesting inflammatory-mediated postinfectious neuronal injury. All patients had no previous history of primary autoimmune disease, or the use drugs that cause myoclonus.
Cranial and peripheral nerves involvement
A wide range of persistent motor symptoms involving the peripheral nervous system were described, as follows: loss of strength in the lower limbs, weakness or muscle weakness, critical illness neuropathy, ICU-related polyneuropathy, ulnar or peroneal nerve lesions, mononeuritis multiplex, difficulty walking, lack of strength in the pelvic muscles, hypotonia, tetraparesis, hemiparesis or paraparesis, hyporeflexia or areflexia, abnormal neuromuscular fatigue, Tapia syndrome (with IX, X and XII cranial nerve deficits), bifacial weakness and paraesthesia, acute motor or sensory neurological deficits and muscle atrophy. The large spectrum of motor peripheral nervous system related symptoms affirms the already described neurotropism of SARS-CoV-2. Several studies described those symptoms24 34 27 29 38 30 39 40 42 44 18 23 48 31, including two cohortsClique ou toque aqui para inserir o texto.8 9 and one prospective study25. Although some studies described weakness as a subjective symptom48, others reported objective paresis or plegy in the neurological exam, as well as electrophysiological study findings30.
Low mood, anhedonia, drowsy, lethargy, irritability, general malaise and lack of appetite were all grouped to summarize depressive manifestations. Across many studies8 24 50 15 33 34 16 38 40 25 17 21 43 22 10 48 11 through self-applied questionnaires or medical interviews, patients reported depressive symptoms or some sort of distress that fit common depression markers such as lethargy or irritability. In particular, in one article the prevalence reached 48% which corresponded to 481 people17 while an Italian cohort study found a 40% prevalence using validated questionnaires such as the Mini Mental State Evaluation (MMSE) and the Hamilton Scale for Depression11.
Sleep disorders and insomnia were reported in studies 8 24 37 9,22 and in studies 16 30 25 21 48, respectively. Sleep difficulties were one of the most common symptoms described in postacute COVID-19851 which were mentioned by 437 of 1655 and 19 of 23 patients, respectively. Moreover, sleep disturbances were common even at 6 months after symptom onset8. However, most studies describe sleep disturbances as a self-assessed symptom, with no consideration of differential diagnosis.
Worsening anxiety, anxiety and agitation were noted to be more prevalent and intense with more severe infection in the acute phase and to have higher prevalence among the female population, as reported in a large cohort article8. Among the studies reporting these types of psychological disturbances8 24 37 28 16 25 43 22 10 18 we noticed that the overall percentage of findings varied extensively, sometimes not reaching 7% of patients24, and others reaching more than 40% of patients16 22. In total, more than five hundred individuals presented these symptoms across all studies.
A total of 5 studies described paraesthesia as a persistent symptom of long COVID-1924 38 40 43 23. Numbness and tingling were added to the paresthesia group, as described in studies16 44, with 44 a case report in which the author specified “distal numbness in the lower limbs and left fingers”, while 16 was an observational cross-sectional study. Paresthesias tended to be more common in men than women23. However, the cohort articles8 51 10 11 12 13 14 did not report these symptoms among their main findings.
Seizures and status epilepticus
Seizures and status epilepticus are infrequent conditions related to long-COVID syndrome. Three articles33 41 49 reported the occurrence of unexplainable new-onset seizures in nonepileptic patients, one of whom presented with refractory status epilepticus33. In this case33, the patient had a prepandemic routine brain MRI and EEG with no signs of epileptic activity or tumor/inflammation in the image, but after the infection, he developed tonic movements and shaking with bilateral discharges on EEG. In the other two cases41 49, patients presented with frontal and temporal lobe discharges. The elementary mechanism for seizures associated with COVID-19 is not clarified. Although some hypotheses have been proposed, such as direct SARS-CoV-2 neurotropism via olfactory neuron axonal transport and hematogenous spread via disruption of the blood brain barrier, with indirect factors such as hypoxia, multiorgan failure and metabolic derangements, as observed in several diseases41.
Vestibulocochlear neuritis, tinnitus, sudden hearing loss and hearing loss were included in auditory disturbances. These manifestations were reported by 4 studies 44 36 16 44 36 25 44. Hearing loss and tinnitus have been seen in patients with both COVID-19 and influenza virus but have not been highlighted36. In Study 16, the 10 most frequent neurologic symptoms were nonspecific cognitive complaints such as tinnitus (29%)16. Aasfara et al.44 in which a patient presenting unilateral sensorineural hearing loss along with vestibular areflexia that mimicked each of two: labyrinthitis and retro-cochlear hearing loss, was reported, which was not the first case report of an acute vestibular neuritis secondary to SARS-CoV-2. Malayala et al. reported a case of infection in which the pathophysiology was likely akin to those of other viral infections which cause damage to the vestibular nerve43.
Psychosis, paranoia and hallucinations were the most common psychiatric disturbances. Studies 29 and 37 documented 1 case of hallucinations and reported 1 case of psychotic symptoms consisting of persecutory delusion and complex visual and auditory hallucinations post COVID-19 infection37 respectively. The patient reported by Study 37also described paranoid delusions.
Cognitive impairment, memory deficits, attention difficulty, poor memory and cognitive decline, as well as formal neuropsychological test score reductions were cited by 18 articles 24 34 37 51 28 29 16 30 40 25 43 22 10 18 23 19 12 26. Despite the difficulty of standardizing the symptom evaluation in these cases, the high prevalence of neuropsychiatric cognitive-related disturbances found in our study requires more directed studies to assess the prevalence, the main clinical presentations and the outcome of the symptoms.
“Brain fog” is a novel term used by some patients to illustrate their cognition-related symptoms and seems to have a different meaning from classical cognitive-related complaints. Interestingly, in a recent study, “brain fog” was reported by 81% of “ long-term” patients16. In this particular study, the researchers theorized that “brain fog” could be “a mild form of post COVID-19 encephalopathy”. Furthermore, memory and attention complaints are a common report in post-COVID syndrome, with at least one cohort study reporting a high prevalence (50%)12 and a lower percentage in other studies16 43. Additionally, a prospective study from England reported a prevalence of memory impairment and attention deficit geater than 25%22.
Quality of life and daily living activities impairment
Three articles8 51 12 with two cohorts8 51 assessed the impact of long-COVID symptoms on daily living activities and quality of life of patients. Huang et al.8 submitted 1733 patients to the EQ-5D-5-L questionnaire and found that 2% had problems with usual activity, while 7% reported mobility impairment. Another study12 found that patients with neurological complications associated with COVID-19 had more abnormal activities of daily living than the control group (measured by Barthel Index, p = 0.002), and, among those working premorbidly, neurological patients were less likely to return to work than controls (p = 0.004)
Myalgia was reported by 9 studies8 24 16 30 25 17 21 22 23, one of which was a cohort study8. Notably, this symptom is often reported during acute disease, suggesting, together with the very frequent symptoms of anosmia and ageusia, affecting, directly, the central nervous system (CNS) and peripheral nervous system (PNS)25. Sykes et al. reported that females were significantly more likely than males to experience myalgia (p = 0.022)22.
Dysphagia was reported by 1 study39 which is a case report. Article8 reported difficulty swallowing and sore throat in the same category. Sore throat was also included in this session and was reported by 4 studies: 1 cohort study8 and 17 21 48, which are a cross-sectional survey, a retrospective observational study and a case report, respectively. Osikomaiya et al. described sore throat as a less common symptom in acute symptomatic COVID 1921.
Double vision, blurred vision and visual blurring were reported by 3 studies: 29 16 and 21, respectively. Study 29 had one patient with double vision symptoms. On the other hand, Graham et al. reported 21/50 (42%) patients with blurred vision16, while Osikomaiya et al. reported 6/274 patients with vision symptoms described as visual blurring21.