Table 1. Possible Pathogenesis of Neurological Manifestations Among COVID-19 Patients.
A consensus has been issued for neurologists to be involved in the prevention and management of COVID-19; this indicates that COVID-19 patients may present with neurological symptoms first. Hence, neurologists and other healthcare providers should pay close attention to these manifestations and have a high index of suspicion when evaluating patients in an endemic area. Early recognition may help in the initiation of proper management strategies such as early isolation to prevent spreading of the virus and avoid clinical deterioration of patients.Reference Jin, Hong and Chen
The aim of this review is to focus and summarize the available published data from inception on neurological manifestations in patients with COVID-19.
This systematic review differs from previous reviewsReference Carod-artal
, Reference Asadi-pooya and Simani
12 in many points. First, it comprised all the published literature on neurological manifestations in COVID-19 patients including analysis and summarization of case reports in addition to the most recent published data (till May 2020). Second, ongoing trials on the neurological manifestations in COVID-19 patients were searched, summarized, and analyzed. Third, neurological manifestations were summarized in detail in terms of symptomatology apart from each study analysis. The strengths and limitations to this review in detail as well as the implications for future studies in this field are discussed later in the paper.
Neurological manifestations can be nonspecific or mild at the early stage of COVID-19 infection.Reference Jin, Hong and Chen
11 A growing number of studies reported this type of manifestations in COVID-19 patients which raises the researcher’s curiosity to study them in depth. The aim of this review is to focus on and summarize the available published data as well as ongoing trials on neurological manifestations in patients with COVID-19.
The incidence of neurological manifestations in our review was 14.5%. A review by Carod-artalReference Carod-artal
6 concluded that the exact incidence of neurological manifestations in SARS-CoV-2 patients is unknown. Another review by Asadi-pooya et alReference Asadi-pooya and Simani
12 marginalized its results regarding the percentage of CNS manifestations incidence (25%) in hospitalized patients in a Chinese study.Reference Mao, Jin and Mengdie W
18 A review by Jin et alReference Jin, Hong and Chen
11 stated that more than one-third of COVID-19 patients experienced various degrees of neurological symptoms.
Regarding the neurological manifestations subgroup in our review, dizziness and headache were the most common CNS manifestations among patients with percentages of 11.9% and 11.8%, respectively, followed by confusion/DCL (8%). In PNS manifestations, taste and smell impairments were more common among patients with percentages of 5.6% and 5.1%, respectively. These findings are in line with Jin et alReference Jin, Hong and Chen
11 review which described dizziness and headache in CNS manifestations as well as and taste and smell impairments in PNS manifestations as the most common symptomatology.
All the included studies categorized neurological manifestations according to COVID-19 disease severity except one study by Chen et al.Reference Chen, Zhou and Dong
20 In our review, CNS manifestations were more frequent in severe COVID-19 patients except headache. In PNS manifestations, visual impairment and nerve pain were more frequent in the severe category of patients with percentages of 66.7% and 80%, respectively, while smell and taste impairments, which are highly common PNS manifestations, were more frequent in the nonsevere category with percentages of 27.3% and 25%, respectively. Previous reviews6,11 mentioned that neurological symptoms are more likely to occur in patients with the severe form of COVID-19 compared to those with milder disease. It was also reported previously that the most common neurological manifestations in severe COV-2 infection are stroke and DCL.
Pediatric age group was discussed only in one study by Sun et alReference Sun, Li and Xia
21 with a limited number of participants (n = 8). Most of the studies in literature investigated neurological manifestations in adult COVID-19 patients. A case reportReference Chacón-Aguilar, Osorio-Cámara, Sanjurjo-Jimenez, González-González, López-Carnero and Pérez-Moneo
32 in our review discussed a case of male neonate (26 days old) with COVID-19 presenting with febrile seizures. This is due to rarity of reports on COVID-19 in the pediatric age group since it seems to be uncommon in children,Reference Lee, Hu and Chen
, Reference Huang, Wang and Li
, Reference Wang, Hu and Zhu
33 which may be attributed to the lower outdoor activity of children compared to adults including international travels.Reference Lee, Hu and Chen
As previously mentioned, various respiratory viruses are associated with neurological manifestations. Human coronavirus (HCoV) is an example which reaches the CNS through olfactory bulb causing inflammation and demyelination. After the infection is set in the respiratory tract, the virus reaches the CSF and brain in less than 7 days, causing various neurological complications including CNS manifestations as encephalitis, meningitis, myelitis as well as PNS manifestations as GBS. This explains the neurological manifestations encountered in our case reports including (a) CNS affection as: (1) demyelinating CNS disorder in a study by Zanin et al,Reference Zanin, Saraceno, Panciani and Fontanella
27 which was successfully treated by steroids (dexamethasone), (2) acute necrotizing hemorrhagic encephalopathy in a study by Poyiadji et al,Reference Poyiadji, Shahin, Noujaim, Stone, Patel and Griffith
28 which was treated by IV Ig with no reported response to medication, (3) encephalitis in a study by Ye et alReference Ye, Ren and Lv
29 with no specific treatment, (4) stroke in a study by Avula et alReference Avula, Nalleballe and Narula
30 with no intervention or conservative medical treatment for acute stroke, and (5) seizures in a study by Sohal et al,Reference Sohal and Mossammat
24 which were treated by antiviral and AED but unfortunately the patient died and (b) PNS affection as: (1) Miller Fisher syndrome in two studiesReference Dinkin, Gao and Mbbs
, Reference Gutiérrez-Ortiz, Méndez-Guerrero and Rodrigo-Rey
25 which was successfully treated by IV Ig and partially improved (2) polyneuritis cranialis in a study by Gutiérrez-Ortiz et al,Reference Gutiérrez-Ortiz, Méndez-Guerrero and Rodrigo-Rey
25 which was resolved completely on nonspecific treatment with acetaminophen, (3) ophthalmoparesis in a study by Dinkin et al,Reference Dinkin, Gao and Mbbs
23 which was treated by hydroxychloroquine for COVID-19 and the neurological symptoms were gradually resolved.
Only in one case report by Liu et al,Reference Liu, Zhou, Xia, Cheng and Lu
22 COVID-19 diagnosis was based on clinical symptoms supported with computerized tomography (CT) chest inspite of the negative antigen testing. Although PCR for SARS-COV-2 is the gold standard method and corner stone in the diagnosis of COVID-19, diagnosis can be made if there is a high clinical suspicious as the infected people may or may not have abnormal laboratory findings or lung changes on CT chest and negative nucleic acid test,Reference Jin, Hong and Chen
11 which renders re-testingReference Hassan, Sheikh, Jamal, Ezeh and Akhtar
1 in such cases. This is explained by the low test sensitivity of around 70%.Reference West, Montori and Sampathkumar
34 In a case series by Fang et al,Reference Fang, Zhang and Xie
35 it was found that the sensitivity of chest CT was higher than that of PCR (98% vs 71%, respectively).
Mortality in patients with neurological disorders were not observed in the studies included in our analysis. The mortality rates differ across different pathogenic types SARS-CoV, MERS-CoV, and SARS-CoV-2 with rates of 9.6%, 34.4%, and 5.3% (till April 3, 2020), respectively.Reference Natoli, Oliveira, Calabresi, Maia and Pisani
36 The difference in mortality rate between COVID-19 patients with and without neurological manifestations needs further studies since there are no available published data. However, a previous reviewReference Carod-artal
6 stated that neurological symptoms are more common with the severe form of COVID-19.
Strengths and limitations of the review
The first strength of this review is that it identifies the gaps in our current knowledge about neurological manifestations in COVID-19 patients. Second, the review comprises all the available articles from inception (December 2019) till May 2020 regarding this issue. Third, it can serve as a model for future studies investigating the neurological manifestations in COVID-19 patients and their proper management. Fourth, it included search and summarizization of ongoing trials about neurological manifestations inpatients with this disease.
Research in this topic has important limitations that should be discussed. First, studies significantly vary in samples, methodologies, and measured outcomes. Second, neurological manifestations were not studied in depth in the available studies and were reported with other symptoms with no specific scales or scores to assess such manifestations or disorders. Third, the incidence of neurological manifestations was extracted only from observational studies since it cannot be deducted from case reports which represent the majority of studies, in terms of number, reporting neurological manifestations. Fourth, all studies did not report a specific management of neurological manifestations in COVID-19 patients except for case reports; however, some of them also did not report a specific treatment. Fifth, all studies were conducted on adult patients except one study with a limited number of patients. Finally, another limitation is the lack of duration of neurological manifestations, since, It is now known that some patients continue to have symptoms for a relatively long time after resolution of their COVID-19 symptoms.
Furthermore, a difficulty which was encountered in the current systematic review is that most of the studies reviewed were case reports, case series, and observational studies with limited number of COVID-19 patients with neurological manifestations and that most of studies included were from china.
Implications for future research
In future studies, more suitable RCTs need to be conducted to determine the spectrum of neurological manifestations in COVID-19 patients and their prognosis and mortality rates. Also, further studies on pediatric COVID-19 patients are needed to define the spectrum of neurological manifestations among this age group.
Long follow-up periods are needed to detect neurological complications in post COVID-19 patients.
Additional studies are needed to get accurate information about the incidence of neurological manifestations in COVID-19 patients with the development of international consensus/guidelines for proper management of such manifestations.